- Synthesis of n-substituted benzamide derivatives and their evaluation as antitumor agents
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Background: Histone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer. Objective: The study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies on this class of bioactive compounds. Methods: Fourteen N-substituted benzamide derivatives were synthesized and their antiproliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB231) by MTT assay. Results: Compared with MS-275, six compounds exhibited comparable or even better antiproliferative activities against specific/certain cancer cell lines. Conclusion: The preliminary SARs showed that (i) the 2-substituent of the phenyl ring in the R group and heteroatoms of amide which can chelate with zinc ion are critical to the antiproliferative activity and (ii) chlorine atom or nitro-group on the same benzene ring largely decreases their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 was observed to be similar to that of MS-275.
- Chen, Taiping,Huang, Wencai,Jiang, Hongwu,Li, Zicheng,Luo, Youfu,Zhao, Yinglan,Zhou, Jianjun
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p. 555 - 562
(2020/06/21)
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- ANTICANCER AGENT DELIVERY MOLECULE
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PROBLEM TO BE SOLVED: To provide a compound which can be used as an anticancer agent targeting a cancer cell that highly expresses Lysine-specific demethylase 1 (LSD1) or salt thereof. SOLUTION: The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, where Ar, R1, R2, L, Z, p, q, *1 and *2 are as defined in the specifications. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0173-0175
(2017/08/04)
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- CRYSTALLINE FORMS OF ENTINOSTAT
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Entinostat is a histone deacetylase inhibitor undergoing clinical investigation in multiple types of solid tumors, such as breast cancer, and hematologic cancers. Crystalline form D and E of Entinostat and crystal form A in high crystal purity are provided. Crystalline form D can be obtained in high chemical purity, exhibits improved water solubility and allows efficient purification of Entinostat with removal of coloured impurities. Processes for the preparation of such crystalline forms and of form A with improved chemical and crystal purity are also provided.
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Page/Page column 15
(2017/05/28)
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- SOLID FORMS OF ENTINOSTAT
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Aspects of the present application relate to stable amorphous Entinostat, its amorphous solid dispersion, processes for their preparation and pharmaceutical compositions thereof. Further, aspects relate to crystalline form of Entinostat, process for its preparation and pharmaceutical compositions thereof
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Page/Page column 20
(2018/01/20)
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- Novel ultrasonic synthesis method for Entinostat
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The invention relates to a novel ultrasonic synthesis method for Entinostat. The method comprises the following steps: (1) 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid is prepared under an ultrasonic condition; (2) the compound is subjected to condensation with o-phenylenediamine under an ultrasonic condition in presence of a condensing agent and a catalyst, and a crude Entinostat product is obtained; (3) the crude Entinostat product is subjected to backflow beating in ethyl alcohol, and the final Entinostat product is prepared. The method has the advantages that the production cycle is short, the process is simple, the yield is high, and the product purity is high.
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Paragraph 0029
(2017/02/02)
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- ANTIMICROBIAL COMPOUNDS
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The invention provides compounds for use in treating microbial infection in an animal. Example compounds include Pyridin-3-ylmethyl (4-((2-aminophenyl)- carbamoyl)benzyl)carbamate ("Entinostat"). The compounds can act via induction of the innate antimicrobial peptide defense system, and stimulation of autophagy.
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Page/Page column 40
(2015/05/19)
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- HISTONE DEACETYLASE INHIBITORS AND USES THEREOF
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The present invention discloses a group of histone deacetylase inhibitors and use thereof. The histone deacetylase inhibitors are useful in the treatment of malignant tumors and the diseases associated with differentiation and proliferation. The histone deacetylase inhibitors are the compounds represented by the following formula or salts thereof
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Page/Page column 17-18
(2011/04/25)
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- Histone deacetylase inhibitors and uses thereof
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The present invention discloses a group of histone deacetylase inhibitors and use thereof. The histone deacetylase inhibitors are useful in the treatment of malignant tumors and the diseases associated with differentiation and proliferation. The histone deacetylase inhibitors are the compounds represented by the following formula or salts thereof:
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Page/Page column 19-20
(2011/07/06)
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- SYNTHESIS METHODS OF HISTONE DEACETYLASE INHIBITORS (HDACIS)
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Simple and efficient procedures for the synthesis of histone deacetylase inhibitors. The procedure may provide MS-275 in 72% overall yields.
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Page/Page column 17
(2009/07/17)
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- Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2)
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A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC i
- Witter, David J.,Harrington, Paul,Wilson, Kevin J.,Chenard, Melissa,Fleming, Judith C.,Haines, Brian,Kral, Astrid M.,Secrist, J. Paul,Miller, Thomas A.
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p. 726 - 731
(2008/12/23)
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- 4-CARBOXYBENZYLAMINO DERIVATIVES AS HISTONE DEACETYLASE INHIBITORS
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The present invention relates to a novel class of 4-carboxybenzylamino derivatives. The 4-carboxybenzylamino compounds can be used to treat cancer. The 4-carboxybenzylamino compounds can also inhibit histone deacetylase and are suitable for use in selecti
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Page/Page column 59
(2009/03/07)
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- Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts
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We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2 + SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2 + SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.
- Gediya, Lalji K.,Belosay, Aashvini,Khandelwal, Aakanksha,Purushottamachar, Puranik,Njar, Vincent C.O.
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p. 3352 - 3360
(2008/09/20)
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- Method of producing benzamide derivatives
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In the case that a selectively monoacylated phenylenediamine derivative which is useful as any of medicines, agricultural chemicals, animal drugs and the intermediates of chemicals is prepared by reacting a benzoic acid derivative with a phenylenediamine derivative, the benzoic acid derivative is converted into a benzoyl imidazole derivative and this benzoyl imidazole derivative is then reaction with the phenylenediamine derivative, whereby the improvement of a preparation efficiency and the high selectivity of the monoacylation can be achieved, the steps of protection and deprotection being omitted.
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- Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives
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Newly synthesized benzamide derivatives were evaluated for their inhibitory activity against histone deacetylase. The structure of these derivatives was unrelated to the known inhibitors, and IC50 values of the active compounds were in the range of 2-50 μM. Structure-activity relationship on the benzanilide moiety showed that the 2'-substituent, an amino or hydroxy group, was indispensable for inhibitory activity. Although the electronic influence of the substituent in the anilide moiety showed only a small effect on inhibitory activity, the steric factor in the anilide moiety, especially at positions 3'and 4', played an important role in interaction with the enzyme. Among these benzamide derivatives, MS-275 (1), which showed significant antitumor activity in vivo, has been selected for further investigation.
- Suzuki, Tsuneji,Ando, Tomoyuki,Tsuchiya, Katsutoshi,Fukazawa, Nobuyuki,Saito, Akiko,Mariko, Yukiyasu,Yamashita, Takashi,Nakanishi, Osamu
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p. 3001 - 3003
(2007/10/03)
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