Mifepristone
Abortifacient.
CAS: 84371-65-3
(11b,17b)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one
17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (Propa-1 ,2-dienyl) estra-4 ,9-dien-3-one.
17β-hydroxy-11β-(4-dimethylaminophenyl) 17α-(prop-2-ynyl) estra-4 ,9-dien-3-one.
11b-[4-(N,N-dimethylamino)phenyl]-17a-(prop-1-ynyl)-D4,9-estradiene-17b-ol-3-one
(11β,17β)-11-[4-(N,N-dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-diene-3-one
RU-486; RU-38486, Mifegyne (HMR)
MF: C29H35NO2
MW: 429.59
C 81.08%, H 8.21%, N 3.26%, O 7.45%
mp 150°.
Optical Rotation: [a]D20 +138.5° (c = 0.5 in chloroform)
Progesterone receptor antagonist with partial agonist activity.
Mifeprex, Mifegyne, RU-486, Corlux, 84371-65-3, Mifepristonum [Latin], Mifepristona [Spanish], RU486, Mifepriston
Molecular Formula: C29H35NO2 Molecular Weight: 429.5937
A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary CUSHING SYNDROME.
Mifepristone (or RU-486) is a synthetic steroid compound with both antiprogesterone and antiglucocorticoid properties. The compound is a 19-nor steroid with substitutions at positions C11 and C17 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl] 17 alpha-[1-propynyl]estra-4,9-dien-3-one), which antagonizes cortisol action competitively at the receptor level.
U.S. Pat. No. 4,386,085 (the ’085 patent) discloses mifepristone starting from estra-5(10), 9(11)-diene-3,17-dione 3-ethylene acetal. The ’085 patent discloses the purification of mifepristone by column chromatography using cyclohexane-ethyl acetate (7:3) mixture as an eluent. However, a drawback to the use of column chromatography is its unsuitability for industrial use.
Mifepristone is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. Mifepristone is also a powerful glucocorticoid receptor antagonist, and has occasionally been used in refractory Cushing’s Syndrome(due to ectopic/neoplastic ACTH/Cortisol secretion). During early trials, it was known as RU-38486 or simply RU-486, its designation at the Roussel Uclaf company, which designed the drug. The drug was initially made available in France, and other countries then followed—often amid controversy. It is marketed under tradenames Korlym and Mifeprex, according to FDA Orange Book.
Mifepristone was the first antiprogestin to be developed and it has been evaluated extensively for its use as an abortifacient. The original target for the research group, however, was the discovery and development of compounds with antiglucocorticoid properties. It is these antiglucocorticoid properties that are of great interest in the treatment of severe mood disorders and psychosis.
In April 1980, as part of a formal research project at Roussel-Uclaf for the development of glucocorticoid receptorantagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486); which was discovered to also be a progesterone receptor antagonist. In October 1981, endocrinologist Étienne-Émile Baulieu, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion in eleven women in Switzerland by gynecologist Walter Herrmann at theUniversity of Geneva‘s Cantonal Hospital, with successful results announced on April 19, 1982. On October 9, 1987, following worldwide clinical trials in 20,000 women of mifepristone with aprostaglandin analogue (initially sulprostone or gemeprost, later misoprostol) for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, with approval announced on September 23, 1988.
On October 21, 1988, in response to antiabortion protests and concerns of majority (54.5%) owner Hoechst AG of Germany, Roussel-Uclaf’s executives and board of directors voted 16 to 4 to stop distribution of mifepristone, which they announced on October 26, 1988. Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone in the interests of public health.French Health Minister Claude Évin explained that: “I could not permit the abortion debate to deprive women of a product that represents medical progress. From the moment Government approval for the drug was granted, RU-486 became the moral property of women, not just the property of a drug company.” Following use by 34,000 women in France from April 1988 to February 1990 of mifepristone distributed free of charge, Roussel-Uclaf began selling Mifegyne (mifepristone) to hospitals in France in February 1990 at a price (negotiated with the French government) of $48 per 600 mg dose.
