126784-99-4 Usage
Oral emergency contraception
Ulinastal acetate is a new oral contraceptive pill, and it is the active chemical composition of Ella, a new generation of emergency contraceptive wildly on the market in United States currently. It can protect women within 120 hours after intercourse without medication, and the emergency contraceptive efficacy will not decline with the delay of treatment time. At the same time, it is safe and durable. Compared with the most commonly used emergency contraceptive levonorgestrel, Ulinastal acetate is more suitable for clinical use, and has the potential to prevent more unwanted pregnancies.
Ulipristal acetate was developed by HRA Pharmaceuticals, Inc., and was marketed by the Food and Drug Administration (FDA) in August 2010 under the trade name Ella. It could be used for the protection of unprotected sex or for the pregnancy prevention in the known or suspected contraceptive failure situation within 120h. Ulipristal acetate is a selective progesterone receptor modulator; and mainly it can take effect by inhibiting the ovulation and plays an emergency contraceptive effect. The study found that Ulastatal acetate was more effective than levonorgestrel in suppressing vomiting after dosing before the estimated ovulation day. And it consequently suggests that Ulatastatin acetate might have a stronger emergency contraceptive effectiveness.
Figure 1 for the structure of ulcaritin acetate
Pharmacological action
Ulinastal acetate is a progesterone agonist/antagonist that inhibits or delays the ovulation; however, changes in the endometrium may also be a cause of efficacy.
Ulinastal acetate belongs to the category of selective progesterone receptor modulator, and it has partial agonistic action to progesterone receptor antagonism and partial agonism. It binds to progesterone receptors in the human body and prevents progesterone receptor binding. The efficacy of Ulinastal acetate depends on the time of administration in the menstrual cycle. Administration during the mid-follicular hyperplasia would suppress follicle formation and decrease the estradiol concentrations. And the administration during the in the peak period of follicular hyperplasia can delay the breakdown of follicles from 5 to 9 days. Although early luteal phase of administration cannot significantly delay the endometrial maturation, it can reduce the thickness of the endometrium within 0.6±2.2mm（average value ±SD）.
Pharmacokinetics
Absorption: The highest fasting plasma concentrations of 20 women reached 176 ng/ mL and 69ng/ mL after 0.9 and 1 hour of using ulipristal acetate and active metabolite (mono-demethyl-ulipristal acetate) in single bolus medication.? And mono palmitoyl-ulipristal acetate was lower by 40% to 45% compared with the high-fat breakfast. And ompared with the fasting state, and the delayed tmax (delayed from median 0.75 h to 3 h) with an average AUC0-∞ of 20% to 25% higher. These differences are not expected to impair the efficacy or safety of Ulinastal acetate. Therefore, Ulatastatin acetate can take effect in both situation: with or without food.
Distribution: This product has a high binding rate (> 94%) with plasma protein, high-density lipoprotein, α-1-acid glycoprotein and albumin.
Metabolism: Ulipristal acetate could be metabolized to mono-desmethyl and bis-nor-metabolites. In vitro data indicates that single demethyl metabolites are pharmacologically active, mainly due to CYP3A4 mediated.
Excretion: The terminal half-life of ulipristal acetate in plasma after a single dose of Ulistatta 30 mg would be estimated to (32.4 ± 6.3) hours.
The pharmacological effects, pharmacokinetics, market prospect and patent intellectual property rights of oral emergency contraceptive Ulinastal acetate were edited by Xiao Nan from Chemical book.
market prospect
Emergency contraception, also known as after-birth control pills, is a kind of contraceptive for women of childbearing age in the situation od non-protective intercourse or contraceptive failure after the use of contraception to prevent accidental pregnancy.
At present, the most widely used emergency contraceptive is levonorgestrel (1evonorgestre1), which is used at intervals of 12hours each serving one piece (0.75mg) or a single taking of two pieces(1.5mg). However, levonorgestrel was only approved for using as an emergency contraceptive only 72 hours (3days) after unprotected intercourse or contraceptive failure. Even though, the efficacy of levonorgestrel emergency contraception will be significantly reduced with the delay of treatment time; it is recommended that it should better used in unprotected intercourse or contraceptive failure within 12h after the start of medication.
