- Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds
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The invention discloses coumarin/pyridone heterozygous derivatives represented by a formula (I) shown in the description or a pharmaceutically-acceptable salt of the derivatives. The preparation method of the coumarin/pyridone heterozygous derivatives comprises the following steps: one pyridone derivative represented by a formula 3 shown in the description is obtained by a series of synthesis by using one hydroxypyrone with different substituent groups represented by a formula 1 shown in the description as a raw material; and a compound represented by a formula 4 shown in the description is subjected to a condensation reaction to obtain a compound represented by a formula 5 shown in the description, one-step bromination is performed to obtain a compound represented by a formula 6 shown inthe description, the compound represented by the formula 6 and the pyridone derivative represented by the formula 3 are subjected to a one-step nucleophilic substitution reaction to obtain a compoundrepresented by a formula 7 shown in the description, and finally an alkyl protecting group in a pyridone structure is removed to obtain one target compound represented by the formula (I). The compounds provided by the invention are a novel series of single-molecular multi-target series drugs, and have iron chelation, targeted MAO-B inhibitory activity, antioxidant activity, unique advantages for an Alzheimer disease with complicated pathogenesis, a clear mechanism of action and excellent activity.
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Page/Page column 12-19
(2019/10/01)
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- Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease
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A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC50 value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.
- Zhang, Changjun,Yang, Ke,Yu, Sihang,Su, Jing,Yuan, Shengli,Han, Jiaxin,Chen, Yan,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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p. 367 - 382
(2019/07/19)
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- Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles
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This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of
- Kawasuji, Takashi,Johns, Brian A.,Yoshida, Hiroshi,Weatherhead, Jason G.,Akiyama, Toshiyuki,Taishi, Teruhiko,Taoda, Yoshiyuki,Mikamiyama-Iwata, Minako,Murai, Hitoshi,Kiyama, Ryuichi,Fuji, Masahiro,Tanimoto, Norihiko,Yoshinaga, Tomokazu,Seki, Takahiro,Kobayashi, Masanori,Sato, Akihiko,Garvey, Edward P.,Fujiwara, Tamio
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p. 1124 - 1135
(2013/03/28)
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- TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
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The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as m PGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (m PGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.
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Page/Page column 69
(2013/11/05)
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- Prediction of 3-hydroxypyridin-4-one (HPO) log K1 values for Fe(iii)
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As a means to aid in the design of 3-hydroxypyridin-4-ones (HPOs) intended for use as therapeutic Fe3+ chelating agents, a novel methodology has been developed using quantum mechanical (QM) calculations for predicting the iron binding affinities of the compounds (more specifically, their log K 1 values). The reported/measured HPO log K1 values were verified through their correlation with the corresponding sum of the compounds' ligating group pKa values. Using a training set of eleven HPOs with known log K1 values, reliable predictions are shown to be obtained with QM calculations using the B3LYP/6-31+G(d)/CPCM model chemistry (with Bondi radii, and water as solvent). With this methodology, the observed log K 1 values for the training set compounds are closely matched by the predicted values, with the correlation between the observed and predicted values giving r2 = 0.9. Predictions subsequently made by this method for a test set of 42 HPOs of known log K1 values gave predicted values accurate to within ±0.32 log units. In order to further investigate the predictive power of the method, four novel HPOs were synthesised and their log K1 values were determined experimentally. Comparison of these predicted log K1 values against the measured values gave absolute deviations of 0.22 (13.87 vs. 14.09), 0.02 (14.31 vs. 14.29), 0.12 (14.62 vs. 14.50), and 0.13 (15.04 vs. 15.17). The prediction methodology reported here is the first to be provided for predicting the absolute log K1 values of iron-chelating agents in the absence of pKa values.
- Chen, Yu-Lin,Barlow, Dave J.,Kong, Xiao-Le,Ma, Yong-Min,Hider, Robert C.
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p. 10784 - 10791
(2013/01/14)
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- Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease
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A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pKa, pFe 3+ and log P) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.
- Gaeta, Alessandra,Molina-Holgado, Francisco,Kong, Xiao L.,Salvage, Sarah,Fakih, Sarah,Francis, Paul T.,Williams, Robert J.,Hider, Robert C.
