- Synthesis and biological evaluation of novel 4-(2-fluorophenoxy)-2-(1h- tetrazol-1-yl)pyridines bearing semicarbazone moieties as potent antitumor agents
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A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their in vitro antitumor potency. Some of the compounds (10b, 10c, 10e-10h, 10m-10p, 10r, and 11b) exhibited moderate to excellent antitumor activity as compared to sorafenib and PAC-1, as well as low levels of toxicity toward the human fetal lung fibroblast cell line WI-38. The most promising compound 10p (IC50 = 0.08, 0.36, 0.97 μM) was 45.1-, 6.1-, and 2.4-fold more active than sorafenib (IC50 = 3.61, 2.19, 2.32 μM), and 17, 3.2, and 2.9 times better than PAC-1 (IC50 = 1.36, 1.17, 2.83 μM) against three cancer cell lines (HT-29, H460, and MKN-45), respectively. In addition, further studies examining enzymatic activity suggested that the marked pharmacological activity observed might be ascribed to an inhibitory action against CRAf kinase. A series of 4-(2-fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines bearing semicarbazone moieties were synthesized and evaluated for their cytotoxic activities in vitro. The most promising compound 10p was further examined for enzymatic activity, with the goal to investigate the molecular mechanisms of action.
- Qin, Mingze,Liao, Weike,Xu, Chen,Fu, Baolin,Ren, Jianguo,Gu, Yucheng,Gong, Ping
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- Synthesis method of imidazopyridine or pyrimidine derivative
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The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of an imidazopyridine or pyrimidine derivative. The imidazopyridine or pyrimidine compound is obtained by taking pyridine or pyrimidinecarboxylic acid as a synthon through amidation, Hofmann degradation and cyclization reaction, and the obtained imidazopyridine or pyrimidine derivative can be further converted to generate a functional product. The method has the advantages of easily available raw materials, simple operation, high reaction efficiency, convenient post-treatment, and diversity of functional groups.
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- Synthesis method of Tucatinib and intermediate product thereof
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The invention discloses a synthesis method of Tucatinib, and the method comprises the following step: carrying out substitution reaction on halate of a compound shown in a formula VI or free alkali thereof serving as a raw material and a compound shown in a formula VII under an alkaline condition to obtain a compound shown in a formula VIII. The raw materials used in the whole synthesis route areeasy to obtain, expensive catalysts are not needed, and the method is suitable for large-scale production and beneficial to industrial production of the Tucatinib.
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- Preparation method of 2-amino-4-fluoropyridine
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The invention discloses a preparation method of 2-amino-4-fluoropyridine, comprising the synthetic steps of 1, subjecting 2-pyridinecarboxylic acid as a raw material to reaction in the presence of thionyl chloride and a salt to obtain 4-chloropyridine-2-acyl chloride, and subjecting 4-chloropyridine-2-acyl chloride the presence of ammonia to obtain 4-chloropyridine-2-amide; 2, subjecting 4-chloropyridine-2-amide to Hofmann rearrangement reaction to obtain 2-amino-4-chloropyridine; 3, subjecting 2-amino-4-chloropyridine to halogen exchange to obtain 2-amino-4-fluoropyridine. The problems of theexisting preparation method, such as long synthetic path, operational complexity, high pollution of three wastes, poor atomic economy, low yield and high manufacture cost, are solved.
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- Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach
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As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC 50 value of 0.056 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 μM) and DLV (EC50 = 0.51 μM). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC50 = 0.034, 0.11, 0.11 and 0.16 μM, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.
