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Studies on a novel, potent and orally effective cholecystokinin A antagonist, FK-480. Synthesis and structure-activity relationships of FK-480 and related compounds

We prepared various novel tricyclic 1,4-benzodiazepine derivatives as cholecystokinin (CCK) A antagonists, which were evaluated preliminarily for inhibition of 125I-CCK-8 binding to rat pancreatic membranes in vitro and inhibiting effect on CCK-8-induced inhibition of charcoal meal gastric emptying in mice. On the basis of structure-activity relationship (SAR) studies, as well as the stability and availability of the starting materials of those compounds, (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo[3,2,1-jk][1 ,4]benzodiazepin-3-yl]1 H-indole-2-carboxamide (9f, FK-480) was selected as a candidate compound for further evaluation. The absolute configuration of the precursor of FK-480, (3S)-amino-1,4-benzodiazepine derivative ((S)-8a, R1 = F) was determined by an X-ray crystallographic study of its ureido derivative with (S)-alpha-methylbenzyl isocyanate. FK-480 is now undergoing clinical studies for the treatment of chronic pancreatitis.

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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HYDANTOINS AND RELATED HETEROCYCLES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-ALPHA CONVERTING ENZYME (TACE)

The present application describes novel hydantoin derivatives of formula (I): or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R3, R4, R5, R 6, R7, R11, and n are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-alpha converting enzyme (TACE), aggrecanase, or a combination thereof.

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Conjugate-base-stabilized bronsted acids as asymmetric catalysts: Enantioselective povarov reactions with secondary aromatic amines

Caught in the act: A new concept for asymmetric Bronsted acid catalysis is presented. Compounds containing an acidic functionality in addition to an anion recognition site act as powerful conjugate-base-stabilized Bronsted acid catalysts. This strategy was applied to the first catalytic enantioselective three-component Povarov reaction of indoline and other secondary aromatic amines (see scheme; M.S.=molecular sieves). Copyright

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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1,2-Dihydro-1-oxopyrrolo<3,2,1-kl>phenothiazine-2-carboxamides and Congeners, Dual Cyclooxygenase/5-Lipoxygenase Inhibitors with Antiinflammatory Activity

A series of 1,2-dihydro-1-oxopyrrolo<3,2,1-kl>phenothiazine, 1,2-dihydro-1-oxopyrrolo<3,2,1-kl>phenoxazine, and 1,2-dihydro-1-oxopyrrolo<3,2,1-de>acridine-2-carboxamides were prepared by reaction of 1,2-dihydro-1-oxopyrrolo<3,2,1-kl>phenothiazine or other corresponding phenoxazine and acridan ethyl or methyl esters with appropriate amines.Several members of this family were found to be potent, dual inhibitors of cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism and to have in vivo antiinflammatory activity in the rat foot edema assay.Structure-activity relationships within this family of compounds are described. 1,2-Dihydro-N-(2-thiazolyl)-1-oxopyrrolo<3,2,1-kl>phenothiazine-1-carboxamide (34) was found to be one of the best compounds to display potent cyclooxygenase/5-lipoxygenase inhibition of arachidonic acid metabolism.Its IC50s against the enzymes sourced from rat basophillic leukemia-1 (RBL-1) cells were 0.07 and 1.4 muM, respectively.It was active in the rat foot edema test for antiinflammatory effect (48percent inhibition at 33 mg/kg po) and in the mouse phenylbenzoquinone induced writhing test for analgesic effect (93percent inhibition at 32 mg/kg po).

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Efficient access to 1,4-benzothiazine: Palladium-catalyzed double C-S bond formation using Na2S2O3 as sulfurating reagent

A novel Pd-catalyzed double C-S bond formation coupling reaction has been developed. This protocol, in which Na2S2O3 was used as sulfurating reagent in metal-catalyzed reactions, provides an efficient method for the synthesis of substituted 1,4-benzothiazine derivates, which are structural elements of numerous bioactivity molecules rendering this protocol attractive to both synthetic and medicinal chemistry.

