57-63-6

Usage

Uses

Used in Pharmaceutical Industry:
Ethinyl estradiol is used as a synthetic estrogen in the development of oral contraceptives, in combination with progestins, for the prevention of pregnancy. It is also used in menopausal hormone therapy, in combination with progestins, for treating menopausal symptoms.
Used in Hormonal Contraceptives:
Ethinyl estradiol is used as an active ingredient in combination oral contraceptives, such as Alesse, Tri-cyclen, Yasmin, and Triphasil, for the prevention of pregnancy. The efficacy of oral administration of ethinyl estradiol is facilitated by the ethynyl substitution at the C-17 position, which inhibits first-pass hepatic metabolism.
Used in Menopausal Hormone Therapy:
Ethinyl estradiol is used as a component in menopausal hormone therapy, in combination with progestins, to alleviate symptoms associated with menopause.
Used in Research and Development:
Ethinyl estradiol is used as a metabolite of 17α-Ethynylestradiol and as a synthetic estradiol analog in various research and development applications, contributing to the understanding of its effects and potential uses in medicine.
Brand Names:
Some of the brand names under which Ethinyl estradiol is marketed include Estinyl (Schering), Feminone (Pharmacia & Upjohn), and Lynoral (Organon).

History

Ethynyl estradiol was first developed in 1930 and officially introduced for medical used in 1943. In the 1960s, the drug was widely used in birth control pills. EE is currently found in most combined forms of birth control pills, which makes it one of the most used estrogens.

Indications

Ethynyl estradiol is used for treatment of moderate to severe vasomotor symptoms such as night sweats, hot flashes, and flushing that are associated with the menopause, prostatic carcinoma-palliative therapy of advanced disease, female hypogonadism, as emergency contraceptive, breast cancer, and as an oral contraceptive.

Pharmacodynamics

Ethynyl estradiol is a synthetic derivative of the natural estrogen estradiol. The drug is one of two widely used in oral contraceptive pills. Mestranol is the other drug that is normally converted to ethinyl estradiol before it becomes biologically active. EE is used together with norethindrone as an oral contraceptive agent.

Mechanism of Action

The estrogen in the drug diffuse into their target cells before interacting with a protein receptor. Notably, target cells include the female reproductive tract, the hypothalamus, the mammary gland, and the pituitary. Estrogens act by increasing the hepatic synthesis of thyroid binding globulin (TBG), sex hormone binding globulin (SHBG) as well as other serum proteins. It also acts by suppressing follicle-stimulating hormone (FSH) from anterior pituitary. All these activities are initiated by fist binding to the estrogen receptors. The hypothalamic-pituitary system is suppressed by the combination of an estrogen with a progestin, which decreases the secretion of gonadorotropin-releasing hormone (GnRH).

Medical Uses

Ethnynyl estradiol is majorly used to control pregnancy after sex as a contraception in combined oral contraceptives (COC), which are also referred to as birth control. EE is not only used in preventing pregnancy but is also employed in the treatment of absence of menstruation, acne, as well as symptoms during menstruation. It majorly works by preventing ovulation (the release of an egg) during the menstrual cycle. Further, it acts by making the vaginal fluid thicker to help in preventing sperm from fertilizing the released egg. It also changes the lining of the uterus to prevent attachment of a fertilized egg. EE also works by making the menstruation cycle more regular, decreasing blood loss and painful periods, and decreasing the risk of ovarian cysts. EE is also used as menopausal hormone therapy (HRT) which has numerous benefits such as vaginal itching, vaginal dryness (which normally causes pain during sexual intercourse), and depressed mood. Previously, it was used as a constituent of feminizing hormone therapy for transgender women; however, the use of estradiol has largely superseded it in this therapy. The drug can also be used in preventing osteoporosis and in treating hypogonadism in women and has been used as palliative care for breast cancer in women and prostate cancer in men.

Contraindications

Ethnynyl estradiol should not be prescribed to individuals with history of susceptibility to venous or arterial thrombosis (blood clots) as it can lead to increased cardiovascular problems such as myocardial infarction, venous thromboembolism, and ischemic stroke. As such, it women with acute deep vein thrombosis or pulmonary embolism, any vascular disease history of DVT/PE, and complicated valvular heart disease are not advised to take the drug.

Side Effects

The side effects of EE include vomiting, nausea, headache, tenderness of the breast, abdominal cramps/bloating, swelling of the feet/ankles, and change in weight. In case of severe effects, one should immediately contact the doctor. EE can also cause irregular periods, which is considered normal.

Precautions

Before taking EE, it is important to inform the doctor or pharmacist if you allergic to the drug or to any other estrogens such as mestranol. It is also important to inform the doctor if one has a medical history of blood clots, for instance in the eyes, legs, and lungs. The medication can also affect blood sugar levels if one is diabetic. However, it is important to monitor the blood sugar levels and share it with the doctor in case one is using the drug.