- Wang, Jun,Zhan, Peng,Li, Zhenyu,Liu, Huiqing,De Clercq, Erik,Pannecouque, Christophe,Liu, Xinyong
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p. 531 - 538
(2014/05/06)
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- ANTIVIRAL DRUGS FOR TREATMENT OF ARENA VIRUS INFECTION
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Compounds, methods and pharmaceutical compositions for treating viral infections, by administering certain compounds in therapeutically effective amounts are disclosed. Methods for preparing the compounds and methods of using the compounds and pharmaceutical compositions thereof are also disclosed. In particular, the treatment and prophylaxis of viral infections such as caused by the Arenavirus family such as Lassa fever, Argentine hemorrhagic fever, Bolivian hemorrhagic fever, and Venezuelan hemorrhagic fever
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Paragraph 0000228
(2013/08/28)
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- Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole and related heterocycles
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A series of potent arenavirus inhibitors sharing a benzimidazole core were previously reported by our group. SAR studies were expanded beyond the previous analysis, which involved the attached phenyl rings and methylamino linker portion, to include modifications focused on the benzimidazole core. These changes included the introduction of various substituents to the bicyclic benzimidazole ring system along with alternate core heterocycles. Many of the analogs containing alternate nitrogen-based bicyclic ring systems were found to retain antiviral potency compared to the benzimidazole series from which we derived our lead compound, ST-193. In fact, 21h, built on an imidazopyridine core, possessed a near tenfold increase in potency against Lassa virus pseudotypes compared to ST-193. As found with the benzimidazole series, broad-spectrum arenavirus activity was also observed for a number of the analogs discovered during this study.
- Burgeson, James R.,Moore, Amy L.,Gharaibeh, Dima N.,Larson, Ryan A.,Cerruti, Natasha R.,Amberg, Sean M.,Hruby, Dennis E.,Dai, Dongcheng
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p. 750 - 756
(2013/02/25)
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- METHOD OF INHIBITING HAMARTOMA TUMOR CELLS
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Dimorpholinopyrimidines are useful for inhibiting growth or proliferation of hamartoma tumor cells. Because the Dimorpholinopyrimidines inhibit the growth and proliferation of hamartoma tumor cells they are also useful in treating PTEN hamartoma tumor syndromes. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a patient in need thereof an amount of a compound of dimorpholinopyrimidine derivative that is effective to inhibit growth or proliferation of the hamartoma tumor cells.
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Page/Page column 22
(2012/08/28)
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- Identification of NVP-BKM120 as a potent, selective, orally bioavailable class i PI3 kinase inhibitor for treating cancer
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Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
- Burger, Matthew T.,Pecchi, Sabina,Wagman, Allan,Ni, Zhi-Jie,Knapp, Mark,Hendrickson, Thomas,Atallah, Gordana,Pfister, Keith,Zhang, Yanchen,Bartulis, Sarah,Frazier, Kelly,Ng, Simon,Smith, Aaron,Verhagen, Joelle,Haznedar, Joshua,Huh, Kay,Iwanowicz, Ed,Xin, Xiaohua,Menezes, Daniel,Merritt, Hanne,Lee, Isabelle,Wiesmann, Marion,Kaufman, Susan,Crawford, Kenneth,Chin, Michael,Bussiere, Dirksen,Shoemaker, Kevin,Zaror, Isabel,Maira, Sauveur-Michel,Voliva, Charles F.
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supporting information; experimental part
p. 774 - 779
(2011/12/03)
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- Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor
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Antagonism of the gonadotropin releasing hormone (GnRH) receptor has resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure-activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule.
- Vera, Matthew D.,Lundquist IV, Joseph T.,Chengalvala, Murty V.,Cottom, Joshua E.,Feingold, Irene B.,Garrick, Lloyd M.,Green, Daniel M.,Hauze, Diane B.,Mann, Charles W.,Mehlmann, John F.,Rogers, John F.,Shanno, Linda,Wrobel, Jay E.,Pelletier, Jeffrey C.
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supporting information; scheme or table
p. 2512 - 2515
(2010/07/06)
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- PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES
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Disclosed here is a process for the preparation of nitropyridine derivatives of Formula (I) and its salt and precursors such as halogenated amino pyridines; Wherein; R1 is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH - C (O) - R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 - 6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group,
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Page/Page column 14
(2010/08/18)
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- BICYCLIC PYRIMIDINONES AND USES THEREOF
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The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compoundof Formula I is also provided.
