36 results about "Enzalutamide" patented technology

This invention relates to talazoparib, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, for the treatment of homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer and methods of increasing overall survival thereof.

Methods and uses of increasing or accelerating liver regeneration in a subject in need thereof are provided. In some aspects, such methods and uses comprise administering an effective amount of an androgen receptor inhibitor to a subject in need thereof, including, but not limited to, a subject suffering from one or more risk factors of post-hepatectomy liver failure. Any androgen receptor is contemplated for use in the methods described herein including, but not limited to, enzalutamide, apalutamide, bicalutamide, darolutamide, flutamide, nilutamide, or proxalutamide.

Provided herein are methods of identifying a subject with prostate cancer (such as a human or veterinary subject) who will respond to enzalutamide therapy. In particular examples, the methods can determine with high accuracy whether a subject is likely to respond to enzalutamide therapy. Also provided are methods for treating a subject who is likely to respond to enzalutamide, for example by administering enzalutamide to the subject.

The invention provides a method for treating AR negative TNBC through combination of quercetin and enzalutamide, the quercetin up-regulates the AR expression level by inhibiting a high-expression solute carrier SLC7A5, so that tumor cells which are not sensitive to enzalutamide originally obtain drug sensitivity again; the combined use of an AR antagonist enzalutamide (1-80 [mu] M) can cooperatively block an AR signal channel and significantly inhibit cell proliferation (the inhibition rate of drug combination is 70%, Plt, 0.01 higher than that of a single drug). In-vitro experiments prove that the scheme has a synergistic effect (the effect is optimal when the mass ratio is 1: 1-5: 1) in MDA-MB-231 cells, and an animal model shows that the tumor volume inhibition rate reaches 70% or above. Safety evaluation shows that the drug combination does not cause abnormity of serum biochemical indexes (ALT / AST / BUN / CREA) or damage of main organs and tissues. The invention further provides a preparation method of an oral preparation (tablets / capsules / nanoparticles) containing quercetin (50-500 mg / day) and enzalutamide (40-160 mg / day), and a new strategy is provided for reversing AR-TNBC drug resistance.

Methods of treating prostate cancer, including castration-resistant prostate cancer and metastatic castration-resistant prostate cancer, comprising administering an effective amount of an androgen receptor (AR) antagonist and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) are disclosed. The AR antagonist may be enzalutamide. The SGRM may be an octahydro fused azadecalin compound, such as exicorilant, ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone which has the structure: The AR antagonist and the SGRM may be administered once per day, and may be administered with food. Enzalutamide doses may be 150-200 mg / day, e.g., 160 mg / day. Exicorilant doses may be 100-350 mg / day, e.g., 240 mg / day, or 280 mg / day, or 320 mg / day.

The inventors have prepared a novel anti-Cath-D antibody (F1M1) that can reduce tumor growth in a Cath-D secreting basal-like TNBC cell line with strong immune infiltration, without significant toxicity. The F1M1 antibody prevents recruitment of immunosuppressive M2 polarized tumor-associated macrophages (TAMs) and induces activation of natural killer cells in the tumor, and the F1M1 also enhances activation of antitumor M1 polarized TAM, recruitment and maturation of conventional cDC1 dendritic cells in the tumor to promote antigen presentation and reduce depletion marker expression of CD4 + and CD8 + T cells in the tumor and drainage lymph nodes. It is worthy of noting that the affinity of the antibody F1M1 to Cath-D is better than that of the antibody F1 prepared by the inventor in advance. The inventors also have prepared a novel Fc-optimized F1M1-Fc + human antibody which can promote ADCC induction of cancer cells and CAF, improve anti-tumor efficacy, and trigger recruitment, activation and cytotoxic activity of NK cells in tumors. The F1M1-Fc + F1M1-Fc + can inhibit the growth of MDA-MB-231 and SUM159 TNBC cell xenografts and two TNBC-PDX (one of the TNBC-PDX is resistant to neoadjuvant chemotherapy), and has no obvious toxicity. In addition, the F1M1-Fc < + > improves the treatment effect of the paclitaxel and enzalutamide combined medicine. Thus, the present invention relates to anti-cathepsin-D antibodies and their use in the treatment of cancer, in particular triple negative breast cancer.

