- Method for efficiently synthesizing nitroacetonitrile
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The invention discloses a method for efficiently synthesizing nitroacetonitrile, which comprises the following steps: by using nitromethane as a starting raw material, carrying out Henry reaction under the action of alkali to obtain nitroacetaldehyde oxime, and dehydrating the nitroacetaldehyde oxime under the action of thionyl chloride to obtain nitroacetonitrile. The method is designed by starting from a commercially available low-cost raw material nitromethane, wherein the nitroacetaldehyde oxime is obtained through a Henry reaction under the action of alkali and is dehydrated under the action of thionyl chloride to obtain nitroacetonitrile; therefore, the efficient synthesis of nitroacetonitrile is achieved through two-step reaction, the requirement for temperature in the synthesis process is relatively wide, operation steps are not complex, and the method is suitable for industrial production. Thus, the product with stable yield and stable purity can be obtained, the production cost is low, the period is short, the problems of unstable yield and quality, high production cost, long production period and the like of a traditional preparation method are solved. Excellent technical support can be provided for subsequent application of nitroacetonitrile in the field of high-density energetic materials.
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Paragraph 0030-0032; 0035-0038
(2021/03/13)
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- QUINOLINO-PYRROLIDIN-2-ONE DERIVATIVE AND APPLICATION THEREOF
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Disclosed are a series of quinolino-pyrrolidin-2-one compounds, and application thereof in preparation of drugs for ATM inhibitor-related diseases. The present disclosure specifically relates to a derivative compound represented by formula (I), tautomers thereof or pharmaceutically acceptable compositions thereof.
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Paragraph 0076; 0078
(2021/07/08)
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- Nitroacetonitrile and Its Synthetic Equivalents
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Nitroacetonitrile (NAN) serves as a cyano(nitro)methylating agent facilitating the construction of polyfunctionalized compounds; however, its explosive property is a significant drawback in terms of practical handling. Alkali metal salts of NAN are therma
- Iwai, Kento,Nishiwaki, Nagatoshi
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p. 13177 - 13185
(2021/09/02)
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- IMIDAZOQUINOLINE-TYPE COMPOUNDS AND USES THEREOF
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Provided in the present disclosure are imidazoquinoline-type compounds, methods for their preparation, pharmaceutical compositions thereof and their use, wherein the imidazoquinoline-type compounds, upon local administration, form depots inducing cell mediated immune response while mitigating a systemic proinflammatory immune response.
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Paragraph 0013; 00106; 00107
(2021/10/11)
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- Design, synthesis, evaluation and molecular modeling study of 4-N-phenylaminoquinolines for Alzheimer disease treatment
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Dual binding site acetylcholinesterase (AChE) inhibitors and butyrylcholinesterase (BChE) inhibitors have recently emerged as two classes of new anti-Alzheimer agents to positively modify the disease's course. In this work, a new series of 4-N-phenylaminoquinolines was synthesized and evaluated for their abilities to inhibit AChE and BChE. Compound 11b showed significant inhibitory activities on AChE and BChE with IC50 values of 0.86 and 2.65 μM, respectively, a lot better than that of reference drug galanthamine. Furthermore, docking study showed that compound 11b interacted simultaneously not only with active and peripheral sites of AChE, but also with all five regions of BChE active site. These findings suggest that these derivatives could be regarded as promising starting points for further drug discovery developments.
- Zhu, Jun,Wang, Li-Ning,Cai, Rong,Geng, Shang-Qi,Dong, Ya-Fei,Liu, Yu-Ming
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supporting information
p. 1325 - 1329
(2019/04/08)
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- INHIBITORS OF MALT1 AND USES THEREOF
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Provided herein are compounds that inhibit MALTl, a protein whose activity is responsible for constitutive NF-κΒ signaling in certain cancers (e.g., activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating MALTl -related diseases and disorders (e.g., cancer) with the compounds in a subject, by administering the compounds and/or compositions described herein.
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Paragraph 00339; 00340
(2018/09/28)
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- Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers
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Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.
- Sun, Qi-Zheng,Lin, Gui-Feng,Li, Lin-Li,Jin, Xi-Ting,Huang, Lu-Yi,Zhang, Guo,Yang, Wei,Chen, Kai,Xiang, Rong,Chen, Chong,Wei, Yu-Quan,Lu, Guang-Wen,Yang, Sheng-Yong
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p. 6337 - 6352
(2017/08/02)
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- COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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The present invention relates to compounds of formula I: in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
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Paragraph 0338
(2015/02/25)
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- COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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The present invention relates to compounds of formula I: in which n, R1, R2, R3 and R4 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a pro
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Paragraph 00202; 00203; 00204; 00205
(2015/02/25)
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- COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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The present invention relates to compounds of formula I in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
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Paragraph 00216; 00217; 00218; 00219
(2015/02/25)
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- A high density pyrazolo-triazine explosive (PTX)
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The fused-ring heterocycle 4-amino-3,7,8-trinitropyrazolo-[5,1-c][1,2,4]triazine (PTX) has promising explosive properties. The Cheetah thermochemical code used its calculated standard enthalpy of formation and its measured crystal density of 1.946 g cm-3 to predict HMX-like explosive performance, while measurements of its thermal stability, sensitivity to impact, friction, and spark showed greater safety margins.
- Schulze,Scott,Chavez
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supporting information
p. 17963 - 17965
(2015/09/02)
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- Discovery of N -(2,4-Di- tert -butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator
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Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high-throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.
- Hadida, Sabine,Van Goor, Fredrick,Zhou, Jinglan,Arumugam, Vijayalaksmi,McCartney, Jason,Hazlewood, Anna,Decker, Caroline,Negulescu, Paul,Grootenhuis, Peter D. J.