Mifegyne was subsequently approved in Great Britain on July 1, 1991, and in Sweden in September 1992, but until his retirement in late April 1994, Hoechst AG chairman Wolfgang Hilger, a devout Roman Catholic, blocked any further expansion in availability. On May 16, 1994, Roussel-Uclaf announced that it was donating without remuneration all rights for medical uses of mifepristone in the United States to the Population Council, which subsequently licensed mifepristone to Danco Laboratories, a new single-product company immune to antiabortion boycotts, which won FDA approval as Mifeprex on September 28, 2000.
On April 8, 1997, after buying the remaining 43.5% of Roussel-Uclaf stock in early 1997, Hoechst AG ($30 billion annual revenue) announced the end of its manufacture and sale of Mifegyne ($3.44 million annual revenue) and the transfer of all rights for medical uses of mifepristone outside of the United States to Exelgyn S.A., a new single-product company immune to antiabortion boycotts, whose CEO was former Roussel-Uclaf CEO Édouard Sakiz. In 1999, Exelgyn won approval of Mifegyne in 11 additional countries, and in 28 more countries over the following decade.
Mifepristone’s production and use as abortifacient may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 8.0X10-14 mm Hg at 25 deg C indicates mifepristone will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase mifepristone will be removed from the atmosphere by wet and dry deposition. Mifepristone does not contain chromophores that absorb light at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, mifepristone is expected to have no mobility based upon an estimated Koc of 89,000. Volatilization from water and moist soil surfaces is not expected to be an important fate process based upon an estimated Henry’s Law constant of 5.0X10-13 atm-cu m/mole. Mifepristone will not volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data were not available. If released into water, mifepristone is expected to adsorb to suspended solids and sediment based upon the estimated Koc. An estimated BCF of 2,800 suggests potential for bioconcentration in aquatic organisms is very high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to mifepristone may occur through inhalation and dermal contact with this compound at workplaces where mifepristone is produced or used. Exposure to the drug among the general population may be limited to those being administered the drug mifepristone, (an abortifacient).
mifepristone
Synthesis
3,3-(Ethylenedioxy)estra-5(10),9(11)-diene-17(beta)-one (I) could react with propynylmagnesium bromine (II) in the presence of THF to produce 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-5(10),9(11)-diene-17(beta)-ol (III), which is epoxidized with H2O2 in hexafluoroacetone-methylene chloride yielding 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)-5(alpha),10(alpha)-epoxyestra-9(11)-en-17(beta)-ol (IV). The reaction of (IV) with 4-dimethylaminophenylmagnesium bromide (V) in THF affords 11(beta)-(4-dimethylaminophenyl)-3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-9-en-17(beta)-ol (VI), which is finally deprotected by a treatment with HCl in metnanol.
Intermediate
11β-[4(N,N-dimethylamino)phenyl]-17β-hydroxy-17α-(3-methyl-1-butynyl)-estra-4,9-dien-3-one from estra-5(10), 9(11)-diene-3,17-dione-cyclic-3-(1,2-ethanediylacetal) of the structural formula 2.
The compound of structural formula 2 can be prepared from (+)-estrone in seven steps. Methylation of hydroxy group at C-3 in (+)-estrone, reduction of 17-ketone to 17β-alcohol followed by Birch reduction of ring A and mild hydrolysis of the enol ether to afford estra-17β-hydroxy-5(10)-en-3-one in four steps (Ref: Wilds, A. L. and Nelson, N. A. J. Am. Chem. Soc. 1953, 75, 5365-5369). This compound in another three steps, namely bromination and dehydrobrominatlon, ketalisation followed by Oppenauer oxidation yield compound having structural formula 2 (Ref: Perelman, M; Farkas, E.; Fornefield, E. J.; Kraay, R. J. and Rapala, B. T. J. Am. Chem. Soc. 1960, 82, 2402-2403).
U.S. Pat. No. 4,386,085 describes the synthesis of steroids of the general formula mentioned therein
………………..
EP0057115A2
ANY ERROr MAIL ME amcrasto@gmail.com
EXAMPLE 15 17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (Propa-1 ,2-dienyl) estra-4 ,9-dien-3-one.Step A: 11β-(4-dimethylaminophenyl) 3,3 – / 1,2-ethane diyl bis (oxy) / 17α-(propa-1 ,2-dienyl) estr-9-en-5α-17β-diol and 11β – (4 – dimethylaminophenyl) 3,3 – / 1,2-ethane diyl bis (oxy) / 17α-(prop-2-ynyl) estr-9-en-5α (-17β-diol. Preparation of lithium compound.