The application discloses a furan amide compound and application thereof, and belongs to the technical field of medicines.The structural general formula of the furan amide compound is shown as formula (I).The application provides a novel furan amide AR antagonist, the compound and the derivative thereof have obvious antagonistic activity on an androgen receptor, and exhibit good biological activity in in-vivo and in-vitro biological evaluation, the androgen receptor antagonistic activity is better than that of enzalutamide, the compound is effective in an AR F877L / T878A double-point mutant cell model resistant to enzalutamide, the activity is better than that of darolutamide, and the compound has good safety.Therefore, the compound can be applied to the treatment of diseases related to the androgen receptor as an androgen receptor antagonist, including but not limited to the treatment of prostate cancer, breast cancer, ovarian cancer and the like.

The application belongs to the field of pharmaceutical chemical industry and particularly relates to a preparation method of enzalutamide. In the application, N-BOC-2-aminoisobutyramide is used as a starting material to form a ring with phenyl chlorothioformate to obtain 5,5-dimethyl-1-tert-butoxycarbonyl-2-thione imidazole-4-ketone, the obtained product is further subjected to nucleophilic substitution with 2-trifluoromethyl-4-bromobenzonitrile, is deprotected, and is subjected to nucleophilic substitution with 2-fluoro-4-bromobenzamide to obtain enzalutamide. The method uses N-BOC-2-aminoisobutyramide as a starting material, does not produce disubstituted impurities, has higher conversion rate, can obtain a product with high yield, and is more suitable for industrial amplification.

This invention relates to talazoparib, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, for the treatment of metastatic castration-resistant prostate cancer and methods of increasing survival thereof.

The invention relates to the technical field of medicine production, and provides an enadostat fumarate crystal, a preparation method thereof and a hydrogel patch. According to the preparation method disclosed by the invention, the enadostat is prepared into the fumarate crystal, so that the solubility of the enadostat can be improved; the hydrogel type patch prepared from the enadostat fumarate crystal can reduce the drug dosage, avoid the first-pass effect, maintain the stable blood concentration and improve the patient compliance, and meanwhile, the hydrogel type patch also has good skin adhesiveness, the characteristic of being suitable for drug release and good physical and chemical stability; wide application prospects are realized.

The application relates to application of PUS1 in improving sensitivity of enzalutamide to prostate cancer treatment. Through bioinformatics analysis and a series of in-vivo and in-vitro experiments, the application first discovers and determines the key role of the expression level of PUS1 in reducing the sensitivity of enzalutamide in treating prostate cancer, and deeply studies the mechanism, and determines that the PUS1 promotes enzalutamide resistance of prostate cancer in dependence on the Psi modification activity. The application enriches the related mechanism of drug resistance generation and regulation in the process of enzalutamide in treating prostate cancer, provides sufficient scientific basis and theoretical basis for exploring new prostate cancer diagnosis, prognosis judgment and treatment molecular target, and developing new targeted drugs, and has important social value and scientific significance.

The invention discloses an enadostat impurity and a preparation method thereof, and belongs to the technical field of pharmaceutical chemicals. The preparation method comprises the following steps: firstly, carrying out nucleophilic substitution reaction on a compound 1 and a compound 2 under the action of an acid-binding agent to generate a compound 4; hydrolyzing the compound 4 in an alkaline solution, and carrying out a decarboxylation reaction under an acidic condition to generate a compound 5; then carrying out amide condensation reaction on the compound 5 and the compound 3 under the action of a condensing agent, a solvent and alkali to generate a compound 6; and finally, carrying out hydrolysis reaction on the compound 6 in an alkaline solution and an organic solvent to generate a compound 7. The enrodostat impurity synthesized by the invention can be used for qualitative and quantitative analysis of impurities in production of enrodostat, and is convenient for effective monitoring and timely reduction of impurity content by adopting necessary means, so that the quality standard of the enrodostat intermediate is improved.