Interactions

Drug interactions may change how EE works or might increase its side effects. Products that can interact with the drug include aromatase inhibitors (such as exemestane and anastrozole), tizanidine, tamoxifen, and tranexamic. It can also interact with certain combination products that are normally used to treat chronic hepatitis C. some drugs interact with EE by decreasing the amount of the drug in the body.

Originator

Estinyl,Schering,US,1944

Manufacturing Process

In about 250 cc of liquid ammonia (cooled with dry ice and acetone) are dissolved about 7.5 g of potassium and into the solution acetylene is passed until the blue color has disappeared (about 3 hours). Then slowly a solution or suspension of 3 g of estrone in 150 cc of benzene and 50 cc of ether is added. The freezing mixture is removed, the whole allowed to stand for about 2 hours and the solution further stirred overnight. Thereupon the reaction solution is treated with ice and water, acidified with sulfuric acid to an acid reaction to Congo red and the solution extracted five times with ether. The combined ether extracts are washed twice with water, once with 5% sodium carbonate solution and again with water until the washing water is neutral. Then the ether is evaporated, the residue dissolved in a little methanol and diluted with water. The separated product is recrystallized from aqueous methanol. The yield amounts to 2.77 g. The 17-ethinyl-estradiol-3,17 thus obtained melts at 142°C to 144°C.

Therapeutic Function

Estrogen

Air & Water Reactions

Air and light sensitive . Insoluble in water.

Reactivity Profile

Ethynyl estradiol may react vigorously with strong oxidizing agents. May react exothermically with reducing agents to generate gaseous hydrogen.

Health Hazard

ACUTE/CHRONIC HAZARDS: When heated to decomposition Ethynyl estradiol emits acrid smoke and fumes.

Fire Hazard

The flash point data for Ethynyl estradiol are not available. Ethynyl estradiol is probably combustible.

Biochem/physiol Actions

17α-Ethynylestradiol is an orally bio-active synthetic estrogen used as an oral contraceptive.

Mechanism of action

Synthetic estrogen with potent activity (inhibition of ovulation), widely used in oral contraceptives. Manufactured from natural estrogen, estrone, by reaction with potassium acetylide (HCRCK) in liquid ammonia. The synthetic 17α-ethynyl derivative of estradiol-17β. The 17α-ethynyl group increases the in vivo potency of estradiol- 17β by blocking the action of 17β-dehydrogenase, a major pathway of estradiol-17β metabolic inactivation. It is thus active orally and is among the most potent of the known estrogenic compounds.

Safety Profile

Confirmed carcinogen with experimental carcinogenic, tumorigenic, and neoplastigenic data. Poison by intraperitoneal route. Moderately toxic by ingestion. Human systemic effects by ingestion: glandular effects. An experimental teratogen. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits acrid smoke and irritating fumes. See also ESTRADIOL

Synthesis

Ethinyl estradiol, 17α-ethinyl-1,3,5(10)-estratrien-3-17β-diol (28.1.26), is made either by condensing estrone with acetylene in the presence of potassium hydroxide (Favorskii reaction), or by reacting sodium acetylenide in liquid ammonia with estrone.

Purification Methods

17--Ethynylestradiol forms a hemihydrate on recrystallising from MeOH/H2O. It dehydrates on melting and remelts on further heating at m 182-184o. The UV has max at 281nm ( 2040) in EtOH. Its solubility is 17% in EtOH, 25% in Et2O, 20% in Me2CO, 25% in dioxane and 5% in CHCl3. [Petit & Muller Bull Soc Chim Fr 121 1951.] The diacetyl derivative has m 143-144o (from MeOH) and [] D 20 +1o (c 1, CHCl3) [Mills et al. J Am Chem Soc 80 6118 1958]. [Beilstein 6 IV 6877.]

Incompatibilities

May react exothermically with reducing agents to generate flammable gaseous hydrogen. Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, and epoxides.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator

InChI:InChI=1/C20H24O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,5,7,12,16-18,21-22H,4,6,8-11H2,2H3/t16-,17+,18+,19-,20+/m1/s1

Synthetic route

norethisterone (68-22-4) → ethinyl estradiol (57-63-6)

Conditions	Yield
With copper(ll) bromide In acetonitrile for 16h; Ambient temperature;	79%
homogenates of human adult liver;
With Cephalosporium aphidicola (IMI 68689) In dimethyl sulfoxide at 29℃; for 192h;	164 mg

Estrone (53-16-7) + potassium acetylide (1111-63-3, 115570-71-3) → ethinyl estradiol (57-63-6)

Estrone (53-16-7) + acetylenemagnesium bromide (4301-14-8) → ethinyl estradiol (57-63-6)

Upstream product

• 53-16-7 Estrone 
• 1111-63-3 potassium acetylide 
• 4301-14-8 acetylenemagnesium bromide 
• 74-86-2 acetylene 
• 68-22-4 norethisterone 
• 28913-23-7 17α-Ethinylestra-3,17β-diol-3-isopropylsulphonat 
• 72-33-3 mestranol 
• 346700-38-7 3-(tert-butyldimethylsilyloxy)-17α-trimethylsilylethynyl-β-estradiol 
• 39845-30-2 3-(tert-butyldimethylsilyloxy)-17α-ethynyl-β-estradiol 

