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We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.

A convenient new method for synthesizing queuine (1 ) (2-amino-5-[ (1 S,2R,3S)-2,3-dihydroxycyclopent-4-enylaminomethyl]pyrrolo [2,3-d]pyrimidin-4(3H)-one}, the base of the naturally occurring hypermodified nucleoside, queuosine, present in certain transfer RNAs, and its biosynthetic precursor, 2-amino-5-aminomethyIpyrrolo[2,3-~ pyrimidin-4(3H) -one (2) (Pre Q1 base), was successfully exploited. This method involved two critical reactions: the Mannich reaction using dibenzylamine-formaldehyde of 2-acylaminopyrrolo[2,3-d]pyrimidin-4(3H)-one (7), which resulted in the selective introduction of the dibenzylaminomethyl group into the 5-position of (7), and an amine exchange reaction of the 5-dibenzylamino function in the resulting Mannich base (1 7) with (1 S,2Rr3S) -2,3-isopropylidenedioxycyclopent-4-enylamine, which yielded the desired queuine (1). Similar reaction of (17) with ammonia gave the biosynthetic precursor of queuine (2) (Pre Q1 base). Thus, a series of queuine analogues with structural variations in their 5-aminomethyl side-chains was synthesized b y the amine exchange reaction of (17) with appropriate amines or b y acylation of (2) with appropriate acylating agents.is the base of a hypermodified nucleoside, queuosine, located in the first position of the anticodon of tRNA molecules from various organisms, including mammalian tissues. Because of its unique structure and particular biosynthesis, much attention has been focussed on its biological function in cells, tissues, and whole mammals. ' Its functional role, however, remains to be clarified.The present study was initiated in order to obtain a sample, sufficient in amount to allow further extensive biological studies of (1) ' The first total syntheses of queuosine, queuine, and its biosynthetic precursor,2 pre Q 1 base (2) (2-amino-5-aminomethylpyrrolo[2,3-d]-pyrimidin-4(3H)-one), were achieved by Goto et ~1 . ~ However, their methods of synthesis, although elegant, require extremely lengthy and multistep procedures which are inefficient when synthesizing large quantities of (1) and its analogues for extensive biological studies.

A novel and efficient synthetic method for the synthesis of pyrrolo [2,3-d] pyrimidine antifolates is described. The key reaction of this method is the photo-initiated free radical addition of bromomalononitrile or ethyl bromocyanoacetate to an enol ether to afford the backbone skeleton of the targeted antifolate molecule. The key intermediates 3 or 4 are smoothly converted to the pyrrolo[2,3-d]pyrimidine antifolates 1 or 2 in three steps and in high overall yield.Folic acid is an important vitamin related to the biosynthesis of nucleic acids and amino acids. Dihydrofolate reductase (DHFR) is one of the most important enzymes involved in the biosynthesis.2 Methotrexate