Anastrozole hmoov CAS 120511-73-1

Nws yog qhia rau cov poj niam postmenopausal afflicted nrog advanced mammary carcinoma refractory rau tamoxifen los yog lwm txoj kev los tiv thaiv - tshuaj estrogen. Rau cov neeg uas pom qhov tsis zoo estrogen receptor raws li txoj cai, kev tswj hwm kuj tuaj yeem xav txog yog tias lawv pom cov lus pom zoo rau tamoxifen. Tus neeg sawv cev no ua rau muaj txiaj ntsig zoo rau cov tib neeg uas raug kev txom nyem los ntawm kev mob qog noj ntshav hauv cheeb tsam lossis metastatic mammary carcinoma, muaj peev xwm txuas ntxiv rov qab ua dua tshiab - muaj sia nyob dawb thiab ua kom cov txiaj ntsig kho mob tau zoo.

Qhov kev kho mob no yog qhia rau cov poj niam postmenopausal kev txom nyem los ntawm kev loj hlob ntawm mammary carcinoma uas ua tsis tau zoo kev kho mob tom qab tamoxifen los yog lwm yam classic anti- tshuaj estrogen kev pab cuam. Rau cov neeg uas tau txheeb xyuas qhov tsis zoo estrogen receptor biomarkers hauv kev kuaj mob hauv paus, kev siv tshuaj kho mob kuj tuaj yeem txiav txim siab yog tias lawv tau txais cov lus pom zoo los ntawm kev kho tamoxifen.

Tus neeg sawv cev no muab cov txiaj ntsig kho tau zoo tshaj plaws ntawm cov neeg mob uas muaj cov kab mob loj heev hauv cheeb tsam lossis metastatic mammary carcinoma. Cov tshuaj rational zoo nkoos kev nce qib neoplastic, impedes lesion aggravation thiab txwv kev nthuav tawm ntawm malignant hlwb. Nws muaj peev xwm txuas ntxiv rov qab los ntawm -kev muaj sia nyob dawb, txo qis neoplasm rov muaj kev phom sij thiab ua kom lub neej ntev dua -kev kho mob, txo qis kev mob qog noj ntshav- cuam tshuam tshwm sim thiab txhawb nqa cov neeg mob lub neej kev noj qab haus huv.

Nws modulates aberrant intracellular teeb liab cascades, subdues pathological angiogenesis nyob rau hauv qog stroma thiab curtails invasive propensity ntawm dysplastic epithelia. Cov txheej txheem txo qis paraneoplastic syndromes, txo qis kev cia siab ntawm kev cuam tshuam palliative cov tsos mob thiab stabilizes systemic homeostasis. Nws kuj alleviates tsis tu ncua asthenia thiab inflammatory derangements tshwm sim los ntawm qog nqaij hlav metabolism, pab txhawb nqa lub cev functionality thiab txhawb kev txhim kho kev puas siab puas ntsws adaptation nyob rau hauv protracted antineoplastic tswj.

Ua haujlwm ua tus neeg saib xyuas kho mob rau thaum ntxov- theem mammary carcinoma nrog cov tshuaj estrogen receptor zoo nyob rau hauv cov poj niam postmenopausal, nws muaj peev xwm hloov tamoxifen los yog siv cov tshuaj raws li cov tshuaj noj. Ib qho kev coj noj coj ua feem ntau suav nrog kev tswj hwm tamoxifen rau 2 mus rau 3 xyoos, ua raws li kev cuam tshuam anastrozole. Ib chav kawm kho mob 5-xyoo adjuvant tuaj yeem txo qhov mob ntawm cov qog nqaij hlav hauv lub cev tsis sib haum xeeb thiab txo qhov kev pheej hmoo ntawm cov kab mob metastasis nyob deb, tshwj xeeb tshaj yog rau siab - cov kab mob sib kis nrog cov kab mob qog noj ntshav zoo.

