- 1,2-Dihydro-2-thioxo-4H-3,1-benzothiazin-4-one: formation from carbon disulfide and isatoic anhydride
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The reaction of isatoic anhydride (1) with carbon disulfide at room temperature unexpectedly afforded 1,2-dihydro-2-thioxo-4H-3,1-benzothiazin-4-one (2). The use of 13C-labeled carbon disulfide elucidated that CS2 was entirely incorp
- Ottersbach, Philipp A.,H?cker, Hans-Georg,Elsinghorst, Paul W.,Schnakenburg, Gregor,Gütschow, Michael
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- Discovery of phthalazino[1,2-b]-quinazolinone derivatives as multi-target HDAC inhibitors for the treatment of hepatocellular carcinoma via activating the p53 signal pathway
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In view of histone deacetylases (HDACs) as a promising target for cancer therapy, a series of phthalazino[1,2-b]-quinazolinone units were hybrided with ortho-aminoanilide or hydroxamic acid to serve as multi-target HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC50 values toward the tested cancer cells and HDAC subtypes, which was more potent than the HDAC inhibitor SAHA (vorinostat). Mechanism study revealed that compound 8h could suppress the HepG2 cell proliferation via prompting the acetylation of histone 3 (H3) and α-tubulin, and activating the p53 signal pathway as designed. In addition, compound 8h exhibited much stronger in vivo antitumor efficacy than SAHA in the HepG2 xenograft tumor model with negligible toxicity. As a novel multi-target HDAC inhibitor, compound 8h deserves further development as a potential anticancer agent.
- Liu, Qingqing,Zhang, Bin,Wang, Yuanjiang,Wang, Xinyi,Gou, Shaohua
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- Design, Synthesis, and Mechanism of Antiviral Acylurea Derivatives Containing a Trifluoromethylpyridine Moiety
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Novel acylurea derivatives 7a-7ab were designed and synthesized by linking the active substructures trifluoromethylpyridine and anthranilic diamide via an acylurea bridge. Most of the title compounds exhibited good activity against tobacco mosaic virus (TMV), particularly compound 7x (EC50 of 211.8 μg/mL), which showed much higher curative activity than ningnanmycin (EC50 of 389.8 μg/mL), and compound 7ab, which showed excellent inactivation activity (EC50 of 36.1 μg/mL), similar to ningnanmycin (EC50 of 23.2 μg/mL). The preliminary mechanism of these derivatives was investigated. Autodocking analysis revealed that compounds 7x and 7ab had good affinity for TMV coat protein (TMV CP), with low binding energies (-7.86 and -8.59 kcal/mol) comparable to ningnanmycin (-8.75 kcal/mol). Molecular dynamics simulation showed that compound 7x had a stable system structure with a better binding free energy (-32.94 kcal/mol) than ningnanmycin (-25.62 kcal/mol). Microscale thermophoresis showed that compound 7x bound more strongly to TMV CP (Kd of 19.8 ± 7.3 μM) than ningnanmycin (Kd of 21.2 ± 7.3 μM). Transmission electron microscopy and self-assembly experiments demonstrated that compounds 7x and 7ab significantly obstructed the self-assembly of TMV RNA and TMV CP. This new acylurea derivative has excellent antiviral activity by targeting TMV CP and inhibiting TMV self-assembly and can be considered a candidate for antiviral applications.
- Chen, Shunhong,Guo, Shengxin,Wang, Yanyan,Wei, Panpan,Wu, Jian,Zhang, Wei,Zhao, Wei
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p. 12891 - 12899
(2021/11/17)
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- New spiro pyrrole[2, 1-b]quinazolone derivative, preparation method and application thereof
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The invention relates to a new spiro pyrrole[2, 1-b]quinazolone derivative, a preparation method and application thereof. The new spiro pyrrole[2, 1-b]quinazolone derivative is synthesized by using asimple method. The yield is high, the production cost is
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Paragraph 0072-0074
(2020/11/09)
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- Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as raw material
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The invention discloses a process for efficiently synthesizing Cetilistat by taking 2-amino-5-methyl benzoic acid as a raw material. The process comprises the steps: taking 2-amino-5-methyl benzoic acid as a raw material, and carrying out transesterification on 2-amino-5-methyl benzoic acid and triphosgene under the action of organic base catalysis to generate an intermediate c, namely 6-methyl-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione; carrying out a reaction on sulfonyl chloride (d) with a specific structure with n-hexadecanol under the condition of base catalysis to generate an intermediatef; and finally, carrying out an alkylation reaction on oxygen atoms of the intermediate c and the intermediate f in the presence of organic base to generate the target product Cetilistat. According tothe method, the reaction steps for synthesizing the Cetilistat are few, the process route is short, side reactions are few, the yield of the final product is high, and the purity is more than 99%.
