- 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 and nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita
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A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were synthesized and characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The bioassay results showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the concentration of 10.0 mg L?1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a concentration of 1.0 mg L?1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing 4,5-dihydro-thiazole-2-thiol could be optimized further.
- Chen, Xiulei,Zhou, Zhen,Li, Zhong,Xu, Xiaoyong
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p. 194 - 200
(2019/09/13)
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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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- Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: Preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives
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A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–buildup strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.
- Jentsch, Nicholas G.,Hume, Jared D.,Crull, Emily B.,Beauti, Samer M.,Pham, Amy H.,Pigza, Julie A.,Kessl, Jacques J.,Donahue, Matthew G.
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p. 2529 - 2536
(2018/10/21)
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- BENZAMIDE DERIVATIVE
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The present invention relates to a benzamide derivative of general formula I, a drug composition containing same and a use thereof as a drug, wherein the definitions of R1, Z and Q are as described in the description.
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Paragraph 0085
(2018/08/20)
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- Quinolinone compound and application thereof in drugs
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The invention relates to a quinolinone compound and application thereof in drugs, particularly relates to a novel quinolinone compound, a pharmaceutical composition thereof and use of the compound or the pharmaceutical composition in preparing drugs. The drug is used for protecting, disposing, treating or alleviating HIF-related and/or EPO-related diseases of patients, wherein the HIF-related and/or EPO-related diseases comprise anemia, vascular diseases, regional myocardial ischaemia, metabolic disturbance, wound healing and the like.
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Paragraph 0268; 0269; 0271; 0272; 0273
(2016/10/07)
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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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- Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors
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Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.
- Bori?ek, Jure,Vizovi?ek, Matej,Sosnowski, Piotr,Turk, Boris,Turk, Du?an,Mohar, Barbara,Novi?, Marjana
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p. 6928 - 6937
(2015/09/22)
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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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- BICYCLIC HETEROCYCLIC DERIVATIVES AS MNK1 AND MNK2 MODULATORS AND USES THEREOF
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The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, Alzheimer's disease), as well as methods of treating these diseases.
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Paragraph 0584
(2015/01/06)
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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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- BICYCLIC HETEROCYCLIC DERIVATIVES AS MNK1 AND MNK2 MODULATORS AND USES THEREOF
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The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, Alzheimer's disease), as well as methods of treating these diseases
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Page/Page column 158
(2013/10/21)
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- ANTINEOPLASTIC DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
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The disclosure concerns heterobicyclic compounds of general formula (I) and acid addition salts, hydrates and solvates thereof, as well as enantiomers, diastereoisomers and mixtures thereof. Methods for preparing the compounds, pharmaceutical compositions, and methods of treatment also are disclosed.
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Page/Page column 17
(2011/10/19)
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- COMPOUNDS FOR TREATING DISORDERS MEDIATED BY METABOTROPIC GLUTAMATE RECEPTOR 5, AND METHODS OF USE THEREOF
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Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.
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Page/Page column 104
(2011/07/07)
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- QUINOLONES AND AZAQUINOLONES THAT INHIBIT PROLYL HYDROXYLASE
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Compounds of Formula I are useful inhibitors of HIF prolyl hydroxylases. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
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Page/Page column 55
(2008/12/08)
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- Synthesis of 123I-labelled analogues of imidazobenzodiazepine receptor ligands
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Reaction of bromo- or iodo-substituted isatoic anhydrides with N-methylglycine, L-proline or D-proline afforded bromo- or iodo-substituted 1,4-benzodiazepinediones which on condensation with ethyl or t-butyl isocyanoacetates gave ethyl or t-butyl bromo- or iodo-imidazobenzodiazepine carboxylates. These aryl halides were converted into the corresponding tributylstannanes with bis(tributyltin) in the presence of (triphenylphosphine)palladium(0), and the stannanes were treated with sodium (123I)iodide in the presence of chloramine-T to give the required 123I-labelled analogues of the imidazobenzodiazepine receptor ligands flumazenil and bretazenil.
- Katsifis, Andrew G.,McPhee, Meredith E.,Mattner, Filomena,Ridley, Damon D.
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p. 1061 - 1069
(2007/10/03)
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- Pyridazinedione compounds useful in treating neurological disorders
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The present invention relates to pyridazino[4,5-b]quinolines, and pharmaceutically useful salts thereof, which are excitatory amino acid antagonists and which are useful when such antagonism is desired such as in the treatment of neurological disorders. The invention further provides pharmaceutical compositions containing pyridazino[4,5-b]quinolines as active ingredient, and methods for the treatment of neurological disorders.
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- 4-Quinolinones having antihypertensive activity
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Compositions which contain a quinolone compound of the general formula STR1 wherein n is 0, 1 or 2; R1 is lower alkyl optionally substituted by hydroxy or C1-4 alkoxycarbonyl; allyl; propynyl or phenyl- lower alkyl in which the phenyl ring is optionally substituted by 1 or 2 C1-4 alkoxy groups; R2 is C1-4 alkyl with the proviso that when n is 0, R2 is methyl; and R3, R4 and R5, which may be the same or different, are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, halo, trifluoromethyl or lower alkylthio show antihypertensive activity. Compounds of general formula STR2 in which n, R1 R2, R3, R4 and R5 are as described above are novel subject to the following provisos (a) when R3, R4 and R4 and R5 are hydrogen R2 is methyl and R1 is lower alkyl, R1 contains more than one carbon atom, and (b) when R3 and R4 are hydrogen, R5 is hydrogen or 7-methyl, and R1 is ethyl, R2 contains more than one carbon atom. The specification describes and claims methods of making the compounds and novel intermediates used in such methods.
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