- HETEROARYL INHIBITORS OF PAD4
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The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.
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Paragraph 00379-00380
(2018/03/28)
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- 2-Aminonicotinic acid 1-oxides are chemically stable inhibitors of quinolinic acid synthesis in the mammalian brain: A step toward new antiexcitotoxic agents
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3-Hydroxyanthranilic acid 3,4-dioxygenase (3-HAO) is the enzyme responsible for the production of the neurotoxic tryptophan metabolite quinolinic acid (QUIN). Elevated brain levels of QUIN are observed in several neurodegenerative diseases, but pharmacological investigation on its role in the pathogenesis of these conditions is difficult because only one class of substrate-analogue 3-HAO inhibitors, with poor chemical stability, has been reported so far. Here we describe the design, synthesis, and biological evaluation of a novel class of chemically stable inhibitors based on the 2-aminonicotinic acid 1-oxide nucleus. After the preliminary in vitro evaluation of newly synthesized compounds using brain tissue homogenate, we selected the most active inhibitor and showed its ability to acutely reduce the production of QUIN in the rat brain in vivo. These findings provide a novel pharmacological tool for the study of the mechanisms underlying the onset and propagation of neurodegenerative diseases.
- Vallerini, Gian Paolo,Amori, Laura,Beato, Claudia,Tararina, Margarita,Wang, Xiao-Dan,Schwarcz, Robert,Costantino, Gabriele
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p. 9482 - 9495
(2014/01/06)
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- An expedient Pd/DBU mediated cyanation of aryl/heteroaryl bromides with K4[Fe(CN)6]
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A practical Pd(PPh3)4/DBU catalytic system for the synthesis of pharmaceutically relevant aminopyridine nitrile intermediates, as well as a variety of other aryl nitriles using non-toxic K4[Fe(CN) 6] has been developed. The key features of our new protocol for cyanation lie in that the reaction can be carried out with readily available Pd(PPh3)4 under mild and green conditions, even without the assistance of other ligands. The Royal Society of Chemistry 2012.
- Zhang, Dengyou,Sun, Haifeng,Zhang, Lei,Zhou, Yu,Li, Chunpu,Jiang, Hualiang,Chen, Kaixian,Liu, Hong
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supporting information; experimental part
p. 2909 - 2911
(2012/03/27)
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- Substituted 2-aminonicotinonitriles
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Aminolysis of the cyanoketene-O,N-acetal 1 Z/E with the amines 2a,b leads to the E-configurated cyanoketeneaminals 3a,b. Compounds 3a,b are reacted with 1,3-biselectrophiles 4, 6a,b, 9 HCl, 12, 13, 15a,b, 17, and 19 to yield the N2-substituted 2-aminonicotinonitriles 5, 7, 8, 10, 11, 14, 16, and 20. Reaction of some 2-aminonicotinonitriles with an α-phenylethyl substituent in position 2 (14b, 16a, 8a, 20b, 5 and 8b) with PPA leads to the primary 2-aminonicotinonitriles 21a-f.
- Troschutz,Dennstedt
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- Synthesis of substituted 2-aminonicotinonitriles
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Mono-, di-, and trisubstituted 2-aminonicotinonitriles 8, 13, 14, and 19 are prepared from ketonic Mannich-bases hydrochlorides 4 · HCl, enones 12, β-aminovinylketones 17, 3-aminoacroleines 18, vinamidinium perchlorates 21, and 3,3-diaminoacrylonitrile (3
- Troschutz,Dennstedt
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- Synthesis and Biological Activity of L-5-Deazafolic Acid and L-5-Deazaaminopterin: Synthetic Strategies to 5-Deazapteridines
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Condensation of 2,4-diamino-6(1H)-pyrimidinone with triformylmethane gives 6-formyl-5-deazapterin (13).Acetylation to 14, followed by reductive amination with dimethyl p-aminobenzoyl-L-glutamate and saponification of the resulting acetylated dimethyl ester 16 then gives L-5-deazafolic acid (12).Condensation of α-cyanothioacetamide with 2-methyl-3-ethoxyacrolein gives 3-cyano-5-methyl-2(1H)-pyridinethione (17), which is converted to 2--3-cyano-5-methylpyridine (18) by arylation with p-nitrofluorobenzene.Free-radical bromination of 18 to the 5-bromomethyl derivate, conversion to the corresponding aldehyde 21 by the Kroehnke procedure, formation of the acetal 22, and amination then gives 2-amino-3-cyano-5-(dimethoxymethyl)pyridine (23).This is condensed with guanidine and the product hydrolyzed selectively with formic acid to give 2,4-diamino-6-formyl-5-deazapteridine (26).Reductive amination of 26 with dimethyl p-aminobenzoyl-L-glutamate followed by saponification then gives L-5-deazaaminopterin (6).An alternative synthesis of 13 results from alkaline hydrolysis of 24 followed by acid cleavage of the resulting acetal 25.Two syntheses of 2,4-diamino-6-methyl-5-deazapteridine (32) are described; functionalization of the C-6 methyl group, however, was not possible.Syntheses of 3-formylthietane (45) and its dimethyl and ethylene acetals (44 and 46, respectively) are described, and their utilization as synthons for the pyridine ring in the 5-deazapteridines 51 and 52 is explored.Difficulties militating against this alternate strategy for the preparation of 26 are dicussed.L-5-Deazaaminopterin (6) is equipotent with methotrexate both as an inhibitor of bovine liver dihydrofolate reductase and of L1210 murine leukemia cells.It is also equipotent with methotrexate in vivo both against L1210 and P388 leukemia in BDF1 mice.
- Taylor, Edward C.,Palmer, David C.,George, Thomas J.,Fletcher, Stephen R.,Tseng, Chi Ping,et al.
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p. 4852 - 4860
(2007/10/02)
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- An Alternate Synthesis of 6-Substituted-5-deazapteridines
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A procedure for synthesis of 2,4-diamino-6-substituted-5-deazapteridines (pyridopyrimidines) is described.Condensation of 1-piperidino-1-propene with ethoxymethylenemalononitrile afforded an enamino malononitrile adduct, which then treated with ammonia yielded 2-amino-3-cyano-5-methylpyridine.Cyclization to 2,4-diamino-6-methyl-5-diazapteridine could be effected with guanidine.Similar condensation of piperidinopropene with ethyl methoxymethylenecyanoacetate followed by cyclization with hydroxylamine gave 2-amino-3-carbethoxy-6-methylpyridine 1-oxide.Reduction with phosphorus trichloride afforded the pyridine base, however, attempts to cyclize the amino ester to 2-amino-4-hydroxy-6-methyl-5-deazapteridine were unsuccessful.
- DeGraw, Joseph I.,Tagawa, Hiroaki
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p. 1461 - 1463
(2007/10/02)
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- Inhibiting the growth of weeds with 2-substituted pyrdidopyimidines and salts thereof
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2-Substituted pyridopyrimidines and their alkali and alkylamine salts as herbicides, and processes for the synthesis of starting materials leading to the preparation thereof.
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