- Crystal form of hepatitis B surface antigen inhibitor and application thereof
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The invention discloses a crystal form of a hepatitis B surface antigen inhibitor and a preparation method of the crystal form. The invention further discloses application of the crystal form in preparation of the hepatitis B surface antigen inhibitor.
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Paragraph 0064-0067
(2021/03/23)
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- HEPATITIS B VIRUS SURFACE ANTIGEN INHIBITOR
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10-oxo-6,1-dihydrobenzo[e]pyrido[1,2-c][1,3]oxazine-9-carboxylic acid derivatives of formula (I) as hepatitis B surface antigen inhibitors or pharmaceutically acceptable salts thereof, and uses of a compound of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof in preparation of medicaments for treatment of viral hepatitis B.
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Paragraph 0117; 0118-0119
(2020/01/22)
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- NOVEL COMPOUND HAVING HSP90 INHIBITORY ACTIVITY OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND MEDICAL USE THEREOF
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The present invention relates to a novel compound having HSP90 inhibitory activity or a pharmaceutically acceptable salt thereof, and a medicinal use thereof, and composition comprising a dihydroxyphenyl compound or a benzamide compound, which is a novel compound having the HSP90 inhibitory activity of the present invention can effectively inhibit HSP90, and thus can be usefully used as a pharmaceutical composition for preventing or treating HSP90-mediated diseases or a health functional food for preventing or improving HSP90-mediated diseases, which selected from the group consisting of cancer diseases, degenerative neurological diseases and viral infections.
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Paragraph 0114; 0116
(2019/02/13)
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- SUBSTITUTED 1,1'-BIPHENYL COMPOUNDS, ANALOGUES THEREOF, AND METHODS USING SAME
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The present invention includes substituted 3,3'-bis(phenoxymethyl)-1,1'-biphenyl compounds, analogues thereof, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a patient.
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Page/Page column 40
(2019/10/23)
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- Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
- Park, Sun You,Oh, Yong Jin,Lho, Yunmee,Jeong, Ju Hui,Liu, Kwang-Hyeon,Song, Jaeyoung,Kim, Soong-Hyun,Ha, Eunyoung,Seo, Young Ho
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p. 390 - 401
(2017/12/07)
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- SUBSTITUTED PYRIDINONE-CONTAINING TRICYCLIC COMPOUNDS, AND METHODS USING SAME
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The present invention includes substituted pyridinone-containing tricyclic compounds, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infection in a patient. In certain embodiments, the compounds and compositions of the invention inhibit and/or reduce HBsAg secretion.
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Page/Page column 122
(2018/05/24)
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- Design, synthesis and pharmacological evaluation of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-arylmethyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamides as potent Hsp90 inhibitors
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Using diverse arylmethyl groups to replace the benzyl moiety of the lead Hsp90 inhibitor 1 (N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-benzyl-1,2,3,4-tetrahydro-3-iso quinolinecarboxamide), thirty four derivatives (10–43) were developed, and exhibited improved Hsp90 inhibitory and antiproliferative activities. SAR analysis indicated that the southeastern aryl substitutions influenced their antiproliferative activities obviously, with the para-pyridyl group (41) outperforming all other substitution patterns. In this regard, compound 41 was selected for further evaluation. CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves for Hsp90α further proved that 41 interacted with intracellular Hsp90α powerfully. Compared with the lead compound 1, docking and MD refinement of the Hsp90α-41 complex revealed a favorable H-bonding interaction between the side-chain of Tyr139 and the pyridine moiety of 41, which is the first time to be used for resorcinol-based Hsp90 inhibitors. With broad-spectral antitumor activity, compound 41 induced time- and dose-dependent growth inhibition and G0/G1 cell cycle arrest on human breast cancer MDA-MB-453 cell line. In addition, flow cytometry and Western blot analyses confirmed that 41 induced apoptosis of human breast cancer MDA-MB-453 cell line. Via degradation of IKKs and suppression of IKKs activity, compound 41 inhibited TNF-α-induced NF-κB activation. The overall properties warrant compound 41 a promising Hsp90 inhibitor and further biological characterizations. This study provides insights into the chemical evolution of Hsp90 inhibitors, and may facilitate the design of next generation Hsp90 inhibitors for the antitumor drug development.
