Sulfadoxin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H317：Kann allergische Hautreaktionen verursachen.

  H411：Giftig für Wasserorganismen, mit langfristiger Wirkung.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P272：Kontaminierte Arbeitskleidung nicht außerhalb des Arbeitsplatzes tragen.

  P273：Freisetzung in die Umwelt vermeiden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P333+P313：Bei Hautreizung oder -ausschlag: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

Sulfadoxine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.

• Beschreibung

  Sulfadoxin is a sulfonamide antibiotic that inhibits dihydropteroate synthetase (DHPS), an enzyme involved in folic acid synthesis. Sulfadoxin competes with 4-aminobenzoate (PABA), the native substrate of DHPS, and inhibits PABA incorporation into folic acid. Folate is essential for purine and pyrimidine synthesis, therefore, sulfadoxin has antiproliferative activity in non-resistant P. falciparum. Sulfadoxin inhibits growth of P. falciparum in vitro, but potency varies between non-resistant (IC₅₀ = 4 ng/ml) and resistant strains (IC₅₀ = 3,970 ng/ml).

• Chemische Eigenschaften

  White Crystalline Solid

• Originator

  Fanasil,Roche,Italy,1973

• Verwenden

  Used as an antibacterial.

• Definition

  ChEBI: A sulfonamide consisting of pyrimidine having methoxy substituents at the 5- and 6-positions and a 4-aminobenzenesulfonamido group at the 4-position. In combination with the antiprotozoal pyrimethamine (CHEBI:8673) it is used as an antimalarial.

• Manufacturing Process

  (a) α-methoxy-cyanoacetic acid methyl ester is condensed with thiourea, in the presence of sodium methylate, to form 2-thio-4-amino-5-methoxy-6- hydroxy-pyrimidine.
  (b) The product thus obtained is methylated in a sodium methylate solution with methyl iodide to form 2-methylthio-4-amino-5-methoxy-6-hydroxypyrimidine of MP 203°C, from water.
  (c) The latter product is methylated with phenyltrimethylammoniumtoluenesulfonate to form 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine of MP 112° to 115°C, from 20% methanol.
  (d) 0.9 gram of 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine are dissolved in 3 ml of absolute pyridine. At 0°C, 1.2 grams of pacetylaminobenzenesulfonyl chloride are added thereto and the mixture is shaken until all the material is dissolved. The solution is allowed to stand for 22 hours at 0°C and the pyridine eliminated in vacuo at 20°C. To the resulting product are added 20 ml of water and 3 ml of glacial acetic acid, whereupon the whole mixture is heated to the boil, thus causing crystallization. The crude product obtained is dissolved in 40 ml of 2.5% soda solution, and the solution obtained is filtered and supersaturated with gaseous carbon dioxide. There is thus obtained 1.5 grams (85%) of 2-methylthio-4-(N4-acetyl-sulfanilamido)- 5,6-dimethoxy-pyrimidine of MP 220° to 221°C, from 50% ethanol.
  (e) 1.3 grams of 2-methylthio-4-(N4-acetyl-sulfanilamido)-5,6-dimethoxypyrimidineare dissolved in 25 ml of water and 0.4 gram of anhydrous sodium carbonate, then refluxed for 3 ? hours in the presence of 6 to 7 grams of Raney nickel. Then, a solution of 1 gram of sodium hydroxide in 3 ml of water is added thereto and heating continued for another hour. The catalyst is filtered off and the filtrate acidified to Congo red with hydrochloric acid. The pH is then brought to 5 by means of ammonia, thus causing crystallization. There is thus obtained 0.51 gram of 4-sulfanilamido-5,6-dimethoxy-pyrimidine of MP 190° to 194°C, from 50% ethanol.

• Trademarks

  Fanasil (Hoffmann-LaRoche-International); Fanzil (Hoffmann-LaRoche).

• Therapeutic Function

  Antibacterial

• Antimicrobial activity

  Its antibacterial activity is relatively poor. Used alone it has a slow and uncertain effect against malaria parasites. Resistance of malaria parasites to the combination with pyrimethamine is common in many endemic areas.

• Pharmazeutische Anwendungen

  An ultra-long-acting sulfonamide. It is no longer prescribed alone, but is used in combination with pyrimethamine as the antimalarial agent Fansidar. It is poorly soluble in water.

• Pharmakologie

  In terms of antibacterial action, this drug is analogous to other sulfanilamides; however, it possesses very prolonged action. Its half-life is from 120 to 200 h. Sulfadoxine is used for infectious diseases caused by microorganisms that are sensitive to the sulfanilamide drugs, such as infections of respiratory organs, gastric and urinary tracts; purulent infections of various localization, osteomyelitis, sinusitis, and other infections. It is used in combination with antimalarial drugs. Synonyms of this drug are sulfarmethoxine, fanasil, and fansidar.

• Pharmakokinetik

  Oral absorption ：Extensive
  C_max 500 mg oral： c. 60 mg/L after 3–4 h
  Plasma half-life：c.6 days
  Volume of distribution：0.13 L/kg
  Plasma protein binding：94%
  The extremely long half-life allows administration at weekly intervals. The acetyl metabolite has a similarly long half-life, but sulfadoxine is less extensively metabolized than many other sulfonamides.

• Clinical Use

  Sulfadoxine is used only in combination with pyrimethamine.

• Nebenwirkungen

  Side effects are those common to the group. There have been many reports of Stevens–Johnson syndrome following its use and the combination with pyrimethamine is no longer recommended for the prophylaxis of malaria.

• Synthese

  Sulfadoxine, 4,5-dimethoxy-6-sulfanilamidopyrimidine (33.1.33), is synthesized by the standard scheme from 4-acetylaminobenzenesulfonyl chloride and 4-amino-5,6-dimethoxypyrimidine. However, the synthesis of 4-amino-5,6- dimethoxypyrimidine (33.1.31) is itself curious?ait is synthesized from methyl ester of methoxyacetic acid. Interacting this with dimethyloxalate in the presence of sodium methoxide gives the methoxy derivative (33.1.25), and the pyrolysis of this compound gives the dimethyl ester of methoxymalonic acid (33.1.26). Reacting this with ammonia gives the diamide of methoxymalonic acid (33.1.27). Heterocyclization of the resulting product by a reaction with formamide in the presence of sodium ethoxide gives 4,6- dioxy-5-methoxypyrimidine (33.1.28), which is then transformed to 4,6-dichloro-5- methoxypyrimidine (33.1.29). The resulting 4,6-dichloro-5-methoxypyrimidine (33.1.29) undergoes a reaction with ammonia to make 4-amino-6-chloro-5-methoxypyrimidine (33.1.30), and the resulting compound is then reacted with sodium methoxide to make the desired 5,6-dimethoxy-5-aminopyrimidine (33.1.31). Reacting this with 4-acetylaminobenzenesulfonyl chloride and subsequent hydrolysis of the acetyl group in (33.1.32) gives sulfadoxine.

  

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