915087-33-1 Usage
Uses
Used in Prostate Cancer Treatment:
MDV-3100 is used as an androgen-receptor antagonist for the treatment of castration-resistant prostate cancer. It inhibits the binding of androgens to the androgen receptor, preventing the nuclear translocation and co-activator recruitment of the ligand-receptor complex, thereby blocking the growth of prostate cancer cells.
Used in Pharmaceutical Industry:
MDV-3100 is used as a second-generation androgen receptor signaling inhibitor in the development of drugs for the treatment of prostate cancer. Its potent inhibition of androgen binding, nuclear translocation, and association with DNA makes it a promising candidate for the development of new therapeutic agents in the pharmaceutical industry.
Pharmacological action
Enzalutamide (XTANDI) is an oral androgen receptor antagonist, which is approved by the current clinical research and the US FDA (Food and Drug Administration), for the development of post-chemotherapy metastatic castration tolerance of prostate cancer Treatment (i.e. patients with prostate cancer after chemotherapy, cancer or cancer cells are still growing in such patients), can extend the survival of patients. The incidence of prostate cancer in the United States is very high, with an annual increase of nearly 240,000 patients (the highest among all cancers), nearly 30,000 deaths every year (second only to lung cancer, breast cancer, colorectal cancer),but its incidence is low in China.
Enzalutamide is an androgen receptor inhibitor, the target of action is different from the approved cabbitaxel in 2010 and the approved abbitolone in 2011, and can competitively inhibit androgen and receptor binding, and can inhibition of androgen receptor nuclear transport and the interaction of the receptor and DNA. Vitro studies have shown that enzalutamide can inhibit prostate cancer cell proliferation and induce death, and enzalutamide reduces tumor volume in mouse prostate cancer xenograft model experiment. The main metabolite of enzalutamide is N-demethylol enamine, which shows similar inhibitory activity with enzalutamide in vitro. The recommended adult dose for the drug is daily 160mg, rapidly absorbed after medication, plasma concentrations to reach the highest level in 0.5~3h, the average terminal half-life is 5.8d, the main metabolic enzymes are CYP2C8 and CYP3A4. The drug should be avoided with strong CYP2C8 inhibitors (such as gemfibrozil), if it is needed for co-administration, should reduce the dose of enzalutamide to 80mg, 1 day.
Treatment
In vitro, enzalutamide suppressed proliferation and induced apoptosis in human prostate cancer cell lines. The sensitivity of prostate cancer cells to T cell-mediated lysis via androgen receptor-dependent immunomodulation was enhanced by enzalutamide. Enzalutamide lacked androgen receptor agonist activity in CRPC cell models and induced tumour regression in CRPC xenograft models.
Indications
For the treatment of metastatic or recurrence of advanced male castration tolerance of prostate cancer.
Clinical evaluation
Enzalutamide is an oral androgen receptor inhibitor that reduces the risk of radiation-related disease progression and death.
Although anti-androgen therapy has been the preferred treatment option for patients with metastatic prostate cancer for more than 70 years, researchers have found that male hormone receptors play an important role in the development of prostate cancer throughout the course of disease with the in-depth exploration of disease at the molecular level. FDA-approved new generation of androgen receptor antagonists such as abiraterone and enzolatamide have shown that it is benefit for patients with advanced prostate cancer after chemotherapy with docetaxel.
Astellas in Japan and Johnson in the United States treat prostate cancer both through the target, according to statistics, similar to the treatment results, only a few differences, such as: abitron to be used simultaneously with steroid drugs , and enzalutamide is not required; abitron need to limit the diet, and enzalutamide does not need. Drugs in different countries is not the same as different the crowd, so there are price differences, but the effect is the same.
This information was compiled by the Editor of the lookchem (2015-09-20).
Side effects
The main side effects of enxtran (XTANDI) are hypertension and fatigue. The most common adverse reactions (≥ 5%) are weakness/fatigue, back pain, diarrhea, joint pain, hot flashes, peripheral blood edema, musculoskeletal pain, headache, upper respiratory tract infection, muscle weakness, dizziness, insomnia, lower respiratory tract infection, spinal cord compression syndrome and cauda equina syndrome, hematuria, paresthesia, anxiety and hypertension.
Biological activity
Enzalutamide (MDV3100) is an androgen receptor (AR) antagonist with an IC50 of 36 nM.
Enzalutamide is an androgen receptor (AR) antagonist with an IC50 of 36 nM in vitro studies. In competitive experiments with 16β-[18F] fluoro-5α-DHT (18-FDHT), enzalutamide was found to have higher affinity for bilirubin than Bicalutamide when administered to AR. While enzalutamide had no effect on LNCaP/AR (AR-overexpression) of prostate cells. In parental LNCaP cells, Enzalutamide inhibits the production of prostate specific antigen (PSA) and transmembrane serine protease 2 (TMPRSS2), and inhibits their binding to the synthetic and rogen R1881. Enzalutamide inhibits the translation activity of the mutant AR protein (W741C, Trp at position 741 mutanting to Cys). MDV310 also blocked the nuclear translocation and coordination receptor complexes that recruit coactivators.
