What Is Anastrozole?

The chemical name of anastrozole is , , , -tetramethyl-5- (1H-1,2,4-triazol-1-methyl) -1,3-benzenediacetonitrile, White or almost white crystalline powder; odorless, bitter. Soluble in acetonitrile or ethyl acetate, soluble in ethanol, and almost insoluble in water. Clinically used for the treatment of advanced breast cancer in postmenopausal women.

Chinese name: Anastrozole
Foreign name: anastrozole

Molecular formula: C17H19N5
Molecular weight: 293.37
CAS number: 120511-73-1

Anastrozole compound profile

Anastrozole Basic Information

Chinese name: Anastrozole

Chinese alias: Alatrazole; Anastrozole; Tetramethyl-5- (1H-1,2,4-triazol-1-ylmethyl) -1,3-benzenediacetonitrile; ICI-1) 1033 : ADRLLIDEX; Anastrozole; Anasulazole; Nalmefene Hydrochloride; Mefam Sodium Hydrochloride; Nalmefene Hydrochloride;

English name: anastrozole

English alias: ANASTRAZOLE; Anastrol; 2,2 '-(5-((1H-1,2,4-Triazol-1-yl) methyl) -1,3-phenylene) bis (2-methylpropanenitrile); Anatrozole; ZD -1033; 1,3-benzenediacetonitrile; Anastrozol; ICI-D-1033; ARIMIDEX; 4-Triazol-1-ylmethyl) -1; Anastrozole; Anastrolozole;

CAS number: 120511-73-1

Molecular formula: C ₁₇ H ₁₉ N ₅

Structural formula:

Molecular weight: 293.36600

Exact mass: 293.16400

PSA: 78.29000

LogP: 2.92876

Anastrozole physicochemical properties

Appearance and properties: crystalline solid

Density: 1.08 g / cm ³

Melting point: 81-82 ° C

Boiling point: 469.7ºC at 760 mmHg

Refractive index: 1.791

Storage conditions: Store in original container in a cool dark place.

Anastrozole Safety Information

Packing level: III

Hazard category: 6.1 (b)

Customs code: 2933990090

Dangerous Goods Transport Code: 3249

Danger category code: R36 / 37/38

Safety instructions: S26; S37 / 39

Dangerous goods mark: Xi ^[1]

Anastrozole safety term

S37 / 39 Wear suitable gloves and eye / face protection

Wear appropriate gloves and goggles or a mask.

S26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.

After accidental contact with eyes, rinse immediately with plenty of water and seek medical advice.

Anastrozole risk term

R36 / 37 / 38Irritating to eyes, respiratory system and skin.

Irritation of eyes, respiratory system and skin.

Anastrozole molecular structure data

1. Molar refractive index: 90.01

2. Molar volume (cm / mol): 270.2

3. Isotonic specific volume (90.2K): 688.7

4. Surface tension (dyne / cm): 42.1

5. Polarizability (10-24cm3): 35.68

Anastrozole Computational Chemical Data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen bond donors: 0

3.Number of hydrogen bond acceptors: 4

4.Number of rotatable chemical bonds: 4

5.Number of tautomers: none

6. Topological molecular polar surface area 78.3

7.Number of heavy atoms: 22

8.Surface charge: 0

9.Complexity: 456

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Anastrozole synthesis method

1. Compound (I) (with a preparation method) is brominated with N-bromosuccinimide (NBS), and the product (II) is treated with sodium triazole to obtain a product.

2. Preparation of 3,5-dibromomethyltoluene

Add 40 g (0.33 mol) of mesitylene, 0.5 g (0.0027 mol) of benzoyl peroxide, and 1000 ml of carbon tetrachloride into the reaction flask, and add 118.5 g (0.67 mol) of NBS in 4 batches under stirring and refluxing. Continue to stir for 1h. Cool to room temperature, filter, and filter the residue with carbon tetrachloride (100ml × 2). The residue is succinimide, which can be recovered to make NBS. The solvent is distilled off from the filtrate to obtain a pale yellow liquid. 200ml, shake well, and stand at room temperature overnight to precipitate white crystals. Filter, dry, and obtain crude product. Recrystallize with anhydrous ethanol to obtain 76g of 3,5-dibromomethyltoluene, 80% yield, mp64ºC.

