a) A synthetic method is presented: Acylation of 1,3-dipropyl-5,6-diaminouracil (I) with a 3-noradamantane carboxylic acid (II) gave (III). Treatment of (III) with aqueous NaOH afforded the cyclized product KW-3902.
The oxidation of tricyclo[3.3.1.03,7]nonane-3-carboxylic acid methyl ester (I) with CrO3 in acetic anhydride/acetic acid gives a mixture of the 9-oxo and 6-oxo isomers (II), which is condensed with 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione (III) by means of LiOH, and after HPLC separation yields the 9-oxo isomer (IV) of the condensation product. The cyclization of (IV) by means of Ca(OH)2 affords the 1,3-dipropylxanthine derivative (V), which is finally reduced with LiBH4 to a mixture of isomers that is separated by HPLC yielding finally metabolite M1.
The condensation of 9-oxotricyclo[3.3.1.03,7]nonane-3-carboxylic acid methyl ester (II) with 5,6-diamino-1-propylpyrimidine-2,4(1H,3H)-dione (VI) by means of LiOH gives the expected condensation product (VII), which by reduction with NaBH4 and HPLC separation yields the exo-hydroxy isomer (VIII). The condensation of (VIII) with bromoacetone (IX) by means of cesium carbonate affords compound (X), which is cyclized with Ca(OH)2 as before to give metabolite M3. Finally, this compound is reduced with NaBH4 to afford metabolite M2.
The selective biological hydroxylation of compounds (XI) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M3.
The selective biological hydroxylation of compounds (XII) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M1.
The selective biological hydroxylation of compounds (XIII) by means of Absidia ramosa FERM BP-4605 in corn steep liquor, glucose, Brig 35 at 28 C, 5-7 days gives metabolites M2.