Nws suppresses peripheral aromatization ntawm adrenal androstenedione, curbing endogenous estrin biosynthesis nyob rau hauv adipose matrix thiab qog microenvironment, yog li thaiv cov tshuaj hormones{0}}tsav proliferative signaling ntawm neoplastic parenchymal hlwb. Qhov txawv ntawm kev xaiv cov tshuaj estrogen receptor modulators, nws tsis muaj ib feem agonistic bioactivity rau cov ntaub so ntswg endometrial, txo qis latent peril ntawm intrauterine hyperplastic aberrations ntsib nyob rau lub sij hawm ntev - lub sij hawm endocrine intervention.Clinically, nws restrains micrometastatic dormant lesions lingering thiab curvature. epithelial- kev hloov mesenchymal uas ua rau cov qog nqaij hlav invasiveness.

Rau cov ncauj lus uas nthuav tawm cov qhab nia nruab nrab ntawm histological thiab nce qib Ki-67 daim ntawv cim npe, cov kab mob endocrine stratagem ua rau muaj kab mob zoo tshaj plaws nyob deb- cov ntsiab lus pub dawb piv nrog tamoxifen monotherapy txuas ntxiv. Tus neeg sawv cev nruab nrab ntawm cov ntawv sau cia ntawm oncogenic cascades qhib los ntawm steroid ligands thiab impedes stromal fibroblast-kev sib haum xeeb 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.

Nws coj cov txiaj ntsig zoo rau cov tib neeg intolerant rau tamoxifen -induced vasomotor cuam tshuam los yog thromboembolic predispositions, optimizing cov tshuaj tiv thaiv nyob rau hauv lub sij hawm ntev adjuvant mus. Stratified biomarker profiling pab hauv kev tshuaj xyuas cov neeg tau txais kev pab, tsis suav nrog cov neeg nqa khoom uas muaj cov kab mob endocrine tsis kam phenotypes kom tsis txhob muaj kev cuam tshuam los ntawm antineoplastic tsis muaj txiaj ntsig thiab tsis muaj kev cuam tshuam tsis zoo rau lub nra hnyav.

Kev txhais ntawm siab - cov neeg muaj kev pheej hmoo siab:
Nws suav nrog cov neeg mob hauv tsev neeg keeb kwm caj ces, BRCA noob hloov pauv, lub mis atypical hyperplasia lossis keeb kwm mob qog noj ntshav mis yav dhau los. Qhov kev pheej hmoo ntawm mob qog noj ntshav mis hauv cov neeg no muaj ntau dua li cov pej xeem.
Cov pov thawj ntawm kev tiv thaiv kev kho mob:
Kev sim tshuaj kho mob qhia tau tias ntev - siv anastrozole ntev tuaj yeem txo qhov tshwm sim ntawm tus mob qog noj ntshav mis hauv cov neeg muaj kev pheej hmoo siab -.

Piv txwv li, hauv IBIS-II sim, anastrozole txo qhov kev pheej hmoo ntawm mob qog noj ntshav ntawm lub mis los ntawm 53%, thiab cov kev mob tshwm sim tuaj yeem tswj tau.
Kev soj ntsuam kev pheej hmoo thiab txiaj ntsig:
Txawm hais tias kev tiv thaiv kev kho mob tuaj yeem txo qhov kev pheej hmoo ntawm tus kab mob, nws yog ib qho tsim nyog yuav tsum tau soj ntsuam nruj me ntsis txog cov kev pheej hmoo thiab cov txiaj ntsig ntawm cov tshuaj. Piv txwv li, kev siv sij hawm ntev - yuav ua rau muaj kev pheej hmoo ntawm pob txha pob txha thiab pob txha, yog li nws yuav tsum tau ua ke nrog kev saib xyuas cov pob txha nrog kev tiv thaiv xws li tshuaj calcium thiab vitamin D.

