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Dideaza compounds

COMPOUNDS MODIFIED IN THE BRIDGE AND PTERIDINE MOIETY 5,10-Dideaza compounds [Pg.93]

Inspired by the very promosing preclinical and clinical activity of 10-deazaAMT and 10-alkyl-10-deazaAMT analogues, Taylor et a/. [140] devel- [Pg.93]

An alternative route to the diethyl ester IV. 176 was also developed, involving a slow heterogeneous reaction (room temperature, 3 weeks) between 2,4-diamino-5-deazapteridine-6-carboxaIdehyde (IV. 181) and the ylide (IV. 182), generated from the corresponding triphenylphosphonium bromide salt with sodium hydride in V-methylpyrrolidone. The yield via this route was 35%. [Pg.95]

For the preparation of the 2-amino-4(3i7)-oxo analogues of this series, the 2,4-diamino-9,10-dehydro derivative (IV.175) was converted to (IV.187) (88%, yield) by heating in 1 M NaOH under reflux for 3 h [140a]. Treatment of (IV.187) with acetic anhydride containing a catalytic amount of 4- NJ -dimethylamino)pyridine afforded the 2-acetamido-4-oxo mixed anhydride (IV. 188) (84%), which on careful alkaline hydrolysis was converted to the protected acid (IV. 189) (77%,). Coupling to diethyl L-glutamate in V-methyl-pyrrolidin-2-one in the presence of phenyl iV-phenylphosphoramidochloridate [Pg.96]

In assays of substrate activity for a partially purified folylpolyglutamate synthetase (FPGS) preparation from mouse liver, (IV. 164) had an apparent [Pg.97]


In assays against cultured L1210/R81 cells [43], a resistant mutant with a severe defect in MTX active transport combined with a 35-fold increase in DHFR with normal MTX affinity [49], (III. 147) was found to have an IC50 value of 46 /rM as compared with 205 /iM for MTX. Similar incomplete cross resistance was observed between MTX and the 5-substituted quinazolines (III.148) and (III.149). From these results it would seem that the 5,8-dideaza compounds may be taken up better than MTX by the MTX-resistant cells. [Pg.36]

The most recent work in this area, the result of intense synthetic efforts by both Montgomery s and Taylor s groups, has been directed at the preparation of alkyl analogues of (368)-(370) [97, 189]. Montgomery s efforts have focused on the synthesis of 5-alkyl compounds, namely, 5-methyl-5,10-dideazaAP (401) and 5-methyl-5,10-dideaza-5,6,7,8-tetrahydroFA (405) as shown in Scheme 3.76 and Scheme 3.77 [97]. For (401), the key aldehyde (397), readily prepared from (133), was condensed with (398) to yield (399), which was carefully reduced to (400). The choice of reaction conditions for the conversion of (399) to (400) was critical to avoid overreduction. Saponification of (400) and incorporation of the glutamic acid moiety then completed the synthesis. [Pg.164]


See other pages where Dideaza compounds is mentioned: [Pg.33]    [Pg.35]    [Pg.37]    [Pg.38]    [Pg.99]    [Pg.111]    [Pg.112]    [Pg.113]    [Pg.116]    [Pg.33]    [Pg.35]    [Pg.37]    [Pg.38]    [Pg.99]    [Pg.111]    [Pg.112]    [Pg.113]    [Pg.116]    [Pg.125]    [Pg.136]    [Pg.141]    [Pg.33]    [Pg.35]    [Pg.36]    [Pg.37]    [Pg.40]    [Pg.98]    [Pg.101]    [Pg.123]    [Pg.172]    [Pg.201]    [Pg.248]   


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Dideaza compounds with N substitution

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