- SUBSTITUTED PYRAZOLE COMPOUNDS, COMPOSITIONS CONTAINING SAME, AND USE THEREOF
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The present invention provides substituted pyrazole compounds, compositions containing same, and use thereof. The substituted pyrazole compounds comprise a compound represented by formula (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. The compound represented by formula (I) can serve as a tissue selective androgen receptor modulator (SARM), particularly serving as a drug for treating prostate cancer and other AR-dependent conditions and diseases in which AR antagonism is desired.
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- Metabolism and mass balance of the novel nonsteroidal androgen receptor inhibitor darolutamide in humans
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The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide.
- Denner, Karsten,Gieschen, Hille,Jungmann, Natalia A.,K?hk?nen, Marja,Korjamo, Timo,Koskinen, Mikko,Niehues, Michael,Nyk?nen, Pirjo,Prien, Olaf,Taavitsainen, P?ivi,Von Bühler, Clemens-Jeremias,Vuorela, Annamari,Zurth, Christian
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supporting information
p. 420 - 433
(2021/05/31)
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- Pyrazoleamide derivative and synthesis method and application
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The present invention discloses a pyrazoleamide derivative and a synthetic method and application as an androgen receptor antagonist and the preparation of anti-prostate cancer drugs. The present invention provides a method of synthesizing a pentabasole r
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Paragraph 0048; 0067-0068
(2022/01/10)
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- Synthesis method of polyamidoamine (by machine translation)
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To the synthesis method, acetyl - 2 2-chlorobenzonitrile and 4 - are reacted to obtain the compound formula DMF · DMA, the synthesis route 2, is synthesized by two methods, the route, efficiency 6: is greatly improved, the, process cost Boc is reduced, and the reaction formula of the final, finished product purity, suitable for amplification: production, is shown below 10; is greatly shortened. (by machine translation)
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Paragraph 0065-0068
(2020/05/11)
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- Method for preparing antitumor drug darolutamide
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The invention relates to a method for preparing an antitumor drug darolutamide. A one-step Suzuki reaction is carried out, and then deprotection, hydroxylamine condensation and amide condensation reactions are carried out to obtain the darolutamide. The method has the advantages of few reaction steps, high reaction yield of each step, and simplicity in operation, so the total yield of the whole route is high, and the method has good experiment operationality.
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Paragraph 0049-0051
(2020/05/30)
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- Novel androgen receptor inhibitor, synthesis method and applications thereof
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The invention discloses a compound represented by a formula I or a stereoisomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The invention also discloses a preparation method and applications of the compound. According to the invention, the compound represented by the formula I is an excellent AR inhibitor, provides new choice for clinical screening and/or preparing of medicines for treating prostatic cancer, and has a good application prospect.
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Paragraph 0102; 0107-0109
(2020/01/25)
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- Preparation method of N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide
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The invention relates to a preparation method of N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide, and in particular relates to two novel methods for preparing an intermediate (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile and a method for preparing N-[(1S)-2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]-1-methylethyl]-5-(1-hydroxyethyl)-1H-pyrazol-3-carboxamide from the intermediate.
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- Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants
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Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.
- Yu, Jiang,Zhou, Peiting,Hu, Mingxing,Yang, Liuqing,Yan, Guoyi,Xu, Ruixue,Deng, Yufang,Li, Xinghai,Chen, Yuanwei
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- Batch and Continuous-Flow One-Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents
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A novel synthesis of trimethylsilyldiazomethane (TMSCHN2) by diazotization of trimethylsilylmethylamine (TMSCH2NH2) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN2. Other silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents. The applicability of the process is highlighted by disclosure of batch and continuous flow one-pot esterification and 1,3-dipolar cycloaddition processes. Furthermore, the high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flow is disclosed. Finally, work-up and purification procedures are reported for the preparation of a 2-MeTHF solution of TMSCHN2, which can be used in rhodium-catalyzed methylenation and homologation reactions.
- Audubert, Clément,Gamboa Marin, Oscar Javier,Lebel, Hélène
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supporting information
p. 6294 - 6297
(2017/05/19)
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- PROCESS FOR THE PREPARATION OF ANDROGEN RECEPTOR ANTAGONISTS AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of carboxamide structured androgen receptor (AR) antagonists such as N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H- pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3- carboxamide (1A) and key intermediates thereof such as 2-chloro-4- (IH-pyrazol-3-yl)benzonitrile (V). AR antagonists are useful in the treatment of cancer, particularly prostate cancer and other diseases where AR antagonism is desired.
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Page/Page column 15
(2016/10/31)
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- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Compounds of formula (I) or (II) wherein Rx, Rz, R9, R10, R14, R14′, R15, R15′, A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
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Page/Page column
(2015/05/06)
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- ANDROGEN RECEPTOR MODULATING CARBOXAMIDES
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Compounds of formula (I) wherein Rx, Rz, R9, R10, R14, R14', R15, R15', A and B are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
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Page/Page column 79
(2012/11/07)
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- ANDROGEN RECEPTOR MODULATING COMPOUNDS
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Compounds of formula (I) wherein R1 to R16, A. B and E are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as tissue-selective androgen receptor modulators (SARM) and are particularly useful as medicaments in the treatment of prostate cancer and other AR dependent conditions and diseases where AR antagonism is desired.
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Page/Page column 50-51
(2011/05/11)
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