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Page/Page column 28
(2008/12/06)
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- PROTEIN KINASE INHIBITORS AND METHODS FOR USING THEREOF
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The invention provides compounds of formula (l) and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of AIk, AbI, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, BIk, Bmx, BTK, c-Kit, c-RAF, CSK, c-SRC, EphBl, EphB2, EphB4, FLTl, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRalpha, PDGFRbeta, PKCalpha, SAPK2alpha, Src, SIK, Syk, Tie2 and TrkB kinases.
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Page/Page column 60
(2009/01/20)
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- PYRIMIDINE DERIVATIVES USED AS PI-3 KINASE INHIBITORS
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Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof ; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
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Page/Page column 96-97
(2010/11/28)
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- A general and efficient 2-amination of pyridines and quinolines
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(Chemical Equation Presented) Pyridine N-oxides were converted to 2-aminopyridines in a one-pot fashion using Ts2O-t-BuNH2 followed by in situ deprotection with TFA. The amination proceeded in high yields, excellent 2-/4-selectivity, and with good functional group compatibility. 2-Amino (iso)quinolines were also obtained in the same manner. Combined with the simple oxidation of pyridines to pyridine N-oxides, this method provides a general and efficient way for amination of 2-unsubstituted pyridines.
- Yin, Jingjun,Xiang, Bangping,Huffman, Mark A.,Raab, Conrad E.,Davies, Ian W.
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p. 4554 - 4557
(2008/02/04)
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- Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
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The present invention relates to Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.
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Page/Page column 14; 21
(2008/06/13)
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- Imidazo-pyridine derivatives as ligands for gaba receptors
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A class of 3-phenylimidazo[1,2-a]pyridine derivatives, substituted at the meta position of the phenyl ring by an optionally substituted aryl or heteroaryl group which is directly attached or bridged by an oxygen atom or a —NH— linkage, are selective ligands for GABAA receptors, in particular having high affinity for the α2 and/or α3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.
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- Imidazo[1,2-a]pyridine C-nucleosides as antiviral agents
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This invention pertains to nucleoside analogs that have antiviral activity and improved metabolic stability, compositions comprising them, and methods of antiviral treatment employing them. More particularly, this invention pertains to imidazo[1,2-a]pyridine C-nucleosides, as exemplified by compounds such as imidazo[l,2-a]pyridine C5-nucleosides and imidazo[1,2-a]pyridine C3-nucleosides, and may be represented by formula (I), wherein exactly one of Q3and Q5is a sugar-like moiety; exactly one of Q3and Q5is —H; and Q2, Q6, Q7and Q8are independently imidazo[1,2-a]pyridine substituents, such as —H, —F, —Cl, —Br and —I.
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- Cyclic ureas as ortho directing substituents
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Six-membered cyclic ureas are shown to have a weak ortho directing ability when linked through nitrogen to benzene and pyridine rings.
- Meigh,Alvarez,Joule
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p. 2012 - 2021
(2007/10/03)
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- Substituted 2-aminopyridines as inhibitors of nitric oxide synthases.
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A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.
- Hagmann,Caldwell,Chen,Durette,Esser,Lanza,Kopka,Guthikonda,Shah,MacCoss,Chabin,Fletcher,Grant,Green,Humes,Kelly,Luell,Meurer,Moore,Pacholok,Pavia,Williams,Wong
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p. 1975 - 1978
(2007/10/03)
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- Substituted 2-aminopyridines as inhibitors of nitric oxide synthase
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Substituted 2-aminopyridine compounds of Formula (I) and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders. STR1
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- An improved large scale synthesis of 2-amino-4-chloropyridine and its use for the convenient preparation of various polychlorinated 2-aminopyridines
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An efficient large scale synthesis of 2-amino-4-chloropyridine (3) has been achieved through a modification of existing literature procedures. Compound 3 was used to prepare the previously unreported 2-amino-4,5-dichloropyridine (4). The known 2-amino-3,4-dichloropyridine (5) and 2-amino-3,4,5-trichloropyridine (6) were pepared from 3 by new routes and in higher yields than previously reported.