Downregulated miR-99b-5p and upregulated mTOR cooperatively promotes the African American (AA) PCa aggressiveness and drug resistance. Nuclear mTOR, AR, and SMARCD1 are highly expressed in AA PCa (MDA PCa 2b) compared to EA PCa (LNCaP) cell line. miR-99b-5p inhibited protein levels of mTOR, AR / AR-V7 and SMARCD1 in cytoplasm and nuclei of EA and AA PCa. miR-99b-5p effectively inhibits cell proliferation / survival and induced cell apoptosis in EA and AA PCa cells. Moreover, combination of miR-99b-5p and enzalutamide (Enz) synergistically enhances the cytotoxicity against aggressive AA PCa and castration resistant prostate cancer (CRPC). miR-99b-5p or miR-99b-5p / Enz significantly reduces the recruitment of mTOR to the genes involved in the metabolic reprogramming in CRPC. miR-99b-5p can function as an epigenomic driver to modulate the mTOR / AR / SMARCD1 signaling axis in AA PCa and resistant CRPC. miR-99b-5p can be utilized as a biomarker for identifying the presence of prostate cancer.

This disclosure provides formulations of enzalutamide and their use for treating hyperproliferative disorders.

The invention belongs to the technical field of biological medicine, and particularly relates to an NTD inhibitor and application thereof. The invention provides a novel NTD inhibitor, a bisphenol A structure of EPI-001 is replaced by utilizing reasonable drug design means such as skeleton transition, the aromaticity of a core skeleton of a compound is increased, and drug design is developed on the basis of the novel core skeleton. The compound prepared by the invention has proliferation inhibition activity on an enzalutamide drug-resistant cell line, has inhibition activity on transcription of a shear mutant AR-V7, and simultaneously shows a good in-vivo half-life period and certain oral bioavailability.

This disclosure provides formulations of enzalutamide and their use for treating hyperproliferative disorders.

An indazole hydrazide compound, as represented in formula (I); wherein, R is selected from substituted alkyl, substituted alkenyl and substituted phenyl; substituent in the substituted alkyl and substituted alkenyl includes phenyl and / or substituted phenyl; R′ is selected from H and alkyl. Compared with the prior art, the above indole hydrazide compound can be used as integrin avβ3 receptor antagonist. Besides, it has obvious anti-prostate cancer activity and has a significant inhibitory effect on enzalutamide-resistant cell lines. In addition, the above-mentioned compound has obvious anti-tumor angiogenesis activity and can be used in the preparation of anti-tumor angiogenesis drugs to inhibit tumor angiogenesis.

The present invention provides a pharmaceutical composition containing enzalutamide having excellent dissolution and dissolution retention properties, and a method for producing the pharmaceutical composition. [Solution] A pharmaceutical composition containing enzalutamide solid dispersion particles and a cellulose-based polymer.

This invention relates to talazoparib, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, for the treatment of metastatic castration-resistant prostate cancer and methods of increasing overall survival thereof.

The invention discloses an aminothiazole compound and an application thereof as an androgen receptor antagonist. The aminothiazole compound comprises pharmaceutically acceptable salts, solvates, prodrugs and isomers of the aminothiazole compound, and pharmaceutical compositions containing the aminothiazole compound and the pharmaceutically acceptable salts, the solvates, the prodrugs and the isomers of the aminothiazole compound. The aminothiazole compound has obvious antagonistic activity to AR, shows better biological activity in in-vivo and in-vitro biological evaluation, and is effective to an enzalutamide drug-resistant ARF876L / T877A two-point mutation model and a comparison caralutamide drug-resistant ARW741C mutant cell model. The percutaneous administration also shows the effect of promoting hair growth on a mouse alopecia model. Therefore, the compound can be used as an AR antagonist to prepare drugs for treating diseases related to androgen receptors, such as prostate cancer, metastatic prostate cancer, castration-resistant prostate cancer, breast cancer, ovarian cancer, androgen-derived alopecia and acne.

