METYRAPONE CAS 54-36-4
Introduction：Basic information about METYRAPONE CAS 54-36-4, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
METYRAPONE Basic information
| Product Name: | METYRAPONE |
| Synonyms: | Metapirone;Metapyron;Metapyrone;Methapyrapone;Methbipyranone;Methopirapone;Methopyrapone;Methopyrinine |
| CAS: | 54-36-4 |
| MF: | C14H14N2O |
| MW: | 226.27 |
| EINECS: | 200-206-2 |
| Product Categories: | Cytochrome P450 isozyme |
| Mol File: | 54-36-4.mol |
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) |
| Fp | >230 °F |
| storage temp. | Inert atmosphere,Room Temperature |
| solubility | H2O: soluble (sparingly) |
| form | solid |
| pka | 4.61±0.10(Predicted) |
| color | White |
| Merck | 13,6181 |
| BRN | 163023 |
| Stability: | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months. |
| InChI | InChI=1S/C14H14N2O/c1-14(2,12-6-4-8-16-10-12)13(17)11-5-3-7-15-9-11/h3-10H,1-2H3 |
| InChIKey | FJLBFSROUSIWMA-UHFFFAOYSA-N |
| SMILES | C(C1=CC=CN=C1)(=O)C(C)(C1=CC=CN=C1)C |
| EPA Substance Registry System | Metyrapone (54-36-4) |
Safety Information
| Hazard Codes | Xn |
| Risk Statements | 22-36/37/38 |
| Safety Statements | 26 |
| WGK Germany | 3 |
| RTECS | UC3050000 |
| HS Code | 2933399090 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Acute Tox. 4 Oral Eye Irrit. 2 Skin Irrit. 2 STOT SE 3 |
| Hazardous Substances Data | 54-36-4(Hazardous Substances Data) |
| Toxicity | A well-known inhibitor of monooxygenasereactions and can also, under some circumstances,stimulate metabolism of xenobiotics in vitro. In either case, theeffect is non-competitive, in that the KM does not changewhereas Vmax does, decreasing in the case of inhibition andincreasing in the case of stimulation. |
| Description | Metyrapone (54-36-4) inhibits cytochrome P450-mediated prostaglandin omega hydroxylation. Inhibits steroid 11β-hydroxylase thereby inhibiting cortisol biosynthesis. |
| Originator | Metopirone,Ciba,US,1961 |
| Uses | Diagnostic aid (pituitary function);steroid 11?-hydroxylase inhibitor |
| Uses | Metyrapone acts as a glucocorticoid synthesis inhibitor, maintaining stress-hormone levels. |
| Definition | ChEBI: Metyrapone is an aromatic ketone that is 3,3-dimethylbutan-2-one in which the methyl groups at positions 1 and 4 are replaced by pyridin-3-yl groups. A steroid 11beta-monooxygenase (EC 1.14.15.4) inhibitor, it is used in the diagnosis of adrenal insufficiency. It has a role as a diagnostic agent, an antimetabolite and an EC 1.14.15.4 (steroid 11beta-monooxygenase) inhibitor. |
| Manufacturing Process | According to US Patent 2,966,493, the 2,3-bis-(3-pyridyl)-2,3-butanediol usedas the starting material may be prepared as follows. A solution of 1,430 g of3-acetyl-pyridine in 7,042 ml of a 1 N aqueous solution of potassiumhydroxide is placed into a cathode chamber containing a mercury cathode witha surface of 353 cm2 and is separated from an anode chamber by an Alundummembrane. As anode a platinum wire is used and the anolyte consists of a 1N solution of aqueous potassium hydroxide which is replenished from time totime. The electrolysis is carried out at a reference potential of -2.4 volts vs astandard calomel electrode. An initial current density of 0.0403 amp/cm2 isobtained which drops to 0.0195 amp/cm2 at the end of the reduction, which iscarried on over a period of 1,682 minutes at 15° to 20°C. The catholyte isfiltered, 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 ofconcentrated sulfuric acid is heated to 76°C and kept at that temperature for7? hours. It is then poured on ice, neutralized with 50% aqueous solution ofsodium hydroxide and the pH is adjusted to 8 with solid sodium carbonate.The aqueous solution is three times extracted with ethyl acetate, theseparated 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 ispurified by distillation. BP 140° to 160°C/0.07 mm. The infrared spectrumshows the presence of a mixture of two compounds, one containing aconjugated, the other one an unconjugated carbonyl group, without thepresence of a compound containing a hydroxyl group; thus the rearrangementhas taken place. The resulting mixture does not crystalize and is converted into a mixture ofoximes by treatment of a solution of the mixture in 20 ml of ethanol with asolution of 1.8 g of hydroxylamine sulfate in 3 ml of water. 