Chromone lipophilic

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 ( ). 

It was time for our first major re-think. Basically we had shown that our general medicinal chemistry approach to oral activity had been successful. These more lipophilic chromones were indeed being absorbed from the gastro-intestinal tract and reaching their required site of action, but we concluded that one could not use the rat PCA test, or indeed any of our newly developed tests, in a quantitatively predictive sense, for the identification of compounds which would be active anti-asthmatic agents, of the cromolyn type, in humans. I suspect that others have more recently come to the same conclusion about the PCA test, following the clinical evaluation of their own selected compounds. 

Rescreening of a number of our more lipophilic chromone-2-carboxylic acids along this new approach identified an already existing series of compounds which possessed an overall profile close to that which we were seeking. These compounds were principally 5-hydro3 -6,8-dialkyl chromone-2-carboxylic acids and the activity profile of one of these, FPL 52757, is shown in Table III. One can contrast this data with that for FPL 52694, which had the following profile (i) log D = -0.65,... 

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... 

Their greater solubility than the acids in lipophilic solvents is sometimes an advantage for example, monobromination only of chromone-2-carboxylic acid occurs in acetic acid because of the insolubility of the product, but when the ethyl ester is brominated, up to three bromine atoms can be introduced without precipitation occurring [25],... 

---