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Bicalutamide

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  • Bicalutamide
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  • Bicalutamide
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  • Bicalutamide
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Bicalutamide Basic information
Bicalutamide Solubility Determination of the content of Bicalutamide tablets by high performance liquid chromatography (HPLC) Bicalutamide tablets Adverse reaction Chemical properties Uses Producing method
Product Name:Bicalutamide
Synonyms:(+-)--2-hydroxy-2-methyl;propanamide,n-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl);Bicalutamide (Subject to patent free);ICI-176334;CASODEX;BICALUTAMIDE;N-[(4-CYANO-3-TRIFLUOROMETHYL)PHENYL]-3-[(4-FLUOROPHENYL)SULFONYL]-2-HYDROXY-2-METHYLPROPANAMIDE;N-[4-CYANO-3-(TRIFLUOROMETHYL)PHENYL]-3-[(4-FLUOROPHENYL)SULFONYL]-2-HYDROXY-2-METHYLPROPIONANILIDE
CAS:90357-06-5
MF:C18H14F4N2O4S
MW:430.3733728
EINECS:
Product Categories:MODRASTANE;API;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;API's;anti-neoplastic;Active Pharmaceutical Ingredients;Antiandrogen;Antineoplastic (Hormonal)
Mol File:90357-06-5.mol
Bicalutamide Structure
Bicalutamide Chemical Properties
Melting point 191-193°C
Boiling point 650.3±55.0 °C(Predicted)
density 1.52±0.1 g/cm3(Predicted)
storage temp. Store at RT
solubility DMSO: >5mg/mL
pka11.49±0.29(Predicted)
form powder
λmax270nm(CH3CN)(lit.)
Merck 14,1200
CAS DataBase Reference90357-06-5(CAS DataBase Reference)
Safety Information
Hazard Codes Xi
Risk Statements 36/37/38
Safety Statements 26-36-24/25
RIDADR 3077
WGK Germany 3
RTECS TX1413500
HazardClass 9
PackingGroup III
HS Code 29242995
Hazardous Substances Data90357-06-5(Hazardous Substances Data)
MSDS Information
ProviderLanguage
Bicalutamide English
Bicalutamide Usage And Synthesis
Bicalutamide Solubilitysoluble in dimethyl formamide; dissolved in tetrahydrofuran; slightly soluble in ethyl acetate and methanol; insoluble in water.
Determination of the content of Bicalutamide tablets by high performance liquid chromatography (HPLC)Using SHIMADZU CLC-ODS (150mm´6.0mm, 5μ) column. 0.1% potassium dihydrogen phosphate solution-acetonitrile (50:50) as the mobile phase, detecting at 272nm wavelength. Result: bicalutamide had a good linear relationship (r=0.9995) when the concentration in the range of 0.05mg*ml-1~0.20mg*ml-1. The average recovery was 99.5%, and RSD=0.9% (n=9 ) Conclusion: The method is simple, good accuracy and high precision.
Bicalutamide tabletsBicalutamide tablet is a non-steroidal androgen antagonist, which competes androgen receptor with the androgen, blocks cellular uptake of androgen, and inhibits the binding of androgens to the target organ. It binds with the androgen receptor that forms receptor complex, which enters the nucleus and combined with the nucleoprotein, consequently inhibiting tumor cell growth. It can be as a first-line drug for palliative treatment of advanced prostate cancer.
Dosage and administration:
Adult: adult males including the elderly: one (50mg), once a day. The treatment should be started simultaneously with LHRH analogue therapy or surgical orchiectomy.
Children: This product is contraindicated in children.
Renal impairment: The patients with renal impairment don’t need dose adjustment.
Hepatic impairment: The patients with mild liver damage don’t need dose adjustment, while the patients with severe liver damage may occur drug accumulation (see precautions).
Precautions:
This product is widely metabolized in the liver. Data show that patients with severe liver damage may slow down drug clearance, which may lead to accumulation. So the patients with moderate and severe liver injury should use it with caution.
The patients may appear liver changes by using it, so it should be considered regular liver function tests. The main changes generally appear within the first 6 months of treatment using this product.
Severe changes in liver function are rarely visible in the treatment of the product (see Adverse Reactions). If there is a serious change in treatment using this product, it should be discontinued.
This product is shown to inhibit the activity of cytochrome P450 (CYP3A4). When combined with drugs metabolised mainly by CYP3A4, the patients should be caution (see Contraindications and Drug Interactions).
Pregnancy and lactation: This product is contraindicated in women, especially for pregnant women or nursing mothers.
Effect on driving and operating machinery ability: This product does not affect the ability of patients of driving and operating the machine.
