Candesartan cilexetil

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

  H400：Sehr giftig für Wasserorganismen.

• Sicherheit

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Candesartan cilexetil Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R20/21/22:Gesundheitsschädlich beim Einatmen,Verschlucken und Berührung mit der Haut.
  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.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  Candesartan cilexetil is a prodrug form of the angiotensin II type 1 receptor (AT1) antagonist candesartan . Atacand was launched in Australia, Belgium, Canada, Denmark, Finland, the Netherlands, Norway, Sweden, S. Africa and the US as an antihypertensive agent. Pharmacological studies have indicated Atacand is about 10-fold more potent than Losartan and has a long elimination half-life. Like losartan, Atacand is converted to its active form during GI absorption (via ester hydrolysis). It is a potent antagonist of angiotensin II type 1 receptors. This occurs through tight binding and slow dissociation, and is more potent than ACE inhibitors. It is well tolerated (can be taken by elderly and those with type II diabetes) and has no gender effects.

• Chemische Eigenschaften

  It appears as a white or off-white powder.It is soluble in methanol but insoluble in water.

• Originator

  Takeda (Japan)

• Verwenden

  N,N-Desmethoxyethyl Candesartan Cilexetil is an impurity of Candesartan Cilexetil(C175580); An antihypertensive used in the treatment of congestive heart failures.

• Definition

  ChEBI: Candesartan cilexetil is a member of biphenyls.

• Manufacturing Process

  3-Nitrophthalic acid (35 g) in 300 ml ethanol and 20 ml concentrated sulfuric acid was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into 700 ml cold water. The mixture was extracted with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. After evaporation of methylene chloride was obtained 29 g (74%) ethyl 2- carboxy-3-nitrobenzoate.
  A mixture of 23.9 g ethyl 2-carboxy-3-nitrobenzoate and 12 ml thionyl chloride in 150 ml benzene were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness. The resultant acid chloride (26 g) was dissolved in 20 ml. The solution was added to a mixture of sodium azide (9.75 g) in 20 ml DMF with stirring. The reaction mixture was poured into 200 ml a mixture of ether-hexane (3:1). The organic layer was washed with water and evaporated. The residue was dissolved in 200 ml tert-butanol and the solution was heated gradually with stirring, followed by heating under reflux for 2 hours. The reaction mixture was concentrated to give an oily ethyl 2- butoxycarbonylamino-3-nitrobenzoate (30 g).
  To a solution of ethyl 2-butoxycarbonylamino-3-nitrobenzoate (29 g) in 50 ml THF was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). After 20 min to the mixture were added 18 g 4-(2-cyanophenyl)benzyl bromide and 0.36 g potassium iodide. After heating for 10 hours under reflux the solvent was evaporated and the residue was partitioned between 250 ml water and 200 ml ether. The organic layer was washed with water, dried and concentrated to give yellow syrup. The syrup was dissolved in a mixture of 60 ml trifluoroacetic acid and 40 ml methylene chloride and the solution was stirred for 2 hour at room temperature. The reaction mixture was concentrated to dryness and to residue was added 200 ml ethyl ether to give crystals of ethyl 2-[(2'-cyanobiphenyl-4- yl)methylamino]nitrobenzoate (22.1 g, 85%), M.P. 118-119°C.
  To a solution of 10.4 g ethyl 2-[(2'-cyanobiphenyl-4-yl)methylamino] nitrobenzoate in 50 ml ethanol was added 28.1 g stannous dichloride dihydrate and the mixture was stirred for 2 hours at 80°C. The solvent was evaporated. To the ice-cooling mixture of the residue in 300 ml ethyl acetate was added dropwise 2 N NaOH (500 ml). The aqueous layer was extracted with ethyl acetate (200 ml x 2). The organic layers were combined and evaporated to dryness. Product was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless crystals ethyl-3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (7.3 g, 79%), M.P. 104-105°C.
  Acetic acid (0.2 g) was added to a solution of ethyl-3-amino-2-[[(2'- cyanobiphenyl-4-yl)methyl]amino]benzoate (1 g) in ethylorthocarbonate (5 ml). The mixture was stirred at 80°C for 1 hours. The reaction mixture was concentrated. The solution was washed with an aqueous solution of NaHCO3 and water. The solvent was evaporeted to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 1-[(2'-cyanobiphenyl-4- yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.79 g, 69%), M.P. 131- 132°C.
  A mixture of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7- carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated, and to the residue were added methanol (20 ml) and 1 N HCl (10 ml). The solution was stirred at room temperature for 30 minutes and adjusted to pH 3-4 with 1 N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was evaporated to dryness to dive a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)bi

• Trademarks

  Atacand (AstraZeneca).

• Therapeutic Function

  Antihypertensive

• Allgemeine Beschreibung

  Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards

• Biochem/physiol Actions

  Candesartan cilexetil is the prodrug form of the potent angiotensin II receptor antagonist, candesartan. The prodrug is cleaved by esterases within the intestine to liberate the active molecule.

• Clinical Use

  Angiotensin-II antagonist:
  
  Hypertension
  
  Heart failure

• Nebenwirkungen

  Candesartan cilexetil may lead to various kinds of adverse reactions including headache, back pain, dizziness, upper respiratory tract infection, pharyngitis, rhinitis, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia and albuminuria. It should be warned that candesartan cilexetil might have remarkable fetal toxicity. Therefore, upon pregnancy, candesartan cilexetil should be discontinued. It could also cause hypotension for heart-failure patients.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anaesthetics: enhanced hypotensive effect.
  Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs.
  Antihypertensives: increased risk of hyperkalaemia hypotension and renal impairment with ACE-Is and aliskiren.
  Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Lithium: reduced excretion, possibility of enhanced lithium toxicity. Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity

• Stoffwechsel

  Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.

Candesartan cilexetil Upstream-Materialien And Downstream Produkte

Candesartan cilexetil Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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