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experimental part
p. 1285 - 1297
(2011/03/23)
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- Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives
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A series of Mannich bases of 2-alkyl-3-hydroxy-pyridine-4-ones, namely 2-alkyl-3-hydroxy-5-N-piperidylmethyl or N,N-dialkylaminomethyl pyridine-4-ones 9, 10 and 15-18, two derivatives of N-aryl-2-methyl-3-hydroxy-pyridine-4-ones 19, 20 and two N-alkyl derivatives of maltol, 21 and 22 were prepared. They were screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue assay (MABA) method. Multiple linear regressions (MLR) analysis was performed for the synthesized compounds as well as a series of pyridinone and pyranone derivatives 23-43 which have been synthesized and evaluated for antimicrobial activity by other researchers previously. Studied compounds showed a better quantitative structure-activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus in comparison with other tested microorganisms.
- Fassihi, Afshin,Abedi, Daryoush,Saghaie, Lotfollah,Sabet, Razieh,Fazeli, Hossein,Bostaki, Ghasem,Deilami, Omid,Sadinpour, Hekmatollah
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body text
p. 2145 - 2157
(2009/09/30)
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- Fluorinated derivatives of deferiprone
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The present invention relates to novel derivatives of deferiprone. In particular, the present invention relates to fluorinated derivatives of deferiprone or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, processes for the manufacture thereof and their use in the treatment of neurodegenerative diseases caused by the presence of free iron or iron accumulation in neural tissues and in diseases wherein excess iron must be removed or redistributed.
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Page/Page column 32
(2008/12/07)
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- Altering pyridinone N-substituents to optimise activity as potential prodrugs for Alzheimer's disease
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Selective design modifications of specifically substituted 3-hydroxy-4(1H)-pyridinones show possibly advantageous ring freedom while maintaining metal-binding ability and antioxidant capacity, moving toward an efficient potential treatment for Alzheimer's disease.
- Scott, Lauren E.,Page, Brent D. G.,Patrick, Brian O.,Orvig, Chris
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supporting information; scheme or table
p. 6364 - 6367
(2009/02/08)
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- Lanthanide containing compounds for therapeutic care in bone resorption disorders
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Lanthanide ions, Ln(iii), are known functional mimics of Ca(ii) ions and have been shown to affect the bone remodeling cycle. Exploiting this disruption to the bone remodeling cycle has potential for the treatment of bone density disorders, such as osteoporosis. In an effort to find new orally active agents for these disorders, a series of Ln(iii) containing complexes incorporating small, non-toxic, bidentate pyrone and pyridinone ligands have been synthesized and characterized (LnL3, Ln = La, Eu, Gd, Tb, Yb, L = 3-oxy-2-methyl-4-pyrone (ma-), 3-oxy-2-ethyl-4-pyrone (ema -), 3-oxy-1,2-dimethyl-4-pyridinone (dpp-) and 3-oxy-2-methyl-4(1H)-pyridinone (mpp-)). Preliminary biological analysis included cytotoxicity, cell uptake and bidirectional transport studies in Caco-2 cells and in vitro hydroxyapatite (HA) binding studies. The proportion of intact compounds bound to HA was calculated based on determination of Ln(iii) concentration by ICP-MS and by UV-vis spectrophotometric assay of the proligand in solution. The LnL3 species were found to have IC 50 values at least 6 times greater than that of cisplatin, ≥ 98% HA-binding capacity, and permeability coefficients in the moderate range. La(dpp)3 was ascertained to be the lead compound for the treatment of bone density disorders with the highest percentage cell uptake of 9.07 ± 2.33% and the highest preliminary Papp value of 3.54 ± 2.86 × 10-6 cm s-1 compared to the other LnL3 complexes tested. This journal is The Royal Society of Chemistry.
- Barta, Cheri A.,Sachs-Barrable, Kristina,Jia, Jessica,Thompson, Katherine H.,Wasan, Kishor M.,Orvig, Chris
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p. 5019 - 5030
(2008/03/13)
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- IRON MODULATORS
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Iron modulator compounds of formula (I) are provided for treating amyloidoses wherein R1 is selected from H, C1-6 alkyl, C1-6 alkenyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkenyl, R2 is selected from H, C1-6 alkyl, C1-6 alkenyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkenyl and C6-10 aralykyl in which the aryl group of the aralkyl group is optionally substituted by hydroxy, halo or C1-4 alkyl R3 is selected from H, C1-6 alkyl, C1-6 alkenyl and C1-12 acyl; R4 is selected from H and C1-3 alkyl R5, R6 and R7 are independently selected from H, C1-6 alkyl, C3-7 aryl, and C1-10 aralkyl; the alkyl, aryl and aralkyl groups being optionally substituted by one or more halo, hydroxy and nitro groups or R5 and R7 together with the nitrogen atom to which they are bonded form a heterocyclic ring optionally substituted by one or more hydroxyl groups or a pharmaceutically acceptable tautomer, ester or addition salt thereof.