The above information is edited by the chemicalbook of Kui Ming.
Adverse reactionPharmacological effects of this product caused certain expected reactions, including flushing, itching, in addition to breast tenderness and feminization of male breast, which can alleviate with orchiectomy. This product may also cause diarrhea, nausea, vomiting, fatigue and dry skin.
Liver function changes (elevated levels of transaminases, jaundice) have been observed in clinical trials of this product, but there were rare serious changes. These changes are often short-lived. The changes then gradually subsided or improved whether to continue treatment or discontinuation of treatment. Patients receiving treatment of this product were very rare liver failure, and its causal relationship has not been established. Regularly check liver function should be considered. (See precautions).
During clinical studies, using this product with LHRH analogues, the following side effects were also observed (clinical investigaters thought it may be related to it and drug-related incidence greater than 1%). Side effects associated with the use of these drugs are no causal relationship, and some of them are daily inherent in the elderly.
Cardiovascular system: heart failure
Digestive system: anorexia, dry mouth, indigestion, constipation, flatulence.
Central nervous system: dizziness, insomnia, somnolence, decreased sexual drive.
Respiratory system: dyspnea.
Urogenital system: impotence, nocturia.
Hematology: anemia.
Skin and its appendages: alopecia, rash, sweating, hirsutism.
Metabolism and nutrition: diabetes, hyperglycemia, peripheral edema, increased or decreased body weight.
Torso: abdominal pain, chest pain, headaches, pelvic pain, chills.
Contraindications:
Contraindicated in women and children.
Can not be used in patients with allergy to the chemicals.
This product can’t use combination with terfenadine, astemizole, or cisapride.
Chemical propertiesCrystallization from 1: 1 (by volume) of ethyl acetate and petroleum ether. Melting point is 191~193 ℃.
UsesV1 taking anti-androgens drug. Prostate cancer therapeutic agents for the treatment of advanced prostate cancer.
Producing methodmethyl methacrylate epoxidized to form epoxide,and then in the presence of sodium hydride reacted with fluorothiophenol to form the compound ,followed by oxidation to form compound. Then hydrolyzed to the acid,with thionyl chloride chloride as acid chloride.And finally condensation with 4-cyano-3-trifluoromethyl-aniline to obtain the product.
DescriptionBicalutamide was launched in the United Kingdom, its first worldwide market, for the treatment of advanced prostate cancer in combination with an LHRH analog or surgical castration. A non-steroidal, peripherally selective antiandrogen, bicalutamide inhibits the action of dihydrotestosterone and testosterone at target sites by competitive binding to the cytosolic androgen receptor. It was reportedly well tolerated with no significant cardiovascular and metabolic side effects due to the benefit of lacking any steroid activity. The efficacy of bicalutamide as a monotherapy has been demonstrated clinically. Promising response rates were also reported in treating colorectal, breast, pancreas and non-small cell lung cancers.
Chemical PropertiesOff-White Crystalline Solid
OriginatorZeneca (United Kingdom)
HistoryBicalutamide was discovered in the 1980s by Tucker et al. at Imperial Chemical Industries (now AstraZeneca). Based on previous works on flutamide, key structural features required for a strong anti-androgenic activity include the presence of an electron-poor aromatic ring, attached to an amide moiety. Electron-withdrawing groups at the para and the meta position of the anilide ring are beneficial for the anti-androgenic activity as compared to monosubstituted derivatives.As far as the meta position is concerned, a chloro or trifluoromethyl substituent is the best choice. Nitro and cyano groups are the best substituents at the para position. Replacement of themethyl group at the tertiary carbinol center by a trifluoromethyl group resulted in compounds with agonistic activity. In contrast to flutamide, the amide moiety of bicalutamide was extended by a sulfur linker with a second aromatic portion. The sulfanyl, sulfinyl, and sulfonyl analogues showed the same activity.The sulfanyl group was found to be oxidized to the active metabolite sulfonyl, thus indicating the sulfonyl derivative as the biologically active entity. An unsubstituted phenylsulfonyl moiety at the eastern part, or corresponding derivatives with small substituents such as fluoro at the para position, seemed to be the best in terms of anti-androgenic activity.
Usesadrenocortical suppressant, antineoplastic, steroid biosynthesis inhibitor
UsesNon-steroidal peripherally active antiandrogen. Used as an antiandrogen, antineoplastic (hormonal)
DefinitionChEBI: A sulfone that is an oral non-steroidal antiandrogen used in the treatment of prostate cancer and hirsutism.