3. Preparation of 3,5-dicyanomethyltoluene

Add 41.7g (0.15mol), KCN23.4g (0.36mol), TBAB (tetrabutylammonium bromide) 1.5g, 120ml of CH2Cl2 and 60ml of water into the reaction flask, stir and reflux, TLC test (GF254 plate, developing solvent is Petroleum ether-ethyl acetate, volume ratio 5: 1) until the reaction is complete, cool down, separate the organic layer, extract the aqueous layer with CH2Cl2 (50ml × 3), combine the organic layers, wash once with water, dry over anhydrous MgSO4, and filter The filtrate was concentrated to dryness, and the remaining viscous solution was added to 120 ml of carbon tetrachloride and shaken.The layers were placed at room temperature, solidified, filtered, washed with a small amount of carbon tetrachloride, dried, and dried to obtain 23 g of 3,5-dicyanomethyl toluene. The yield is 90%, mp72 ~ 73ºC.

4. Preparation of 3,5-bis [(2,2-dimethyl) ethylcyano] toluene

Add 34 g (0.15 mol) of 3,5-dicyanomethyltoluene, 124 g (0.87 mol) of methyl iodide, and 700 ml of DMF to the reaction flask. Add 44.5 g (0.96 mol) of sodium hydride in 6 batches while cooling in an ice-water bath, and stir After 2.5 hours of addition, naturally rise to room temperature and stir overnight. TLC detection (GF254 plate, developing solvent is ethyl acetate-petroleum ether, volume ratio 1: 3), the reaction is complete. Add the reaction solution to 2500ml of water, stir well, Allow to stand, filter, and wash the filter cake 3 times with water, and dry to obtain 52 g of crude product, and recrystallize from absolute ethanol to obtain 40 g of 3,5-bis [(2,2-dimethyl) ethylcyano] toluene, yield 88.5%. , mp126 ~ 128ºC.

5. Preparation of 3,5-bis [(2,2-dimethyl) ethylcyano] bromomethylbenzene

Add 34 g (0.15 mol) of 3,5-bis [(2,2-dimethyl) ethylcyano] toluene to the reaction flask, 27 g (0.15 mol) of NBS, 1.5 g (0.007 mol) of benzoyl peroxide, and four 300 ml of carbon chloride, stirred under reflux for 2.5 h, cooled, filtered, and the filter residue was washed twice with CCl4. The filtrate and the washing solution were combined, and the solvent was distilled off to obtain a red viscous liquid 3,5-bis [(2,2-dimethyl ) Ethylcyano) bromomethylbenzene was used directly in the next step without purification.

6. Synthesis of Alastrozole

Add 8.2g (0.12mol) of 1,2,4-triazole in the reaction bottle, 16.6g (0.12mol) of anhydrous K2CO3, 6.7g (0.12mol) of KOH, 2.0g of tetrabutylammonium bromide (TBAB) 200 ml of xylene and 30.5 g (0.10 mol) of 3,5-bis [(2,2-dimethyl) ethylcyano] bromomethylbenzene, stirred under reflux, TLC detection (GF254 plate, developing solvent is petroleum ether- Ethyl acetate (volume ratio 3: 1), the reaction is complete in about 7h. Cool to room temperature, filter out insolubles, wash with xylene, combine the filtrate and washings, evaporate the xylene under reduced pressure, and dissolve the remaining viscous material in ethyl acetate In 150 ml of ester, wash with water, dry with anhydrous magnesium sulfate, evaporate the ethyl acetate to obtain a thick crude product, and recrystallize with ethyl acetate-petroleum ether to obtain 18.9 g of alastrozole, yield 64.5%, mp81 ~ 83ºC. ^{[2 ]}

Anastrozole uses

Third generation aromatase inhibitor. Used to treat patients with advanced breast cancer after menopause.
This product is a non-steroidal aromatase inhibitor, which is clinically used to treat advanced metastatic breast cancer in postmenopausal women. ^[2]

Anastrozole Pharmacopoeia Standard

Anastrozole source (name), content (potency)

This product is , , ''-tetramethyl-5- (1H-1,2,4-triazol-1-ylmethyl) -1,3-diacetonitrile benzene. Calculated on dry basis, containing C17H19N5 shall not be less than 98.5%.

Anastrozole traits

This product is white or off-white crystalline powder; odorless and bitter.

This product is easily soluble in acetonitrile or ethyl acetate, soluble in ethanol, and almost insoluble in water.

Anastrozole melting point

The melting point of this product (Appendix VIC in Part Two of the 2010 Pharmacopoeia) is 81-84 ° C.

Anastrozole identification

(1) Take about 5mg of this product, put it in a dry test tube, add about 50mg of malonic acid and 2ml of acetic anhydride, and heat it in a water bath at 85-95 ° C for 10 minutes. The solution is brown-red.

(2) Take an appropriate amount of this product and anastrozole reference substance, add about 5ml of acetonitrile to dissolve each, and dilute with mobile phase to make a solution containing about 10g per 1ml, and test according to the method under the relevant substance. The retention time of the main peak of the solution should be consistent with the retention time of the main peak of the reference solution.

