- Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor
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Efficient syntheses of 3,3-difluorooxindoles and 3-fluorooxindoles via fluorination of hydrazonoindolin-2-one with Selectfluor are reported. Under different solvent conditions, this method produced 3,3-difluorooxindoles and 3-fluorooxindoles selectively. The broad substrate scope and mild reaction conditions make this transformation a valuable method in drug discovery and development.
- Yang, Qiong,Dai, Guo-Li,Yang, Yu-Ming,Luo, Zhuangzhu,Tang, Zhen-Yu
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Read Online
- New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells
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Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC50 of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 μM, showed an IC50 value of 35.8 μM (imatinib, IC50 = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.
- Bastos, Monica,Boechat, Nubia,Dantas, Rafael,Moura, Stefany,Neto, Jo?o,Oliveira, Andressa,Pimentel, Luiz,Silva, Floriano
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- INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THE TREATMENT OF DISEASE
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Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.
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Paragraph 0719-0721
(2021/04/02)
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- ISATIN-DERIVED COMPOUNDS, USE OF THE COMPOUNDS FOR THE TREATMENT OF AIDS AND METHOD OF TREATMENT USING THESE COMPOUNDS
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This invention relates to HIV-inhibiting compounds consisting of other Formulae I, II or III isatin derivatives, as shown below (Formulae I, II and III), whereby in Formulae I, II and III, R1 is selected from H, CH3 or Cl; R2 is selected from one of the following radicals: zidovudine, amprenavir or an acyclic phosphonate chain, as shown below. This invention also relates to the use and treatment method using the Formulae I, II and III compounds. According to this invention, these compounds are also used for the treatment of infections caused by HBV or co-infection caused by HIV and HBV.
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Paragraph 0085; 0086
(2019/04/05)
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- PHARMACEUTICAL COMPOUNDS
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Benzimidazole derivatives of formula (I): (Formula (I)) wherein: R1is -(CH2)m-R7, (Formula (II)) or (Formula (III)); R2 is H, halo, -(CH2)m-NH2, -(CH2)n-C(=NH)-NH2 or -(CH2)n-NH-(CH2)m-NHR9; R3 is H, F or Cl; each of R4, R5 and R6 is independently H or F; R7 is C1-C6 alkyl, CF3, -SO2R11, -NH-(CH2)2-(NH)r-R8, -NH-CH(R8R9) or a group of the following formula (A): (Formula (A)): W is -(CH2)m-, -CH2-O-CH2-, -CH2-S-CH2-, -(CH2)r-S(O)2-CH2-or -(CH2)r-NR8-CH2-; m is an integer of 1 to 3; n is 1 or 2; p is 1 and V is CH; or p is 0 and V is N; q is 0 or 1; r is 0 or 1; R8 is H, -SO2R11,-SO2CF3, -COR11, -C(O)OR11, -CON(R9)2 or -(CH2)nSO2R11; R9 is H or C1-C6 alkyl, each R9 being the same or different when two are present; R10 is -SO2R11, -SO2CF3, -COR11, -CON(R9)2 or -(CH2)nSO2R11; and R11 is C1-C6 alkyl; and the pharmaceutically acceptable salts thereof are inhibitors of RSV and can therefore be used to treat or prevent an RSV infection.
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Page/Page column 17
(2019/07/13)
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- Selective fluorination method for isatin hydrazones compounds
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The invention discloses a selective fluorination method for an isatin hydrazones compound. The method comprises the steps that one pot reaction is carried out on isatin hydrazone, 1-chloromethyl-4-fluorine-1,4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and alkali compounds, corresponding 3,3-difluoro indolone and fluorooxindole fluorination products are selectively synthesized; the method fills up technical gaps in the prior art that isatin hydrazones compound is selectively synthesized by using a three-position single fluorination or double fluorination technology starting fromisatin, the operation is simple, the process is short, the product yield is high, and industrial production requirements are met.
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Paragraph 0151-0155
(2020/01/11)
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- Copper/B2pin2-catalyzed C-H difluoroacetylation-cycloamidation of anilines leading to the formation of 3,3-difluoro-2-oxindoles
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An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C-H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield.
- Ke, Miaolin,Song, Qiuling
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supporting information
p. 2222 - 2225
(2017/02/23)
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- Visible-Light-Promoted Tandem Difluoroalkylation-Amidation: Access to Difluorooxindoles from Free Anilines
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An efficient and synthetically convenient method for the synthesis of 3,3-difluoro-2-oxindole through a visible-light-induced photoredox difluoromethylation-amidation is described. The process can generate a broad range of difluorooxindoles using bromodifluoroacetate and broadly available free anilines. The wide range of substrate tolerance and mild reaction conditions make this transformation a highly valuable method in applications for drug discovery and development.
- Yu, Ling-Chao,Gu, Ji-Wei,Zhang, Shu,Zhang, Xingang
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p. 3943 - 3949
(2017/04/11)
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- Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy
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Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.
- Lin, Shu-Yu,Yeh, Teng-Kuang,Kuo, Ching-Chuan,Song, Jen-Shin,Cheng, Ming-Fu,Liao, Fang-Yu,Chao, Min-Wu,Huang, Han-Li,Chen, Yi-Lin,Yang, Chun-Yu,Wu, Mine-Hsine,Hsieh, Chia-Ling,Hsiao, Wenchi,Peng, Yi-Hui,Wu, Jian-Sung,Lin, Li-Mei,Sun, Manwu,Chao, Yu-Sheng,Shih, Chuan,Wu, Su-Ying,Pan, Shiow-Lin,Hung, Ming-Shiu,Ueng, Shau-Hua
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p. 419 - 430
(2016/01/28)
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- Regenerative glycosylation under nucleophilic catalysis
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This article describes 3,3-difluoroxindole (HOFox)-mediated glycosylation. The uniqueness of this approach is that both the in situ synthesis of 3,3-difluoro-3H-indol-2-yl (OFox) glycosyl donors and activation thereof can be conducted in a regenerative fashion as is a typical reaction performed under nucleophilic catalysis. Only a catalytic amount of the OFox imidate donor and a Lewis acid activator are present in the reaction medium. The OFox imidate donor is constantly regenerated upon its consumption until glycosyl acceptor has reacted.