Downstream Products

• 2553-34-6 17α-ethylestradiol 
• 122426-84-0 3-(3-phenyl-propionyloxy)-19-nor-17βH-pregna-1,3,5(10)-trien-20-yn-17-ol 
• 13258-68-9 ethynylestradiol diacetate 
• 5779-47-5 3-acetoxy-17α,19-norpregna-1,3,5(10)-triene-20-yn-17β-ol 
• 105044-33-5 3'-cyclohexyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1,5(10)-dien-20-yno[4,3-e][1,3]oxazin-17-ol 
• 105044-34-6 3'-cyclohexyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1(10),4-dien-20-yno[2,3-e][1,3]oxazin-17-ol 
• 104744-75-4 3'-phenethyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1,5(10)-dien-20-yno[4,3-e][1,3]oxazin-17-ol 
• 106766-20-5 3'-phenethyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1(10),4-dien-20-yno[2,3-e][1,3]oxazin-17-ol 
• 106763-72-8 3'-benzyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1,5(10)-dien-20-yno[4,3-e][1,3]oxazin-17-ol 
• 107631-95-8 3'-benzyl-3',4'-dihydro-2'H-(17βH)-19-nor-pregna-1(10),4-dien-20-yno[2,3-e][1,3]oxazin-17-ol 
• 2685-03-2 3,17β-dihydroxy-17α-(2'-phenyl-1'-ethyn-1'-yl)estra-1,3,5(10)-triene 
• 50-28-2 estradiol 
• 7678-95-7 17α-vinylestradiol 
• 50394-90-6 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,4,17β-triol 

Relevant academic research and scientific papers

Aromatization of norethindrone in human adult liver

Homogenates of human adult liver are capable of aromatization norethindrone (17-α-ethynyl-19-nortestosterone) to ethynylestradiol (17α-ethynylestradiol).The evidence of ethynylestradiol formation was obtained using a Boi-Rad AG1-X2 column, thin layer chromatography and co-crystallization.

Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer

1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.

O-(Aminosulfonylation) of phenols and an example of slow hydrolytic release

Sequential replacement of imidazole from sulfonyldiimidazole by phenols and then amines leads to O-arylsulfamate esters. Application of this coupling method to 19 phenols and 6 amines generates a library of 114 sulfamate esters, Ar-OSO2-NR2. A sulfamate based conjugate of ethinyl estradiol was prepared by using the steroid 3-hydroxyl as the phenol component, and an amino amide derived from linoleic acid as the amine. Hydrolysis of this conjugate was studied in aqueous buffer at pH values 2, 5, and 7.4, and (essentially identical) respective half-lives of 6.8, 6.6, and 6.7 days were observed.

THERAPEUTIC FOR HEPATIC CANCER

A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same

Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.

Pharmaceutical composition with tumor necrosis factor A and 2-methoxyestrone-3-0-sulphamate for inhibition of estrone sulphatase

A composition is described. The composition comprises i) a compound comprising a sulphamate group (“a sulphamate compound”); and ii) a biological response modifier.

Microbial transformation of antifertility agents, norethisterone and 17α-ethynylestradiol

The microbial transformation of oral contraceptive norethisterone (1) by Cephalosporium aphidicola afforded an oxidized metabolite, 17α- ethynylestradiol (2), while the microbial transformation of 2 by Cunninghamella elegans yielded several metabolites, 19-nor-17α-pregna-1,3,5 (1O)-trien-20-yne-3,4,17β-triol (3), 19-nor-17β-pregna-1,3,5 (10)-trien-20-yne-3,7α,17β-triol (4), 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,11α,17β-triol(5), 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,6β,17β-triol (6) and 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17β-diol-6β-methoxy (7). Metabolite 7 was found to be a new compound. These metabolites were structurally characterized on the basis of spectroscopic techniques.

Halogenated sulphamate-, phosphonate-, thiophosphonate-, sulphonate- and sulphonamide- compounds as inhibitors of steroid sulphatase

A compound is described. The compound has the formula (Ia) as presented in the FIG. 1; wherein: X is a ring having at least 4 atoms in the ring; K is hydrocarbyl group; Rh1 is an optional halo group; Rh2 is an optional halo group; at least one of Rh1 and Rh2 is present; Rs is any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group. The compound is capable of inhibiting steroid sulphatase (STS) activity.

17-Aryl linker derivatised estrogen 3-sulphamates as inhibitors of steroid sulphatase

There is provided a compound comprising a steroidal ring system and a group R1 selected from any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group; wherein the D ring of the steroidal ring system is substituted by a group R2 of the formula —L—R3, wherein L is an optional linker group and R3 is an aromatic hydrocarbyl group.