In vivo studies
Enzalutamide treatment of castrated male mice carrying LNCa/AR xenografts, mice treated with 10 mg MDV310 per kilogram of body weight, can induce significant tumor regression.
Originator
University of California (United States)
Clinical Use
In August 2012, the FDA approved enzalutamide, marketed by Medivation and Astellas Pharma US
for the treatment of metastatic castration-resistant prostate cancer (CRPC), specifically for those patients
who had previously received docetaxel. Enzalutamide is an inhibitor of androgen receptors (AR)—
whose increased expression has been closely linked with castration-resistant prostate cancer (CRPC),thus, AR inhibitors have seen increased recent attention from the medicinal chemistry community.
Phase I/II trials were particularly promising for enzalutamide, as 43% of patients showed >50%
sustained suppression of a key serum biomarker.
Synthesis
Of the several patents and papers describing
synthetic approaches, a 2011 patent represents the most likely scale production route to
enzalutamide, and this is described in the scheme.Commercially available carboxylic acid 70 was first converted to the corresponding acid chloride 71,
followed by amide formation with methylamine to furnish benzamide 72 in 90% yield over two steps.
Bromide 72 was then coupled with amine 73 using copper (I) catalysis to afford trisubstituted benzene
74 in 76% isolated yield. Esterification of 74 to 75 with iodomethane furnished one fragment for the
key ring-forming event. Isothiocyanate 76, available in one step from the corresponding aniline 77, was
then exposed to aminoester 75 in the presence of warm isopropyl acetate, resulting in construction of the
lynchpin thiohydantoin and delivering enzalutamide (XI) in an impressive 78% yield. This 5-step
process has successfully generated multi-gram quantities of the drug in 50.7% overall yield.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly reduces concentration effect
of coumarinsAnxiolytics: concentration of midazolam reduced.Cytotoxics: concentration of palbociclib possibly
reduced - avoid. Lipid-regulating drugs: concentration increased by
gemfibrozil - avoid or halve enzalutamide dose.
Metabolism
Clearance of enzalutamide is mainly via hepatic
metabolism, producing an active metabolite that is equally
as active as enzalutamide and circulates at approximately
the same plasma concentration as enzalutamide. Under
conditions of clinical use, enzalutamide is a strong
inducer of CYP3A4, a moderate inducer of CYP2C9
and CYP2C19, and has no clinically relevant effect on
CYP2C8Excreted mainly as metabolites 71% in urine and 14% via
faeces.
References
Tran et al. (2009), Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer; Science 324 787
Jung et al. (2010), Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonist for Castration-Resistant Prostate Cancer (CRPC); J. Med. Chem. 53 2779
Check Digit Verification of cas no
The CAS Registry Mumber 915087-33-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,1,5,0,8 and 7 respectively; the second part has 2 digits, 3 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 915087-33:
(8*9)+(7*1)+(6*5)+(5*0)+(4*8)+(3*7)+(2*3)+(1*3)=171
171 % 10 = 1
So 915087-33-1 is a valid CAS Registry Number.
InChI:InChI=1/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
915087-33-1Relevant articles and documents
Synthesis method of enzalutamide
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, (2021/04/14)
The invention discloses a synthesis method of enzalutamide. According to the method, 4-amino-2-trifluoromethyl benzonitrile is adopted as an initial raw material, and the initial raw material, benzoyl isothiocyanate (a reaction product of ammonium thiocyanate and benzoyl chloride), methyl 2-methyl-2-chloropropionate and N-methyl-4-bromo-2-fluorobenzamide are sequentially subjected to a multi-step substitution reaction to obtain the enzalutamide. The synthesis method not only can guarantee the yield and the product quality, but also can protect the health and safety of personnel, is safe in production, and is suitable for industrial production.
PROCESS FOR PREPARATION OF ENZALUTAMIDE
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Page/Page column 18, (2021/01/23)
The presented invention relates to a process for preparation of Enzalutamide, compound (1) or a salt or a solvate thereof Formula (1). The presented invention also related to 1,4-dioxane solvate of compound (1).
Preparation process of medicine enzalutamide of prostate cancer (by machine translation)
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, (2020/03/17)
The preparation process, of the present invention overcomes the major drawbacks N - of the prior art by catalyzing the nucleophilic substitution reaction, with 2 - methyl - 4 4 (methylcarbamoyl, phenyl,methyl propionic acid 2 - (3 -) to generate)-trifluoromethyl) - 2 - phenyl,(methylcarbamoyl,phenylamino 2 -methyl propionate 2 - ((3 -) by esterification.). The method of the present invention overcomes the major drawback, of the prior art, by catalyzing the nucleophilic substitution reaction) to react with) - 2 -methoxyethyl,yl 2 -methylpropanoic acid in the presence of a nucleophilic substitution reaction with, methyl - 4 4-(methylamino) isobutyric acid in the presence. of a nucleophilic substitution. 4 - (3 - (4 - The present invention provides, a method for producing prostate cancer, drug enrolirubin) by, a catalytic reaction with isothiocyanobenzonitrile in accordance with the present, invention in the, state of the present invention in the present invention . and is suitable for large-scale industrial production of the product) - 5,5 - cyano - 3 3- (methylcarbamoyl) N-methylpropanoic acid is shown in Table) - 2 . (by machine translation)
Preparation method of enzalutamide intermediate
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, (2020/07/13)
The invention provides a preparation method of an enzalutamide intermediate (formula A). The R group is selected from C1-C4 alkyl, benzyl and phenyl groups, an intermediate (formula A) is synthesizedthrough the method and used for preparing enzalutamide, the reagents such as halogenated hydrocarbon with high toxicity are prevented for producing enzalutamide, meanwhile, by-product impurities generated due to use of inorganic base are avoided, and the yield and purity are high.
