|Company Name:||INTATRADE GmbH |
|Product Categories:||Active Pharmaceutical Ingredients;chiral;Antineoplastic (Hormonal);Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Pfizer compounds;Steroid and Hormone;API;Anti-cancer&immunity;Inhibitors|
|Exemestane Chemical Properties|
|Exemestane Usage And Synthesis|
|Introduction||Exemestane is a kind of irreversible nonsteroidal aromatase inhibitors, whose structure is similar to its substrate the natural androstenedione. It’s an effective and optional approach to treat postmenopausal women steroid-dependent breast cancer by inhibiting the aromatase to deprive estrogen. It’s used for advanced breast cancer of naturally or artificially postmenopausal women who have been treated with tamoxifen while the illness has yet to progress.
|Function and Use||Exemestane, steroidal aromatase inactivator, whose structure is similar with natural substrate the androstenedione of aromatase, is the pseudosubstrate of aromatase. As postmenopausal women’s estrogen is mainly transferred under the effected by aromatase in peripheral tissues with androgen (produced in adrenal cortex), this product makes the aromatase inactive through combining the irreversible active site of aromatase, and hence to significantly reduce postmenopausal estrogen level in blood circulation. This product had no obvious effect on adrenal cortical hormone biosynthesis, even if the concentration is higher than 600 times the effect of aromatase inhibition concentration, it has also no obvious effect on other enzymes in cortical hormone production. |
Oral absorption of this product is rapid, and the oral bioavailability is 42%, which is influenced by the food. In postmenopausal women, the absorption rate of the drug is higher than that of the healthy subjects, and the peak concentration of blood drug is 2 ~ 4 hours after oral administration. The peak time is 1.2 hours, and is shorter than that of healthy subjects (2.9 hours). The binding rate of total protein is 90%, which is mainly related to the α-acid glycoprotein and protein. Mainly through the liver metabolism, and the metabolite is inactive 17 - hydrogen exemestane, and elimination half-time is 24h. Primarily excreted by urine or feces, each accounting for 42% of the amount of dosis.
The above information is edited by the Chemicalbook He Liao Pu.
|Synthesis||Take androst-4-ene-3 and 17-dione (2) as raw material, firstly condense triethyl orthoformate, n-methylaniline and 40% formaldehyde solution to get 6-methylene androst-4-ene-3 and 17-dione (3), and then make dioxidation of 2,3-dichloro-5,6-DDQ to get 1. In the oxidative dehydrogenation reaction, the addition of a certain amount of weak acid can shorten the reaction time from 15h to 8h, and the yield can be increased from 47% to 62%. This method has mild reaction conditions, simple separation with total yield of 45%. The synthetic route is as follows:|
|Indications||Suitable for estrogen and progesterone receptor positive postmenopausal women with advanced breast cancer.
|Usage and dosage||25mg for 1 time per day, oral admiration after meals. For patients with mild hepatic and renal insufficiency, it is not required to adjust the dosage of the drug.|
|Adverse Reactions||The main adverse reactions of this product are nausea, dry mouth, constipation, diarrhea, dizziness, insomnia, skin rash, fatigue, fever, edema, increased pain, vomiting, abdominal pain, increased appetite, weight gain, etc. Furthermore it’s reported to cause high blood pressure, depression, anxiety, dyspnea, cough, etc. Also there is decrease of lymphocyte count and liver function (such as alanine aminotransferase) abnormality.
|Contraindications||1. Forbidden for patients allergic to this drug.|
2. Forbidden for pregnant, lactation women, and kids.
|Clinical assessment||Exemestane is an oral potent irreversible steroidal aromatase inhibitor. Patients on tamoxifen resistant, exemestane 25mg, qd, can get 15% to 28% of objective efficiency and 69 to 76 weeks of continuous time.
Exemestane is better than megestrol acetate, which can prolong the time of disease progression. For the deterioration of patient after megestrol acetate therapy, exemestane still can reach 11% ~ 13% objective efficiency. Exemestane 25 mg/d, for non-steroidal aromatase inhibitor treatment failure patients, the objective response rate is 6.6%; there is no cross resistance between those two drugs.
|Attentions||1.Premenopausal women generally do not use exemestane tablets. |
2.Patients in severe liver and renal function insufficiency need to use it with caution. Excessive use of exemestane can lead to increased non-fatal adverse reaction.
3.Pregnancy safety grade of this drug in FDA is D grade.
4.No special attention for the elderly to use this drug.
|Drug interactions||1.This product can’t be combined with estrogen drugs, so as to avoid the effect of this product.|
2.Exemestane mainly metabolized by CYP3A4, but when it’s in combination with potent CYP3A4 inhibitor (ketoconazole), pharmacokinetics of the product doesn’t change, therefore it seems that CYP isoenzyme inhibitors doesn’t have significant effect on pharmacokinetics of this product, but it does not rule out the possibility that the known CYP3A4 inducers decreases exemestane concentration in plasma.
|Specification||Tablet: 25mg. Capsule: 25mg.
|Chemical properties||White solid, melting point 190 ~ 192℃.|
|Applications||1.The second generation aromatase inhibitors, used for the treatment of metastatic breast cancer and used as adjuvant therapy for early breast cancer.|
2.Pharmaceutical raw materials, is a kind of irreversible steroid body aromatase extinguishing agent, can inhibit the synthesis of estrogen, and reduce circulating estrogen levels, applicable to the progression of disease after treatment with tamoxifen in postmenopausal patients with advanced breast cancer.
|Producing method||Androst-4-ene-3, 17-dione (2) and triethyl orthoformate dissolved in tetrahydrofuran and anhydrous ethanol, reacting under the presence of p-toluenesulfonic acid, and then add into N-methyl aniline and formaldehyde solution to continue the reaction. The obtained Mannich reaction product dissolved in anhydrous benzoic acid and anhydrous two alkyl, under the action of DDQ, to get exemestane, and the total yield is 45%.
|Chemical Properties||white to light yellow crystal powder|
|Usage||An antineoplastic (hormonal)|
|Usage||Labeled Exemestane, intended for use as an internal standard for the quantification of Exemestane by GC- or LC-mass spectrometry.|
|Exemestane Preparation Products And Raw materials|