Naphthyridine derivatives

This class of compounds comprises a series of synthetic agents patterned after nalidixic acid, a naphthyridine derivative introduced in 1963 for the treatment of urinary tract infections. Isosteric heterocyclic groupings in this category include the quinolones (e.g., norfloxacin, ciprofloxacin, lome-floxacin, gatifloxacin, sparfloxacin, moxifloxacin, and ofloxacin), the naph-thyridones (e.g., nalidixic acid, enoxacin, and trovafloxacin), and the cin-nolones (e.g., cinnoxacin) [2] (Fig. 1). 

Table 6.6. IN VITRO ACTIVITY OF 7-(AMINO-SUBSTITUTED ALICYCLICAMINO)NAPHTHYRIDINE DERIVATIVES [73]...

The cyclizations of 4-pyridinylamino(50JOC1224 57MI3 65USP3225 055) and 4-quinolinylaminomethylenemalonates (589) (50JOC1224 70JMC230) were carried out in boiling Dowtherm A for 4-30 min to give 1,6-naphthyridine derivatives (590) in 83-93% yields. 

Diethyl 7V-ethyl-A-[6-(4-ethoxycarbonyl-l-piperazinyl)-5-fluoro-2-pyri-dyl]aminomethylenemalonate (1027) was cyclized on the action of boron trifluoride etherate complex in diphenyl ether at 228-231 °C for 30 min to give the 1,8-naphthyridine derivative (1028) in 90% yield [84JAP(K)80683]. 

The reaction of 2-amino-5,7-dimethyl-1,8-naphthyridine and EMME in boiling Dowtherm A for 45 min gave the pyrido[l,2-o]-1,8-naphthyridine derivative (1602) in 40% yield. The same product (1602) was obtained in 44% yield in the reaction of N-( 1,8-naphthyridin-2-yl)aminomethylene-malonate (1603) and EMME in boiling Dowtherm A for 1 hr. The thermal ring closure of 1603 was unsuccessful. An ethanolic suspension of 1603 was treated with concentrated aqueous ammonium hydroxide at reflux for 24 hr to give 2-aminopyrido[ 1,2-a]-1,8-naphthyridine (1604) in quantitative yield (80FES1052). 

A similar strategy can also be applied for the analogous synthesis of naphthyridine derivatives [93]. Here A-allyl derivatives of o-aminobenzaldehyde,... 

The NMR spectra of all of the parent naphthyridines (l)-(6) can be interpreted by first order splitting rules including meta, para and cross-ring spin-spin coupling. The various chemical shifts are shown in Table 4. As it is now common practice to report H NMR data of naphthyridine derivatives, which are far too numerous to list individually, further information can be obtained from the references given in the table as well as from references in the sections on reactivity (2.11.3) and synthesis (2.11.4). 

The condensation of 4-aminonicotinaldehyde (148) with active methylene compounds (the Friedlander synfhesis) gives good yields of 1,6-naphthyridines (149) (72JHC703, 74JHC151,73JMC849,75CR(C)(280)381>. The hexahydro- 1,6-naphthyridine derivative (150) has... 

The condensation of the N- methylpiperidine (270) with cyanoacetamide gives the hexahydro-2,7-naphthyridine (271) (67AK(26)489), and the reaction between a-oxoketene S,S- acetals (272) and N- methylcyanoacetamide gives the 2,7-naphthyridine derivatives (273) <78JCS(P1)554>. 

Whilst many alkaloids contain the pyridine ring system, the combination of two pyridine rings as exemplified in the naphthyridines is rather uncommon in nature. The alkaloid jasminine (436), a 2,7-naphthyridine derivative, has been isolated from Jasminium species (68AJC1321) whilst 4-methyl-2,6-naphthyridine (437) occurs in the aerial parts of Antirrhinum majus and aronticus (71P2849). 

The alkaloids of perennial rye grass, perloline (438) and perlolidine (302), have been shown to be benzo[/][2,7]naphthyridine derivatives <66JCS(B)454), whilst degradation of calycanthine (439) affords calycanine or dibenzo[c,fc][2,6]naphthyridine (356), the structure of which was proven by an unequivocal synthesis from leucoisoindigo (60MI21100). A number... 

The microwave-assisted synthesis of imidazo[l,2- ][l,8]naphthyridin-l(2//)-ones from 2-chloro[l,8]naphthyridine derivatives has been reported (Scheme 18) <2002SC857>. 