1.8 g of sodiumacetate 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 washedwith a saturated aqueous sodium chloride solution and dried over sodiumsulfate. After evaporating the solvent, the residue is triturated with warmether 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 acidand the mixture is refluxed for 3 hours and allowed to stand overnight. Afterbeing rendered basic by adding a concentrated aqueous solution of sodiumhydroxide and adjusted to a pH of 8 with sodium carbonate, the mixture isextracted 3 times with ethyl acetate; the organic layer is washed with water,dried and evaporated. Upon distillation of the residue an oily product isobtained, BP 130° to 160°C/0.3 mm. Infrared analysis shows the presence ofa uniform compound, containing a conjugated carbonyl group. The 2-methyl-1,2-bis-(3-pyridyl)-propane-1-one crystallizes upon standing at roomtemperature or by covering the oily distillate with pentane and cooling to -80°C and filtering the oily crystals. It melts after recrystallization from amixture of ether, hexane and petroleum ether at 48° to 50°C. |
| Brand name | Metopirone Ditartrate (Ciba-Geigy). |
| Therapeutic Function | Diagnostic aid (pituitary function) |
| Biological Activity | Cytochrome 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 action | Metyrapone (Metopirone) produces its primary pharmacologicaleffect by inhibiting 11-β-hydroxylase,thereby causing diminished production and release ofcortisol. The resulting reduction in the negative feedbackof cortisol on the hypothalamus and pituitarycauses an increase in corticotrophin release and in thesecretion of precursor 11-deoxysteroids. |
| Clinical Use | Metyrapone is used in the differential diagnosis of bothadrenocortical insufficiency and Cushing’s syndrome(hypercortisolism). The drug tests the functional competenceof the hypothalamic–pituitary axis when theadrenals are able to respond to corticotrophin; that is,when primary adrenal insufficiency has been ruled out. After metyrapone administration, a patient with adisease of pituitary origin cannot achieve a compensatoryincrease in the urinary excretion of 17-hydroxycorticosteroidsor 11-deoxysteroids. Moreover, if pituitarycorticotrophin is suppressed by an autonomously secretingadrenal carcinoma, there will be no increase in responseto metyrapone. On the other hand, if pituitarycorticotrophin secretion is maintained, as occurs in adrenalhyperplasia, the inhibition of corticoid synthesis producedby metyrapone will stimulate corticotrophin secretionand the release of metabolites of precursor urinarysteroids, which can be measured as 17-hydroxycorticosteroids.Metyrapone is now used less frequently in thedifferential diagnosis of Cushing’s syndrome because ofthe ability to measure plasma corticotrophin directly. The steroid-inhibiting properties of metyraponehave also been used in the treatment of Cushing’s syndrome,and it remains one of the more effective drugsused to treat this syndrome. However, the compensatoryrise in corticotrophin levels in response to fallingcortisol levels tends to maintain adrenal activity.This requiresthat glucocorticoids be administered concomitantlyto suppress hypothalamic–pituitary activity.Although metyrapone interferes with 11β- and 18-hydroxylation reactions and thereby inhibits aldosteronesynthesis, it may not cause mineralocorticoid deficiencybecause of the compensatory increased productionof 11-desoxycorticosterone. |
| Side effects | Side effects associated with the use of metyrapone includegastrointestinal distress, dizziness, headache, sedation,and allergic rash. The drug should not be used incases of adrenocortical insufficiency or when hypersensitivityreactions can be expected. When administeredto pregnant women during the second or third trimesters,the drug may impair steroid biosynthesis in thefetus. Because metyrapone is relatively nontoxic, it isused in combination therapy with the more toxic aminoglutethimideto reduce its dosage. |
| storage | Store at +4°C |
METYRAPONE Preparation Products And Raw materials
| Raw materials | Sulfuric acid-->3-Acetylpyridine-->Hydroxylamine sulfate-->Hydrogen |
