84371-65-3 Usage
Description
Mifepristone is an orally-active progesterone and glucocorticoid receptor antagonist, primarily used for the treatment of hypercortisolism in patients with nonpituitary Cushing syndrome and as a post-coital contraceptive. It functions by interfering with the binding of cortisol to its receptor, reducing the effects of excess cortisol without causing decreased cortisol production. Additionally, it has potential therapeutic effects in hormone-dependent tumors and ocular hypertension.
Used in Pharmaceutical Industry:
Mifepristone is used as a treatment for hypercortisolism in nonpituitary Cushing syndrome for reducing the effects of excess cortisol without causing decreased cortisol production.
Mifepristone is used as a post-coital contraceptive for preventing pregnancy after unprotected sex.
Mifepristone is used as a glutamate uptake inhibitor and AMPA blocker for its potential therapeutic effects in neurological conditions.
Mifepristone is used as a progesterone and glucocorticoid antagonist to suppress VEGF production, which may have implications in treating certain types of cancer.
Mifepristone is used as a progesterone receptor antagonist with partial agonist activity, functioning as an abortifacient to end a pregnancy by inducing bleeding during the luteal phase and in early pregnancy.
Mifepristone is used in the investigation of its potential therapeutic effect in hormone-dependent tumors, as it has shown promise in this area.
Originator
Roussel-Uclaf (France)
Indications
Mifepristone is a progesterone receptor antagonist that
has a high affinity for glucocorticoid receptors and little
agonist effect.This drug has recently been approved for
use in the United States for the treatment of hypercortisolism.
At high doses, mifepristone blocks negative
feedback of the hypothalamic–pituitary axis, thereby increasing
endogenous corticotrophin and cortisol levels.
Because mifepristone exerts its effects at the receptor
level and not by altering glucocorticoid production, elevated
serum cortisol and corticotrophin levels may not
accurately reflect the effectiveness of the therapeutic
regimen. Mifepristone does not inhibit cortisol binding
to the mineralocorticoid receptor, so that the resulting
corticotrophin disinhibition may cause potassium depletion.
Thus, administration of a mineralocorticoid receptor
antagonist such as spironolactone may be indicated
with mifepristone. Hypoadrenalism, nausea, and
drowsiness have been reported during prolonged administration
of mifepristone.
Manufacturing Process
1st method of synthesis of mifepristone:A solution of 24 g of 4-(N,N-dimethylaminoethoxy)bromobenzene was addeddropwise over 45 min to magnesium in 90 ml of anhydrous tetrahydrofuran. 2ml of 1,2-dibromoethane were added as catalyst. After the addition, themixture was stirred at 25°C for one hour to obtain a solution of 0.7 M of 4-(N,N-dimethylaminoethoxy)-benzene magnesium bromide which was thenadded to a solution of 6.16 g of dimethylsulfide-cuprous bromide complex in20 ml of tetrahydrofuran. The mixture was stirred at room temperature for 20min and a solution of 3.7 g of 3,3-[1,2-(ethanediyl-bisoxy)]-5α,10α-epoxy-17α-prop-1-ynyl-δ(9(11))-estrene-17β-ol in 50 ml of tetrahydrofuran was addedthereto dropwise over a few minutes. The mixture was stirred under an inertatmosphere for one hour and was then poured into a solution of 15 g ofammonium chloride in 20 ml of iced water. The mixture was extracted withether and the organic phase was washed with aqueous saturated sodiumchloride solution, was dried and evaporated to dryness under reducedpressure. The 18.3 g of oil were chromatographed over silica gel and elutedwith chloroform to obtain 4.5 g of 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-δ9-estrene-5α,17β-diol with aspecific rotation of [α]D20=-44(+/-)1.5° (c = 1% in chloroform).9.5 ml of 2 N hydrochloric acid were added to a solution of 4.5 g of 3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-δ9-estrene-5α,17β-diol in 20 ml of methanol and the solution was stirredat room temperature for 2 hours. 260 ml of ether and 110 ml of an aqueoussaturated sodium bicarbonate solution were added to the mixture which wasstirred at room temperature for 15 min. The decanted aqueous phase wasextracted with ether and the organic phase was dried and evaporated todryness under reduced pressure. The 3.3 g of residue were chromatographedover silica gel and eluted with a 92.5/7.5 methylene chloride-methanolmixture to obtain 1.8 g of amorphous 11β-[4-(N,N-dimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-δ4,9-estradiene-17β-ol-3-one with a specificrotation of [α]D20=+71° (c = 1% in chloroform).2th method of synthesis of mifepristone (see scheme):The oxidation of the diene I, which constitutes an intermediate for totalsynthesis of 19-nor steroids, with a reagent prepared from trifluoroaceticanhydride/hydrogen peroxide was obtained exclusively α-epoxide II. Thecondensation of II with the Grignard reagent from 4-bromo-N,N-dimethylaniline results in addition of the reagent at the 11β-position. Thisresults in rearragement of the olefin to 9,10 and opening of the epoxide. Thestereochemistry of the product obtained III is consistent with trans-opening ofthe oxirane, albeit at a remove of two carbon atoms. Mild hydrolysis removesthe silyl cyanohydrin protecting group at the 17-position to give a ketone IV.Reaction of the ketone with propargyl lithium leads to V. Hydrolysis of thatproduct under more strenuous condition results in removal of the acetal at 3;the resulting β-hydroxyketone then dehydrates to afford the 4,10(9)-dienoneVI. Another name of VI is estra-4,9-dien-3-one, 11-(4-(dimethylamino)phenyl)-17-hydroxy-17-(1-propynyl)-, (11β,17β)- or mifepristone.