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Biotransformation of organic sulfides. Part 12. Conversion of heterocyclic sulfides to chiral sulfoxides by Helminthosporium sp. NRRL 4671 and Mortierella isabellina ATCC 42613

The enantioselective oxidation of a series of heterocyclic prochiral sulfides to chiral sulfoxides has been examined using the fungal biocatalysts Helminthosporium species NRRL 4671 and Mortierella isabellina ATCC 42613. Methylthiofuranyl and -thiophenyl substrates gave (S)-configuration products in low to moderate enantiomeric purity on biotransformation with H. species, but pyridyl sulfides with the nitrogen atom located at an optimal distance of 8-10 A from the sulfur centre gave (S) sulfoxides of high enantiomeric purity. The biotransformation of appropriately substituted benzothiane substrates by M. isabellina also gave products of high enantiomeric purity, but with (R) configuration at sulfur. The acceptability of the substrate and the configuration of sulfur oxidation by both H. species and M. isabellina for the range of substrates examined were found to be consistent with predictions based on cubic space models for these oxidations.

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Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Quinolonecarboxylic Acids. 2. Synthesis and Antibacterial Evaluation of 7-Oxo-2,3-dihydro-7H-pyrido<1,2,3-de><1,4>benzothiazine-6-carboxylic Acids

A series of pyridobenzothiazine acid derivatives was synthesized and their in vitro antibacterial activity was evaluated.The 1,4-benzothiazine intermediates, which by Gould-Jacobs quinoline synthesis produced pyridobenzothiazine acids, were prepared by hydrolytic basic cleavage of substituted 2-aminobenzothiazoles and successive cyclocondensation with 1-bromo-2-chloroethane or alternatively with monochloroacetic acid, hence reduction by LiAlH4.The pyridobenzothiazine acids 10c, 30, and 31 show potent antibacterial activities against Gram-positive and Gram-negative pathogens.Structure-activity relationships are discussed.The compound 9-fluoro-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido<1,2,3-de><1,4>benzothiazine-6-carboxylic acid (31) (MF-934) has been found to possess, together with the antibacterial activity, a weak acute toxicity and interesting pharmacokinetic characteristics in several animal species (rat, dog, monkey, man).

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Selective N-alkylation of arylamines with alkyl chloride in ionic liquids: Scope and applications

An efficient N-selective alkylation of primary aromatic amines in molten quaternary ammonium salts, as the solvent, under relatively mild and base-free conditions is presented. On the basis of the Kamlet-Taft parameters and the nucleophilicity of the IL (ionic liquid) anions, the influence of the ionic liquid was evaluated. This protocol was validated on a larger multigram scale and with the syntheses of bioactive heterocycles (e.g., 1,4-benzothiazine and quinoxalines) and new efficient MALDI matrixes. Copyright

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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REACTION BETWEEN N-ACYL-2,3-DIHYDROBENZO-1,4-THIAZINE AND N-ACYLPHENOTIAZINE WITH ORGANOMETALLIC REAGENTS

The title N-acyl-derivatives react with n-BuLi and Grignard reagents leading to products, which, formally, can be considered as derived from a Claisen-type condensation reaction.

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem

 

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Synthesis, anti-cancer evaluation of benzenesulfonamide derivatives as potent tubulin-targeting agents

A series of benzenesulfonamide derivatives were synthesized and evaluated for their anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferative and tubulin polymerization. Compound BA-3b proved to be the most potent compound with IC50value ranging from 0.007 to 0.036 muM against seven cancer cell lines, and three drug-resistant cancer cell lines, which indicated a promising anti-cancer agent. The target tubulin was also verified by dynamic tubulin polymerization assay and tubulin intensity assay.

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Reference£º
Thiazine – an overview | ScienceDirect Topics,
Thiazine | C4H5NS – PubChem