(3) The infrared light absorption spectrum of this product should be consistent with the control spectrum (Figure 1151 of "Infrared Spectra of Drugs").

Anastrozole check

relative substance

Take an appropriate amount of this product, add about 5ml of acetonitrile to dissolve, and dilute with mobile phase to make a solution containing about 100g per 1ml as the test solution; take 1ml precisely, place it in a 100ml measuring flask, and dilute to the mark with mobile phase. Shake well as control solution. As determined by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), octadecylsilane bonded silica gel was used as the filler; acetonitrile-water (45:55) was used as the mobile phase; the detection wavelength was 210 nm. The theoretical plate number is calculated to be not less than 2500 according to the anastrozole peak. Take 20l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full range; and then accurately measure 20l each of the test solution and the control solution, and inject them into the liquid chromatograph Record the retention time of the chromatogram to the main component peak twice. If there are impurity peaks in the chromatogram of the test solution, the area of a single impurity peak must not be greater than 0.5 times (0.5%) the area of the main peak of the control solution, and the sum of the area of each impurity peak must not be greater than the area of the main peak of the control solution (1.0%).

Cyanide

Weigh 1.0g of this product, add 10ml of ethyl acetate to dissolve, add 15ml of water for extraction, and take the water layer according to the cyanide inspection method (2010 Pharmacopoeia Part II Appendix F first method), starting from "add 10% tartaric acid solution 3ml", Inspection according to law shall not show blue or green.

Loss on drying

Take this product and dry it under reduced pressure at 60 ° C to constant weight, and the weight loss should not exceed 0.5% (Appendix L of the Pharmacopoeia of the Second Edition of 2010).

Residue on ignition

Weigh 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.

Heavy metal

Take the residue left under the burning residue and check it according to law (Appendix H, the second method of the 2010 edition of the Pharmacopoeia, the second method). The content of heavy metals must not exceed 20 parts per million.

Anastrozole determination

Take about 0.23g of this product, accurately weigh, add 30ml of glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, titrate to green with perchloric acid titration solution (0.1mol / L), and use the blank test Correction. Each 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 29.34mg of C17H19N5. ^[3]

Anastrozole pharmacological action

This product is a potent and selective non-steroidal aromatase inhibitor. It can inhibit the conversion of androstenedione produced in the adrenal glands of postmenopausal patients to estrone, thereby significantly reducing the plasma estrogen level and inhibiting the growth of breast tumors. In addition, this product has no significant effect on the production of adrenal corticosteroids or aldosterone. ^[4]

Anastrozole Toxicology Study

Genotoxicity: In in vitro tests such as the Ames test, E. coli test, and CHO-K1 gene mutation test, no mutagenicity was observed for this product. In human lymphocyte chromosome aberrations and rat micronucleus tests, this product has not been shown to induce fission.

Reproductive toxicity: The effect of this product on fertility has not been studied, but the long-term dose of this product in rats is greater than or equal to 1 mg / kg / day (the plasma Cssmax and AUC0-24h are higher than the recommended dose in postmenopausal healthy people, respectively). 19 times and 9 times), ovarian hypertrophy and follicular cysts can be seen. In addition, uterine hyperplasia can be seen when female dogs are given a dose of 1 mg / kg / day or more (the plasma Cssmax and AUC0-24h are 22 times and 16 times higher than the recommended dose in postmenopausal healthy people, respectively) for a long time. It is unclear whether the above effects on animal reproductive organs are related to damage to human fertility.

Pregnant women taking this product can cause embryo toxicity. Rats and rabbits orally administered this product at 0.1 mg / kg (based on body surface area, equivalent to approximately 3/4 and 1.5 times the clinically recommended dose, respectively), and found that this product could penetrate the placental barrier. Rats and rabbits are given this product during the organogenesis period at doses greater than or equal to 0.1 and 0.02 mg / kg / day (calculated based on body surface area, approximately equivalent to 3/4 and 1/3 of the clinically recommended dose, respectively). It can be seen that the pregnancy loss rate is increased (increased loss before and after implantation, increased absorption of fetuses, decreased number of live babies), and these effects in rats are dose-dependent. At a dose of 0.1 mg / kg / day or more in rats, placental weight increased significantly. Rats were given embryonic toxicity, including delayed embryonic development (eg, Cssmax and AUC0-24h of plasma at 19 and 9 times higher than the recommended dose in postmenopausal healthy people, respectively) when given a dose of 1 mg / kg / day : Insufficiency of ossification and growth of fetal body were suppressed), the rats did not show teratogenicity at this dose. Rabbits given this product at doses greater than or equal to 1.0 mg / kg / day (based on body surface area, approximately 16 times the clinically recommended dose) can cause pregnancy failure. When rabbits were given a dose of 0.2 mg / kg / day (based on body surface area, approximately 3 times the clinically recommended dose), no teratogenicity was seen. There are no adequate and strictly controlled research data on pregnant women's medication. If this product is used during pregnancy or pregnant during the use of this product, patients should be informed of the potential harm of the drug to the fetus and the potential danger of miscarriage.

