Flutamide

To a solution of 130 parts cyclopropyl-di-(4-fluorophenyl)-carbinol in 240 parts benzene are added dropwise 43 parts thionylchloride. The whole is refluxed until no more gas is evolved. The reaction mixture is then evaporated. The residue is distilled in vacuo, yielding 4-chloro-l,l-di-(4-fluorophenyl)-l-butene, boiling point 165° to 167°C at 6 mm pressure  

A mixture of 7.3 parts l-chloro-4,4-di-(4-fluorophenyl)-butane, 5.1 parts l-phenyl-4-oxo-l,3,8-triaza-spiro(4,5)-decane, 4 parts sodium carbonate, a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone is stirred and refluxed for 60 hours. After cooling the reaction mixture is treated with water. The organic layer is separated, dried, filtered and evaporated. The solid residue is recrystallized from 80 parts 4-methyl-2-pentanone, yielding l-phenyl-4-oxo-8-[4,4-di-(4-fluorophenyl)-] butyl-1,3,8-triaza-spiro(4,5)decane, melting point 187.5° to 190°C. 

Chemical Name 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl] -propanamide Common Name Niftolid 

To a stirred, cooled solution of 100 g of 4-nitro-3-trifluoromethylaniline in 400 ml of pyridine, slowly and in a dropwise fashion, add 54 g of isobutyrylchlorlde and then heat the reaction mixture on a steam bath for 1.5 hours. Cool and pour the resulting mixture into Ice water, filter and water-wash the crude an Hide and crystallize the product of this example from benzene to obtain analytically pure material, MP 111,5°C to 112.5°C. 

Molecular formula CuHnFjNaOa Molecular weight 276.2 CAS Registry No. 13311-84-7 

Sample preparation 150 j-L Plasma -l- 150 xL MeCN, vortex for 15 s, centrifuge at 13000 g for 10 min, inject a 50 m-L aliquot of the supernatant 

Guard column 30 mm long 40-50 pm pellicular CIS (Replace guard column and prefilter before each run.) 

Mobile phase MeCN l% acetic acid 50 50, pH 2.9 (dog) or MeCN MeOH water 30 20 50 (human) 

A solution of 61 parts 4-chloro-l,l-di-(4-fluorophenyl)-l-butene in 400 parts 2-propanol is hydrogenated at normal pressure and at room temperature In the presence of 5.5 parts palladium-on-charcoal catalyst 10% (exothermic reaction, temperature rises to about 30°C). After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filered off and the filtrate is evaporated. The oily residue is distilled in vacuo, yielding 1-chloro-4,4-di-(4-fluorophenyl)-butane, boiling point 166° to 168°C at 6 mm pressure no ° = 1.5425 d o = 1.2039. 

Janssen, P.A.J. U.S. Patent 3,238,216 March 1,1966 assigned to Research Laboratorium Dr. C. Janssen NV, Belgium 

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USP (Sandostatiu) flutamide (Rulexin) [13311-84-7] C11H11F3N2O3 276.21 (66) tumors vasoactive intestinal peptide-secretory tumors metastatic prostatic stools vomit-ing abdomiaal pain pain on iujection diarrhea... 

Interest contmues in prodrugs of 5-fluorouracil (5-FU) Doxifluridine (8) was recently mtroduced and appears to be more potent and less toxic than 5 FU [10 Flutamide (9) and nilutamide (/O) are both available for the treatment of prostatic cancer [//, 12]... 

A simple aniline derivative acts as a prostatic antiandro-t (>n. Its synthesis involves simple acylation of disubstituted iiriiline 13 with isobutyryl chloride to give flutamide (14). 

Hormone antagonists (tamoxifen and toremifen bind to the estradiol receptor, flutamide binds to the androgen receptor) are used for treating breast and prostate cancer. 

Bicalutamide may increase the effect of oral anticoagulants. Flutamide enhances the action of leuprolide. Additive antineoplastic effects may occur when leuprolide is administered with megestrol or flutamide. Estrogens decrease the effectiveness of tamoxifen. 

C4H7CIO 79-30-1) see Atorvastatin calcium Flutamide Ibopamine Mibefradil hydrochloride Ritonavir isochroman... 

C7HjFjN 98-16-8) see Bendroflumethiazide Flufenamic acid Flutamide Hydroflumethiazide Niflumic acid... 

Flutamide is an androgen receptor antagonist that achieves peak concentrations approximately 2 to 4 hours after an oral dose. Flutamide is metabolized extensively, with a terminal half-life of about 8 hours. Bicalutamide achieves peak concentrations approximately 6 hours after the dose, with a terminal half-life of 6 to 10 days. Bicalutamide undergoes stereospecihc metabolism, where the S-enantiomer is cleared more rapidly by the liver than the -enantiomer. Nilutamide achieves peak serum concentrations between 1 to 4 hours after an oral dose and has a terminal half-life of 38 to 60 hours. Nilutamide is metabolized extensively, with less than 2% excreted as unchanged drug by the kidney. Side effects common to these agents are hot flashes, gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three-times-daily administration, whereas bicalutamide is dosed once daily. Nilutamide may cause interstitial pneumonia and is associated with the visual disturbance of delayed adaptation to darkness. 

Flutamide 750 mg/day Gynecomastia Hot flushes Gastrointestinal disturbances (diarrhea) Liver function test abnormalities Breast tenderness Methemoglobinemia... 

Combining an LHRH agonist with flutamide demonstrated response rates greater than 90% in previously untreated patient, and the median survival was 61 months in the combination arm and 41 months in the leuprolide-alone arm in patients with minimal disease.38 However, in a comparison of goserelin with goserelin and flutamide conducted in 589 patients with 10 years of follow-up, combined androgen blockade (CAB) showed no benefit over goserelin alone.39... 

The most recent meta-analysis of 27 randomized trials in 8275 patients (4803 treated with flutamide, 1683 treated with nilutamide, and 1784 treated with cyproterone) comparing maximal androgen blockade with conventional medical or surgical castration showed a small survival benefit at 5 years for those treated with flutamide or nilutamide (27.6%) compared with those treated with castration alone (24.7% p = 0.0005).40... 

Boccardo F, Rubagotti A, Barichello M, et al. Bicalutamide monotherapy versus flutamide plus gosrelin in prostate cancer patients Results of an Italian Prostate Cancer Project study. J Clin Oncol 1999 17 2027-2038. 

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