- Gudmundsson, Kristjan S.,Hinkley, Jack M.,Brieger, Michael S.,Drach, John C.,Townsend, Leroy B.
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p. 861 - 870
(2007/10/03)
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- Synthesis of (2R)-1-(4-chloro-2-pyridyl)-2-(2-pyridyl)ethylamine: A selective oxime reduction and crystallization-induced asymmetric transformation
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Reduction of 1-(4-chloro-2-pyridyl)-2-(2-pyridyl)ethanone oxime (3) using zinc in trifluoroacetic acid gave the corresponding racemic pyridylethylamine 4 in excellent yield without reductive removal of the chlorine atom. A subsequent diastereomeric crystallization of the amine 4 with an optically active cis-cyclohexanecarboxylic acid derivative in the presence of a catalytic amount of 3,5-dichlorosalicylaldehyde was found to give the desired R-amine 6 in 42% yield via a 'crystallization-induced asymmetric transformation'.
- Negi, Shigeto,Matsukura, Masayuki,Mizuno, Masanori,Miyake, Kazutoshi,Minami, Norio
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p. 991 - 996
(2007/10/03)
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- Kinetics and Mechanism of the Reaction of Pyridinamine 1-Oxides with Acetylating Agents in Water and Aprotic Solvents
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Pyridin-2-amine 1-oxides react with acetic anhydride in dioxan and with p-nitrophenyl acetate in water by rate-determining O-acetylation followed by rapid intramolecular rearrangement to give the amide.The rearrangement is so favoured that no hydrolysis of the intermediate was detected in the aqueous solvent.This behaviour in aprotic solvents contrasts with that of pyridin-2-amine, previously shown to undergo acetylation directly at the amino group.Acetylation of pyridin-4-amine 1-oxide, with acetic anhydride in acetone, occurs by way of an analogous O-acetyl intermediate which reacts slowly with a second molecule of amine 1-oxide.Pyridin-4-amine reacts in the same manner at a surprisingly similar rate.In water, both compounds catalyse the hydrolysis of p-nitrophenyl acetate, with the amine 1-oxide being very much less efficient.
- Deady, Leslie W.,Stanborough, Mark S.
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p. 1841 - 1849
(2007/10/02)
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- Substituent Effects on the Isomer Ratios in the Rearrangement of Some 2- and 4-Nitraminopyridines
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The preparation, and rearrangement in 92percent sulfuric acid, of 4-X-2-nitramino- (1), 2-X-4-nitramino- (2), and 6-X-2-nitramino-pyridines (3) is reported (X=H,Me,MeO,Br,Cl,CO2H).The product isomer ratios can be explained by differential electronic stabilization of the appropriate ? complexes for aromatic nitration and steric effects seem relatively unimportant.Deuteration had no effect on the product distribution
- Deady, Leslie W.,Korytsky, Olga L.,Rowe, Jeffrey E.
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p. 2025 - 2034
(2007/10/02)
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- Studies on 1,3-Benzoxazines. I. Synthesis of Primary 2-Amino-pyridines via the Reaction of Imidoyl Chlorides of 1,3-Benzoxazines with Pyridine N-Oxides
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A new synthetic method for primary 2-aminopyridine derivatives is described.Treatment of the imidoyl chlorides of 1,3-benzoxazines (1a-i) with pyridine N-oxides resulted in the introduction of an oxazine moiety into the α-position of the pyridine ring through rearrangement of the initially formed reaction adduct.Acid hydrolysis of the rearrangement products afforded 2-aminopyridine derivatives in excellent yields.When methoxypyridine N-oxides were used, products of a different type (10 and 14) were obtained.
- Wachi, Kazuyuki,Terada, Atsusuke
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p. 465 - 472
(2007/10/02)
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