Irbesartan

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Achtung

• Gefahrenhinweise

  H413：Kann für Wasserorganismen schädlich sein, mit langfristiger Wirkung.

• Sicherheit

  P273：Freisetzung in die Umwelt vermeiden.

Irbesartan Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R22:Gesundheitsschädlich beim Verschlucken.

• S-Sätze Betriebsanweisung:

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

• Beschreibung

  Avapro was launched in Germany, the UK and the US for hypertension. It can be prepared in six steps starting with cyclopentanone or in three steps from 1- aminocyclopentanecarboxylic acid ethyl ester and pentanimidic ethyl ester. Avapro is an angiotensin Ⅱ receptor antagonist that is non-competitive and selective for AT, subtypes and has no AT₂ activity at postsynaptic receptors compared to presynatpic. It has no affinity for various non angiotensin Ⅱ receptor types in binding, no interaction with calcium channels or antiports, and no affinity for α₁- and α₂--adrenoreceptors, serotonergic receptors, muscarinic m₁ and m₂ or other receptors. It is as potent as saralasin but with no agonist activity and is 10 times more potent than DuP753 in rats. It is similar in efficacy to enalapril (in those with severe hypertension) and atenolol, while more effective than losartan for mild to moderate hypertension.

• Chemische Eigenschaften

  Crystalline Solid

• Originator

  Sanofi (France)

• Verwenden

  For the treatment of hypertension, as well as diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. Irbesartan is also used as a second line agent in the treatment of conges

• Verwenden

  antidepressant

• Verwenden

  An angiotensin II type 1 (AII1)-receptor antagonist

• Definition

  ChEBI: A biphenylyltetrazole that is an angiotensin II receptor antagonist used mainly for the treatment of hypertension.

• Manufacturing Process

  1. Synthesis of 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one
  Method 1:
  The ethyl ester of 1-aminocyclopentanecarboxylic acid is prepared according to Adkins and Billica (J. Amer. Chem. Soc., 1948, 70, 3121).
  Ethyl valerimidate hydrochloride is prepared according to Mac Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827) and then freed from its hydrochloride by reaction with potassium carbonate and extraction with CH2Cl2.
  The ethyl ester of 1-aminocyclopentanecarboxylic acid (1.57 g) and ethyl valerimidate (1.56 g) are dissolved in 12 ml of xylene containing 6 drops of acetic acid. After refluxing for 6.5 h, the reaction medium is concentrated under vacuum, the residue is chromatographed on silica gel using a chloroform/methanol/acetic acid mixture (94/4/2; v/v/v) as the eluent. The fraction containing the expected product is evaporated several times in the presence of xylene and then benzene in order to remove the acetic acid. 1.91 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one are obtained in the form of a thick oil.
  Method 2:
  1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a roundbottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% aqueous ammonia is added; finally, 3 g of cyclopentanone in 3.8 ml of methanol are added to the flask. After stirring for 1.5 h, the mixture is heated at 60°C for 45 min, heating is then stopped, stirring is continued for 45 min and the mixture is then cooled to 25°C. It is extracted several times with methylene chloride.
  The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone, and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added, with stirring. The precipitate of 1-aminocyclopentanenitrile formed is filtered off.
  5.1 g of the oxalate obtained in the previous step are treated with 7.65 ml of concentrated sulfuric acid (d = 1.84) over 45 min, with stirring. The evolution of a gas is observed and the temperature rises to 100°C. The mixture is cooled to about 35°C and poured into a mixture of ice and concentrated aqueous ammonia (10 g/2.8 ml). The suspension formed is extracted with chloroform containing 5% of methanol. The 1-aminocyclopentanecarboxamide was obtained.
  3 g of the compound prepared in the previous step are placed in 70 ml of anhydrous THF and 3.3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous THF are added, with stirring. A white suspension is formed. The intermediate which is formed, but not isolated, is 1-(Nvaleryl)aminocyclopentanecarboxamide. 6 g of potassium hydroxide pellets, 7 ml of water and 16 ml of methanol are added. The mixture is refluxed for 2.5 h and 9 g of ammonium chloride are then added. After stirring for 15 min, the mixture is concentrated under vacuum. The residue of the 2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one obtained is taken up in water and extracted with ethyl acetate.
  2. Synthesis of 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4- yl)-methyl]-2-imidazolin-5-one
  A mixture containing 250 mg of sodium hydride (as an 80% dispersion in mineral oil) and 5 ml of DMF is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5- one in 10 ml of DMF is added dropwise. The mixture is stirred for 30 min at 20°C and a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of DMF is then added. After stirring for 1 h at 20°C, the DMF is evaporated off under reduced pressure, the residue is then taken up with ethyl acetate,filtered and evaporated. The residue of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-nbutyl-4-spirocyclopentane-2-imidazolin-5-one is purefied by chromatography
  1.56 g of the previous product, 2.6 g of tributyltin azide and 30 ml of xylene are refluxed for 66 h. The xylene is then evaporated off and the residue is dissolved in 20 ml of CH2Cl2 and 5 ml of THF with the addition of 0.8

• Trademarks

  Avapro (Sanofi Aventis);Aprovel/Avapro.

• Therapeutic Function

  Antihypertensive

• Allgemeine Beschreibung

  Irbesartan, 2-butyl-3-[[29-(1H-tetrazol-5-yl)[1,19-biphenyl]-4-yl]methyl]1,3-diazaspiro[4,4]non-1en-4-one (Avapro), like losartan, possesses the acidic tetrazolesystem, which most likely plays a role, similar to the acidicgroups of angiotensin II, in binding to the angiotensin II receptor.In addition, the biphenyl system that serves to separatethe tetrazole from the aliphatic nitrogen is still present.A major difference in this agent is that it does not possessthe acidic side chain. Even so, irbesartan has good affinityfor the angiotensin II receptor because of hydrogen bondingwith the carbonyl moiety of the amide system. Also, thisparticular agent does not require metabolic activation ascandesartan does.

• Biochem/physiol Actions

  Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist with antihypertensive activity. It also elicits selective peroxisome proliferator-activated receptor γ (PPARγ)-modulating activity and possesses anti-inflammatory properties. Irbesartan shows protective cardiovascular effects and provides protection against chronic glomerulonephritis.

• Clinical Use

  Angiotensin-II receptor antagonist:
  
  Hypertension
  
  Diabetic nephropathy

• Veterinary Drugs and Treatments

  Although experience in veterinary medicine is minimal irbesartan may be useful in treating canine hypertension associated with renal insufficiency. It may be effective in treating heart failure when dogs are unable to tolerate ACE inhibitors, but documentation for this use is lacking. One study, using very high irbesartan dosages (60 mg/kg PO twice daily) in dogs with subacute mitral regurgitation, demonstrated no improvement in left ventricular function or prevention of left ventricular remodeling (Perry, Wei et al. 2002).

• 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

  Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of [14C]-irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces.

• Lager

  Store at +4°C

Irbesartan Upstream-Materialien And Downstream Produkte

Irbesartan Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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