In 50 cm3 of anhydrous tetrahydrofuran at 0, +5 ° C, bubbled up Allène the absorption of 2.1 g. Cooled to -70 ° C. and 15 minutes in 23.9 cm3 of a 1.3 M solution of butyllithium in hexanne. The resulting mixture is stirred for 15 minutes at -70 ° C.
Condensation
A solution of lithium derivative obtained above was added at -70 ° C in 25 minutes a solution of 3.5 g of the product obtained in Step A of Example 7 in 35 cm3 of anhydrous tetrahydrofuran. Stirred for 1 hour at -70 ° C, slowly poured into a saturated aqueous solution iced ammonium chloride. Extracted with ether, the organic phase washed with saturated sodium chloride, dried and the solvent evaporated. 3.4 g of product which was chromatographed on silica eluting with petroleum ether-ethyl acetate (1-1) to 1 mile triethylamine. Thus isolated: a) 1.73 g of isomer 17α-(propa-1 ,2-dienyl) F = 178 ° C. / Α / D = -32 ° ± 2 ° (c = 0.7% chloroform) b) 1.5 g of isomer 17o (- (prop-2-ynyl) F = 150 ° C. / α / D = -15 ° ± 2 ° (c = 0.9% chloroform).
Step B: 17β-hydroxy-11β-(4-dimethylaminophenyl)-17α (propa-1, 2 – dienyl) estra-4 ,9-dien-3-one.
Inert gas mixing 1.73 g of 17α isomer (- (propa-1, 2 – dienyl) obtained in Step A, 51.8 cm3 of 95% ethanol and 3.5 cm3 of 2N hydrochloric acid. stirred at 20 ° C for 1 hour, add 50 cm3 of methylene chloride and 50 cm3 of a 0.25 M solution of sodium bicarbonate, decanted, extracted with methylene chloride, washed with water, dried and the solvent evaporated. obtained 1.51 g of product was dissolved in 10 cm3 of methylene chloride hot. was added 15 cm3 of isopropyl ether, concentrated and allowed to stand. thus isolated 1.23 g of the expected product was crystallized again in methylene chloride-isopropyl ether. finally obtained 1.11 g of the expected product. F = 228 ° C.
/ Α / D - 139, 5 ° ± 3 ° (c = 0.8% chloroform). ANY ERROr MAIL ME amcrasto@gmail.com
Prepn: J. G. Teutsch et al., EP 57115;eidem, US 4386085 (1982, 1983 both to Roussel-UCLAF).
Pharmacology: W. Herrmann et al., C.R. Seances Acad. Sci. Ser. 3294, 933 (1982).
Pituitary and adrenal responses in primates: D. L. Healy et al., J. Clin. Endocrinol. Metab. 57, 863 (1983).
Mechanism of action study: M. Rauch et al., Eur. J. Biochem. 148, 213 (1985).
Clinical study as abortifacient: B. Couzinet et al.,N. Engl. J. Med. 315, 1565 (1986); as postcoital contraceptive: A. Glasier et al., ibid. 327, 1041 (1992).
Review of mechanism of action and clinical applications: E. E. Baulieu, Science 245, 1351-1357 (1989).
Reviews: I. M. Spitz, C. W. Bardin, N. Engl. J. Med. 329, 404-412 (1993); R. N. Brogden et al., Drugs 45, 384-409 (1993).