In May 2009, the European Union approved a new emergency contraceptive ulipristal acetate, also called as Ella One, which is not only allowed to be taken within 120 hours (5 days) of unprotected intercourse or contraceptive failure, but the? emergency contraceptive efficacy would not delay and decline with the medication time.
Ulastat is one of the first oral contraceptives approved worldwide to be administered within 120 hours of unprotected intercourse or contraceptive failure, which has the potential to prevent more unwanted pregnancies than levonorgestrel. As a new oral emergency contraceptive, Ulinastal acetate can not only be used within 120 hours after unprotected intercourse, but the efficacy of emergency contraception would not decrease with the delay of administration, and it is safe and durable as well. Compared with the most commonly used emergency contraceptive levonorgestrel, Ulinastal acetate is more suitable for clinical use, and it has the potential to prevent more unwanted pregnancies.
intellectual property rights
The original research manufacturer in China has already applied for a patent for Ulinastal acetate tablets and its indications as well as for its indications. However, it has not been authorized yet. There are not any intellectual property barriers.
Other clinical researches
February 2, 2012, The New England Journal of Medicine published two clinical trials found that Ulinastal acetate has an excellent effect in the treatment of uterine fibroids. The results show that Ulinastal acetate is as effective as leuprolide in controlling uterine fibroid bleeding, reducing the volume of myoma and comforting the pain;
According to statistics, about a quarter of women have suffered from uterine fibroids symptoms. Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, has been approved for preoperative treatment of uterine fibroids since its approval in 1995. Ulinastal acetate can successfully challenge leuprolide and it becomes become a new choice for preoperative uterine fibroids drug therapy. Let’s wait for the post-trial to reveal the answer.
References
[1] Shilpa P. Jadav, Dinesh M. Parmar (2012) Ulipristal acetate, a progesterone receptor modulator for emergency contraception, J Pharmacol Pharmacother, 3, 109-111
[2] Ulipristal acetate for fibroids, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155051/
[3] Elena Rosato, Manuela Farris, Carbo Bastianeli (2015) Mechanism of Action of Ulipristal Acetate for Emergency Contraception: A Systematic Review, Front Pharmacol, 6, 315
[4] https://www.glowm.com/Critical_current_issue/page/5
Originator
Research Triangle Institute (US)
Biochem/physiol Actions
Ulipristal acetate is a selective progesterone receptor modulator (SPRM) with tissue-selective partial antagonist activity. It has clinical use both as an emergency contraceptive and as a treatment for uterine fibroids. Ulipristal acetate acts as a partial antagonist on the hypothalamic–pituitary–ovarian axis to inhibit or delay ovulation without affecting human embryo implantation. As a progesterone antagonist, Ulipristal acetate selectively suppresses neo-vascularization, cell proliferation, and survival in uterine fibroid cells, but not in normal myometrial cells.
Clinical Use
Ulipristal acetate, a selective progesterone receptor modulator
(SPRM), was developed at the Research Triangle Institute. In
2009, HRA Pharma received FDA approval for emergency contraception
within 120 h (5 days) of unprotected sexual intercourse or contraceptive failure. Ulipristal acetate is a well-known steroid
that possesses antiprogestational and antiglucocorticoid activity.
It is the first SPRM that was specifically designed as an oral
emergency contraceptive. Unlike earlier levonorgestrel-based
emergency contraceptives, this SPRM drug maintains efficacy for
5 days after unprotected intercourse while having safety profile
comparable to levonorgestrel.
