Anastrozole Powder CAS 120511-73-1

It is indicated for postmenopausal females afflicted with advanced mammary carcinoma refractory to tamoxifen or alternative anti-estrogen interventions. For subjects exhibiting negative estrogen receptor status, administration can also be contemplated provided they manifest favourable clinical feedback to tamoxifen. This agent yields prominent therapeutic efficacy in individuals suffering from regionally advanced or metastatic mammary carcinoma, capable of extending relapse-free survival and ameliorating clinical outcomes.

This therapeutic modality is indicated for postmenopausal females suffering from progressive mammary carcinoma that fails effective clinical management after tamoxifen or other classic anti-estrogen therapeutic interventions. For subjects identified with negative estrogen receptor biomarkers in baseline examinations, clinical implementation can also be deliberated if they acquire satisfactory therapeutic feedback from tamoxifen treatment.

This agent delivers remarkable therapeutic outcomes among sufferers with regionally advanced or metastatic mammary carcinoma. Rational medication efficiently halts neoplastic advancement, impedes lesion aggravation and restrains dissemination of malignant cells. It is able to extend relapse-free survival, cut down neoplasm recurrent hazards and ameliorate long-range clinical outlook, mitigating malignancy-associated manifestations and lifting sufferers' holistic life wellbeing.

It modulates aberrant intracellular signal cascades, subdues pathological angiogenesis within tumoral stroma and curtails invasive propensity of dysplastic epithelia. The regimen attenuates paraneoplastic syndromes, lessens reliance on palliative symptomatic interventions and stabilizes systemic homeostasis. It also alleviates persistent asthenia and inflammatory derangements triggered by tumoral metabolism, facilitating sustained physical functionality and fostering improved psychosocial adaptation amid protracted antineoplastic management.

Serving as an adjuvant therapeutic agent for early-stage mammary carcinoma with positive estrogen receptor status in postmenopausal females, it is capable of substituting tamoxifen or implementing sequential medication regimens. A typical regimen involves initial tamoxifen administration for 2 to 3 years, followed by anastrozole intervention. A 5-year adjuvant treatment course can substantially lower the morbidity of contralateral mammary neoplasms and mitigate the risk of distant metastasis, particularly for high-risk cohorts with lymph node-positive lesions.

It suppresses peripheral aromatization of adrenal androstenedione, curbing endogenous estrin biosynthesis within adipose matrix and tumoral microenvironment, thereby blocking hormone-driven proliferative signaling of neoplastic parenchymal cells. Distinct from selective estrogen receptor modulators, it lacks partial agonistic bioactivity toward endometrial tissues, diminishing the latent peril of intrauterine hyperplastic aberrations encountered during long-term endocrine intervention.Clinically, it restrains micrometastatic dormant lesions lingering after curative resection and hinders epithelial-mesenchymal transition which fuels tumoral invasiveness.

For subjects exhibiting intermediate histological grading and elevated Ki-67 labeling indices, sequential endocrine stratagem yields superior distant disease-free endpoints compared with continuous tamoxifen monotherapy. The agent moderates oncogenic transcript cascades activated by steroid ligands and impedes stromal fibroblast-mediated paracrine stimulation sustaining neoplastic viability. Though accompanied by musculoskeletal malaise and mineral density attenuation as prevalent untoward responses, tailored bone-protective adjunctive protocols can counteract osteoclastic overactivation.

It brings tangible advantages to individuals intolerant to tamoxifen-induced vasomotor disturbances or thromboembolic predispositions, optimizing sustained medication adherence throughout prolonged adjuvant cycles. Stratified biomarker profiling aids in screening eligible recipients, excluding carriers possessing intrinsic endocrine resistance phenotypes to avoid futile antineoplastic exposure and unwarranted adverse toxic burden. 

Definition of high-risk population:
It includes patients with family genetic history, BRCA gene mutation, breast atypical hyperplasia or previous breast cancer history. The risk of breast cancer in these populations is significantly higher than that in the general population.
Evidence of preventive treatment:
Clinical trials show that long-term use of anastrozole can reduce the incidence rate of breast cancer in high-risk population.

For example, in the IBIS-II trial, anastrozole reduced the risk of breast cancer by 53%, and the side effects were controllable.
Risk and Benefit Assessment:
Although preventive treatment can reduce the risk of disease, it is necessary to strictly evaluate the risks and benefits of medication. For example, long-term use may increase the risk of osteoporosis and fractures, so it is necessary to combine bone density monitoring with preventive measures such as calcium supplements and vitamin D.

Definition of high-risk cohorts: This population encompasses individuals with hereditary familial predisposition, BRCA genetic aberrations, atypical mammary hyperplasia or prior mammary carcinoma medical records. Such susceptible groups manifest markedly elevated malignancy susceptibility compared with ordinary populations. Evidence of prophylactic intervention: Clinical trials have validated that prolonged anastrozole administration is capable of diminishing the morbidity of mammary carcinoma among high-risk cohorts.

