90357-53-2

Usage

Uses

Used in Pharmaceutical Industry:
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide is used as a chemical intermediate for the synthesis of selective androgen receptor modulators (SARMs). These SARMs are designed to selectively target androgen receptors, which play a crucial role in the development and maintenance of muscle mass, bone density, and other physiological processes. N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide's unique structure allows for the development of SARMs with improved selectivity and reduced side effects compared to traditional anabolic steroids.
Used in Research and Development:
In addition to its applications in the pharmaceutical industry, N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide can also be used in research and development settings. Scientists can utilize N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide to study the interactions between androgen receptors and potential modulators, leading to a better understanding of the underlying mechanisms and the development of more effective therapeutic agents.
Used in Drug Design and Optimization:
The unique properties of N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide make it a valuable tool in drug design and optimization processes. Researchers can use N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide as a starting point to develop new drugs with improved efficacy, selectivity, and safety profiles. By modifying the structure of N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide, chemists can explore various chemical modifications and their effects on the compound's biological activity, ultimately leading to the discovery of novel therapeutic agents.

InChI:InChI=1/C12H9F3N2O/c1-7(2)11(18)17-9-4-3-8(6-16)10(5-9)12(13,14)15/h3-5H,1H2,2H3,(H,17,18)

Upstream product

• 654-70-6 4-amino-2-trifluoromethylbenzonitrile 
• 920-46-7 Methacryloyl chloride 
• 79-39-0 Methacrylamide 
• 194853-86-6 4-fluoro-2-(trifluoromethyl)benzonitrile 
• 79-41-4 poly(methacrylic acid) 
• 80-62-6 methacrylic acid methyl ester 

Downstream Products

• 90357-51-0 N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide 
• 888071-40-7 3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethylphenyl)-amide 
• 888071-58-7 3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 
• 888072-26-2 5-(4-cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-3,4-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 
• 316373-93-0 (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2,3-dihydroxy-2-methylpropanamide 
• 316373-94-1 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2,3-dihydroxy-2-methylpropanamide 
• 888071-36-1 5-(4-fluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 
• 888071-90-7 5-(4-acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 
• 888071-76-9 3,5-dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 
• 888071-78-1 5-ethyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 

Relevant academic research and scientific papers

Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 μM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 μM) and enzalutamide (IC50 = 11.47 – 53.04 μM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

Synthetic method N-(4-cyano -3-(trifluoromethyl) phenyl)-2- methyl epoxy acrylate -2- amide (by machine translation)

The synthesis method N - (4 of) cyano - 3 3 3-(trifluoromethyl) - 2 - phenyl, methyl epoxy acrylate - 2 2-amide :S1,) comprises the following processing steps 4 - dissolving, amino - 2 2-trifluoromethyl-phenyl, methacrylamide 10-65 °C, into a solvent 1-10h;S2, and heating to, filtering and drying to obtain N - (4 - cyano - 3 3-trifluoromethyl-phenyl)-methacrylamide. The present invention provides ;S3,cyano - 3 3 (trifluoromethyl N - (4 - phenyl)-methyl-epoxypropane - 2 2-amide) is obtained by filtration and drying, below, ° C. The reaction 1-3h;S4, is stirred 10-24h, and dried to obtain a mixture solution of the two-phase, catalyst and manganese dioxide 20-25 °C, by filtration and drying at a temperature of about N - (4 °C. after the reaction) of the reaction mixture, is dried by filtration and drying in a mixed, solution at a, temperature in a range of) - 2 - ° C. or lower; ° C. or less. (by machine translation)

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.

Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC50 = 2.67–13.19 μM) compared to bicalutamide (IC50 = 20.44 μM) in LNCaP. Remarkably, novel double branched bicalutamide analogues (27 and 28) were isolated as major by-products and found to have the best activity across three human prostate cancer cell lines (LNCaP, VCaP and PC3). The most active compound 28 shows sub-micromolar activity (IC50 = 0.43 μM in LNCaP), which represents more than 40-fold improvement over the clinical anti-androgen bicalutamide (IC50 = 20.44 μM) and a more than 3 fold improvement over enzalutamide (IC50 = 1.36 μM). Moreover, strong reduction of PSA expression in LNCaP cells upon treatment with compounds 27, 28 and 33 was observed during qPCR analysis, confirming their AR antagonist activity. Molecular modelling studies revealed a novel binding mode of these structurally distinct double branched analogues within the ligand binding domain (LBD) of the androgen receptor.

Preparation method of bicalutamide epoxy intermediate

The invention relates to synthesis of chemical drugs, and relates to a preparation method of a bicalutamide epoxy intermediate, in particular to a preparation method of N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2-epoxy-2-methylpropionamide. According to the method, lower fatty acid ester serves as a solvent, 4-cyano-3-(trifluoromethyl)aniline as a raw material is subjected to two-step reaction of methyl propene acylation and epoxidation to generate N-[4-cyano-3-(trifluoromethyl)phenyl]-2,3-epoxy-2-methylpropionamide, an acid-binding agent is used as a catalyst in methyl propene acylation reaction, and hydrogen peroxide serves as a peroxide source in epoxidation reaction. According to the method, the preparation and reaction conditions are mild, the use of trichloroethane and diethyl ether with extremely high danger is avoided, the intermediate product can be directly applied to the epoxidation reaction without separation and refining, the operation is convenient, and the working time isrelatively short.

Novel trifluoromethylated enobosarm analogues with potent antiandrogenic activity in vitro and tissue selectivity in vivo

Prostate cancer often develops antiandrogen resistance, possibly via androgen receptor (AR) mutations, which change antagonists to agonists. Novel therapies with increased anticancer activity, while overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone while having no effect on the prostate. Here, we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bistrifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity—by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/ ARLuciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the ARLuc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other ARexpressing tissues, e.g., testes, seminal vesicles, and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen, thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-Pten deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared with enobosarm and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.

METHODS OF TREATING ADVANCED PROSTATE CANCER

Provided herein are methods for treating metastatic prostate cancer using anti-androgen compounds and radionuclide-labeled androgens.

Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer

Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

Rational design and synthesis of novel anti-prostate cancer agents bearing a 3,5-bis-trifluoromethylphenyl moiety

Prostate cancer is a major cause of male death worldwide and the identification of new and improved treatments is constantly required. Among the available options, different non-steroidal androgen receptor (AR) antagonists are approved also to treat castration-resistant forms. Most of these drugs show limited application due to the development of resistant mutants of their biological target. Following docking-based studies on a homology model for the AR open antagonist conformation, a series of novel 3,5-bis-trifluoromethylphenyl compounds was designed with the aim to improve the antiproliferative activity of anti-androgen drugs bicalutamide and enzalutamide. The new structural modifications might impede the receptor to adopt its closed agonist conformation also in the presence of adaptive mutations. Among the novel compounds synthesised, several displayed significantly improved in vitro activity in comparison with the parent structures, with IC50values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145, 22Rv1). Selected hits demonstrated full AR antagonistic behaviour and promising candidates for further development were identified.

Antitumor agents 290. Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens

In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC 50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-anti-androgen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, anti-androgens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.