Synthesis
Recently, an industrial scale route
was published and is described in the scheme.89 Alkylation of
commercially available 3-(ethylenedioxy)-19-estra-5(10),9(11)-
diene-17-one (129, multiple vendors) with tBuOK and acetylene
in THF at 0°C gave alcohol 130 in 95% yield, which was subsequently
treated with phenylsulfenyl chloride in the presence of
TEA and AcOH in DCM/CHCl3 at 5°C to 0°C to effect thiolester
formation followed by sulphinate-sulphoxide rearrangement to
give allene sulphoxide 131 in 88% yield. Compound 131 was treated
with NaOMe/MeOH at 64°C to give the corresponding enol
ether and then the enol ether was treated with trimethyl phosphite
at the same temperature for sulphoxide-sulphinate rearrangement
to furnish hydroxyl enol ether 132 in 67% yield. Compound 132
was demethylated with 1 M HCl in methanol to give the corresponding
ketone 133 in 95% yield which was protected using ethylene
glycol, pTsOH and trimethyl orthophosphate in DCM to
afford cyclopentyl ketal 134 in 87% yield. Epoxidation of 134 in
the presence of hexachloroacetone and H2O2 in pyridine and
DCM at 0°C provided a 55:45 mixture of the 5-a,10-a epoxides
(135, 136). The crude epoxides 135 and 136 were reacted with
4-( N,N-dimethylamino)-phenyl magnesium bromide in THF in
the presence of CuCl in DCM to furnish the mixture of diastereomers
137 and 138 in 46% yield over two steps. The mixture (137
and 138) was then treated with KHSO4 in water at 5°C to affect
dehydration and liberation of the keto functional group to give
139 which was used in the next step without isolation. Compound
139 was acetylated with acetic anhydride and perchloric acid in
DCM at 30°C to afford the ulipristal acetate (XXI) in 66% yield
over the final two steps.
Check Digit Verification of cas no
The CAS Registry Mumber 126784-99-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,6,7,8 and 4 respectively; the second part has 2 digits, 9 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 126784-99:
(8*1)+(7*2)+(6*6)+(5*7)+(4*8)+(3*4)+(2*9)+(1*9)=164
164 % 10 = 4
So 126784-99-4 is a valid CAS Registry Number.
InChI:InChI=1/C30H37NO4/c1-18(32)30(35-19(2)33)15-14-27-25-12-8-21-16-23(34)11-13-24(21)28(25)26(17-29(27,30)3)20-6-9-22(10-7-20)31(4)5/h6-7,9-10,16,25-27H,8,11-15,17H2,1-5H3/t25-,26+,27-,29-,30-/m0/s1
126784-99-4Relevant articles and documents
One-pot preparation method for ulipristal acetate
-
, (2019/10/04)
The invention discloses a one-pot preparation method for ulipristal acetate, belonging to the technical field of drug synthesis. The method comprises the following steps: with a Grignard's substance CW-b as a raw material, performing acidolysis via an org
Synthesis method of ulipristal acetate
-
Paragraph 0054; 0055, (2018/04/02)
The invention discloses a synthesis method of ulipristal acetate. The synthesis method comprises the following steps: 1), producing a compound VI from gestadienol under the action of ethylene glycol,p-toluenesulfonic acid and trimethyl orthoformate; 2), oxidizing the compound VI by using hydrogen peroxide to obtain a compound VII; 3), preforming a reaction on the compound VII and a 4-(N, N-dimethylamino) phenylmagnesium bromide Grignard reagent to obtain a compound VIII; 4), hydrolyzing a compound VIII to obtain a compound XI; 5), preforming a reaction on the compound XI, glacial acetic acidand acetic anhydride under the catalytic action of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine and iron perchlorate to obtain the ulipristal acetate. In the synthesis method, reaction conditions for obtaining the ulipristal acetate from ulipristal are relatively mild, demethylated ulipristal or ulipristal oxynitride is unlikely to produce, and the production process is more controllable.
Acetic acid wu lisi he and its intermediate preparation method
-
, (2017/09/19)
The invention discloses a preparation method of ulipristal acetate and an intermediate thereof, and belongs to the field of pharmaceutical synthesis. The preparation method of the ulipristal acetate comprises the following steps: by taking 3,3-(ethylenedioxy)-19-methylestra-5(10),9(11)-diene-3,17-diketone as raw material, enabling the raw material to react with sodium acetylide or potassium acetylide to obtain a compound III, carrying out high-selectivity epoxidation by oxide to obtain a compound IV, subsequently enabling the compound IV to react with 4-(N,N-dimethyl amino) phenyl magnesium bromide Grignard reagent to obtain a compound V, then enabling the compound V to react with phenyl sulfonic acid chloride to obtain a compound VI, enabling the compound VI to respectively react with sodium methoxide and trimethyl phosphate to obtain a compound VII, hydrolyzing and removing a protection group to obtain a compound VIII, finally carrying out acetylation reaction to obtain the ulipristal acetate, wherein the reaction formulae are as shown in the description. The method is short in synthetic route, mild in reaction conditions, high in yield and purity of products, low in cost, stable and controllable in quality, and is suitable for industrial production.