For instance, the IBIS-II clinical trial demonstrated that anastrozole intervention cuts mammary carcinoma susceptibility by 53%, with all adverse reactions remaining clinically manageable. Risk and Benefit Evaluation: Despite the prophylactic efficacy of pharmaceutical intervention in lowering malignant morbidity, rigorous medicative risk-benefit appraisal is indispensable prior to clinical application. Long-term medication may elevate the prevalence of osteopenia and bone fracture events. Accordingly, regular bone mineral density detection, alongside adjunctive prophylaxis including calcium.

1) Synthesis of α,α,α′,α′-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile

Charge a 2000 mL three-necked flask with 25 g of anastrozole bromo-intermediate and 200 mL DMF. Agitate the mixture at ambient temperature until a transparent solution is formed. Maintain the system temperature within 25–30 °C, then introduce 9 g of sodium 1,2,4-triazolate. Sustain stirring to proceed with the transformation; HPLC analysis is adopted to monitor the reaction endpoint. Once the reaction completes, pour in 250 mL of 0.2 mol/L dilute acid and 500 mL toluene, followed by agitation to facilitate phase separation.

Treat the organic phase twice with 100ml and 100ml of 0.2mol/L dilute hydrochloric acid, merge the dilute acid phase,treat the organic phase twice with 100ml and 100ml of 0.2mol/L dilute hydrochloric acid, merge the dilute acid phase, wash once with 200ml of toluene, merge the toluene phase, wash twice with 300ml and 200ml of 2N hydrochloric acid, merge the acid phase, add sodium carbonate to the acid phase, adjust the pH to 6-7, stir to crystallize, and reduce to 0. Incubate at ℃ for 2 hours, filter and wash with cold water to obtain 15.2g of crude Anatrazole with a weight yield of 60.8%;

2) Purification of Anatrazole:

Add 15g of crude Anastrozole into a mixed solvent composed of 30 mL isopropanol and 30 mL purified water. Maintain continuous stirring and gradually heat the suspension to 40–45 °C until the solid raw material is fully dissolved. Subsequently, introduce 0.075 g activated carbon into the homogeneous solution, keep stirring for 15 minutes for decolorization and impurity adsorption, followed by hot filtration to remove carbon residues.

Slowly add 120 mL water dropwise into the obtained filtrate under agitation to induce crystallization. Afterwards, cool the system down to 0 °C and hold stirring for 2 hours to complete crystal growth. Collect solids by filtration, rinse thoroughly with cold water, and finally obtain 14.3 g purified Anastrozole with a weight yield of 95.3%.

1) Sequentially charge the glass reactor with 30 g of 5-bromomethyl-α,α,α′,α′-tetramethyl-1,3-phenylenediamine, together with 30 g of 4-amino-1,2,4-triazole and 80 mL acetonitrile. Start continuous stirring and gradually raise the temperature to maintain solvent reflux state. The reaction mixture is kept under reflux for 12 hours to ensure sufficient conversion of raw materials. Upon completion of the reaction, stop heating and cool the reaction system slowly. The mixture is maintained at 0 ℃ for 8 hours under stirring to facilitate full crystal precipitation. 

2) Add 30g of intermediate I30g, 225ml of anhydrous methanol, 2ml of purified water, and 2g of copper sulfate to the glass reactor in sequence. Stir and add 24.0g of concentrated sulfuric acid dropwise. After stirring, heat until reflux is achieved. Slowly add 12.0g of sodium azide, complete the addition, and continue the reflux reaction for 1 hour. Filter the reaction solution while it is hot, discard the filter residue, reduce the pressure and concentrate the filtrate to 0.5 times the original volume, cool and crystallize, filter the solid, and then adjust the pH of the solution with saturated potassium carbonate solution to a pH value of 8.0-9.0.

Extract twice with dichloromethane, 75ml each time, merge the organic layers, and wash the organic layers twice with purified water, 75ml each time. Dry anhydrous sodium sulfate, concentrate the filtrate under reduced pressure until no dichloromethane drips out, and cool and solidify the residue. Dry, obtain 18.04g of crude Anatrazole (single impurity less than 0.1%, total impurity less than 0.3%), with a yield of 79.8%.

3) 150ml of isopropanol and 15g of crude anastrozole were added to a glass reactor, heated and refluxed. After the solid was completely dissolved, 0.75g of medicinal charcoal was added for refluxing and decolorization for 1 hour. The medicinal charcoal was removed by filtration. The filtrate was placed at 0 ℃ and crystallized for more than 48 hours. After filtration, it was dried under reduced pressure at 60 ℃ to obtain 12.3g of refined anastrozole with a yield of 82.0%. The isomer was not detected, with a purity of 99.84%.