|Company Name:||J & K SCIENTIFIC LTD. |
|Mifepristone Chemical Properties|
|Mifepristone Usage And Synthesis|
|Pharmacological effects||Mifepristone belongs to the anti-progesterone drug. It was first successfully developed by the French company Roussel-Uolsf in the early 1980s for acting as a novel anti-fertility drug acting at receptor levels. It has no progesterone, testosterone, estrogen activity. It first entered into market in France at 1988 with its major role in acting on the endometrial progesterone receptor which is capable of binding with the progesterone receptor and glucocorticoid receptor with high affinity. The affinity to the endometrial progesterone receptor of it is five time as strong as that of progesterone without significant effects on the cortisol levels, and can produce a strong anti-progesterone effect thus causing the degeneration of decidua and chorionic villi of pregnancy. It can also cause release of endogenous prostaglandins which causes uterine contractions while resulting in the decreased production of the human chorionic gonadotropin hormones and dissolution of corpus luteum, and finally causing the embryo abortion. Because the drug can’t trigger enough uterine activity so single application for anti-pregnancy yields a relative high rate of incomplete abortion, but it can increase uterine sensitivity to prostaglandins, so that it not only reduces the adverse effects of prostaglandins after adding a small dose of prostaglandin but also make the complete abortion rate increased significantly. In addition mifepristone also has a softening and expansion effect of the cervix.|
Mifepristone is rapidly absorbed after oral administration with a bioavailability being 70% and a plasma protein binding rate of 98%. The plasma concentration reaches peak at 0.7 to 1 hours after oral administration with duration of 12 hours and being non-detective after 48 hours. It has a half-life of 24 to 33 hours. It is mainly distributed in the brain and pituitary gland, adrenal cortex and endometrium. More than 90% of this product is metabolized by the liver into the bile and further excreted by the digestive tract, 10% is excreted by the urinary tract. It can be clinically used for anti-pregnancy, inducing menstruation, post-coital contraception, abortion and stillbirth cervical ripening, but also for gynecological surgical procedures, such as IUD placement and removal, taking samples of endometrial, laser separation of cervical dysplasia, and cervical dilation as well as curettage.
|Instructions||Oral administration has anti-pregnancy effect, currently applied for people with pregnancy <49 days. Specific usage in three: |
The first usage: orally administration of 600 mg mifepristone in single dose, place 1mg PGF2α (Kaposi prostaglandin) or PGO5 (Kaposi prostaglandin methyl ester) at the vaginal fornix at third or fourth day with the complete abortion rate being as high as 92.3 %. Currently Mifepristone dose has been reduced to a single dose of 200mg, or divided doses of 125-150mg with clinical results not being affected.
The second usage: oral administration of single dose of 600 mg; apply intramuscular injection 0.25 mg of a single oral dose; at 36-48 hours after oral administration, apply intramuscular injection 0.25 mg, or 0.375 mg or 0.5 mg of sulprostone with complete abortion rate of 96%; with the larger amount of sulprostone applied, the sooner the embryonic will be discharged.
The third usage: apply a single oral-administrated dose of 600mg; at 48 hours after oral administration, place 1 mg of ONO802 (gemeprost) pessary suppository inside of the vagina with the complete abortion rate being 95%.
For people with amenorrhea longer than seven weeks, orally administrate 100 mg of mifepristone each time with 2 times per day, and continue for 4 days. You can also apply 1 mg of Kaposi forefront methyl suppository for vagina at 36 to 48 hours after treatment. Have rest in bed for 2 hours and clinic observation for 6 hours. Pay attention to the condition of bleeding after medication to check whether there are pregnancy products being discharged and any adverse reactions.
For labor induction of middle and late dead fetal, take 200 mg each time and 2 times daily. Consecutively take for two days for inducing menstruation and terminating pregnancy. During the 23 to 26 days at menstrual cycle, take 100 ~ 200mg each time with once daily. Consecutively take four days.
|Precautions||1. Patients of heart, liver, kidney disease and adrenal insufficiency, hypertension, pregnancy with IUD, suspected ectopic pregnancy are not allowed to apply. |
2. for patients of incomplete abortion or invalid to treatment, they should be treated using vacuum aspiration abortion. Pregnant of over 35 years-old should avoid using it. Patients of allergy are forbidden for using. Follow-up treatment should be performed after 8 to 12 days in order to check the occurrence of complete abortion or stop of bleeding.
3. this drug can’t be combined with rifampin, carbamazepine, griseofulvin, barbiturates, phenytoin, non-steroidal anti-inflammatory drugs and adrenal hormones.
4. this drug can’t be combined with salicylates, indomethacin, and other analgesics.
5. for people with a long duration of bleeding time, in order to prevent the occurrence of infection, antibiotics and uterotonics should be added. Patients of heart, liver, kidney disease and adrenal insufficiency should be disabled.
6. mifepristone should be kept in darkness and sealed.
7. At 8 to 15 days after taking the drug, the patients should go to medical center for return visit; when incomplete abortion happens or pregnancy, continues, apply artificial abortion for termination of pregnancy.
The above information is edited by the chemicalbook of Dai xiongfeng.
|Chemical Properties||Melting point: 150 °C. [α] D20 + 138.5°(C = 0.5, chloroform). Acute toxicity: mice LD50 (g / kg):> 2.6 with intraperitoneal injection.
|Applications||It is a novel anti-progestin and has anti-glucocorticoid activity without the activity of progesterone, estrogen, androgen and anti-estrogen. It has a progesterone receptor affinity five times as high as progesterone. It is used for anti-pregnancy, inducing menstruation and terminating pregnancy, intrauterine inducer labor for dead fetal.
|Production methods||Method 1: Take the 3’ ketal compound of estra 4,9-diene-3,17-dione (I) as the raw materials, have it be reacted with propargyl magnesium bromide Grignard reagent to introduce the propynyl group in the 17 position, to give compound (II); further selectively epoxidize the 5’ ethylenic bonds to give the compound (III). Then it is reacted with dimethylaminobenzaldehyde magnesium bromide in tetrahydrofuran containing copper bromide-dimethyl sulfide complex in order to introduce the p-dimethylaminophenyl group in the 11th position to get the compound (IV). Finally, use hydrochloric acid for hydrolysis and dehydration in methanol to obtain mifepristone with the yield being 21.5%.|
Method 2: Use the same estra 4,9-diene-3,17-dione as a raw material with 3-carbonyl being protected; then first epoxidize it, and then introduce the propynyl group at 17th position, introduce the p-dimethylaminophenyl group at 11th position, finally hydrolyze it to obtain the mifepristone. Compared with Route 1, the only difference is the order of epoxidation and propynyl group introduction propynyl. But they share the same reaction step. The total yield of method II is around 35% -40%.
|Chemical Properties||Pale Yellow Solid|
|Usage||A progesterone receptor antagonist with partial agonist activity. Abortifacient.
|Usage||glutamate uptake inhibitor, AMPA blocker|
|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.|
|Mifepristone Preparation Products And Raw materials|