- 3,6-Diazaphenothiazines as potential lead molecules – synthesis, characterization and anticancer activity
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3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3′-nitro-2,4′-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation r
- Morak-M?odawska, Beata,Pluta, Krystian,Latocha, Ma?gorzata,Suwińska, Kinga,Jeleń, Ma?gorzata,Ku?mierz, Dariusz
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- Synthesis, spectroscopic characterization, and anticancer activity of new 10-substituted 1,6-diazaphenothiazines
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New phenothiazine derivatives as 10-substituted dipyridothiazines of the 1,6-diazaphenothiazine structure were obtained in the cyclization reaction of 3-amino-3′-nitro-2,2′-dipyridinyl sulfide and 3,3′-dinitro-2,2′-dipyridinyl disulfide, and in the reaction of 2-chloro-3-ntropyridine with sodium 3-amino-2-pyridinethiolate followed by various alkylation and arylation reactions. The reaction of the thiazine ring formation ran via the Smiles rearrangement of the S-N type. As the alkylation reactions could proceed at the thiazine, azine or both nitrogen atoms, the product structure elucidation was based on the 2D NMR (Rotating-frame Overhauser Effect Spectroscopy, Correlated Spectroscopy, Heteronuclear Single Quantum Coherence, and Heteronuclear Multiple Bond Correlation) spectra of the N-methylated product. Some 10-substituted 1,6-diazaphenothizines (5, 10, 12, 13) were at least anticancer active against melanoma C-32 and breast cancer MCF-7 cell lines as a reference drug – cisplatin. The monoazaphenothiazine drug, prothipendyl, turned out to be less active than least 6 derivatives of the 1,6-diazaphenothiazine structure.
- Morak-M?odawska, Beata,Pluta, Krystian,Latocha, Ma?gorzata,Jeleń, Ma?gorzata
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- Catechol diethers as selective PDE IV inhibitors
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This invention relates to 4-substituted catechol diether compounds which are selective inhibitors of phosphodiesterase (PDE) type IV. The compounds of the present invention are useful in inhibiting PDE IV and in the treatment of AIDS, asthma, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases. This invention also relates to pharmaceutical compositions comprising the compounds hereof
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- Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1- phthalazineacetic acid (zopolrestat) and congeners
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A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10-8 M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1- phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10-9 M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.
- Mylari,Larson,Beyer,Zembrowski,Aldinger,Dee,Siegel,Singleton
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p. 108 - 122
(2007/10/02)
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- 3-thiazolylthio carbacephem antibacterial agents
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The present invention provides compounds of the formula STR1 wherein R is hydrogen, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C6 cycloalkyl, or C1 -C6 haloalkyl; A and A' are independently hydrogen, C1 -C6 alkyl, nitro, amino, a 5-6 membered organic heterocycle containing 1, 2 or 3 hetero atoms selected from nitrogen or sulfur, C1 -C6 alkoxy, or phenyl; or A and A' taken together form a group of the formulae STR2 wherein X is hydrogen, halo, C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 alkoxycarbonyl, amino, nitro, or carboxy; and Y is nitrogen or carbon; or a pharmaceutically acceptable salt thereof; pharmaceutical compositions and methods of treatment using the above compounds.
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- THE FIRST BRANCHED BENZOXAZINOPHENOTHIAZINE RING SYSTEM AND ITS AZA-ANALOGUES
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The synthesis of a branched benzoxazinophenotiazine heterocycle is described.The parent compound benzo-benzoxazinophenothiazine (12), was obtained from 2,3-dichloro-1,4-naphthoquinone (6), 2-aminophenol and 2-aminothiophenol.Monoaza-, diaza- and triaza- analogues of this novel heterocycle were also synthesized.The parent compounds, 16-oxa-15-thia-4,5,10,14-tetraazabenzopentaphene (18) and 16-oxa-15-thia-4,5,10,14-tetraazabenzopentaphene (22, R=H) were also synthesized as well as 4-amino-16-oxa-15-thia-4,5,10,14-tetraazabenzopentaphene (24).They are intensely coloured high-melting solids suitable for application as pigments.Their ease of reduction with Na2S2O4 and the ready oxidation of the reduced compounds to applicability also as vat dyes.
- Okafor, Charles O.
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p. 1187 - 1194
(2007/10/02)
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- Process for preparing chloromethyl thiazoles or oxazoles, and intermediates for use therein
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Chloromethyl group substituted heterocyclic compounds of the formulae STR1 wherein X is O or S; Y together with the two carbons to which Y is attached forms phenyl, pyridyl or pyrimidyl, each of which may be substituted by R; R is one of iodo or trifluoromethylthio or one or two of fluoro, chloro, bromo, (C1 -C4)alkyl, (C1 -C4)alkoxy, (C1 -C4)alkylthio, (C1 -C4)alkylsulfinyl, (C1 -C4)alkylsulfonyl or trifluoromethyl; and R1 is hydrogen or R, are prepared by reacting a bifunctional compound of the formulae STR2 with a 2-chloro-1,1,1-tri(C1 -C6)alkoxyethane. Most of the compounds of formulae I and II are novel. These compounds are intermediates of use in the preparation of compounds having pharmaceutical activity. The 2-chloro-1,1,1-tri(C1 -C6)alkoxyethanes are prepared from the corresponding tri(C1 -C6)alkoxyethanes by chlorination with N-chlorosuccinimide or with chlorine in pyridine and a chlorohydrocarbon cosolvent.
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