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Page/Page column 9; Figure 2
(2010/11/24)
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- Synthesis and antiviral evaluation of cyclic and acyclic 2-methyl-3-hydroxy-4-pyridinone nucleoside derivatives
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A series of cyclic and acyclic nucleoside analogues derived from 3-hydroxy-4-pyridinone were synthesized using the Vorbrüggen reaction. Iron chelation studies, and antiviral evaluation against a broad panel of viruses, were performed. The pKa value of ligand 25 and the stability constant of the corresponding iron-(III) complex were compared to those of deferiprone. The pFe3+ values were found to be similar. Some compounds showed moderate activity against both wild-type HSV-1 and HSV-2, as well as against a thymidine kinase deficient strain of HSV-1. These results suggest a novel mode of action for this group of nucleoside analogues.
- Barral, Karine,Balzarini, Jan,Neyts, Johan,De Clercq, Erik,Hider, Robert C.,Camplo, Michel
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- POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITORY ACTIVITY
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The present invention is to provide a novel compound (I), having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. Compound (I) wherein Z1 is NR4; R1 is hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R2 is optionally substituted aryl; R3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R4 and Z2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.
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Page/Page column 79-80
(2010/11/24)
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- Compositions and methods for chelation therapy
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The invention relates to compositions and methods of treatment using an iron chelator, an antioxidant, estrogen, and/or combinations thereof, optionally, linked to a nanoparticle, to treat a subject in need thereof. The compositions and methods may be used to restore or protect the normal functions of osteoblast and osteoclast by depleting iron and inhibiting oxidative damage. The compositions and methods may also be used to increase the bone formation rate in a subject.
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Page/Page column 16; 20-21
(2010/02/15)
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- Synthesis and antiviral evaluation of 3-hydroxy-2-methylpyridin-4-one dideoxynucleoside derivatives
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We describe the synthesis and the antiviral evaluation of novel α and β dideoxynucleoside derivatives in which the base has been replaced by a 3-hydroxy-2-methylpyridin-4-one. The syntheses were successfully achieved by the use of the standard Vorbrueggen coupling conditions. Moderate activity of these compounds were found on herpes simplex virus (HSV) type 1 and type 2.
- Barral, Karine,Hider, Robert C.,Balzarini, Jan,Neyts, Johan,De Clercq, Erik,Camplo, Michel
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p. 4371 - 4374
(2007/10/03)
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- Novel synthetic approach to 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones
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Novel methods for the synthesis of high pFe3+ iron chelators, 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones, have been developed. The products are obtained, via N-oxide intermediates, from either maltol or ethyl maltol.
- Piyamongkol, Sirivipa,Liu, Zu D,Hider, Robert C
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p. 3479 - 3486
(2007/10/03)
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- PICOLINAMIDE DERIVATIVES AND PEST CONTROLLERS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
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Disclosed are novel compounds useful for the control of harmful organisms, harmful organism control agents using the same, and processes for producing the novel compounds. The useful novel compounds according to the present invention include compounds represented by formula (1). The compounds represented by formula (1) have potent activity against harmful organisms, and do not have phytotoxicity against agricultural and gardening plants, as objects to which the compounds of the present invention are applied for preventive and exterminating purposes, and human beings and beasts. wherein A represents a bond or an optionally substituted alkylene chain; R1 represents one or more groups, which may be the same or different, selected from the group consisting of a hydrogen atom, alkoxy, and haloalkoxy; R2 represents a hydrogen atom, benzyl, alkyl or alkanoyl, in which the groups other than the hydrogen atom may be substituted; and R3 represents a hydrogen atom, cycloalkyl, cycloalkenyl, aryl or a heterocyclic group, in which the groups other than the hydrogen atom may be substituted, excluding the case where R1 represents a hydrogen atom, A represents a bond or a methylene chain, and R3 represent phenyl or cyclohexyl, and the case where A represents an alkylene chain and R3 represents a hydrogen atom.
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- Synthesis, physicochemical properties, and biological evaluation of N- substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential
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The synthesis of a range of novel bidentate ligands containing the chelating moiety 3-hydroxy-4(1H)-pyridinone is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. The crystal structures of one of the ligands and one of the iron(III) complexes are presented. The distribution coefficients of the ligands are reported and are related to the ability of the ligands to remove iron from hepatocytes. The influence of 3-hydroxy-4(1H)-pyridinones on oxidative damage to cells is described. In contrast to the iron chelator in current therapeutic use, desferrioxamine-B, many of the bidentate ligands described in this study are orally active in iron-overloaded mice.