- Nigudkar, Swati S.,Stine, Keith J.,Demchenko, Alexei V.
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supporting information
p. 921 - 923
(2014/02/14)
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- 4-(Benzoimidazol-2-yl)-thiazole Compounds and Related Aza Derivatives
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The invention relates to compounds of Formula (I) wherein ring A, X, (R1)n, R2, R3, R4, R4′, R5, n, and p are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.
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Paragraph 0887
(2015/01/06)
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- 4-(BENZOIMIDAZOL-2-YL)-THIAZOLE COMPOUNDS AND RELATED AZA DERIVATIVES
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The invention relates to compounds of Formula (I) wherein ring A, X, (R1)n, R2, R3, R4, R4', R5, n, and p are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.
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Page/Page column 126
(2013/08/15)
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- CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
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There are described cydohexyl amide derivatives useful as corticotropin releasing factor (CRF) receptor antagonists
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Page/Page column 91
(2016/02/02)
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- Copper-mediated fluoroalkylation reactions with iododifluoroacetamides: Controlling the selectivity among cross-coupling, intramolecular cyclization, and homocoupling reactions
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Cu-mediated fluoroalkylation reactions with iododifluoroacetamides 1 have been systematically investigated. It was found that three types of reactions may coexist in Cu-mediated reactions between iododifluoroacetamides and aryl/alkenyl iodides: cross-coupling, intramolecular cyclization, and homocoupling reactions. The selectivity among these three types of reactions could be controlled by tuning the substituents on the nitrogen atom of iododifluoroacetamides, and/or by removing the cross-coupling reaction partner (aryl/alkenyl halides). The general rule is as follows: (a) in the presence of proper aryl/alkenyl iodides, the cross-coupling products 2 (or 6) are generally formed as the major products; (b) in the absence of aryl/alkenyl iodides, and when R1 = alkyl and R2 = aryl groups, or when R 1 = R2 = aryl groups, the intramolecular cyclization products 3 can be formed predominantly; and (c) in the absence of aryl/alkenyl iodides, and when R1 = R2 = alkyl groups, or when R 1 = H and R2 = alkyl, aryl groups, the homocoupling products 4 can be formed dominantly. Our experimental results also indicate that in many cases when cross-coupling, homocoupling, and intramolecular cyclization reactions coexist in the Cu-mediated reaction system, the reactivity decreases in the following order: cross-coupling > intramolecular cyclization > homocoupling.
- Zhu, Jieming,Zhang, Wei,Zhang, Laijun,Liu, Jun,Zheng, Ji,Hu, Jinbo
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experimental part
p. 5505 - 5512
(2010/11/17)
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- INHIBITORS OF JUN N-TERMINAL KINASE
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The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula (I): or a salt or solvate thereof, wherein ring A, Ca, Cb, Z, R5, W and Cy are defined herein. The disclosure further provides pharmaceutical compositions including the compounds of the present disclosure and methods of making and using the compounds and compositions of the present disclosure, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.
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Page/Page column 158
(2010/08/18)
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- Development of fluorination methods using continuous-flow microreactors
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The safe and reliable use of various fluorination methods including nucleophilic fluorination (DAST), trifluoromethylation (Ruppert's reagent) and electrophilic fluorination (Selectfluor) in a continuous-flow microreactor is reported. Special a
- Baumann, Marcus,Baxendale, Ian R.,Martin, Laetitia J.,Ley, Steven V.
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experimental part
p. 6611 - 6625
(2011/02/25)
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- The use of diethylaminosulfur trifluoride (DAST) for fluorination in a continuous-flow microreactor
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The convenient and safe use of diethylaminosulfur trifluoride as a fluorinating agent in a continuous-flow microreactor is described using an in-line purification method to obtain clean reaction products. Georg Thieme Verlag Stuttgart.
- Baumann, Marcus,Baxendale, Ian R.,Ley, Steven V.
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experimental part
p. 2111 - 2114
(2009/04/08)
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- A synthesis of 3-fluoroindoles and 3,3-difluoroindolines by reduction of 3,3-difluoro-2-oxindoles using a borane tetrahydrofuran complex
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A borane tetrahydrofuran complex has been used to study the reduction of 3,3-difluoro-2-oxindoles and been found to yield either 3-fluoroindoles or 3,3-difluoroindolines. The latter have been found to be reasonably stable when the aromatic nucleus is subs
- Torres, Jose C.,Garden, Simon J.,Pinto, Angelo C.,Da Silva, Filipe S. Q.,Boechat, Nubia
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p. 1881 - 1892
(2007/10/03)
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- Substituted biphenyl isoxazole sulfonamides
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Compounds of the formula STR1 inhibit the activity of endothelin. The symbols are defined as follows: R1, R2, R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) --C(O)H or --C(O)R5 ; (h) --CO2 H or --CO2 R5 ; (i) --Z4 --NR6 R7 ; (j) --Z4 --N(R10)--Z5 --NR8 R9 ; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; and the remaining symbols are as defined in the specification.
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