The present invention relates to compounds according to formula (I) or a pharmaceutical acceptable salt thereof: (formula I) wherein R1 is alkyl, alkenyl, alkynyl, aryl, OH, or NH2; R2 is selected from H, alkyl, alkenyl, alkynyl, aryl and can optionally form a 4 to 7-membered ring with R3; R3 is selected from H, alkyl, alkenyl, alkynyl, aryl and can optionally form a 4 to 7-membered ring with R2; R4 is selected from H, alkyl, alkenyl, akynyl, aryl and can optionally form 4 to 7-membered ring with R5; R5 is selected from H, alkyl,alkenyl, alkynyl, aryl, and can optionally form 4 to 7-membered ring with R4; and R6 is selected from the group consisting of =O, OH, =NH, NH2, SH, P(O)nHm substituted imines, and substituted amines, wherein n is 2-4 and m is 1-3; with the proviso that only one of either R2 and R3 or R4 and R5 optionally form a 6-membered ring, resulting in a compound of formula (I) comprising three fused 6-membered rings, and compositions useful in treating or preventing conditions and diseases related to Mycobacterium infection, and methods of use directed thereto.

Pyranocoumarin compounds as a novel pharmacophore with anti-tb activity

Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Calanolide analogues and methods of their use

The present invention relates to the preparation of chiral glucocorticoid receptor agents via biaryl atropisomers.

Process for the preparation of chiral glucocorticoid receptor agents

The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (-)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.

Methods for preparing antiviral calanolide compounds

This invention relates to a method for separating enantiomers of a substituted 2-trifluoromethyl-2H-chromene-3-carboxylic acid or ester, a substituted 2-trifluoromethyl-1,2-dihydro-quinoline-3-carboxylic acid or ester, a substituted 2-trifluoromethyl-2H-thiochromene-3-carboxylic acid or ester, a substituted 3-trifluoromethyl-3,4-dihydro-naphthalene-2-carboxylic acid or ester, or a pharmaceutically acceptable salt of the acids or esters, using enantioselective fractional crystallization, enantioselective high performance liquid chromatography, enantioselective steady state recycling chromatography, or enantioselective multicolumn chromatography.

Enantioselective separation method

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Method for the preparation of (+)-calanolide a and analogues thereof

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (±)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Sergey Dzekhster

Papers

Method for the preparation of (+)-calanolide a and analogues thereof

calanolide A and analogues thereof