IndicationsBicalutamide was the third nonsteroidal anti-androgen that was used for the treatment of prostate cancer. Flutamide, although effective in the treatment of prostate cancer, is a pure antagonist that also affects the hypothalamus pituitary axis, thus preventing the negative feedback mechanism of androgen. Consequently, the production of LH is increased, which subsequently stimulates the synthesis of testosterone, counteracting the effectiveness of the anti-androgen. Furthermore, the half-life of the active metabolite of flutamide, hydroxyflutamide, is fairly short, and a dosing scheme of 250 mg three times daily is therefore required. The main adverse effects reported for flutamide are gynecomastia, diarrhea, and reversible liver abnormalities. Nilutamide has a longer half-life than flutamide and therefore can be administered once daily. Adverse events reported include problems with light/dark adaptation and interstitial pneumonitis. The goal that ultimately led to the discovery of bicalutamide was the identification of a novel peripherally selective anti-androgen with longer half-life than flutamide and with better tolerability as compared to both, flutamide and nilutamide.
Manufacturing Process[(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4-yl]acetic acid. Bromal (25.0 g; 89.1 mmol) and (S)-citramalic acid (11.0 g; 74.2 mmol) were cooled to 0°C under inert atmosphere. Sulfuric acid/acetic acid (1/1; 25 ml) was added dropwise with stirring. After 2 h the contents were a yellow solution with a white precipitate. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ice and extracted 4 times with ethyl acetate. The organic layer was back extracted with water and then was dried with MgSO4. After filtration, the filtrate was concentrated to an oil. The product was obtained as a white solid after crystallization from toluene/hexanes. Yield: 23.2 g (77%); mp 151°C (sublime).
(5R)-5-(Bromomethyl)-5-methyl-2-(tribromo-methyl)-l,3-dioxolan-4-one. The above obtained [(4S)-4-Methyl-5-oxo-2-(tribromomethyl)-1,3-dioxolan-4- yl]acetic acid (102.5 mg; 0.250 mmol) and 2-mercaptopyridine- N-oxide (34.4 mg; 0.280 mmol) were suspended in CBrCl3 (1.5ml). The reaction mixture was heated to reflux and a solution of dicyclohexyl carbodiimide (DCC) (103 mg; 0.500 mmol) in CBrCl3 (1.0 ml) was added slowly over the course of 30 min. The reaction mixture was stirred for an additional hour. The product was purified by silica gel chromatography (CH2Cl2/hexanes (1:2)) and was obtained as white needles from the same solvents. Yield: 72 mg (65%); mp 110-113°C.
(2R)-3-[(4-Fluorophenyl)thio]-2-hydroxy-2-methyl-propanoic acid. The above prepared protected hydroxyacid (184 mg; 0.413 mmol) was dissolved in 4 ml of a 1:1 mixture of isopropanol:1 M NaOH. After 3 h, the reaction mixture was a solution and no starting material was detectable by TLC. 4-Fluorobenzenethiol (70 ml; 0.65 mmol) was then added and the reaction mixture was stirred overnight. The reaction mixture was then adjusted to pH 8 with HCl and was extracted twice with CH2Cl2. The aqueous layer was then adjusted to pH 1 and was extracted with CH2Cl2. This organic layer was concentrated to an oil, which crystallized on standing. The hydroxyacid was either used in the next reaction without further purification or was recrystallized from chloroform/petroleum ether. Yield 76 mg (80%). (2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenul)thio]-2- hydroxy-2-methylpropanamide was prepared from above hydroxyacid (1.89 g; 8.22 mmol) and 4-amino-2-trifluoromethylbenzonitrile (2.05 g; 11.0 mol) were in dry DMA (15 ml) under inert atmosphere. After the solution had been cooled to -10°C, the thionyl chloride (0.75 ml; 10 mmol) was added slowly. The reaction mixture was stirred for 15 min at -10°C and then the ice bath was removed. After stirring overnight at room temperature, the reaction mixture was deluted with CH2Cl2 and was extracted one time with saturated NaHCO3. The organic layer was dried with MgSO4 and concentrated. The product was purified by silica gel chromatography (6% ethyl acetate in CH2Cl2). Yield 1.38 g (42%).
(2R)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2- hydroxy-2-methylpropanamide.
To a solution of the sulfide (1.27 g; 3.19 mmol) in CH2Cl2 (43 mL) was added mCPBA (1.65 g; 9.57 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and extracted with Na2SO3 and NaHCO3 (2x). The organic layer was dried with MgSO4 and concentrated. After purification by silica gel chromatography using a step gradient of ethyl acetate in CHCl3, the product was obtained as white crystals from benzene/petroleum ether. Yield 1.29 g (94%); ee>>99%; mp 178°C. (2S)-N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2- hydroxy-2-methylpropanamide ee>>99%.
Product may be prepared from the starting materials.