Therapeutic Function
Antiprogesterone
World Health Organization (WHO)
Mifepristone, an antiprogesterone used in combination with a
prostaglandin for the termination of early pregnancy, was introduced in 1990. Use
of the combination has been associated with episodes of coronary spasm that are
attributed to administration of the prostaglandin and which have resulted in several
cases of cardiac infarction and ventricular fibrillation. At least one of these
incidents has been fatal.
Biological Activity
Selective antagonist at progesterone (PR) and glucocorticoid (GR) receptors in vitro and in vivo . Is a silent antagonist at PR and has a higher affinity than progesterone. Has higher affinity for GR than dexamethasone.
Biochem/physiol Actions
Therefore, mifepristone is considered to be a potent abortifacient. It is also known to inhibit human chorionic gonadotropin. Mifepristone results in decidual necrosis.
Pharmacokinetics
Following oral administration, mifepristone is rapidly absorbed, with a peak plasmaconcentration in approximately 90 minutes , an oral bioavailability of approximately 70%, and a term inal elimination half-life of 18 hours. It is 98% protein bound, primarily to album in and α1-acid glycoprotein. Mifepristone is metabolized primarily via CYP3A4 pathways involving mono- and di-N-demethylation and terminal hydroxylation of the 17-propynyl chain. The fact that approximately 83% of the drug is recovered in the feces and 9% in the urine suggests a biliary route of elimination. Mifepristone also demonstrates antiglucocorticoid activity.
Clinical Use
An antiprogestin is a substance that competes with progesterone for its receptor and, ultimately, prevents progesterone from binding to and activating its receptor. Because progesterone is integral to the continuation of an early pregnancy, it is expected that antipro-gestins will interfere with pregnancy maintenance. In 1982, the first antiproges tin, mifepristone (RU 486), was reported. Mifepristone was shown to interrupt early stages of implantation and pregnancy in humans.
References
https://pubchem.ncbi.nlm.nih.gov/compound/mifepristone#section=Top
https://www.drugbank.ca/drugs/DB00834
https://www.drugs.com/cdi/mifepristone-tablets.html
Check Digit Verification of cas no
The CAS Registry Mumber 84371-65-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,4,3,7 and 1 respectively; the second part has 2 digits, 6 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 84371-65:
(7*8)+(6*4)+(5*3)+(4*7)+(3*1)+(2*6)+(1*5)=143
143 % 10 = 3
So 84371-65-3 is a valid CAS Registry Number.
InChI:InChI=1/C29H35NO2/c1-5-15-29(32)16-14-26-24-12-8-20-17-22(31)11-13-23(20)27(24)25(18-28(26,29)2)19-6-9-21(10-7-19)30(3)4/h6-7,9-10,17,24-26,32H,8,11-14,16,18H2,1-4H3/t24?,25-,26?,28+,29+/m1/s1
84371-65-3Relevant articles and documents
Method alleviating migraine headache with mast cell degranulation blocking agents
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, (2008/06/13)
A method of preventing or alleviating a migraine headache which comprises administering a pharmaceutically effective amount of a mast cell degranulation blocking agent just prior to or during the prodromal phase of the migraine in the absence of an analgesic. The agent can also be administered in combination with a central nervous system stimulant.