Bismuth(lll) chloride catalyzes the intramolecular hetero-Diels-Alder reaction of aldimines, generated in situ from aromatic amines and the A -allyl derivative of o-aminobenzaldehyde, in acetonitrile at reflux to generate [l,6]naphthyridine derivatives <2002TL1573>. The hetero-Diels-Alder reaction of 3-aryl-2-benzoyl-2-propeneni-triles and enol ethers yields 2-alkoxy, 6-diaryl-3,4-dihydro-2//-pyran-5-carbonitriles (Scheme 29) <1997M1157>. 

A similar vinylogous Mannich reaction has been used by Martin in the total syntheses of the heteroyohimboid alkaloids (—)-ajmalicine and (—)-tetrahydroalstonine <1995JOC3236>. An attempted synthesis of an opioid analgesic 2,4-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one-l,5-dicarboxylate (piperidone) by a double Mannich reaction of oxoglutarate, 2 equiv of phenylacetaldehyde, and methylamine did not give the expected product but instead gave rise to an unexpected [l,6]naphthyridine derivative (Scheme 57) <1998PHA442>. 

Quinolones are synthetic compounds designed around nalidixic acid, a naphthyridine derivative used to treat urinary tract infections in the 1960s. By replacing various functional groups within the nalidixic acid pharmacophore with bioistosteric substitutions, three structural classes of quinolones were devised ... 

Very few synthetic compounds other than the sulfa drugs have shown useful activity against systemic bacterial infections, particularly those due to Gram-negative bacteria. Activity of this kind was discovered in a series of l-alkyl-4-quinolones (60BRP830832), but the most active of these, l,2-dimethyl-6-nitro-4-quinolone and l-methyl-6-nitro-4-quin-olone-3-carboxylic acid, produced eye damage (opacity of the lens) that precluded clinical trial. A closely related 1,8-naphthyridine derivative, nalidixic acid (255), was later found to be effective, and it is largely used for urinary tract infections. The quinolone oxolinic acid (256) is also used for this purpose. These compounds inhibit enzymes concerned in DNA synthesis. 

All four pyrrolo[2,3]pyridines can be prepared by photochemical ring contraction of naphthyridine derivatives, e.g. (210). Although reliable, multistep syntheses are needed for the photolysis substrates, which can only be irradiated in small quantities (Scheme 67) <58LA(612)153>. 

The spectra of the many naphthyridine derivatives that have been reported are too numerous to list individually. The references in Table V can be used as guides leading to more complete compilations. 

Murray and Hauser 62 reported that the cyclization of the condensation product of 3-aminopyridine N-oxide and EMME affords the 1,7-naphthyridine derivative (54). This compound was converted into the chloro derivative (55) by the steps outlined below. Both Ikekawa9 and Albert11 converted compound 55 into the parent 1,7-naphthyridine (3) by oxidation of the hydrazino derivative. This synthetic route constituted the first preparation of the parent compound. 

The benzo[6]2,6-naphthyridine derivative (95) prepared from compound 94 has been converted into the benzo-2,6-naphthyridine-trione (96).122 Aside from a few derivatives of this isomer, prepared in... 

The hydroxy groups in 2-oxo- and 4-oxo-l,X-naphthyridines and in the corresponding 2,7-naphthyridine derivatives are readily replaced by either... 

A large number of 4-oxo derivatives of the 1,8-naphthyridine ring system have been synthesized and screened for their antibacterial activity. In general, the active compounds are similar to the 1,5-naphthyridine derivative nalidixic acid.114-117... 

Nitration, suggested to involve nitrosation/oxidation, occurs during diazotization of some substituted 2-amino-1,8-naphthyridine derivatives (15).41 The selectivity of this process was contrasted with that of the nitronium ion reaction. 

A similar study has been carried out for the self-association of l,8a-dihydro-l, 8-naphthyridine derivatives using DFT methods (B3LYP/6-31+G and B3LYP/ 6-311++G ) [28]. Two possible dimers can be obtained from chiral 1,8a-dihydro-1,8-naphthyridine derivatives homochiral C2 dimers and heterochiral Q symmetry... 

The geometrical characteristic of the minima and transition states of the 1H-l,6a-dihydropirrolo[2,3-b]pyrrole and l,8a-dihydro-l,8-naphthyridine derivatives have been analyzed using a Steiner-Limbach relationship [124—127]. This model is based on the assumption that the total valence of the hydrogen atom involved in the HB is equal to 1 (3.1). The rx and r2 distances are defined in Fig.3.17 (right), and r0 corresponds to the N-H distance for the isolated case (for the definition of rx and r2 see [128]. The reformulation of (1) provides (2) that is expressed as a function of (ri +r2) and (rj — r2), which in lineal systems, corresponds to the distance between the heavy atoms and the relative position of the hydrogen, respectively. As shown in Fig. 3.17, all the geometries nicely fit in the same equation. 

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