This invention discloses a method for synthesizing an intermediate of ennadustat, belonging to the pharmaceutical field. The method uses ethyl cyanoacetate and benzaldehyde as starting materials, undergoing a Knevengel condensation reaction, followed by reduction to obtain compound 4. Compound 4 undergoes nucleophilic substitution with compound 5 to obtain compound 6. Compound 6 is then hydrolyzed and decarboxylated to obtain the key intermediate compound 7. This invention uses inexpensive and readily available ethyl cyanoacetate and benzaldehyde as starting materials, and successfully constructs the key intermediate of ennadustat through a tandem process of Knevengel condensation, Hans ester reduction, nucleophilic substitution, and hydrolysis decarboxylation. The entire process avoids the use of expensive palladium catalysts, fundamentally solving the problem of heavy metal residues. Furthermore, the reaction conditions are mild, the operation is simple, the yield is greatly improved, the product purity is high, and the reduced cost makes it more suitable for industrial production.

The application belongs to the field of chemical drugs, and discloses a protein degrading agent taking noradamantane as a hydrophobic group, a preparation method, a pharmaceutical composition and application thereof. The application provides a protein degrading agent capable of degrading AR, which is based on noradamantane with a hydrophobic tag function as a hydrophobic group and an enzalutamide parent core as a target protein ligand. The protein degrading agent prepared by the application can effectively induce degradation of AR and AR-V7 in a cancer cell line. Compared with the AR protein degrading agent based on adamantane as a hydrophobic tag reported by the previous person, the protein degrading agent has considerable improvement in liver microsomal metabolic stability, can exhibit excellent in-vivo anti-prostate cancer effect in low-frequency drug administration, can be applied to preparation of an AR degrading agent, can form a pharmaceutical composition, and is suitable for development of a cancer drug such as a prostate cancer drug.

The application belongs to the field of chemical drugs, and discloses a protein degrading agent with borneolamine as a hydrophobic group, a preparation method, a pharmaceutical composition and application thereof. The application provides a degradable AR protein degrading agent based on a hydrophobic label function of noradamantane as a hydrophobic group and an enzalutamide parent nucleus as a target protein ligand. The protein degrading agent prepared by the application can effectively induce degradation of AR and AR-V7 in a cancer cell line. Compared with a previously reported AR protein degrading agent based on adamantane as a hydrophobic label, the protein degrading agent has considerable improvement in plasma metabolic stability, can exhibit excellent in-vivo anti-prostate cancer effect in low-frequency drug administration, can be applied to preparation of an AR degrading agent, and can form a pharmaceutical composition, and is suitable for development of a cancer drug such as a prostate cancer drug.

This invention discloses the application of a locally acting androgen receptor antagonist, namely, 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)-2-fluorobenzoate tert-butyl ester as shown in Formula I, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of diseases related to androgen abnormalities. 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)-2-fluorobenzoate tert-butyl ester exhibits good skin stability and slow metabolism, thus exerting an anti-androgenic alopecia effect. However, it has extremely poor stability in plasma and can be directionally and rapidly metabolized into the inactive metabolite enzalutamide, avoiding the systemic androgen antagonistic side effects caused by systemic distribution.

Provided is a method for synthesizing a key intermediate of enzalutamide, relating to the technical field of organic synthesis. The method comprises: 4-bromo-2-fluorobenzoic acid, as a starting material, undergoing an esterification reaction with an ethanol solution of sulfuric acid to obtain ethyl 4-bromo-2-fluorobenzoate; and ethyl 4-bromo-2-fluorobenzoate and ammonium chloride undergoing an Ullmann reaction under the action of a ligand, a catalyst and an acid-binding agent to obtain ethyl 4-amino-2-fluorobenzoate. By means of an esterification reaction and an Ullmann reaction, the key intermediate of enzalutamide, ethyl 4-amino-2-fluorobenzoate, is synthesized. The synthesis method involves simplified operations, reduced costs, and improved yields of the intermediate and a product, thereby being suitable for industrial production to provide the high-quality intermediate for the preparation of enzalutamide.