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p. 9776 - 9795
(2015/01/16)
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- Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines
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Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c] quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.
- Kokatla, Hari Prasad,Yoo, Euna,Salunke, Deepak B.,Sil, Diptesh,Ng, Cameron F.,Balakrishna, Rajalakshmi,Malladi, Subbalakshmi S.,Fox, Lauren M.,David, Sunil A.
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p. 1179 - 1198
(2013/03/29)
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- Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines
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Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/β which plays essential functions in the control of adaptive immunity. We had previously examined structure-activity relationships (SAR) in TLR7/8-agonistic imidazoquinolines with a focus on substituents at the N 1, C2, N3 and N4 positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c] pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N6-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl-aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N6-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.
- Yoo, Euna,Crall, Breanna M.,Balakrishna, Rajalakshmi,Malladi, Subbalakshmi S.,Fox, Lauren M.,Hermanson, Alec R.,David, Sunil A.
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p. 6526 - 6545
(2013/09/24)
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- Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline
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Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N1-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC50 value of 7.5 μM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7.
- Shukla, Nikunj M.,Kimbrell, Matthew R.,Malladi, Subbalakshmi S.,David, Sunil A.
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supporting information; body text
p. 2211 - 2214
(2009/12/07)
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- Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB 2) agonists
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The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB 2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB 1 EC50 > 10 μM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
- Cheng, Yuan,Albrecht, Brian K.,Brown, James,Buchanan, John L.,Buckner, William H.,DiMauro, Erin F.,Emkey, Renee,Fremeau Jr., Robert T.,Harmange, Jean-Christophe,Hoffman, Beth J.,Huang, Liyue,Huang, Ming,Lee, Josie Han,Lin, Fen-Fen,Martin, Matthew W.,Nguyen, Hung Q.,Patel, Vinod F.,Tomlinson, Susan A.,White, Ryan D.,Xia, Xiaoyang,Hitchcock, Stephen A.
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experimental part
p. 5019 - 5034
(2009/07/19)
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- A3 ADENOSINE RECEPTOR ALLOSTERIC MODULATORS
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The present invention relates to allosteric modulation of A3 adenosine receptor (A3AR) and provides for the use of an A3 adenosine receptor modulator (A3RM),for the preparation of pharmaceutical compositions for
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Page/Page column 19-20
(2008/06/13)
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- Low-temperature processes in the system aluminum chloride-nitroalkane: III.1 products of solid-phase low-temperature reactions of aluminum chloride with nitroalkanes
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Solid-phase reactions of aluminum chloride with nitroalkanes, with nitromethane and 1-nitro-propane as examples, were studied by low-temperature IR spectroscopy. Reaction of the components in the 2 : 1 (Al2Cl6·RNO2) and 1 : 1 (AlCl3·RNO2) complexes at 170-230 K results in dehydration of the nitro compounds to form nitro oximes and furoxane derivatives. The intermediate ionic complexes of the reactants were detected under conditions of limited molecular mobility. The resulting condensation products of nitroalkanes are bound in molecular complexes with anhydrous or partially hydrolyzed aluminum chloride.
- Shilina
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p. 1687 - 1692
(2007/10/03)
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- Ring Transformation of 1-Substituted 3,5-Dinitro-4-pyridones to 4-Nitro-5(2H)-isoxazolone by Hydroxylamine
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New ring transformations of 3,5-dinitro-1-(4-nitrophenyl)-4-pyridone and its homologues with hydroxylamine were found to give 4-nitro-5(2H)-isoxazolone.These results were rationalized by double ring transformations in sequence.The fact that the 4-position of the 4-pyridone behaved as an electrophilic site was the first example in this series of ring transformations, and was caused by the alpha-effect of the reagent.Some reactions of the isoxazolone were carried out.
- Ariga, Masahiro,Tohda, Yasuo,Nakashima, Hiroko,Tani, Keita,Mori, Yutaka,Matsumura, Eizo
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p. 3544 - 3547
(2007/10/02)
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- Syntheses with nitriles, LXXXVIII; cyanonitropropenides - Synthons for the preparation of nitropyridines
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Nitroacetonitrile reacts with triethyl orthoformate, orthoacetate and orthopropionate, respectively in presence of pyridine to the pyridinium salts of 1,3-dicyano-1,3-dinitro-2-propen-1-ides. With ethoxymethylenemalononitrile nitroacetonitrile yields 1,1,3-tricyano-3-nitropropenide, which can be cyclized with sodium methoxide or ethoxide to 2-alkoxy-6-amino-3-cyano-5-nitropyridines. Ether cleavage of the latter leads to 6-amino-3-cyano-5-nitro-2(1H)-pyridone, subsequent chlorination gives the corresponding 2-chloropyridine, suitable for nucleophilic substitutions. By hydrolysis of the nitrile group 6-amino-5-nitro-3-pyridine-carboxylic acid derivatives are obtained.
- Reidlinger,Junek
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p. 835 - 838
(2007/10/02)
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- Naphthyridines. IV. Synthesis of Benzo-1,7-naphthyridines
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Benzo-1,7-naphthyridines have been synthesized from 3-nitrolepidine (3) by a sequence involving monobromination of the methyl group of 3, oxidation of the bromomethyl group to the carboxyaldehyde group by Franzen's trimethylamine N-oxide procedure, and
- Baumgarten, Henry E.,Barkley, Raymond P.,Chiu, Shuet-Hing Lee,Thompson, Robert D.
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p. 925 - 928
(2007/10/02)
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