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Paragraph 0053-0055; 0060-0062
(2020/04/02)
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- Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using p Ka-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam
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An anionic annulation strategy employing isatoic anhydrides and a wide assortment of enolizable partners was developed to afford over 80 novel ring-fused, N-substituted 4-quinolinones, an underrepresented privileged template. Multiple factors governing the efficiency of the transformation were determined, resulting in a reliable and tunable synthetic platform applicable for a broad range of substrates with variable deprotonation susceptibility, such as tetramic and tetronic acids, cyclic 1,3-diketones, and cycloalkanones. Application to the synthesis of bioactive, pyrrolizine-fused 4-quinolinone, penicinotam 3, resulted in the most brief and highest yielding total synthesis of the alkaloid in three steps and a 36% overall yield.
- Khalifa, Muhammad M.,Philkhana, Satish Chandra,Golden, Jennifer E.
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p. 464 - 481
(2019/12/24)
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- Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase
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Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.
- Cui, Menghan,Kuang, Chunxiang,Li, Yuanyuan,Liu, Wei,Wang, Rong,Yang, Qing,Zhang, Shengnan
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supporting information
(2020/04/10)
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- APPLICATION OF N-BENZYL TRYPTANTHRIN DERIVATIVE AS TRYPTOPHAN DIOXYGENASE (TDO) INHIBITOR
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The present invention provides an application of N-benzyl tryptanthrin derivative as tryptophan dioxygenase (TDO) inhibitor, and more specifically an application of N-benzyl tryptanthrin derivative or a pharmaceutically acceptable salt thereof. Said derivative has a structural general formula as represented by formula 1, wherein each group is defined as in the specification. The derivative of the present invention has a good TDO inhibiting activity and can be used to prepare a treatment for diseases associated with TDO activity and expression.
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Paragraph 0102; 0103
(2020/04/24)
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- Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation
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In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4–6.25 μg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (30% inhibition at 50 μg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 μg/mL] and the compound 6d [MIC (H37Rv) of 0.78 μg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 μg/mL, respectively.
- Chakraborti, Asit K.,Dhameliya, Tejas M.,Jadhavar, Pradeep S.,Krishna, Vagolu Siva,Patel, Kshitij I.,Saha, Nirjhar,Sriram, Dharmarajan,Vaja, Maulikkumar D.
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- Green synthesis of novel phosphonate derivatives using ultrasonic irradiation
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[Figure not available: see fulltext.] A novel and efficient procedure for the generation of quinazolinone phosphonate derivatives employing the reaction of euparin, isatin or its derivatives, primary amines, dialkyl acetylenedicarboxylates, trimethyl phosphite or triphenyl phosphite, and acidic solution of hydrogen peroxide in aqueous media at ambient temperature under ultrasonic irradiation was developed. Without ultrasonic irradiation, the reaction does not proceed and agitation of the reaction mixture is difficult. Some advantages of this procedure are: short time of reaction, high yields of products, easy isolation of products.
- Sharafian, Shirin,Hossaini, Zinatossadat,Rostami-Charati, Faramarz,Khalilzadeh, Mohammad A.
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p. 1283 - 1291
(2020/11/19)
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- Carbene-Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones
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A direct decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza-o-QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis–Ferrier rearrangement sequence. Complementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
- Lee, Ansoo,Zhu, Joshua L.,Feoktistova, Taisiia,Brueckner, Alexander C.,Cheong, Paul H.-Y.,Scheidt, Karl A.