Method for synthesizing enzalutamide (by machine translation)
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, (2020/12/29)
The invention provides a method for synthesizing enzalutamide. , The preparation method comprises the following steps: (1) in first solvent, reacting the compound 8 with the hydrochloride of the compound of formula I in the presence of an inorganic base, a catalyst and a ligand to obtain the compound 9. The first solvent is composed of an organic solvent 1 and water. And (2) In 2nd-solvent, the compound 9 and the compound 7 are reacted in the presence of an organic base, thereby obtaining enzalutamide. The preparation method has the advantages of short synthetic route, high yield, mild reaction conditions, simple operation and post-treatment, high product purity and suitability for industrial production. (by machine translation)
Prostatic cancer treatment medicine
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, (2019/03/26)
The invention relates to a compound with a prostatic cancer treatment function and nontoxic pharmaceutically acceptable salt of the compound. The structure of the compound is as shown in a formula I,wherein X is C or N, R1 is alkyl of C1-C3 or halogen substituted alkyl, R2 is alkyl of C1-C3 and halogen substituted alkyl or halogen, R3 and R4 are independently selected from H, alkyl and substituted alkyl, and R3 and R4 are connected to form cycloalkyl. The compound has high inhibiting effects on in-situ prostate cancer and transfer of the prostate cancer, and eclamptogenic side effects are lower.
PROCESS FOR PREPARATION OF ENZALUTAMIDE USING NOVEL INTERMEDIATE
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Page/Page column 42; 43, (2019/06/17)
Process for preparation of Enzalutamide using novel intermediate Provided herein is a process for the preparation of a novel [4-cyano-3- (trifluoromethyl)phenyl]carbamodithioic acid and its use in preparation of Enzalutamide being cost effective with higher yield, higher HPLC purity with reduced impurities.
A preparation method of graciousness mixed lu an (by machine translation)
-
, (2019/11/13)
The invention belongs to the technical field of pharmaceutical synthesis method, provides a method for preparing graciousness mixed lu an, including: (1) the preparation of compound B: to 2 - ((3 - fluoro - 4 - (methyl carbamoyl) phenyl) amino) - 2 - methyl propionic acid as the starting material, in the organic solvent in the environment, adding inorganic base or organic base, under an appropriate temperature reaction to obtain compound B; (2) the step (1) with a compound B 4 - different sulfo- cyanogen acyl - 2 - (trifluoromethyl) benzonitrile graciousness mixed lu an reaction to obtain the target product. The method of the invention not only avoids the toxic reagent such as methane [...], shorten the compound B preparation reaction time, also to avoid product graciousness mixed lu an after-treatment process complicated operation, greatly simplifying the post-treatment process, thereby saving the resources, is more suitable for industrial scale production. (by machine translation)
Preparation method of enzalutamide of formula (VIII)
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, (2019/05/02)
The invention discloses a preparation method of enzalutamide of formula (VIII). The method comprises the following steps: carrying out a condensation reaction on a compound of formula (I) and an aminoprotecting group PG-containing compound of formula (II) to produce a compound of formula (III); carrying out a protecting group PG removal reaction on the compound of formula (III) to form a compoundof formula (IV); carrying out a coupling reaction on the compound of formula (IV) and a compound of formula (V) at 25-160 DEG C to form a compound of formula (VI); and converting the compound of formula(VI-a) into a compound of formula (VII) when W is a C1-8 alkoxy group, and converting the compound of formula (VI-b) into into the compound of the formula (VIII) when the W is a methylamino group.The method has the advantages of high yield, omitting of the production of an intermediate isothiocyanate with poor stability, mild reaction conditions, simplicity in operation, and cheap and easily available reagents, is suitable for small-scale preparation in the laboratory, and is also suitable for large-scale industrial production.
Production Method of Enzalutamide Crystal Form
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Paragraph 0081-0088, (2018/06/09)
The present invention aims to provided a novel production method of an enzalutamide crystal form in which wet crystals of enzalutamide are obtained in a step of crystallizing in the production process of the enzalutamide crystal form, and then 2-propanol which is solvated with enzalutamide and the B-type crystals are reduced. The present invention relates to a production method of an enzalutamide crystal form, which comprises a step of crystallizing for obtaining wet crystals of enzalutamide, and a step of drying the wet crystals, and comprises a step of washing using a mixed solvent of a good solvent and a poor solvent after the step of crystallizing.