Whether this product is excreted in human milk is unclear, as many drugs can be excreted in human milk, lactating women should use this product with caution.

Carcinogenicity: There is no data on carcinogenicity of long-term administration of this product in animals. ^[4]

Anastrozole pharmacokinetics:

Anastrozole is rapidly absorbed orally. About 40% of anastrozole binds to plasma proteins in the body. Most of it is metabolized to inactive products and eliminated by urine. About 10% of anastrozole is eliminated from the urine in its original form. According to data reports, after oral administration of 2mg of this product in healthy subjects, the peak concentration time of blood drug was 1.56 ± 0.41 hours, the peak concentration of blood drug was 36.52 ± 6.91ng / ml, and the elimination half-life was 42.57 ± 10.15 hours. ^[4]

Anastrozole indications:

It is suitable for advanced breast cancer in postmenopausal women who cannot be controlled by tamoxifen and other anti-estrogen therapies.
Adjuvant therapy for estrogen-positive early breast cancer in postmenopausal women.
For patients with estrogen receptor negative, if the clinical response to tamoxifen is positive, consider using this product. ^[4]

Anastrozole dosage:

Take 1 tablet (1mg) orally once daily. For patients with mild hepatic or mild to moderate renal impairment, dosage adjustment is generally not required. ^[4]

Anastrozole adverse reactions:

The side effects of this product mainly include flushing of the skin, vaginal dryness, excessive secretion of fat from the hair, gastrointestinal disorders (anorexia, nausea, vomiting and diarrhea), fatigue, depression, headache or rash. Side effects are usually mild or moderate and easily tolerated by patients.

Occasional reports of uterine bleeding in this product occur mainly in the first few weeks of the patient's change from existing hormonal therapy to this product. If continuous bleeding occurs, further evaluation is required.

Hepatic function changes have been reported in patients with advanced breast cancer using this product (such as elevated transpeptidase and alkaline phosphatase), but many of these patients have liver metastases or bone metastases. The cause of these changes has not been studied. Clinical observations show that this product can slightly increase total plasma cholesterol levels. ^[4]

Anastrozole contraindications:

The following conditions are prohibited for this product:

1. Premenopausal women;

2. Pregnant or lactating women;

3. Patients with severe renal impairment (creatinine clearance <20ml / min);

4. Patients with moderate to severe liver damage;

5. Patients known to be highly sensitive to anastrozole and its formulation excipients. ^[4]

Anastrozole precautions:

For patients with moderate to severe liver damage and severe renal damage, there is no data on the safety of anastrozole tablets.

When in doubt about hormone levels, amenorrhea should be considered due to the disruption of hormone balance.

This product has no significant effect on the patient's ability to drive and operate machinery, but there are reports of fatigue and depression in some patients. When the above symptoms persist, patients should pay special attention when driving and operating machinery.

Anastrozole for pregnant and lactating women:

Anastrozole tablets are contraindicated in pregnant and lactating women.

Anastrozole for children:

Trials on the safety and effectiveness of anastrozole tablets have not been conducted in children, so the drug is not intended for use in children.

Anastrozole for the elderly:

Same as for adults. ^[4]

Anastrozole Drug Interactions:

Studies on the clinical interaction between antipyrine and cyanocorin have shown that this product is unlikely to cause a drug response mediated by cytochrome P-450 when combined with other drugs.

Clinical trials have not found a significant interaction between this product and other commonly used clinical drugs.

There is no evidence that this product should be used in combination with other anti-tumor drugs.

Therapies containing estrogen can reduce the efficacy of this product, so it should not be combined with this product

Combined with warfarin, it does not affect the pharmacokinetics and anticoagulant activity of warfarin.

When anastrozole is used in combination with other drugs mediated by CYP450, no obvious clinical inhibitory effect will occur. ^[4]

Anastrozole overdose:

There is no special remedy for the overdose of this product, and the treatment can only be symptomatic. If overdose, vomiting can be performed when the patient is awake, because dialysis of this product has a low plasma protein binding rate, dialysis can also work. ^[4]

Anastrozole expert review

Anastrozole is a third-generation aromatase inhibitor. It is used in postmenopausal advanced breast cancer with strong specificity, few adverse reactions, high efficacy, and convenient administration. Phase III clinical studies have shown that this product can significantly prolong the median survival time of patients with advanced breast cancer (22.5 months vs. 26.7 months) compared with medigestone, and the adverse reactions are lower than medigestone. ^[5]