4 -Quinazolones

One of the first quinazolone-based drugs, the sedative hypnotic methaqualone (83-4), gained considerable notoriety as a drug of abuse under the alias ludes after the original tradename Quaalude. The compound is prepared in a straightforward fashion by fusion of anthranilamide (83-1) with orf/zo-toluidine (83-2) [93] the reaction can be envisaged as proceeding via the di-amide (83-3). 

Condensation of an aminoketone with urea leads to the formation of a quinazolone by incorporation of carbonyl carbon and one amino group. Thus reaction of the aminobenzophenone (84-1) with urea can be rationalized by assuming the initial formation of the urea exchange intermediate (84-2). Cyclization will then give fluproquazone (84-3) [94], a nonopioid analgesic that shows NSAID-like activity in the absence of a typical acidic function. 

A quinazolone moiety also provides the nucleus for a highly simplified leukotriene antagonist (compare this compound with verlukast (29-6), discussed earlier in this chapter). Condensation of the anthranilate ester (85-1) with formamide leads to the formation of the quinazolone (85-2). Reaction of the salt from the reaction of this product with a strong base with ethyl 3-bromoacrylate leads to vinylation on nitrogen by what is probably an addition-elimination sequence the product is largely the E isomer (85-3). Saponification then affords tiacrilast (85-4) [95]. 

The discovery that the cyclization of one of the sulfonamide groups and the adjacent amine in classic monocyclic diuretics leads to an increase in potency is discussed in the next section. A similar increase in potency is also observed in the anthranilic acid based diuretics. Thus the fusion of anthranilic acid (87-1), which may show diuretic activity in its own right, with propionamide leads to the ring closure and formation of (87-2). Reduction of the unsaturation in the heterocyclic ring then affords the diuretic quinethazone (87-3) [97]. 

The reaction of anthranilamide (88-1) with benzaldehyde, in a reaction clearly modeled on the sulfonamides, can be envisaged as involving hrst the formation of the carbinolamine (88-2) displacement of hydroxyl by amino leads to the aminal and thus the diuretic agent fenquizone (88-3) [98]. The same product 

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Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

In contrast to the 3-amino derivatives, 3-hydroxy-2,l-benzisoxazoles are relatively labile. With nitrous acid they undergo ring fission to anthranilic add. Its 3-acetoxy derivative (258) reacts with primary amines to form the quinazolone (259) (67AHC(8)277, p. 297). 

They also state that analytical studies of the oxidation products of dichroine-a indicate that the dichroines are quinazoline derivatives, as already indicated by Koepfli et al. for their alkaloids. With the probable exception of dichroine-a, these bases are active against malaria in chicks in the descending order dichroine-y (1), dichroine- (4) dichroidine quinazolone (40) the figures in brackets are effective doses (mgm./kilo.). There are also two neutral substances present, umbelliferone (dichrin-A) and dichrin-B, m.p. 179-181°. 

The quinazoline ring also gives some anomalous quatemization reactions, which presumably reflect the influence of the unusual 3,4-bond. 3-Methyl-4-quinazolone (71 Y = O) and, more... 

The lack of structural specificity among sedative-hypnotic drugs has been alluded to before. It is perhaps not too surprising that quinazolones, too, show this activity. The prototype, methaqualone (149), is obtained in a single step from the condensation of the"anthranilamide, 148, with o-toluidine.(The reaction may well involve first formation of the bisamide cycli-zation will then give the quinazolone ring system.) Condensation... 

Trifluoroacetimidoyl chlorides reacted with compounds containing an active methylene group to give enamines that thermally cyclized in cumene to 2-trifluoromethylquinolines (89TL4821). With N.N -disubstituted trifluoroacetamidines, the N-group determined whether cyclization gave triazoles or quinazolones (90TL2717). 

In a similar vein, condensation of the substituted anthranilamide 96 with trimethyl orthoformate affords directly the quinazolone 98. Reaction with phosphorus... 

The solubilities in water and octanol of the pyrazino[l,2-A]quinazolones 23 (R1 =Me, R4 = H R1 = R4 = Me) with various N-2 substituents were determined. Solubility ratios and partition coefficient values were fitted to a predictive equation to evaluate the possibility of aqueous solubility estimates <1997IJP233>. 

A series of piperazine-based antagonists was disclosed as potential obesity agents [77]. Compound 30 shows an hH3R K of 11 nM. Quinazolone 31 was highlighted, and may be of further interest as the specific synthesis and a crystal structure was disclosed [78]. 

In the case of a [l,2,3]triazolol,5- ]quinazolone derivative (closely related to 489) a direct one-step amination has been reported where the cyclic amide moiety is replaced by an amino substituted structural unit <2006OL2425>. 

Coupling 1-aminoanthraquinone onto pyrazolo-(5,lb)-quinazolone with the general structure... 

P.O.67 is a member of the pyrazolo-quinazolone pigment series. Its constitution is listed in the Colour Index under Constitution No. 12915. Coupling component is the heterocycle shown on p. 503. The diazonium component is 2-nitro-4-chloroani-line. Coupling affords the pigment, which was found to exhibit the hydrazone structure ... 

Many other 6-membered ring systems have been explored as the basis for high-temperature polymers, including anthrazoline, quinazolone, benzoxazinone, and j-triazine [Cassidy, 1980 Critchley et al., 1983],... 

When the 6-position of the 4(377)-quinazolone is blocked, nitration occurs at the 5-position <1975JOC363>, but when the 7-position is also substituted, as with 6-bromo-7-chloro-4(3/7)-quinazolinone 44, the 8-substituted product 45 is obtained as the sole product <1996JME918>. 

Electrocyclic ring closure reactions of phenyl ketenimides 331 allow the construction of the quinazolone ring (Scheme 73). For instance, quina-zolones 332 were synthesized some years ago in 4-85% yield by heating 331 (R2 = Ph) in addition, dimerization through a [4 + 2] cycloaddition leading to 333 (30-73% yield) was observed (78S760). Compound 331 (R1 = CF3) has been employed for the preparation of the trifluoromethy-lated quinazolone 334 (71% yield) [90TL(31 )2717]. 

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