- Liang, Chuanpeng,Wu, Xingkang,Li, Zhenyu,Zhu, Jing,Lu, Chunhua,Shen, Yuemao
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- Tetrahydroisoquinoline-3-carboxylic acid heat shock protein 90 inhibitor and application thereof
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The invention discloses a tetrahydroisoquinoline-3-carboxylic acid heat shock protein 90 inhibitor. The heat shock protein 90 inhibitor is a compound with a formula (I), or is an optical isomer, a diastereoisomer or a despinner mixture, or a pharmaceutically acceptable salt, a solvate or a predrug. The invention further discloses the application of the inhibitor to preparation of a medicine used for preventing or treating a heat shock protein 90 related disease. The experiment proves that the tetrahydroisoquinoline-3-carboxylic acid heat shock protein 90 inhibitor has a remarkable effect of inhibiting various tissues like tumor cells from the mammary gland and respiratory and reproductive systems, the toxicity to the normal hepatocyte of human is low, and the druggability is relatively good. The tetrahydroisoquinoline-3-carboxylic acid heat shock protein 90 inhibitor has a broad clinical application prospect.
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Paragraph 0050; 0051
(2017/11/18)
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- Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide
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The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50= 50.3 nM). Furthermore, it effectively inhibits the proliferation of H1975 non-small cell lung cancer (NSCLC) and Skbr3 breast cancer cell lines with GI50values of 0.31 μM and 0.11 μM, respectively. Compound 19 induces the degradation of the Hsp90 client proteins including EGFR, Her2, Met, c-Raf, and Akt, and consequently promotes apoptotic cancer cell death. Compound 19 also inhibits the growth of H1975 xenografts in NOD-scid IL2R gammanullmice without any apparent body-weight loss. The immunohistologic evaluation indicates that compound 19 decreases the expression of Akt in xenograft tumor tissue via an inhibition of the Hsp90 chaperon function. Additionally, the cytochrome P450 assay indicates that compound 19 has no effect on the activities of five major P450 isoforms (IC50> 50 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between compound 19 and the substrate drugs of the five major P450 isoforms are not expected. Overall, compound 19 represents a new class of Hsp90 inhibitor with its 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl-amide structure, and it has the therapeutic potential to overcome drug resistance in cancer chemotherapy.
- Jeong, Ju Hui,Oh, Yong Jin,Lho, Yunmee,Park, Sun You,Liu, Kwang-Hyeon,Ha, Eunyoung,Seo, Young Ho
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p. 1069 - 1080
(2016/11/09)
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- Design and synthesis of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as novel Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is an attractive chemotherapeutic target for antitumor drug development. Herein, we reported the design and synthesis of two series of novel N-(5-chloro-2,4-dihydroxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as Hsp90 inhibitors using (S)-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) (A1-13) and (R)-Tic (B1-13) as scaffold, respectively. Cellular thermal shift assay (CETSA) screening showed that compounds B1-13 with (R)-Tic scaffold exhibited potent ability to stabilize Hsp90α. Compound B7 showed not only the most potent ability to induce thermal stabilization of Hsp90α but also the strongest cytotoxicity. The IC50 values of B7 were 0.98 μM and 1.74 μM against the proliferation of human breast cancer MDA-MB-231 and human cervical cancer HeLa cell lines, respectively. Moreover, CETSA melt and ITDRFCETSA (isothermal dose-response fingerprint) curves confirmed that B7 bound to Hsp90α in 293T cells. Western blotting results indicated that B7 induced the degradation of Hsp90 clients CDK4, Her2, Cdc-2 and C-raf. In addition, docking and Molecular dynamics (MD) refinement of the B7-Hsp90 complex showed that the binding model of B7 to Hsp90 was similar with that of 8-benzyladenines. The overall properties warrant compound B7 a promising lead for the development of Hsp90 inhibitor antitumor drugs.
- Liang, Chuanpeng,Hao, Huilin,Wu, Xingkang,Li, Zhenyu,Zhu, Jing,Lu, Chunhua,Shen, Yuemao
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p. 272 - 282
(2016/07/06)
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- DIHYDROOROTIC ACID DEHYDROGENASE INHIBITOR
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The present invention provides a novel dihydroorotic acid dehydrogenase inhibitor which is applicable to various diseases. When used as an active ingredient, a compound represented by formula (I): (wherein X represents a halogen atom, R1 represents a hydrogen atom, R2 represents an alkyl group containing 1 to 7 carbon atoms, R3 represents -CHO, and R4 represents -CH2-CH=C(CH3)-R0 (wherein R0 represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, etc.)), an optical isomer thereof or a pharmaceutically acceptable salt thereof has a high inhibitory effect on dihydroorotic acid dehydrogenase and can be used as an immunosuppressive agent, a therapeutic agent for rheumatism, an anticancer agent, a therapeutic agent for graft rejection, an antiviral agent, an anti-H. pylori agent, a therapeutic agent for diabetes or the like.