http://www.jmcs.org.mx/PDFS/V50/special1/12-D%20pp%20166-187.pdf
http://journals.iucr.org/c/issues/1995/03/00/vj1006/vj1006.pdf
mifepristone
EP0817769
5-27-1999
BORNEOL ESTERS, PROCESS FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL USE
WO9907692
2-19-1999
NEW EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING SAME AND THEIR PHARMACEUTICAL USE NEW EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING SAME AND THEIR PHARMACEUTICAL USE
EP0896819
2-18-1999
Use of insect pheromones to treat pathologies induced by excess of glucocorticoid ANTIGLUCOCORTICOID DRUG
EP0758316
11-19-1998
BORNEOL DERIVATIVES AFFECTING TUBULIN POLYMERIZATION AND DEPOLYMERIZATION
WO9735839
10-3-1997
NOVEL BORNEOLS, PROCESSES FOR PRODUCING THEM AND PHARMACEUTICAL USE THEREOF
EP0648778
8-14-1997
11-Benzaldoximeestradiene-derivates, a process for their preparation and pharmaceutical compositions containing them
EP0648779
3-6-1997
New 11-benzaldehyde oxime, 17-beta methoxy, 17 alpha methoxymethyl derivates of estradiene, a process for their preparation and pharmaceutical compositions containing them
US5450857
9-20-1995
Method for the diagnosis of cervical changes
US5272140
12-22-1993
11-aryl steroid derivatives
WO0049019
8-25-2000
NOVEL EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING THEM AND THEIR PHARMACEUTICAL USE NOVEL EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING THEM AND THEIR PHARMACEUTICAL USE
WO0049020
8-25-2000
NOVEL EPOTHILON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL APPLICATION NOVEL EPOTHILON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL APPLICATION
WO0049021
8-25-2000
16-HALOGEN-EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING THEM AND THEIR PHARMACEUTICAL USE 16-HALOGEN-EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING THEM AND THEIR PHARMACEUTICAL USE
WO0047584
8-18-2000
EPOTHILON DERIVATIVES, METHOD FOR THE PRODUCTION AND THE USE THEREOF AS PHARMACEUTICALS EPOTHILON DERIVATIVES, METHOD FOR THE PRODUCTION AND THE USE THEREOF AS PHARMACEUTICALS
WO0000485
1-7-2000
EPOTHILON DERIVATIVES, THEIR PREPARATION PROCESS, INTERMEDIATE PRODUCTS AND THEIR PHARMACEUTICAL USE
WO9964393
12-17-1999
NOVEL ANTIESTROGENS, A METHOD FOR THE PRODUCTION THEREOF, AND THEIR PHARMACEUTICAL APPLICATION
WO9959596
11-26-1999
GLUCOCORTICOID RECEPTOR ANTAGONISTS FOR THE TREATMENT OF DEMENTIA
US5965623
10-13-1999
Anti-glucocorticoid drug
EP0909764
9-30-1999
11 Beta-Benzaldoxim-9 Alpha, 10 Alpha-epoxy-estr-4-en-derivatives, a process for their production and pharmaceutical compositions containing them
WO9945023
9-11-1999
S-SUBSTITUTED 11 beta -BENZALDOXIME-ESTRA-4,9-DIENE-CARBONIC ACID THIOLESTERS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS
EP0595133
1-6-2011
PRODRUGS, THEIR PREPARATION AND USE AS MEDICAMENTS
US2010135956
6-4-2010
STEROID MODULATORS OF PROGESTERONE RECEPTOR AND/OR GLUCOCORTICOID RECEPTOR
EP1005465
7-26-2007
NEW EPOTHILONE DERIVATIVES, METHOD FOR PRODUCING SAME AND THEIR PHARMACEUTICAL USE
US2007105828
5-11-2007
Novel polymorph form M of mifepristone and process for its preparation
EP0879605
7-27-2006
GLYCOSYL PRODRUG CONJUGATE WITH ENHANCED TOLERANCE
EP1023074
7-13-2006
METHODS FOR TREATING PSYCHOSIS ASSOCIATED WITH GLUCOCORTICOID RELATED DYSFUNCTION
EP0795334
2-2-2006
Prodrugs for the treatment tumors and inflammatory diseases
EP0730448
2-7-2002
USE OF NITRIC OXIDE SYNTHASE SUBSTRATE AND/OR DONOR, OR A NITRIC OXIDE INHIBITOR FOR THE MANUFACTURE OF MEDICAMENTS FOR THE TREATMENT OF UTERINE CONTRACTILITY DISORDERS
EP0809627
9-13-2001
NOVEL BORNEOL DERIVATIVES, METHODS OF MANUFACTURING THEM, AND THEIR PHARMACEUTICAL USE
US6150349
11-22-2000
Methods for treating psychosis associated with glucocorticoid related dysfunction
Filed under: Uncategorized Tagged: MIFEPRISTONE