105590-03-2Relevant academic research and scientific papers
Synthesis of methylene- and difluoromethylenephosphonate analogues of uridine-4-phosphate and 3-deazauridine-4-phosphate
Taylor, Scott D.,Mirzaei, Farzad,Sharifi, Ali,Bearne, Stephen L.
, p. 9420 - 9430 (2007/10/03)
(Chemical Equation Presented) Cytidine triphosphate synthetase (CTPS) catalyzes the formation of cytidine triphosphate from glutamine, uridine-5′-triphosphate (UTP), and adenosine-5′-triphosphate. Inhibitors of CTPS are of interest because of their potential as therapeutic agents. One approach to potent enzyme inhibitors is to use analogues of high energy intermediates formed during the reaction. The CTPS reaction proceeds via the high energy intermediate UTP-4-phosphate (UTP-4-P). Four novel analogues of uridine-4-phosphate (U-4-P) and 3-deazauridine-4-phosphate (3-deazaU-4-P) were synthesized in which the labile phosphate ester oxygen was replaced with a methylene and difluoromethylene group. The methylene analogue of U-4-P, compound 1, was prepared by a reaction of the sodium salt of tert-butyl diethylphosphonoacetate with protected, 4-O-activated uridine followed by acetate deprotection and decarboxylation. It was found that this compound undergoes relatively facile dephosphonylation presumably via a metaphosphate intermediate. The difluoromethylene derivative, compound 2, was prepared by electrophilic fluorination of protected 1. This compound was stable and did not undergo dephosphonylation. Synthesis of the methylene analogue of 3-deazaU-4-P, compound 3, was achieved by ribosylation of protected 4-(phosphonomethyl)-2- hydroxypyridine. Electrophilic fluorination was also employed in the preparation of protected 4-(phospho-nodifluoromethyl)-2-hydroxypyridine which was used as the key building block in the synthesis of difluoro derivative 4. These compounds represent the first examples of a nucleoside in which the base has been chemically modified with a methylene or difluormethylenephosphonate group.
Optionally substituted pyrido[2,3-d]pyridine-2,4(1H,3H)-diones and pyrido[2,]pyrimidine-2(1H,3H)-ones
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, (2011/03/17)
The present invention relates to optionally substituted pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones or optionally substituted pyrido[2,3-d]pyrimidine-2(1H,3H)-ones, i.e., compounds of Formula I: STR1 wherein: Y is --CH2 -- or --C(O)--; R1 is hydrogen or --(CH2)n --R7, wherein: R7 is aryl or heteroaryl, and n is 1 or 2, provided that when Y is --C(O)--, R7 is heteroaryl; and R2, R3, R4, R5 and R6 are hydrogen, or one is selected from lower alkyl, halo, carboxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, di-methylcarbamoyl, methylcarbonyl, methylthio, methylsulfinyl, methylsulfonyl, hydroxymethyl, amino, trifluoromethyl, cyano or nitro; or R2, R3, R4 and R5 are independently selected from hydrogen, lower alkyl, nitro, chloro, fluoro, methoxycarbonyl or methylcarbonyl, provided at least one is hydrogen, and R6 is hydrogen; or a pharmaceutically acceptable ester, ether or salt thereof.