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supporting information
p. 5941 - 5945
(2019/04/03)
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- GLUN2C/D SUBUNIT SELECTIVE ANTAGONISTS OF THE N-METHYL-D-ASPARTATE RECEPTOR
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A compound according to Formula (I) or salts or prodrugs thereof and pharmaceutical formulations comprising the compound are provided herein for the treatment of neurological disorders. The disorders may include providing neuroprotection, preventing neurodegeneration, treating neuropathic pain or treating schizophrenia, psychoses or depression. Furthermore, the compounds may be used in combination with another active ingredient.
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Page/Page column 41
(2019/10/23)
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- Tryptamine derivative and its use (by machine translation)
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The invention discloses a having the following general formula (I) compounds, of formula (I) in, Respectively and The invention also discloses the indocyanine comprising above-mentioned compound - 2, 3 - dioxygenase and/or tryptophan - 2, 3 - dioxygenase inhibitor and the compounds in the preparation of medicament for the treatment of cancer in the application. The compounds of this invention, can effectively inhibit cell proliferation, to various diseases such as cancer have a good therapeutic effect, to breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, oophoromas, peritoneal tumor, IV [...] pigment lump, glioma, neuroblastoma neural rubber mother, hepatocellular carcinoma, mastoidal kidney natural lump, sarcoma, leukemia, lymphoma, myeloma and non-small cell lung cancer has significant therapeutic effect, very broad application prospects. (by machine translation)
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Paragraph 0056-0061
(2019/07/16)
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- Tryptanthrin containing 1, 2, 3-triazole as well as preparation method and application of tryptanthrin
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The invention discloses tryptanthrin containing 1, 2, 3-triazole as well as a preparation method and application of tryptanthrin. The preparation method comprises the following steps: connecting 2-bromomethyl-8-fluorotryptamine with 1, 2, 3-triazole to obtain tryptanthrin containing 1, 2, 3-triazole; refluxing 2-bromomethyl-8-fluorotryptamine and propargylic acid in a mixed solvent of acetone andwater in the presence of sodium azide and cuprous iodide to obtain a crude product; and separating the obtained crude product by column chromatography to obtain 2-(1, 2, 3-triazolylmethyl)-8-fluorotryptamine. The 1, 2, 3-triazole can play a variety of non-covalent bond roles and has quite strong stability under metabolic transformation, redox and acid-base conditions; 1, 2, 3-triazole ring is widely used to design novel drug molecules and can enhance pharmacological activity of compounds; tryptanthrin derivatives provided by the invention can be used for treating pathological characteristic diseases with IDO-mediated tryptophan metabolic pathway, and has wide application prospects; and on the other hand, the preparation method provided by the invention has advantages of simple operation, mild conditions and easy industrial production.
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Paragraph 0044-0047; 0059-0062; 0072-0075; 0085-0088
(2019/10/01)
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- Method, tryptanthrin derivative and preparation method and application thereof for improving water solubility of tryptanthrin (by machine translation)
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The invention discloses a method for improving the water solubility of tryptanthrin, belonging to the technical field of cosmetics. The chromone is modified under the condition that the reactive group of the amine ketone is not changed; and the tryptamine is adopted as an intermediate to modify the tryptanthrone. The invention further discloses a method for synthesizing the mono-bromochromone derivative and N - benzylic ring - N N-alkanoic acid tryptanthrin derivative as well as a preparation method and application. N -benzyl ring - N N-alkanoic acid tryptanthrin derivative has excellent indoleamine -2, 3 - dioxygenase (IDO) inhibitor activity, and the like. The invention has wide application prospect, and can be used for treating diseases of cancer, 's disease, depression, cataract and the like with IDO-mediated pathologic characteristics of the tryptophan metabolic pathway. Under the condition that the active group of the amine ketone is not changed, the solubility. The method has the advantages, such as simple operation, mild conditions and the like, and is easy for industrial production. (by machine translation)
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Paragraph 0042-0045; 0056-0059; 0066-0069; 0076-0079
(2019/08/02)
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- N-benzyl amino acid water-soluble trptanthrin and preparation method and application thereof
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The invention discloses N-benzyl amino acid water-soluble trptanthrin and a preparation method and application thereof. The preparation method uses 2-bromomethyl-8-fluorotrptanthrin as a substrate toconnect various amino acids to improve the water solubility of the trptanthrin. The 2-bromomethyl-8-fluorotrptanthrin reacts with the various amino acids in an acetonitrile solvent in the presence oftriethylamine and potassium iodide, and a synthesized product is separated by column chromatography to obtain the N-benzyl amino acid water-soluble trptanthrin. Most amino acids have good water solubility. The amino acid modified trptanthrin has enhanced water solubility, enhanced bioavailability and pharmacological activity, and broad application prospects. The N-benzyl amino acid water-soluble trptanthrin derivatives can be used to treat pathologically characterized diseases with IDO mediated tryptophan metabolic pathway, such as cancer, Alzheimer's disease, depression, cataract, and the like. The preparation method has simple operation, mild conditions and easy industrial production.
