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METYRAPONE Basic information
METYRAPONE Chemical Properties
  • Melting point:52-55 °C(lit.)
  • Boiling point:367.89°C (rough estimate)
  • Density 1.0852 (rough estimate)
  • refractive index 1.6419 (estimate)
  • Flash point:>230 °F
  • storage temp. Inert atmosphere,Room Temperature
  • solubility H2O: soluble (sparingly)
  • pka4.61±0.10(Predicted)
  • form solid
  • Merck 13,6181
  • BRN 163023
  • EPA Substance Registry SystemMetyrapone (54-36-4)
Safety Information
METYRAPONE Usage And Synthesis
  • OriginatorMetopirone,Ciba,US,1961
  • UsesMetyrapone acts as a glucocorticoid synthesis inhibitor, maintaining stress-hormone levels.
  • UsesDiagnostic aid (pituitary function);steroid 11?-hydroxylase inhibitor
  • Usesglucocorticoid synthesis inhibitor
  • Manufacturing ProcessAccording to US Patent 2,966,493, the 2,3-bis-(3-pyridyl)-2,3-butanediol used as the starting material may be prepared as follows. A solution of 1,430 g of 3-acetyl-pyridine in 7,042 ml of a 1 N aqueous solution of potassium hydroxide is placed into a cathode chamber containing a mercury cathode with a surface of 353 cm2 and is separated from an anode chamber by an Alundum membrane. As anode a platinum wire is used and the anolyte consists of a 1 N solution of aqueous potassium hydroxide which is replenished from time to time.
    The electrolysis is carried out at a reference potential of -2.4 volts vs a standard calomel electrode. An initial current density of 0.0403 amp/cm2 is obtained which drops to 0.0195 amp/cm2 at the end of the reduction, which is carried on over a period of 1,682 minutes at 15° to 20°C. The catholyte is filtered, the solid material is washed with water and dried. 430 g of the 2,3- bis-(3-pyridyl)-butane-2,3-diol is recrystallized from water, MP 244° to 245°C.
    A mixture of 3.43 g of 2,3-bis-(3-pyridyl)-2,3-butane-diol and 25 ml of concentrated sulfuric acid is heated to 76°C and kept at that temperature for 7? hours. It is then poured on ice, neutralized with 50% aqueous solution of sodium hydroxide and the pH is adjusted to 8 with solid sodium carbonate. The aqueous solution is three times extracted with ethyl acetate, the separated organic layer dried over sodium sulfate and evaporated to dryness.
    The residue is distilled and 1.86 g of viscous, colorless oil is obtained which is purified by distillation. BP 140° to 160°C/0.07 mm. The infrared spectrum shows the presence of a mixture of two compounds, one containing a conjugated, the other one an unconjugated carbonyl group, without the presence of a compound containing a hydroxyl group; thus the rearrangement has taken place.
    The resulting mixture does not crystalize and is converted into a mixture of oximes by treatment of a solution of the mixture in 20 ml of ethanol with a solution of 1.8 g of hydroxylamine sulfate in 3 ml of water. 1.8 g of sodium acetate in 5 ml of water is added, and the mixture is refluxed for 5 hours, then extracted with ethyl acetate, and the ethyl acetate solution is washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating the solvent, the residue is triturated with warm ether and 1.1 g of a crystalline oxime is obtained, MP 168° to 171°C.
    0.1 g of the resulting oxime is dissolved in 5 ml of 2 N aqueous sulfuric acid and the mixture is refluxed for 3 hours and allowed to stand overnight. After being rendered basic by adding a concentrated aqueous solution of sodium hydroxide and adjusted to a pH of 8 with sodium carbonate, the mixture is extracted 3 times with ethyl acetate; the organic layer is washed with water, dried and evaporated. Upon distillation of the residue an oily product is obtained, BP 130° to 160°C/0.3 mm. Infrared analysis shows the presence of a uniform compound, containing a conjugated carbonyl group. The 2-methyl- 1,2-bis-(3-pyridyl)-propane-1-one crystallizes upon standing at room temperature or by covering the oily distillate with pentane and cooling to - 80°C and filtering the oily crystals. It melts after recrystallization from a mixture of ether, hexane and petroleum ether at 48° to 50°C.
  • brand nameMetopirone Ditartrate (Ciba-Geigy).
  • Therapeutic FunctionDiagnostic aid (pituitary function)
  • Biological ActivityCytochrome P450 inhibitor. Blocks glucocorticoid synthesis via inhibition of steroid 11- β hydroxylase (CYP11B1) activity (IC 50 = 7.83 μ M). Also inhibits CYP3A4 and cytochrome P450-mediated ω / ω -1 hydroxylase activity.
  • Mechanism of actionMetyrapone (Metopirone) produces its primary pharmacological effect by inhibiting 11-β-hydroxylase, thereby causing diminished production and release of cortisol. The resulting reduction in the negative feedback of cortisol on the hypothalamus and pituitary causes an increase in corticotrophin release and in the secretion of precursor 11-deoxysteroids.
  • Clinical UseMetyrapone is used in the differential diagnosis of both adrenocortical insufficiency and Cushing’s syndrome (hypercortisolism). The drug tests the functional competence of the hypothalamic–pituitary axis when the adrenals are able to respond to corticotrophin; that is, when primary adrenal insufficiency has been ruled out.
    After metyrapone administration, a patient with a disease of pituitary origin cannot achieve a compensatory increase in the urinary excretion of 17-hydroxycorticosteroids or 11-deoxysteroids. Moreover, if pituitary corticotrophin is suppressed by an autonomously secreting adrenal carcinoma, there will be no increase in response to metyrapone. On the other hand, if pituitary corticotrophin secretion is maintained, as occurs in adrenal hyperplasia, the inhibition of corticoid synthesis produced by metyrapone will stimulate corticotrophin secretion and the release of metabolites of precursor urinary steroids, which can be measured as 17-hydroxycorticosteroids. Metyrapone is now used less frequently in the differential diagnosis of Cushing’s syndrome because of the ability to measure plasma corticotrophin directly.
    The steroid-inhibiting properties of metyrapone have also been used in the treatment of Cushing’s syndrome, and it remains one of the more effective drugs used to treat this syndrome. However, the compensatory rise in corticotrophin levels in response to falling cortisol levels tends to maintain adrenal activity.This requires that glucocorticoids be administered concomitantly to suppress hypothalamic–pituitary activity. Although metyrapone interferes with 11β- and 18- hydroxylation reactions and thereby inhibits aldosterone synthesis, it may not cause mineralocorticoid deficiency because of the compensatory increased production of 11-desoxycorticosterone.
  • Side effectsSide effects associated with the use of metyrapone include gastrointestinal distress, dizziness, headache, sedation, and allergic rash. The drug should not be used in cases of adrenocortical insufficiency or when hypersensitivity reactions can be expected. When administered to pregnant women during the second or third trimesters, the drug may impair steroid biosynthesis in the fetus. Because metyrapone is relatively nontoxic, it is used in combination therapy with the more toxic aminoglutethimide to reduce its dosage.
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