152810-05-4Relevant articles and documents
Effect of the Chromone Core Substitution of Dirchromone on the Resultant Biological Activities
St-Gelais, Alexis,Alsarraf, Jér?me,Legault, Jean,Plourde, Joanne,Pichette, André
, p. 2786 - 2794 (2021/12/02)
Dirchromone is a bioactive vinyl sulfoxide-bearing chromone first isolated from the shrub Dirca palustris. Altogether, 32 of its derivatives were prepared to assess the effect of substitution of its chromone core upon activities against cancer cell lines, Gram-positive bacteria, and fungi (such as Candida albicans). All compounds were synthesized following a synthetic strategy involving Pummerer and soft-enolization Baker-Venkataraman rearrangements. Substituent position changes induced little variability on the activities tested. There was no correlation between cytotoxic and antibacterial effects, suggesting different underlying mechanisms of action. In particular, hydroxy group and cyanide substituents diminished cytotoxicity, with the latter featuring enhanced antibacterial activity. Higher homologues of 6-alkoxydirchromones also exhibited progressively emerging antifungal activity. Other modifications had moderate effects on cytotoxicity with some derivatives leading to increased potency. This behavior highlights the robustness of the natural dirchromone pharmacophore toward decoration, thus paving the way for more elaborate future drug design.
Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate
Konoike, Toshiro,Matsumura, Ken-ichi,Yorifuji, Tadahiko,Shinomoto, Shoji,Ide, Yutaka,Ohya, Takashi
, p. 7741 - 7749 (2007/10/03)
A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ETA receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon - carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition - elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon - carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.
Structure-activity relationships of a novel class of endothelin-A receptor antagonists and discovery of potent and selective receptor antagonist, 2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4- (4-methoxyphenyl)-2H-chromene-3-carboxylic acid (S-1255). 1. Study on structure-activity relationships and basic structure crucial for ETA antagonism
Ishizuka, Natsuki,Matsumura, Ken-Ichi,Sakai, Katsunori,Fujimoto, Masafumi,Mihara, Shin-Ichi,Yamamori, Teru
, p. 2041 - 2055 (2007/10/03)
A novel series of endothelin-A (ETA) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3] dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ETA receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-,and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 ? such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ETA receptor. The most potent compound is (R)-48 (S-1255), which binds to the ETA receptor with an IC50 value of 0.19 nM and is 630-fold selective for the ETA receptor than for the ETB receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.
Chromene-3-carboxylate derivatives
-
, (2008/06/13)
The present invention provides a compound of the formula (I): wherein R1, R2, R3and R4are each independently hydrogen, optionally substituted alkyl, hydroxy, optionally substituted alkoxy or the like, R5/s