Brand nameCasodex (AstraZeneca).
Therapeutic FunctionAntitumor
General DescriptionBicalutamide, N-4-cyano-3-(trifluoromethyl)phenyl-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide (Casodex), is more potent than flutamideand has a much longer half-life (5.9 days vs. 6 hoursfor hydroxyflutamide). Because of the longer half-life, bicalutamideis used for once-a-day (50 mg) treatment of advancedprostate cancer. Bicalutamide is available as aracemic mixture, but both animal and human studies withthe AR show that the R-enantiomer has higher affinity forthe AR than the S-enantiomer.
Biological ActivityOrally active non-steroidal androgen receptor antagonist (IC 50 = 190 nM). Displays peripheral selectivity and does not effect serum levels of LH and testosterone. Exhibits potent anticancer activity in vivo .
Mechanism of actionBicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, which has an approximately fourfold higher affinity for the prostate AR than hydroxyflutamide does. The (S)-enantiomer has no antiandrogenic activity. (R)-Bicalutamide is slowly absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life of 1 week and accumulates approximately 10 times in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma. At steady state, the plasma levels of (R)-bicalutamide are 100 times higher than those of (S)-bicalutamide. Although mild to moderate hepatic impairment does not affect pharmacokinetics, evidence suggests slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment.
PharmacologyBicalutamide is a competitive AR antagonist, which shows in vitro a lower affinity for the AR as compared to the synthetic androgen R1881 as well as the natural DHT. However it displays a fourfold higher affinity as compared to hydroxyflutamide as assessed by a binding assay. Bicalutamide inhibits the growth of the LNCaP/FGC prostate carcinoma cell line, in which hydroxyflutamide was not effective at all. In vivo anti-androgenic activity of bicalutamide was confirmed by dose-dependent weight reduction of the seminal vesicles and ventrical prostate gland in rats, followed by an antitumor efficacy using Dunning R3327-GH prostate carcinomas in intact and castrated rats.A full overview on all clinical trials including bicalutamide would be out of scope.
Clinical UseBicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localized or locally advanced) nonmetastatic prostate cancer. It also can be used at a lower dosage in combination with a LHRH analogue or surgical castration for the treatment of advanced prostate cancer.
Side effectsBicalutamide was well tolerated in monotherapy as well as in combination. No dose-related increase in adverse events was reported. Adverse events were partially due to pharmacological effects of an anti-androgen, which include gynecomastia, breast tenderness, and hot flushes. Other non-pharmacological adverse events, with incidence equal or higher than 10% were, for example, constipation, nausea, diarrhea, asthenia, pain, and infection. The frequency of non-pharmacological adverse events was in the same range as reported for comparator in clinical trials. In contrast to flutamide, the incidence of diarrhea and liver abnormalities was much lower for bicalutamide. As compared with castration, monotherapy with bicalutamide allowed patients to maintain libido and have better physical capacity, thus resulting in better quality of life.Based on the results of the clinical trials mentioned above, bicalutamide was first approved in 1995. Bicalutamide is indicated for the use in combination with an LHRH-A analogue for metastatic prostate carcinoma (50mg).
MetabolismBicalutamide metabolites are excreted almost equally in urine and feces, with little or no unchanged drug excreted in urine. Unmetabolized drug predominates in the plasma. Following oral administration, the racemate displays stereoselective oxidative metabolism of its (R)-enantiomer, with an elimination half-life of approximately 6 days. (R)-Bicalutamide is cleared almost exclusively by CYP3A4-mediated metabolism, but glucuronidation is the predominant metabolic route for (S)-bicalutamide.
Tag:Bicalutamide(90357-06-5) Related Product Information
PHENYL VALERATE Phenylhydrazine Florfenicol Transfluthrin Cyano 4-cyano-3-trifluoromethyl-N-[3-(4-fluorophenylthio)-2-hydroxyl-2-methylpropionyl]aniline (intermediate of bicalutamide),INTERMEDIATE OF BICALUTAMIDE,BICALUTAMIDE-SULFIDE (BICALUTAMIDE ASH),Bicalutamide Intermediate 4-Methyl-3-(trifluoromethyl)aniline 4-amino-2-methylbenzonitrile (R)-BICALUTAMIDE,(R)-(-)-BICALUTAMIDE 4-CYANO-3-(TRIFLUOROMETHYL)ACETANILIDE Bicalutamide intermediate F 4-ACETAMIDOBENZONITRILE 4-ACETAMIDO-2-METHYLBENZONITRILE 2-(Trifluoromethyl)benzonitrile Bicalutamide 4-Fluorobenzaldehyde Methylene dithiocyanate Trifluoromethyl