The present disclosure provides therapeutic combinations of chimeric antigen receptor T cells (e.g., AZD0754) that specifically bind to human STEAP2 with an androgen receptor antagonist (e.g., enzalutamide). Methods of administering the combination to treat cancer (e.g., prostate cancer) are also provided.

The invention belongs to the technical field of plant irrigation, and particularly relates to a uniconazole drip irrigation regulation and control method for strip-shaped composite planting of high-oil soybeans, which comprises the following steps: carrying out pre-planting preparation of a strip-shaped composite planting mode of soybeans and corns, and according to the structural parameters of a corn-soybean row ratio 2: 3 mode, the width of a production unit is 2.2 m, the corn row spacing is 40cm, the soybean row spacing is 30cm, and the soybean-corn spacing is 60cm; in the 2: 4 mode, the width of a production unit is 2.7 m, the line spacing of corn is 40 cm, the line spacing of soybean is 30 cm, and the line spacing of soybean and corn is 70 cm; the corn is sowed in a single-grain hole mode, the hole distance is 13-15 cm, and the effective plant number is 3500-4000 plants per mu; double-grain hole sowing is conducted on the soybeans, the hole distance is 9 cm, and the effective plant number is 9000-10000 plants per mu; according to the application, traditional directional foliage spraying is replaced by drip application, and for a soybean and corn strip-shaped composite planting intercropping mode, the dosage is 9-12 g / mu; for a soybean and corn strip-shaped composite planting relay intercropping mode, soybean sowing is affected by corn shading, uniconazole is dripped and applied in a three-leaf restoring period where soybeans are most sensitive to shading, and the dosage is about 7-9 g / mu; by means of the method, the plant height of the soybeans can be reduced by 6.5%-10.3%, and the stem diameter can be increased by about 8.9%-10.1%.

The invention belongs to the technical field of cancer treatment, and discloses an application of an AR-DHCR7-7-DHC axis in castration resistant prostate cancer enzalutamide resistance. According to the application disclosed by the invention, the effect of 7-DHC in the drug resistance of enzalutamide is explored by combining single-cell multi-omics analysis, metabolic spectrum analysis and functional research. By illustrating the action mechanism of the AR-DHCR7-7-DHC axis, the research reveals how a steroid intermediate regulates mitochondrial apoptosis and an immunosuppressive tumor microenvironment, and provides an intervention approach with clinical transformation potential, namely inhibiting DHCR7-to block the drug-resistant pathway. These achievements not only deepen the understanding of castration resistant prostate cancer (CRPC) metabolic heterogeneity, but also provide a biomarker-based framework for using existing therapies to combat fatal therapeutic resistance.

The present invention provides an NTD inhibitor compound of formula (I) as follows. The compound has proliferation inhibitory activity on an enzalutamide-resistant cell line, has inhibitory activity on transcription of a splice mutant AR-V7, and exhibits good half-life period in vivo and certain oral bioavailability.

The invention relates to the technical field of medicinal chemistry, in particular to synthesis and application of an AR protein degradation agent. The AR protein degradation agent modified by using norbornene, adamantanecarboxylic acid and adamantanacetic acid as hydrophobic labels can effectively inhibit proliferation of tumor cells and induce androgen protein degradation, and dose dependence and time dependence are shown; according to the compound disclosed by the invention, by changing the chain length, the combination of a target protein ligand and a receptor is not influenced, and the target protein can be recognized by ubiquitin ligase; according to the preferable protein degradation agent, norbornene is used as a hydrophobic label, the groups are smaller than those of adamantanecarboxylic acid and adamantanacetic acid which are used as hydrophobic label groups, and the druggability is good; the parent nucleus of the AR protein degradation agent compound is paired with AR protein, target protein is degraded through a hydrophobic tag, and the tumor inhibition effect is better than that of an existing AR inhibitor enzalutamide; the compound provided by the invention is few in preparation steps, simple in purification method and high in yield.