Txhais tau hais tias muaj kev pheej hmoo siab - pawg neeg: Cov pej xeem no suav nrog cov tib neeg uas muaj keeb kwm ntawm tsev neeg predisposition, BRCA genetic aberrations, atypical mammary hyperplasia lossis cov ntaub ntawv kho mob mammary carcinoma ua ntej. Cov pab pawg neeg raug tsim txom no pom tau tias muaj qhov ua rau muaj kev cuam tshuam loj heev rau cov neeg laus. Cov ntaub ntawv pov thawj ntawm kev tiv thaiv kev tiv thaiv: Cov kev sim tshuaj ntsuam xyuas tau lees paub tias kev siv tshuaj anastrozole ntev ntev tuaj yeem txo qis kev mob qog noj ntshav ntawm mammary carcinoma ntawm cov neeg muaj kev pheej hmoo siab -.

Piv txwv li, IBIS-II qhov kev sim tshuaj ntsuam xyuas pom tau tias kev cuam tshuam anastrozole txo cov qog nqaij hlav cancer ntawm lub mis los ntawm 53%, nrog rau tag nrho cov kev tsis zoo tshwm sim tseem tuaj yeem tswj tau. Kev soj ntsuam kev pheej hmoo thiab txiaj ntsig: Txawm hais tias muaj txiaj ntsig zoo ntawm kev siv tshuaj hauv kev txo qis kev mob qog noj ntshav, kev pheej hmoo tshuaj kho mob nruj heev- kev soj ntsuam cov txiaj ntsig yog qhov tseem ceeb ua ntej kev siv tshuaj kho mob. Kev siv tshuaj ntev ntev - yuav ua rau muaj qhov tshwm sim ntawm osteopenia thiab pob txha pob txha. Raws li, kev tshawb nrhiav cov pob txha pob txha pob txha tsis tu ncua, nrog rau kev tiv thaiv kev tiv thaiv nrog calcium.

1) Synthesis ntawm , , ', '-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile

Them ib 2000 mL peb- caj dab caj dab nrog 25 g ntawm anastrozole bromo- nruab nrab thiab 200 mL DMF. Agitate qhov sib tov ntawm ambient kub kom txog thaum lub pob tshab tov yog tsim. Ua kom lub cev kub hauv 25-30 degree, tom qab ntawd qhia 9 g ntawm sodium 1,2,4-triazolate. Sustain stirring mus rau kev hloov pauv; Kev tshuaj xyuas HPLC raug coj los saib xyuas qhov kawg ntawm cov tshuaj tiv thaiv. Thaum cov tshuaj tiv thaiv tiav, ncuav 250 mL ntawm 0.2 mol / L dilute acid thiab 500 mL toluene, ua raws li kev ntxhov siab los pab txhawb kev sib cais.

Kho cov theem ntawm cov organic ob zaug nrog 100ml thiab 100ml ntawm 0.2mol / L dilute hydrochloric acid, ua ke lub dilute acid theem, kho cov organic theem ob zaug nrog 100ml thiab 100ml ntawm 0.2mol / L dilute hydrochloric acid, ua ke lub dilute acid theem, ntxuav ib zaug nrog 200ml ntawm toluene, 3 merge 0. 200ml ntawm 2N hydrochloric acid, ua ke lub acid theem, ntxiv sodium carbonate rau acid theem, kho pH rau 6-7, do kom crystallize, thiab txo mus rau 0. Incubate ntawm℃rau 2 teev, lim thiab ntxuav nrog dej txias kom tau 15.2g ntawm crude Anatrazole nrog ib tug luj tawm los ntawm 60.8%;

2) Purification ntawm Anatrazole:

Ntxiv 15 g ntawm crude Anastrozole rau hauv ib qho hnyav hnyav uas muaj 30 mL isopropanol thiab 30 mL purified dej. Khaws nruam nplawm thiab maj mam ua kom sov lub ncua mus rau 40-45℃kom txog rau thaum cov khoom raw khoom yog tag nrho yaj. Tom qab ntawd, qhia 0.075 g activated carbon rau hauv homogeneous tov, stirring rau 15 feeb rau decolorization thiab impurity adsorption, ua raws li kub pom kom tshem tawm cov pa roj carbon residues.

