Quinazolines and Quinazolinones

QUINAZOLINES AND QUINAZOLINONES Doxazosin (84) is an adrenergic postsynaptic a-1 receptor antagonist with antihypertensive 

Alfuzosin (91) is a prazosin-like hypotensive adrenergic a-1 receptor blocker with the special structural feature that two carbons have been excised conceptually from the piperazine ring normally present in this series. Following the usual sequence for this series, reaction of 4-amino-2-chloro-7-dimethoxyquinazoline (89) with the tetrahydro-2-furyl amide of 3-methylaminopropyla-mine (90) gives alfuzosin (91) [25], Alfuzosin is claimed to cause less orthostatic hypotention (dizziness or fainting upon sudden rising) than prazosin. 

Fluproquazone (97) contains a 2-quinazolinone nucleus and is found to be an analgetic agent useful in mild to moderate pain. One of the preparations involves reaetion of 2-isopropylamino-4-methyl-4 -fluoro-benzophenone (96) with potassium cyanate in hot acetic acid [27], 

Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2-bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28]. 

A series of 2-amino-3/4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 (9) with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 [55]. A pharmacophore model was recently published based on this and related structures [56], but no other selectivity or in vivo activity have been disclosed since the original report. 

A series of 4,4-disubstituted quinazolin-2-ones derived from HTV nonnucleoside reverse transcriptase inhibitor leads have shown good in vitro potency and in vivo efficacy [28]. Using FLIPR assays on cell lines with different resting membrane potentials, TTA-Q3 (10) and TTA-Q6 (11) 

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The same methodology can be applied to the synthesis of pharmaceutically relevant quinazolines and quinazolinones containing a fused alicyclic ring [45,46]. 

Alkoxylation in the benzene ring of quinazolines and quinazolinones is readily achieved in the presence of an ortho-nitro group, and even in the absence of a nitro group, displacement of fluorine is still quite facile. Examples of haloquinazolines to have been alkoxylated include 5-chloro-8-nitro-4(3//)-quinazolinone 187 <2005BMC5613>, 7-chloro-6-nitro-4(377)-quinazolinone 188 <1996JME267>, 4-arylamino-7-fluoro-6-nitroquinazolines 189... 

A considerable number of quinazolines and quinazolinones are still being prepared by conventional and well known syntheses, but only new and unusual modifications of known synthesis are described in this section. The section is divided into four parts. The first is on the synthesis of quinazolines in which the pyrimidine ring retains its complete aromatic character (i.e., three conjugated double bonds), and the other three parts are on the synthesis of quinazolines with oxygen, and/or sulfur atoms at the 2-, 4-, and 2,4-positions. 

There are few general methods for the direct functionalization of quinazolines and quinazolinones because of their deactivated nature. TTierefore, these compounds are more commonly constructed from acyclic precursors. For those examples that do exist, SeAr reactions generally take place on the benzene ring, while nucleophilic substitution reactions generally occur on the diazine ring and are selective for the C4 position due to the electropositive nature of this position. Reactions can take place at the C2 position, but generally only if the C4 position is already occupied. 

The Bischler and Niementowski syntheses are the most important methods for the synthesis of quinazolines and quinazolinones, with the latter and more well-known reaction being m improvement on the Bischler synthesis. Additional methods for the synthesis of quinazoline and quinazolinone ring systems involve various rearrangement reactions and metal-mediated processes. Examples of these reactions are illustrated below. 

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

The Niementowski synthesis, first described in 1895, remains one of the most important methods for synthesizing quinazolines and quinazolinones. This reaction involves condensation of anthranilic acids with formamide or acetamide derivatives to form the intermediate quinazoline-4(3//)-ones under thermal conditions. 

The Niementowski synthesis is still used today to prepare a host of quinazolines and quinazolinones of biological significance. For example, the original Niementowski synthesis was used as a key step in the synthesis of gefitinib (Iressa) by Richards and co-workers. ° Fusion of 4,5-dimethyoxyanthranilic acid and formamide fiimished the desired quinazolinone in 20% yield. This yield was significantly improved in later work by Orfi and co-workers using formadine acetate and formamide under microwave conditions to provide the product in quantitative yield. 

Transition metal-promoted reactions have recently become important in the synthesis of the basic core structures of quinazolines and quinazolinones. While many of the examples below are not necessarily biologically relevant in and of themselves, they highlight important areas of development in the synthesis of these ring classes that can be employed in the future synthesis of compounds with greater biological significance. 

The synthesis of several commercially available and biologically significant quinazolines and quinazolinones are illustrated below. In most cases, the quinazoline or quinazolinone ring system is constructed from acyclic precursors and then functionalized accordingly. 

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