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Paragraph 0041-0044; 0056-0059; 0069-0072; 0082-0085; 0095-0
(2019/10/15)
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- N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase
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Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and rate-limiting step of the kynurenine pathway of tryptophan catabolism, has emerged as a key target in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the same reaction and play a potential role in cancer immunotherapy. Starting from our previously discovered tryptanthrin IDO1 inhibitor scaffold, we synthesized novel N-benzyl/aryl substituted tryptanthrin derivatives and evaluated their inhibitory efficacy on IDO1, TDO, and IDO2. Most compounds showed similar high inhibitory activities on both IDO1 and TDO, which were significantly superior over that of IDO2 with magnitude difference. We showed that N-benzyl/aryl substituted tryptanthrin directly interacted with IDO1, TDO, and IDO2, significantly augmented the proliferation of T cells in vitro, blocked the kynurenine pathway, and suppressed tumor growth when administered to LLC and H22 tumor-bearing mice.
- Yang, Dan,Zhang, Shengnan,Fang, Xin,Guo, Leilei,Hu, Nan,Guo, Zhanling,Li, Xishuai,Yang, Shuangshuang,He, Jin Chao,Kuang, Chunxiang,Yang, Qing
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p. 9161 - 9174
(2019/10/16)
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- Tryptanthrin derivative containing olefine acid, and preparation method and application thereof
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The invention discloses a tryptanthrin derivative, and a preparation method and application thereof. The preparation method comprises the following steps: with 5-methylisatin as a raw material, oxidizing 5-methylisatin into 5-methylisatoic anhydride; under the weak alkaline condition of triethylamine, subjecting 5-methylisatoic anhydride and 5-fluoroisatin to reflux with acetonitrile as a solvent,and carrying out filtration and washing to obtain 2-methyl-8-fluorotryptanthrin; subjecting 2-methyl-8-fluorotryptanthrin and N-bromosuccinimide to reflux in a carbon tetrachloride solvent; and reacting a concentrated product with malonic acid in pyridine, and carrying out acidification, washing and filtering to obtain the desired tryptanthrin derivative. The tryptanthrin derivative of the invention has excellent inhibitory activity against indoleamine-2,3-dioxygenase (IDO), increases the water solubility of tryptanthrin, has broad application prospects and can be used for treating diseases with pathological features of the IDO-mediated tryptanthrin metabolism pathway, e.g., cancer, Alzheimer's disease, depression and cataract. The preparation method of the invention has the advantages ofsimple operation, mild conditions and the like, and is easy to be industrialized.
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Page/Page column 12-21
(2019/11/20)
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- PHARMACEUTICAL COMPOSITION AND APPLICATION REPLACING QUINOLONE DERIVATIVE, PHARMACEUTICAL ACCEPTABLE SALT, OR STEREOISOMER
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Provided are a substituted quinolone derivative as shown by formula (I), or a pharmaceutically acceptable salt and a prodrug molecule thereof, and a pharmaceutical composition thereof, as well as the use of same in preparing drugs for the prevention and treatment of a tumor. The quinolone derivative, salt, prodrug molecule, and pharmaceutical composition thereof can be used as a protein kinase inhibitor, which is effective in inhibiting the activity of AXL protein kinase, and is capable of inhibiting the proliferation, migration and invasion of various tumor cells; and can be used in the preparation of anti-tumor drugs, especially drugs for treating hyperproliferative diseases such as a tumor in human beings and other mammals.
