4- substituted quinolones

Fig. 14.13 Various quinolones substituted by 3-aminomethyl-1 -pyrrolidinyl rings with the aminomethyl group inserted into a fused or spirocyclic ring system.

A comparison of catalyst activities for a series of quinolone-substituted Cp chromium complexes, presented in Figure 7.4, indicates the following trends ... 

The 5-position of quinolones can be substituted by small groups such as halogens, hydroxyl, or amino (54—56). The amino group at this position can be advantageous, particularly when appHed to 6,8-difluoro-7-piperazinyl or 6,8-difluoro-7-pyrrohdinyl quinolones. In contrast to 6,8-difluoro quinolones, when this replacement is appHed to ofloxacin, the resulting derivative has reduced antibacterial activity (57). Replacement of the 5-amino group with methylamine or dimethylamine causes activity to drop substantially. Sparfloxacin [110871-86-8] (21), a representative of 5-amino-6,8-difluoro quinolones, affords modest improvements in gram-positive activity as well as increased in vivo potency when compared with both ciprofloxacin and ofloxacin (54). 

The 8-position of the quinolone nucleus can often be advantageously substituted by fluorine (58) or chlorine (59) to give compounds with improved antibacterial potency over hydrogen in this position. With 1,8-naphthyridines, activity is reported to be approximately equivalent to the quinolone bearing a hydrogen in this position (60). As an example of this, see the data for norfloxacin (8) and enoxacin (7) in Table 2. 

The facile a,a diacylation with arylisocyanates has been applied to the synthesis of polymers (434-436), while the monoacylation products have been used as intermediates for the synthesis of substituted a-quinolones and their sulfur analogs (437). 

A -cyclopropylquinolone 63 and iV-fused pyrrolidinyl 66 and piperidinyl 69 quinolones were reported as intermediates for the preparation of potent antibacterial agents. Use of acids as reaction solvent allow for the cyclization of these iV-substituted... 

When iV-substituted acylanilides 9 are treated under the same reaction conditions, the corresponding lV-substituted-2-quinolones 10 are isolated in high yields. This reaction was initially misinterpreted, but it has since been demonstrated to follow a similar mechanistic pathway to the Meth-Cohn quinoline synthesis. ... 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

Pyridyl-4-bromo-6-oxo-5,6,7,8-tetrahydrothiazolo[5,4-g]quinolones and analogues were prepared and tested as potential inotropic agents for treatment of heart failure. For example, the 2-(4-pyridyl) substituted thiazoloquinolone 38 gave a 122% increase in contractility of guinea pig papillary muscle (89EUP1). 

In cyclization of 6-aminoethylene substituted 1-methylbenzimidazole, an angularly annelated l//-l-methyl-8-ethoxycarbonyl-9-oxo-6,9-dihydroimidazo[5,4-/] quinolone 122 prevails over the sterically less hindered (9-oxo group vs 1-methyl group) linearly annelated imidazo[4,5-g]quinoline 123. Hydrolysis of the cyclization product produced the corresponding acid 124 (Scheme 39) (94CCC1145). 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

As a part of the total synthesis of (+ )-corydalic acid methyl ester (12), a reaction of a cyclic enolate with an imine has been applied. The 2-toluamide enolate 9, which in this case is substituted at the methyl group, adds stereospecifically to imine 10, affording mainly tram-iso-quinolone 11 with a d.r. (transjds) > 95 525. 

Selective C4 monochlorination can be accomphshed when the reaction is performed with Ml-substituted 2-quinolones, however, when performing the transformation on N-unsubstituted 2-quinolones both the 2 and... 

A related reaction has been described for the synthesis of 2-quinolones, reacting substituted secondary anilines with malonic acid derivatives. The reaction was carried out neat under microwave irradiation at 290 °C for 15 min. These harsh conditions were reqiured for the elimination of two... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

Fig. 6 Microwave promoted intramolecular cyclization of o-vinyl substituted isocyanates 16 leading to 2-quinolones...

A cme-substitution occurred on the addition of triethylamine to a mixture of 2-quinolone 67 and a 1,3-dicarbonyl compound to give 68 <96BCJ(69)1377>. 

Silylation-amination of 6-acetoxymethyl-5-deazapterine 265 with NH3, HMDS 2, and TsOH for 120 h at 155-160°C in an autoclave affords, after subsequent trans-silylation with boiling methanol, the diamino compound 266 in 74% yield [76]. Silylation-amination-cychzation of the substituted 4-quinolone 267 gives the alkaloid isoaptamine hydrochloride 268 in 51% yield [77, 78] (Scheme 4.30). 

A series of l-cyclopropyl-6,8-difluoro-l,4-dihydro-7-(2,6-dimethyl-4-pyri-dinyl)-4-substituted-quinolones (XIX) was synthesized by Kuo et al. [72] and their inhibitory activities against topo II evaluated. Using their data, we developed Eq. 20 (Table 16) ... 

The synthesis of this aminoquinoline starts with one of the standard sequences for preparation of 4-hydroxyquinolines, i.e., with the formation of the Shiff base (5) from the appropriately substituted aniline and diethyl oxaloacetate. Thermal cycliza-tion gives the quinolone (6) this then spontaneously tautomerizes to the enol form (7). Saponification followed by decarboxylation gives the desired quinolol... 

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

A novel reaction for the synthesis of 4-amino-substituted quinolines 80 or 4-quinolones 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted anilines 84 and 85 in the presence of a catalytic amount of /Mol ucncsul tonic acid (p-TSA) in dry w-butanol led to 80 and 81, respectively <06T9365>. To the authors surprise, the reaction of acetophenones 82 lead to a different outcome than that of the cyclic or acyclic ketones 83 containing more than one carbons a to the ketone. 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

In 1984, the results of a study investigating amino-substituted alicyclic amino groups as replacements for the 7-piperazinyl group, common to many of the most potent quinolones, was reported [73], This comprehensive study systematically examined variations at the 7-position of the 1,8-naphthyridine nucleus. The in vitro antibacterial activities for several of these enoxacin analogues (19) are summarized in Table 6.6. The most noteworthy feature of these data is that replacement of the piperazin-l-yl group with a 3-aminopyr-rolidin-l-yl moiety (compound (19b)) results in an enhancement in potency... 

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