Quinazolinone Derivatives

The clinical acceptance of the dihydrochlorothiazide diuretics led to the synthesis of a quinazolinone bioisostere, fenquizone (54). The synthesis follows the usual pattern of heating 

Synthesis of the CNS depressant/tranquil izer tioperidone (59) begins by alkylation of piperazine derivative with 4-chlorobutyronitrile to give Lithium aluminum hydride 

A related antiinflammatory agent prepared via a more traditional route is fluproquazone (65). Heating with urea in acetic acid results in transamidation by synthon 64 and 

An antipsychotic agent with a chemical structure somewhat similar to that of tioperidone (59) is ket an serin (68). The synthesis involves the straightforward thermal alkylation of 

N 3-(2-chloroethy1 )quinazo1 inedione (66) with pi peridinyl ketone 

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Magyar T, Miklos F, Lazar L, Fiilbp F. Application of a ball milling technique for the condensation of anthranilic hydrazides with aromatic aldehydes towards 4-quinazolinone derivatives. Ghem Heterocycl Gomp 2015 50 1463-9. Khim Geterotsikl Soedin 2014 10 1590-5. 

Application of the condensation process to per-O-benzylated OZTs led to new homochiral quinazolinone derivatives in satisfactory yields (Scheme 61). 

Alkenyl quinazolinone derivatives can also be prepared under Lewis acid conditions, as demonstrated by the synthesis of analogs of the anticonvulsant piriqualone 574, where aldehyde condensation and elimination of water was conveniently effected with zinc chloride and acetic anhydride <2001BML177>. 

Due to the electron-withdrawing nature of the pyrimidine ring, alkenylpyrimidines can undergo addition reactions at the /3-carbon, and while this is a well-established route to substituted pyrimidine derivatives <1994HC(52)1, 1996CHEC-II(6)93>, it has also been used to prepare quinazolinone derivatives 578 from 2-alkenyM(3//)-quinazo-linones 577 <2000T7245>. 

Bergnes (3) prepared quinazolinone derivatives, (III), that were effective in the treatment of cellular proliferative diseases by causing mitotic arrest and monopolar spindle formation. 

Path A leads to tryptophan derivatives (116), some of which are potent cholecystoki-nin antagonists (73). Some quinazolinone derivatives (117) of disconnection pathway B showed extremely high potency and excellent selectivity as cholecystokinin-B receptor sub-type ligands (44). A combination of X-ray crystallography and computational chemistry was used in the decision-making process in the bond disconnection (44) and in the design cf the specific target molecules. 

Chiral molecules with an axis of dissymmetry (atrop isomers) can also be stereochemically resolved on the CTA-ICSE The resolution and pharmacological testing of the enantiomers of methaqualone illustrate this type of application (44). Methaqualone (Fig. 3) is a quinazolinone derivative that possesses hypnotic and anticonvulsive activities. The molecule exists in two enantiomeric forms, M(+) and M(—), due to the hindered rotation around the N-phenyl bond. Mannschreck et al. (44) were able to partially resolve this compound using the CTA-I CSP to optical purities of 0.75 for the (+) isomer and 0.68 for the (—) isomer. The anticonvulsive activity of the two enantiomers was evaluated by the mouse electroshock test, and the (—) isomer was found to be significantly more potent than the (+) isomer. 

AF 11377 is a 15 residue peptide that acts as a CYTOKINE RECEPTOR ANTAGONIST both in terms of competing for binding with IL-1 at the IL-lRl receptor subtype and also blocks functional responses to IL-1 in human and monkey cells, afloqualone [inn, jan] is a quinazolinone derivative. It is a centrally acting SKELETAL MUSCLE RELAXANT. 

In recent studies, 4(3H)-Quinazolinone derivatives have been reported to possess both antimicrobial and antiallergic properties [25], In a cell culture study, 6-Bromo-2-phenyl-3-[(4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl]-4(3H)-quinazolinone exhibited antiviral activity against VACV in E6SM cell culture at a concentration of 1.92 pg/mL. 

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

Hagiwara, Y., M. Kurihara, and N. Yoda Intramolecular Rearrangement — IV. Intramolecular Alkyl Rearrangements and Tautomerism of Quinazolinone Derivatives. Tetrahedron 25, 783 (1969). 

Scheme 9.26 Synthesis of quinazolinone derivatives from 2-halobenzamides.

Since Watanabe s synthesis of 4(3H)-quinazolinones in 1993 via transition-metal catalyzed reductive N-heterocychzation [ 181 ], several catalytic methods for quinazoline synthesis have been developed [182-186]. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives [182] and indoloquinazolines [184]. Also selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed by Sonoda et al. [183]. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-l,2,3,4-tetrahydroquinazolin-4-ones 64 by Kimdu et al. [ 185] (Scheme 12). Recently, condensation of anthranylamide with various aldehydes to 4-quinazotinones has been found to give excellent yields in the presence of cupric chloride [186]. 

Quinazolinone derivatives have been reported with various biological and medicinal properties, such as inhibitors of the epidermal growth factor (EGF) receptors of tyrosine kinase, and as anticancer, antiviral, and anti-tubercular agents. They are also used as ligands for benzodiazepine and... 

Elimination of lorazepam occurs by metabolism within the hver and renal excretion of the metabolites. Glucuronidation to form lorazepam-glucuronide is the major pathway for metabolism. Minor metabolites include a hydroxylated derivative, a quinazolinone derivative and a quinazoline carboxylic acid. Seventy... 

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