Quinazoline analogues

A British group headed by T.R. Jones at the Institute of Cancer Research has concentrated on the synthesis and evaluation of quinazoline analogues of FA and AP as specific TS inhibitors. They prepared (214a), (214b), (221),... 

Continuing interest in quinazoline analogues of FA has led to the synthesis of 10-acetyl-5,8-dideazaFA (678) via acetylation of (677) (Scheme 3.149) [276]. Improvements in the synthesis of the diethyl ester of (677) and in the formylation of (677) were also described. 

The presence of a substituted amino group at position 2 contributes to protonability and stabilization of the charge on the N whereas is not mandatory for activity [39], as supported in Table 1 by the data for abanoquil, a very potent but non subtype-selective a,-blocker, in conq)arison to its quinazoline analogue 1 [37], The modelling and QSAR for a series of quinazoline derivatives has recently been published [40],... 

QSAR of EGFR inhibitory activity of quinazoline analogues... 

Deeb, O. and Clare, B.W. (2008a) QSAR of aromatic substances EGFR inhibitory activity of quinazoline Analogues, / Enz. Inhib. Med. Chem. 23, 763-775. 

Table 5.2 Fused anilino-quinazoline analogues are EGFR kinase inhibitors.

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Quinazolin-2(and 4)-one were first shown to exist as 0x0 tautomers by IR and UV spectroscopic comparisons akin to those above (52JA4834, 51JCS3318) like its pyrimidinone analogue, the quinazolinone (41) prefers that configuration to the pczra-quinonoid tautomer (57JCS4874), a conclusion upheld by the NMR study of simple analogues (69T783). 

There is a scattered body of data in the literature on ordinary photochemical reactions in the pyrimidine and quinazoline series in most cases the mechanisms are unclear. For example, UV irradiation of 4-aminopyrimidine-5-carbonitrile (109 R=H) in methanolic hydrogen chloride gives the 2,6-dimethyl derivative (109 R = Me) in good yield the 5-aminomethyl analogue is made similarly (68T5861). Another random example is the irradiation of 4,6-diphenylpyrimidine 1-oxide in methanol to give 2-methoxy-4,6-diphenyl-pyrimidine, probably by addition of methanol to an intermediate oxaziridine (110) followed by dehydration (76JCS(P1)1202). 

Pyrimidines and quinazolines have not been very successful in the antihistamine field. However, thonzylamine (1041 R = OMe) is used in some countries, while its demethoxy-lated analogue, hetramine (1041 R = H), and the quinazoline HPT909 (1042) both have strong support in the literature (63JCS2256, 65AF613, 60MI21301). 

The pyridazine ring of 111 is formed from [4+2] atom fragments in the cyclization of 3-amino-2-chloromethyl-quinazolin-4-one with activated acrylthioamides. The saturated pyridazine ring of 111 aromatized spontaneously to give 112 (Equation 12). Reaction with io-nitrostyrene yielded the 3-nitro analogue of 112 <2003MOL401>. 

The crystal and molecular structures of 6,6-dimethyl-3-methylthio-6,7-dihydro[l,2,4]triazino[l,6-c]quinazolin-5-ium-l-olate 461, obtained by condensation of 455 with acetone, confirmed its zwitterionic structure (75CSC295). Analogues of 461 were also prepared for thermolysis studies (74T3997). 

Thiation of [l,2,4]triazino[3,2-h]quinazoline-3,10-dione 782 with phosphorus pentasulfide in pyridine proceeded selectively to give the 3-thioxo analogue 783. The latter was converted to the corresponding 3-methylthio derivative 784 by reaction with methyl iodide. Treatment of 784 with hydrazine gave 785, which was converted to 786 and 787 by cyclization with formic acid or carbon disulfide (90JHC591). Cyclization of 785 with sodium nitrite in hydrochloric acid gave 788 (90JHC591). 

Similar to their 1,3,4-thiadiazolo analogues, l,3,4-selenadiazolo[2,3-a]quinazolines (380) were synthesized by the reaction of diazotized anth-ranilic acid or its esters with either 2-selenocyano-1,3-diketones or 2-chloro-1,3-diketones, followed by treatment with potassium seleno-cyanate (82G545 83JHC719). 

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