Ulipristal acetate impurities and preparation and detection method thereof
-
, (2016/10/31)
The invention provides ulipristal acetate impurity compounds and a preparation method thereof, and particularly provides novel compound impurities including A (a compound A), G (a compound G), H (a compound H) and J (a compound J). The invention further provides a detection method of the impurities and application of the impurities on quality analysis of an ulipristal acetate bulk drug and a preparation thereof.
Impurity of ulipristal acetate and preparation and detecting method of impurity
-
Paragraph 0118; 0119; 0120, (2017/01/02)
The invention provides an impurity compound of ulipristal acetate and a preparation method of the impurity compound, particularly provides a new compound impurity B (compound B) and an impurity C (compound C), and further provides a detecting method of the impurities and application of the impurities to quality analysis of ulipristal acetate crude drugs and preparations of the ulipristal acetate crude drugs.
First synthesis and characterization for the stereoisomers of Ulipristal acetate
Zhao, Yi,Li, Xiaolong,Liu, Hong,Yu, Yongguo,Hai, Li,Guo, Li,Wu, Yong
, p. 7 - 16 (2015/01/30)
The three stereoisomers, 11α,17α-isomer I, 11α,17β-isomer II and 11β,17β-isomer III are related substances of the selective progesterone receptor modulator Ulipristal acetate. Herein, we presented an efficient and practical synthesis approach to deliver t
INDUSTRIAL PROCESS FOR THE SYNTHESIS OF ULIPRISTAL ACETATE AND ITS 4'-ACETYL ANALOGUE
-
, (2015/04/22)
The present invention relates to a new process for the synthesis of compounds of formula (I) (wherein the meaning of R is dimethylamino or acetyl group) using the compound of formula (II) (wherein the meaning of R is dimethylamino or 2-methyl-1,3-dioxolan-2-yl group) as starting material, as well as to the intermediate of the process.
Method for preparing ulipristal acetate and key intermediate thereof
-
, (2014/10/16)
A method as well as new intermediates for preparing Ulipristal acetate (a compound I) and a method for preparing the new intermediates are provided. The intermediate in a constitutional formula IV is conductive to reacting with methyl lithium or methyl Grignard reagent, a protective group is easy to be removed after a reaction, side reactions are few, a mid-term treatment is simple, the reagents used are cheap, costs are low and a yield is high, if a compound in a constitutional formula V is obtained by the reaction of a compound in a constitutional formula III and the intermediate in the constitutional formula IV, the yield of a two-step reaction is 75%, a purity is above 98%. wherein R is defined in the specification.
ULIPRISTAL ACETATE PREPARATION METHOD AND INTERMEDIATE THEREOF
-
, (2014/09/29)
A method as well as new intermediates for preparing Ulipristal acetate (a compound I) and a method for preparing the new intermediates are provided. The intermediate in a constitutional formula IV is conductive to reacting with methyl lithium or methyl Grignard reagent, a protective group is easy to be removed after a reaction, side reactions are few, a mid-term treatment is simple, the reagents used are cheap, costs are low and the yield is high, if a compound in a constitutional formula V is obtained by the reaction of a compound in a constitutional formula III and the intermediate in the constitutional formula IV, the yield of a two-step reaction is 75%, a purity is above 98%. wherein R is defined in the specification.
NOVEL PROCESS AND INTERMEDIATE FOR PREPARATION OF ULIPRISTAL
-
, (2014/05/07)
The present invention is related to a novel process for the preparation of ulipristal (I) that comprises reaction of 17-α-ethynyl-17-β-hydroxy-11-β-(4-N,N-dimethylamino phenyl)- 9-norpregna-4,9-diene-3-one (III) with phenyl sulphenyl chloride (IVa) or p-nitro phenyl sulphenyl chloride (IVb) in the presence of organic base and solvent to give sulfoxide (Va) or (Vb) respectively. Sulfoxides (Va) or (Vb) are reacted with alkali metal alkoxide in alcoholic solvent followed by treatment with aqueous acid. The present invention also relates to novel intermediate 11-β-(4-N,N-dimethylaminophenyl)-21(p- nitro-phenyl-sulphinyl)-19-norpregna-4(5), 9(10), 17(20) 20-tetraene, 3-one (Vb).
