- Novel micro-channel preparation process of 2-hydroxy-3-trifluoromethyl-5-nitropyridine
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The invention discloses a novel micro-channel preparation process of 2-hydroxy-3-trifluoromethyl-5-nitropyridine, and belongs to the technical field of pharmaceutical chemicals. The novel micro-channel preparation process comprises the following steps of: (1) stirring 2-hydroxy-3-trifluoromethylpyridine and a solvent sulfuric acid for 10-30 minutes; (2) stirring nitric acid and sulfuric acid for 30-60 minutes to obtain nitro-sulfur mixed acid; (3) filling a micro-channel pipeline with the mixed solution obtained in the step (1) at a low speed; (4) introducing the nitro-sulfur mixed acid obtained in the step (2) into the micro-channel, controlling the material flow rate to be 9-15mL/min and the reaction time to be 10-40s, and introducing a nitryl positive ion group on 2-hydroxy-3-trifluoromethylpyridine; (5) introducing the reaction liquid obtained in the step (4) into ice water from the outlet end of a reactor for quenching; and (6) carrying out suction filtration on the solid-liquid mixed solution obtained in the step (5), and repeatedly washing with water to obtain the 2-hydroxy-3-trifluoromethyl-5-nitropyridine. The method has the advantages of excellent production safety, high yield, high product purity, simple steps and production cost saving.
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Paragraph 0031-0071; 0081-0082
(2021/08/14)
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- Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists
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Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients.
- Bian, Jinlei,Chen, Xijing,Du, Qianming,Ge, Raoling,Li, Yan,Li, Zhiyu,Lu, Xiaoyu,Meng, Ying,Wang, Jubo,Wu, Hongxi,Xu, Xi,Xue, Siqi,Yang, Yong,Zhao, Zhili
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- Solid dispersions containing an apoptosis-inducing agent
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A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.
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Page/Page column 208-209
(2019/03/15)
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- Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles
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A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax), and nearly doubled its drug exposure in plasma (AUC0–∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.
- Pang, Xuehai,Wang, Yingwei,Chen, Yuanwei
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supporting information
p. 2803 - 2806
(2017/05/29)
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- ANDROGEN RECEPTOR MODULATOR FOR TREATMENT OF PROSTATE CANCER AND ANDROGEN RECEPTOR-ASSOCIATED DISEASES
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PROBLEM TO BE SOLVED: To provide a series of compounds that modulate the function of the nuclear hormone receptors, especially the androgen receptor. SOLUTION: The present invention relates to hydantoin compounds, methods of using such compounds in the treatment of androgen receptor-associated conditions, such as age-related diseases, for example, prostate cancer, and to pharmaceutical compositions containing such compounds. In an embodiment, a pharmaceutical composition includes a therapeutically effective amount of a compound according to the formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or adjuvant. The present invention provides a series of compounds that modulate the function of the nuclear hormone receptors, especially the androgen receptor. These compounds can cause disappearance of prostate cancer cells and tumors. COPYRIGHT: (C)2016,JPOandINPIT
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- Substituted diazaspiroalkanes as androgen receptor modulators
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This invention provides for compounds of the Formula II: wherein A, B, Het, R1, R2 and R3 are as described herein. These compounds are androgen receptor modulators useful for the treatment of androgen receptor-associated conditions.
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- IMIDAZOLE DIKETONE COMPOUND AND USE THEREOF
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Provided are imidazolidinedione compounds of formula (I), processes for preparation, uses and pharmaceutically compositions thereof. Said imidazolidinedione compounds possess androgen receptor antagonist activity and can be used for preventing and treating diseases and disorders related to androgen receptor, such as prostate cancer, alopecia, hair regeneration, acne and adolescent acne.
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Paragraph 0073; 0074; 0075
(2016/06/28)
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- NOVEL COMPOUNDS AS REARRANGED DURING TRANSFECTION (RET) INHIBITORS
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This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
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Page/Page column 83; 84
(2016/04/20)
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- PYRIDINE-BASED COMPOUND AND SELECTIVE ANDROGEN RECEPTOR AGONIST COMPRISING THE SAME
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The present invention relates to a novel compound, a pharmaceutical composition containing the compound, and a method for producing the compound. The pyridine-based compound acts on an androgen receptor to increase activities of the androgen receptor, and thus can be favorably used as an agent for treating and preventing diseases or conditions, in which the increased activities of the androgen receptor can lead to improvement of symptoms or the responsiveness to treatment, for example, various hormone-related diseases of the male or female, muscle-wasting disease, osteoporosis, and the like.COPYRIGHT KIPO 2016
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Paragraph 0105-0109
(2016/11/07)
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- PYRIDINE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
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This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
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Page/Page column 87; 59; 63; 49;124
(2014/09/29)
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- NOVEL COMPOUNDS AS REARRANGED DURING TRANSFECTION (RET) INHIBITORS
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This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.
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Paragraph 0257; 0258
(2014/09/30)
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- Acid secretion inhibitor
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The present invention provides a compound having a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. The present invention provides a compound represented by the formula (I) wherein R1 is a nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle, the nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), R2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, R3 and R4 are each a hydrogen atom, or one of R3 and R4 is a hydrogen atom and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and R5 is an alkyl group or a salt thereof.
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Page/Page column 39
(2008/06/13)
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- SUBSTITUTED BIARYL QUINOLIN-4-YLAMINE ANALOGUES
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Substituted biaryl quinolin-4-ylamine analogues of Formula I are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.
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Page/Page column 52
(2010/11/08)
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- Biaryl derived amide modulators of vanilloid VR1 receptor
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The invention is directed to novel vanilloid receptor type 1 (VR1) ligands. More specifically, the invention relates to novel biaryl-derived amides that are potent antagonists or agonists of VR1. Pharmaceutical and veterinary compositions and methods of treating mild to severe pain and various diseases using compounds of the invention are also described.
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Page/Page column 40
(2010/11/24)
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