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Paragraph 0050; 0051
(2018/07/06)
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- Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
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Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
- Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
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p. 8072 - 8076
(2017/12/08)
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- Mechanistic insights into a catalyst-free method to construct quinazolinones through multiple oxidative cyclization
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A novel one-pot benign oxidative cyclization of alcohols with 2-aminobenzamides was successfully developed without catalyst to afford the quinazolinones under O2. This one-pot protocol involved oxidations and cyclizations to construct the skeleton of quinazolinones through possibly three kinds of distinct reaction mechanisms.
- Wang, Zhen-Zhen,Tang, Yu
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p. 1330 - 1336
(2017/02/15)
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- 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors
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Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1,4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds, 9im, tightly bound with Axl prote
- Tan, Li,Zhang, Zhang,Gao, Donglin,Luo, Jinfeng,Tu, Zheng-Chao,Li, Zhengqiu,Peng, Lijie,Ren, Xiaomei,Ding, Ke
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p. 6807 - 6825
(2016/08/05)
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- Isatoic anhydride and its process for synthesis of derivatives of
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The invention discloses a synthesis method of isatoic anhydride and a derivative thereof, relating to the technical field of chemical synthesis. In the presence of catalysis of an organic selenium catalyst, isatin or a derivative thereof is oxidized by using hydrogen peroxide to prepare the isatoic anhydride and the derivative thereof. The synthesis method disclosed by the invention is simple and easily available in raw materials, low in cost, clean in oxidizing agent, free from a metal catalyst, and environmentally friendly, can be carried out in a neutral environment, and is small in corrosion to equipment.
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Paragraph 0048; 0049; 0050; 0051; 0052; 0053; 0054
(2017/01/12)
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- N-benzyl tryptanthrin derivative, and preparation method and application thereof
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The present invention relates to an N-benzyl tryptanthrin derivative, and preparation method and use thereof. The N-benzyl tryptanthrin derivative of the present invention is characterized in that the derivative has a structural general formula as represented by formula 1, wherein each group is defined as in the specification. The preparation method of the compound is simple, has mild conditions and high yield, and is suitable for industrial production. The N-benzyl tryptanthrin derivative has good indoleamine-2,3-dioxygenase (IDO) inhibitory activity, and can be used for treating diseases having the pathological feature of IDO-mediated tryptophan metabolism.
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Paragraph 0120; 0121
(2016/10/31)
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- Structure-activity relationship and properties optimization of a series of Quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway
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Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.
- Nencini, Arianna,Pratelli, Carmela,Quinn, Joanna M.,Salerno, Massimiliano,Tunici, Patrizia,De Robertis, Alessandra,Valensin, Silvia,Mennillo, Federica,Rossi, Marco,Bakker, Annette,Benicchi, Tiziana,Cappelli, Federico,Turlizzi, Elisa,Nibbio, Martina,Caradonna, Nicola P.,Zanelli, Ugo,Andreini, Matteo,Magnani, Matteo,Varrone, Maurizio
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supporting information
p. 526 - 545
(2015/04/14)
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- Synthesis and Nematicidal Activities of 1,2,3-Benzotriazin-4-one Derivatives against Meloidogyne incognita
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A series of novel 1,2,3-benzotriazin-4-one derivatives were synthesized by the reaction of 3-bromoalkyl-1,2,3-benzotriazin-4-ones with potassium salt of 2-cyanoimino-4-oxothiazolidine in the presence of potassium iodide. Nematicidal assays in vivo showed that some of them exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita, up to 100% at the concentration of 10.0 mg L-1, which indicated that 1,2,3-benzotriazin-4-one derivatives might be potential for novel promising nematicides. The nematicidal activity was influenced by the combination of substituent type, substituted position, and linker length in the molecule. The inhibition rate data at the concentrations of 5.0 and 1.0 mg L-1 for the compounds with high inhibitory activities were also provided. When tested in vitro, none of them showed direct inhibition against M. incognita. The investigation of a significant difference between in vivo and in vitro data is in progress.
