Deaza compounds

REPLACEMENT OF C BY N IN THE PYRAZINE RING 5-Deaza compounds Chemical synthesis 

In the Taylor synthesis of (III.28) [31], aldehyde (HI.32) was obtained by reaction of2-amino-3-cyano-5-(dimethoxymethyl)pyridine and guanidine, followed by cleavage of the acetal with aqueous formic acid. The pyridine aminonitrile was elaborated in a sequence of high-yield steps from 3-cyano-5-methylpyridine-2-thione. These steps consisted of the following (yields in 

Because the yields of diesters (III.30) and (III.44) from nitriles (III.35) and (III.36) were only 15%, an alternative route was sought [32a]. Nitrile (III.38) was converted to aldehyde (III.39) by treatment with formic acid and Raney Ni, and the aldehyde was reduced with NaBH4 and converted directly to 2,4-diamino-6-bromomethyl-5-methylpyrido [1,3-d] -pyrimidine (III.40) by bromination with dibromotriphenylphosphorane in N,7V-dimethylacetamide (DMA). Coupling of (III.40) to dimethyl A-[4-(N-methylamino)benzoyl]-L-glutamate and diethyl A-[4-(A-ethylamino)benzoyl]-L-glutamate afforded the diesters (III.45) and (III.46), respectively. While the yield of (III.45) from (III.40) was 27%, that of (III.46) was unfortunately only 8%. Hydrolysis of the diesters gave the acids (III.42) and (III.43). 

In a follow-up study [34] it was discovered that the condensation of cyanothioacetamide with ethyl 2-ethoxymethylene-3-oxobutanoate in the presence of piperidine in fact gave a 41 % yield of 3-cyano-5-ethoxycarbonyl-6-methylpyridine-2(l//)-thione (III.92), and not the isomeric 4-methyl derivative as previously thought [32]. Methylation of (III.92) (Mel-KjCOj-DMF) followed by reduction (LiAlH4-Et20), methoxymethylation, and oxidation with w-chlorobenzoic acid led to the alcohol (III.98) (50%), the ether (Ill.lOO) 

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Recently, Broom s group has reported the synthesis of a series of 8-deaza compounds, including the AP (161b) and MTX (162b) analogues as well as (144) and 8-deaza-A 10-methylFA (165) [86]. It is noteworthy that their... 

Several additional examples of 8-deaza compounds are known. DeGraw s approach to 8-deazahomoFA (180) is detailed in Scheme 3.34 [ 109a,b]. Treatment of (173) with diazomethane-HCl produced the chloromethyl ketone (174), from which the ylide (175) was obtained by sequential reaction with triphenyl-phosphine and Na2C03. Condensation of (175) with the silyl pyrimidine... 

Base I is quatemized to CCLVIII, which now undergoes the normal hydrogenolysis with Na/Hg to give base CCLIX, Hofmann degradation of which gives trimethylamine and a deaza compound which could not be characterized (203). 

In the SBDD project that produced (86), the design work was initiated through use of the X-ray structure of the PNP apoenzyme, but was more successful when the structures of the PNP-guanine complex and other complexes were available (199). The PNP-guanine crystal structure showed no important interactions with N9, and indicated a potential for hydrophobic interaction in the vicinity of the substrate ribose (Fig. 10.19). To test this, the 9-deaza compound (87) was synthe-... 

Analysis of the plasma clearance kinetics of (IV.91) and (IV.107)-(IV.109) in mice [130] revealed an overall similarity to MTX, except that the 10,10-dimethyl analogue (IV.109) was subject to more rapid biliary and renal excretion. The rapid clearance of this compound was consistent with its lower in vivo potency. The pharmacokinetics of retention of the lO-alkyl-lO-deaza compound (IV. 108) in mouse small intestine and tumour were exactly the same as those of the parent compound (IV.91), showing that introduction of an ethyl group at position 10 does not decrease selective accumulation in the tumour. 

Deaza compounds with carbon insertion in the bridge... 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

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