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Paragraph 0102; 0104; 0113
(2015/04/15)
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- NOVEL DIHYDROXYBENZENE DERIVATIVES AND ANTIPROTOZOAL AGENT COMPRISING SAME AS ACTIVE INGREDIENT
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Novel compounds below are useful for preventing or treating diseases caused by protozoans. At least one of a compound represented by Formula (I) (wherein, X represents a hydrogen atom or a halogen atom; R1 represents a hydrogen atom; R2 represents a hydrogen atom or a C1-7 alkyl group; R3 represents -CHO, -C(=O)R5, -COOR5 (wherein R5 represents a C1-7 alkyl group), -CH2OH or -COOH; and R4 represents a C1-16 alkyl group having one or more substituents on a terminal carbon atom and/or non-terminal carbon atom(s), a C2-16 alkenyl group having one or more substituents on a terminal carbon atom and/or non-terminal carbon atom(s), or a C2-16 alkynyl group having one or more substituents on a terminal carbon atom and/or non-terminal carbon atom(s)), an optical isomer thereof, and a pharmaceutically acceptable salt is used.
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Paragraph 0114; 0122; 0124
(2013/09/26)
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- NOVEL COMPOUNDS USEFUL AS CC CHEMOKINE RECEPTOR LIGANDS
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The present invention relates to novel morpholine, oxazapane and piperidine derivatives that act as ligands for CC chemokine receptors, such as CCR1. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.
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Page/Page column 78
(2010/07/08)
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- A PROCESS FOR THE PREPARATION OF INTERMEDIATES AND THEIR US IN THE SYNTHESIS OF SPIROPIPERIDINE COMPOUNDS
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The present invention relates to new processes for the preparation of compounds of formula I, especially the compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[l- benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-5[(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid and to new intermediates useful in the preparation thereof.
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Page/Page column 21-22
(2009/03/07)
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- PROCESS FOR THE PREPARATION OF CYCLIC SPIROPIPERIDINES
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The present invention relates to new processes for the preparation of compounds of formula I, especially the compound 2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1- benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4-5 [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid and to new intermediates useful in the preparation thereof.
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Page/Page column 11-12
(2009/03/07)
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- SPLROPIPERIDINE COMPOUNDS, A PROCESS OF THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THEIR USE IN THE TREATMENT OF AIRWAY DISEASES, INFLAMMATORY DISEASES, COPD OR ASTHMA
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The present invention relates to new polymorphs of compounds 2-{2-Chloro-5-{[(2S)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid, and the hydrochloride and sodium hydroxide salts thereof,and compound 2-{2-Chloro-5-{[(2R)-3-(5-chloro-1'H,3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl)-2-hydroxypropyl]oxy}-4- [(methylamino)carbonyl]phenoxy}-2-methylpropanoic acid. The invention further relates to pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.
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Page/Page column 29, 37-38
(2009/03/07)
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- NOVEL TRICYCLIC SPIROPIPERIDINE COMPOUNDS, THEIR SYNTHESIS AND THEIR USES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Compounds of formula (I) wherein R1, R3, R4, R5, R6, R7, and R10 are as defined in the specification, are described. The present invention also relates to pharmaceutical composition comprising said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof. Beside, the invention relates to salts and polymorphic forms of the new compounds as well as the preparation thereof.
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Page/Page column 70-71
(2008/06/13)
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- Heat shock protein 90 inhibitors
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Novel compounds useful for inhibiting the 90 kDa heat shock proteins containing a quinone-like moiety and a di-hydroxy phenol like moiety, similar to geldanamycin and radicicol.
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Page/Page column 22
(2008/06/13)
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- NOVEL TRICYCLIC SPIRODERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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The invention provides compounds of formula (I) wherein m, R1, n, R2, q, p, X, Y, R3, R4, t and, R5 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 50
(2008/06/13)
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- Radester, a novel inhibitor of the Hsp90 protein folding machinery
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(Chemical Equation Presented) The antitumor antibiotics radicicol and geldanamycin are potent inhibitors of the Hsp90 protein folding machinery. Radester is a hybrid composed of radicicol's resorcinol ring and geldanamycin's quinone through an isopropyl ester. Radester was prepared, and the cytotoxicity of it and the corresponding hydroquinone were determined in MCF-7 breast cancer cells to be 13.9 and 7.1 μM, respectively. Protein degradation assays were performed on Hsp90-dependent client proteins, Her-2 and Raf, to correlate Hsp90 inhibition to cytotoxicity.
- Shen, Gang,Blagg, Brian S. J.
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p. 2157 - 2160
(2007/10/03)
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- NOVEL TRICYCLIC SPIROPIPERIDINES OR SPIROPYRROLIDINES
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The invention provides compounds of formula (I) wherein m, R1, n, R2, q, X, Y, Z, R3, R4, R5, R6, R7, R8, t and R9 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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