- Wang, Gaolei,Chen, Xiulei,Deng, Yayun,Li, Zhong,Xu, Xiaoyong
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p. 6883 - 6889
(2015/08/18)
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- Recyclable (PhSe)2-catalyzed selective oxidation of isatin by H2O2: a practical and waste-free access to isatoic anhydride under mild and neutral conditions
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After a series of careful conditional optimizations and catalyst screenings, a methodology to prepare isatoic anhydrides through organoselenium-catalyzed selective oxidation of isatins by H2O2 under mild and neutral conditions was developed. The reactions were very practical because of the recyclability of the catalyst and solvent and the convenient isolation procedures of the products. This work reports the organoselenium-catalyzed oxidation of heterocycles that greatly expands the application scopes of organoselenium catalysis. It also indicates that the organoselenium catalysts are robust enough to be recycled in industrial production if suitable isolation procedures are developed.
- Yu, Lei,Ye, Jianqing,Zhang, Xu,Ding, Yuanhua,Xu, Qing
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p. 4830 - 4838
(2015/10/05)
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- Palladium-catalyzed carbonylation of o-iodoanilines for synthesis of isatoic anhydrides
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A novel palladium-catalyzed oxidative double carbonylation of o-iodoanilines for the synthesis of isatoic anhydrides has been developed. The reaction employs readily available o-iodoanilines as the starting materials and proceeds under mild conditions. For extension, palladium-catalyzed oxidative carbonylation of anthranilic acids was developed for the synthesis of substituted isatoic anhydrides in high to excellent yields.
- Gao, Sha,Chen, Ming,Zhao, Mi-Na,Du, Wei,Ren, Zhi-Hui,Wang, Yao-Yu,Guan, Zheng-Hui
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p. 4196 - 4200
(2014/05/20)
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- A phosgene and peroxide-free one-pot tandem synthesis of isatoic anhydrides involving anthranilic acid, boc anhydride and 2-chloro-N-methyl pyridinium iodide
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A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The synthesis involves the carbamate formation with boc anhydride followed by in situ cyclization to afford the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability and preparation from readily available raw materials.
- Verma, Chhaya,Sharma, Somesh,Pathak, Arunendra
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supporting information
p. 6897 - 6899
(2019/04/10)
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- Is the 2,3-carbon-carbon bond of indole really inert to oxidative cleavage by Oxone?-Synthesis of isatoic anhydrides from indoles
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A recent report has indicated that the oxidizing agent Oxone does not possess the ability to cleave the 2,3-carbon-carbon bond of indole. Work in our laboratory shows that this is not the case. Indole and a variety of aryl ring substituted derivatives readily react to form synthetically important isatoic anhydrides.
- Nelson, Amber C.,Kalinowski, Emily S.,Czerniecki, Nikolas J.,Jacobson, Taylor L.,Grundt, Peter
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supporting information
p. 7455 - 7457
(2013/11/06)
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- Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists
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Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC 50 of 0.17-0.22 μM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
- Acker, Timothy M.,Khatri, Alpa,Vance, Katie M.,Slabber, Cathryn,Bacsa, John,Snyder, James P.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 6434 - 6456
(2013/09/23)
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- TUMOR NECROSIS FACTOR ALPHA INHIBITORS AND THEIR USE IN THE TREATMENT OF HUMAN DISEASES
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treatment of a variety of disorders, including the treatment of pathological conditions associated with tumor necrosis factor alpha. The inhibitors of tumor necrosis factor alpha have the following structures: including stereoisomers, pharmaceutically acceptable salts, and solvates thereof, wherein substituents are as defined herein. Compositions containing an inhibitor of tumor necrosis factor alpha in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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- PROLYL HYDROXYLASE ANTAGONISTS
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This invention relates to certain 2-[(quinolin-3-yl)carbonyl]aminoacetic acid derivatives of formula (I), where the various groups are defined herein, and which are useful in treating anemia.
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Page/Page column 68
(2010/11/26)
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- 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase
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Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
- Tedesco, Rosanna,Shaw, Antony N.,Bambal, Ramesh,Chai, Deping,Concha, Nestor O.,Darcy, Michael G.,Dhanak, Dashyant,Fitch, Duke M.,Gates, Adam,Gerhardt, Warren G.,Halegoua, Dina L.,Han, Chao,Hofmann, Glenn A.,Johnston, Victor K.,Kaura, Arun C.,Liu, Nannan,Keenan, Richard M.,Lin-Goerke, Juili,Sarisky, Robert T.,Wiggall, Kenneth J.,Zimmerman, Michael N.,Duffy, Kevin J.
