Reflections chromonics

Nitration of hydroxypropiophenone (7-1) followed by conversion of the phenol to its methyl ether by means of methyl iodide provides the intermediate (7-2) the nitro group is then reduced to the corresponding amine (7-3) by catalytic reduction. The newly introduced amine is then replaced by a nitrile group by successive conversion to the diazonium salt by means of nitrous acid followed by treatment with cuprous cyanide (7-4). Reaction with aluminum chloride removes the methyl ether to afford the ortho acylphenol (7-5). This is converted to the chromone (7-6) as above by reaction with benzoyl chloride and sodium benzoate. The nitrile is next hydrolyzed to the carboxylic acid (7-7) by means of sulfuric acid. The acid is then converted to its acid chloride by means of thionyl chloride and that treated with 2-(A -piperidyl)ethanol (7-8). There is thus obtained flavoxate (7-9) [8], a muscle relaxant whose name reflects its flavone nucleus. 

At that time we considered our stock data on anti-asthmatic compounds from experimental asthma studies in humans. Thus, we knew that mono- and bischromones were highly active by inhalation, but that none of the compounds which we had prepared up to that time were orally effective. This lack of oral activity was, we decided, due to the high polarity and low lipophilic character of the chromone derivatives that we had prepared up to that time. For example, cromolyn had a pKa of about 1.5 and an octanol/water (pH 7.4 aqueous buffer) log D value of about -3.5. Such a compound would be expected to have a very poor absorption profile. This was reflected in its short plasma half-life following intravenous administration and the fact that its plasma levels following oral administration in a number of species were extremely low ( ). 

This particular study proved extremely fruitful and many of the compounds produced were active in our screens. As can be seen in Table IV, the introduction of a propyl substituent into the 10 position of FPL 52845, to give FPL 57579, produced a noticeable improvement in the oral properties of this tricyclic compound. Thus the lipophilicity of the compound was increased over 10 fold and this was reflected in an improved PCA ratio, higher plasma levels after oral dosing in the dog and a longer plasma half-life following intravenous administration in the dog. However, the plasma tj of FPL 57579 was considered to be rather short for a potential oral product. A further consideration of our previous studies indicated that the introduction of a hydroxyl substituent into the 5-position of the chromones would lead to an increase in lipophilicity and this proved to be the case also in this... 

Chromonic phases can in general be oriented by surface alignment or magnetic fields, but when samples are introduced into untreated glass tubes for an X-ray study, there is usually sufficient spontaneous alignment for axial and equatorial reflections to be easily distinguished. (In rare cases a sample in the M phase will form a large scale zig-zag texture like that observed by Bernal and Fankuchen for TMV solutions [49].)... 

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