Maj mam ntxiv 120 mL dej dropwise rau hauv cov tau pom nyob rau hauv agitation kom induce crystallization. Tom qab ntawd, txias lub kaw lus mus rau 0℃thiab tuav stirring rau 2 teev kom tiav crystal kev loj hlob. Sau cov khib nyiab los ntawm kev pom, yaug kom huv si nrog dej txias, thiab thaum kawg tau 14.3 g purified Anastrozole nrog qhov hnyav ntawm 95.3%.

1) Sequentially them lub iav reactor nrog 30 g ntawm 5-bromomethyl- , , ′, ′-tetramethyl-1,3-phenylenediamine, ua ke nrog 30 g ntawm 4-amino-1,2,4-triazole thiab 80 mL acetonitrile. Pib nruam nplawm thiab maj mam nce qhov kub kom tswj tau qhov hnyav reflux xeev. Cov tshuaj tiv thaiv sib xyaw yog khaws cia hauv qab reflux rau 12 teev kom ntseeg tau tias muaj kev hloov pauv ntawm cov ntaub ntawv raw. Thaum ua tiav cov tshuaj tiv thaiv, nres cua sov thiab txias cov tshuaj tiv thaiv maj mam. Cov sib tov yog khaws cia ntawm 0℃rau 8 teev nyob rau hauv stirring los pab txhawb tag nrho cov crystal nag lossis daus.

2) Ntxiv 30g ntawm nruab nrab I30g, 225ml ntawm anhydrous methanol, 2ml ntawm purified dej, thiab 2g ntawm tooj liab sulfate rau lub iav reactor nyob rau hauv ib theem zuj zus. Do thiab ntxiv 24.0g ntawm concentrated sulfuric acid dropwise. Tom qab stirring, cua sov kom txog thaum reflux tiav. Maj mam ntxiv 12.0g ntawm sodium azide, ua kom tiav qhov ntxiv, thiab txuas ntxiv cov tshuaj tiv thaiv reflux rau 1 teev. Lim cov tshuaj tiv thaiv thaum nws kub, muab pov tseg cov lim residue, txo qhov siab thiab mloog zoo rau 0.5 npaug ntawm qhov ntim thawj, txias thiab crystallize, lim cov khoom, thiab tom qab ntawd kho cov pH ntawm cov tshuaj nrog saturated potassium carbonate tov rau pH nqi ntawm 8.0-9.0.

Extract ob zaug nrog dichloromethane, 75ml txhua zaus, sib koom ua ke cov organic txheej, thiab ntxuav cov organic txheej ob zaug nrog dej huv, 75ml txhua zaus. Qhuav anhydrous sodium sulfate, mloog zoo rau cov filtrate nyob rau hauv lub siab txo kom txog thaum tsis muaj dichloromethane drips tawm, thiab txias thiab solidify cov residue. Qhuav, tau 18.04g ntawm crude Anatrazole (ib qho impurity tsawg dua 0.1%, tag nrho impurity tsawg dua 0.3%), nrog ib tug yield ntawm 79.8%.

3) 150ml ntawm isopropanol thiab 15g ntawm crude anastrozole tau ntxiv rau iav reactor, rhuab thiab refluxed. Tom qab cov khoom tiav lawm, 0.75g ntawm cov tshuaj charcoal ntxiv rau refluxing thiab decolorization rau 1 teev. Cov tshuaj charcoal raug tshem tawm los ntawm kev pom. Cov lim tau muab tso rau ntawm 0℃thiab crystallized rau ntau tshaj 48 teev. Tom qab pom, nws tau qhuav hauv qhov txo qis ntawm 60℃kom tau 12.3g ntawm refined anastrozole nrog 82.0%. Cov isomer tsis raug kuaj pom, nrog rau kev purity ntawm 99.84%.