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p. 971 - 983
(2007/10/03)
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- PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides compounds represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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- 4,4-DISUBSTITUTED PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides 4,4-(disubstituted)piperidine derivatives represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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Page/Page column 373
(2008/06/13)
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- INHIBITORS OF MACROPHAGE MIGRATION INHIBITORY FACTOR AND METHODS FOR IDENTIFYING THE SAME
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Inhibitors of MIF are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures (Ia), (Ib) including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R1, R2, R3, R4, X, and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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- Substituted imidazo [1,5-a] [1,2,4] triazolo [4,3-d] [1,4] benzodiazepine derivatives
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The present invention is a compound of formula The compound and derivatives or pharmaceutically acceptable salts thereof of the invention have a good affinity and selectivity to the GABA A α5 receptor and are useful for the treatment of diseases related t
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- Intramolecular 1,3-Dipolar Cycloadditions. Part 1. A Facile Synthesis of Benzimidazo- and Quinazolinotriazolobenzodiazepines
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The synthesis of hitherto unknown 9H-benzimidazotriazolobenzodiazepines (4, 11a-e and 12a-c) and 9H-quinazolinotriazolobenzodiazepin-11-ones (5 and 18a-g) is reported. 2-(2-Azidoaryl)benzimidazoles (6 and 10a-h) and 2-(2-azidoaryl)quinazolin-4(3H)-ones (7 and 17a-g) react with propargyl bromide to give non-isolable intermediates which undergo an intramolecular 1,3-dipolar cycloaddition to the title compounds.
- Mohiuddin, Ghulam,Reddy, Padala Satyanarayana,Ahmed, Khalil,Ratnam, Chengalvala Venkata
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p. 1839 - 1868
(2007/10/02)
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- The Chemistry of 2-Aminobenzoyl Hydrazides. 1. Effects of Orthoester Substituents on the Mode of Cyclization
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Treatment of substituted 2-aminobenzoyl hydrazides with orthoesters has been found to yield different products depending upon the type of orthoester employed.Equimolar quantities of orthoester and hydrazide yield 3-amino-4(3H)-quinazolinones, whereas utilization of a two-fold excess (or greater) of orthoester yields, in some cases, 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones as minor products in addition to N-imidate esters as major products.Treatment of hydrazides with trimethyl orthobenzoate yields substituted 5-(2-aminophenyl)-1,3,4-oxadiazoles and 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones.The steric bulk of the phenyl group in trimethyl orthobenzoate effects the formation of adduct at the β-nitrogen of the hydrazide which cyclized to the oxadiazole and benzotriazepinone products.In the aliphatic orthoester series, the formation of adduct to the aromatic amino group appears to be favored which gives rise to quinazolinone and benzotriazepinone products.
- Leiby, Robert W.
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p. 1825 - 1832
(2007/10/02)
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- Pyrazoloquinazolin-9-ones: A New Series of Antiallergic Agents
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A new series of antiallergic agents, pyrazoloquinazolin-9-ones, was synthesized and evaluated for inhibitory effects in the rat reaginic passive cutaneous anaphylaxis (PCA) screen.Several analogues were found to be more potent than cromolyn sodium intravenously.Structure-activity relationships are discussed.One of the compounds, 4,9-dihydro-5-methoxy-9-oxopyrazoloquinazoline-2-carboxylic acid (36), was found to be approximately 250 times more potent than cromolyn sodium intravenously.
- Sircar, Jagadish C.,Capiris, Thomas,Kesten, Stephen J.,Herzig, David J.
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p. 735 - 742
(2007/10/02)
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- Substituted benzodiazepines and method of use
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Aminoacyl derivatives of 2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c] [1,4]benzodiazepines in the form of their racemic mixtures, optical isomers and salts, their method of preparation and method of use are described. The compounds are useful in treating anxiety in warm-blooded animals.
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