- Dobbin,Hider,Hall,Taylor,Sarpong,Porter,Xiao,Van der Helm
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p. 2448 - 2458
(2007/10/02)
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- Syntheses of 2-Acetyl-3-hydroxy-1-n-propylpyrrole from Isomaltol and 1-n-Alkyl-3-hydroxy-2-methyl-4-pyridones from Maltol
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2-Acetyl-3-hydroxyfuran (2) reacts with n-propylamine affording 2-acetyl-3-hydroxy-1-n-propylpyrrole (3) in 63percent yield.The transformation of 2-methyl-3-hydroxy-4-pyrone (4) into 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones is achieved by benzylation of the 3-hydroxyl group whereupon the product reacts with ammonia and the corresponding pyridone is obtained.The pyridone is alkylated with alkyl bromides and after hydrobromic acid in acetic acid cleavage of the 3-position ether function, 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones are obtained in 48percent overall yield.
- Bartulin, J.,Belmar, J.,Gallardo, H.,Leon, G.
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p. 1017 - 1019
(2007/10/02)
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- Monobactam hydrazide derivatives
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Compounds having the formula I and pharmaceutically acceptable salts thereof which possess antibacterial activity. Rs is a substituted hydroxy pyridone of the formulae: II and III wherein Y1 is CH2X; COOR6; CONR7R8; OH; OCH2R9; CHF2; CHO; CH=N-OR10; CH=CH-R11; CN; CH=N-NHR12, and Y2 is hydrogen; COOH; CONH2; CN; CSNH2; COO lower alkyl; CONR7/R8
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- 3-Acylamino-1-[[[(substituted sulfonyl)amino]carbonyl]amino]2-azetidinones
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Compounds having the formula and pharmaceutically acceptable salts thereof, exhibit antibacterial activity.
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- Physical and structural studies of N-substituted-3-hydroxy-2-methyl-4(1H)-pyridinones
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A series of 3-hydroxy-2-methyl-4(1H)-pyridinones has been prepared with the sunstituents H, CH3, n-C6H11, and CH2CH2NH2 at the ring N.The dipyridinone 1,6-bis(3-hydroxy-2-methyl-4(1H)-pyridinon-1-yl)hexane has also been synthesized.The products with H and CH3 subtituents have been studied by single crystal X-ray diffraction.Crystals of 3-hydroxy-2-methyl-4-pyridinone are monoclinic, a=6.8351(4), b=10.2249(4), c=8.6525(4) Angstroem, β=105.215(4) deg, Z=4,space group P21/n and those of 3-hydroxy-1,2-dimethyl-4-pyridinone are orthorhombic, a=7.3036(4), b=13.0490(6), c=13.7681(7) Angstroem, Z=8, space group Pbca.Both structures were solved by direct methods and were refined by full-matrix least-squares procedures to R=0.037 and 0.044 for 914 and 857 reflections with I>/=3?(I), respectively.Bond lengths and angles in the compounds were normal.All the compounds have been studies by mass spectrometry, and by infrared and proton nmr spectroscopies.The importance of hydrogen bonding to both the solution and solid state properties of these compounds has been confirmed by these techniques.
- Nelson, William O.,Karpishin,Timothy B.,Rettig, Steven J.,Orvig, Cris
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p. 123 - 131
(2007/10/02)
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- Iron-pyridone complexes for anemia
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Pharmaceutical compositions containing an iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionizable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by aliphatic hydrocarbon groups, are of value for the treatment of iron deficiency anemia.
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- Pharmaceutical compositions
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Pharmaceutical compositions containing a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionizable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by aliphatic hydrocarbon groups, or a salt thereof containing a physiologically acceptable ion or ions, are of value for removing toxic amounts of metals, particularly iron, from the body.
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- Synthesis of 3-Hydroxy-2- and 4-pyridone Nucleosides as Potential Antitumor Agents
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The ribo- and arabinofuranosyl nucleosides of antitumor active 2- and 4-pyridones 1a and 2a were prepared by direct condensation of the silylated bases with either 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4a) or 2,3,5-tri-O-benzyl-1-p-nitrobenzoyl-D
- Mao, David T.,Driscoll, John S.,Marquez, Victor E.
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p. 160 - 164
(2007/10/02)
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