2.7- Naphthyridine ketones

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

Azolo[1,5]naphthyridines. Imidazonaphthyridines can be prepared by the reaction of ammonium acetate with appropriately substituted naphthyridinium salts. For example, reaction of the ketone 236 in acetic acid with iron(m) chloride produces the tetracycle 237 <2001AJC105> (Equation 64). 

The Friedlander condensation of 2-aminonicotinaldehyde (221) with ketones and other active methylene compounds gives, as expected, good yields of the 2-substituted or 2,3-disubstituted 1,8-naphthyridines (222) (66JCS(C)315, 67JCS(C)1564, 71JCS(C)2991>. 2-Amino-... 

The Friedlander condensation of 2,6-diaminopyridine-3,5-dicarbaldehyde (393) with various ketones has been reported (77JOC3410). Reaction of the aldehyde with acetophenone, with deoxybenzoin and with a-tetralone generates the 5,10-dihydro-l,9,10-anthyridine derivatives (394 R = H), (394 R = Ph) and (395) respectively, whilst with acenaphthenone the nonacyclic anthyridine (396) is obtained. The condensation between 2-amino-3-ethoxy-carbonyI-l,8-naphthyridine (225) and alkyl carboxylates under basic conditions produces 4-hydroxy-1,9,10-anthyridin-2-ones (397) (79BAP571). 

The synthetic utility of these derivatives towards the preparation of condensed heterocycles has been demonstrated. Thus, treatment of 252 with cyclohexanone under acidic conditions (66JOC3852) (Friedlander reaction) and molten urea affords the naphthyridine 253 and pyridopy-rimidinone 251, respectively (Scheme 76) (89JHC105). Application of these reactions on the isomeric iV-pivaloylamino pyridine ketones affords analogue heterocycles 254-257. 

A novel synthesis75 of, presumably, a hexahydro-l,5-naphthyridine (27) resulted as a by-product of the preparation of a dipyrrolenyl derivative by reductive cyclization of the ketone 26. The stereochemistry about the bridgehead carbon atoms was not established. 

As in the case of the 1,5-naphthyridines, the Skraup reaction can be modified to prepare various methyl derivatives. The use of crotonalde-hyde, methacrolein, and methyl vinyl ketone affords the 2-methyl-,40 3-methyl-,41 and 4-methyl-l,6-naphthyridines,40 respectively. 

Under nonhydrolytic conditions, 2-amino-1,8-naphthyridines (82) do, however, undergo the normal cyclization reactions with a-bromo ketones. Thus, imidazo[l,2- ]naphthyridines (83) are readily obtained.45... 

This chapter summarizes the sparse existing data on those 1,5-naphthyridines that bear functional groups that are joined to the nucleus through their carbon atoms carboxylic acids, esters, amides, nitriles, aldehydes, and ketones. 

Such ketones have been made by direct C-acylation of alkyl-1,5-naphthyridines (see Section 2.2.2). 

The ketone, 2-picolinoylmethyl-l,5-naphthyridine (23), underwent a-bromination and subsequent cyclization with thiourea to give 2-[2-amino-4-(pyridin-2-yl)thiazol-5-yl]-l,5-naphthyridine (24) [substrate, Br2, dioxane, 20°C, 1 h solid, EtOH, (H2X)2CS, reflux, 4 h 16%].268... 

This chapter deals with the carboxylic acids, carbonyl halides, carboxylic esters, carbonitriles, carbaldehydes, and ketone of 1,8-naphthyridine. 

S.C. Zimmermann et al. developed an efficient synthesis of 2-amino-1,8-naphthyridines that can serve as building blocks for host-guest and self-assembling systems. The synthesis commenced with the Reimer-Tiemann formyiation of 2,6-diaminopyridine to afford 2,6-diaminopyridine-3-carbaldehyde in modest yield. Next, the Friediander reaction using activated ketones gave rise to the target compounds. 

A modified Skraup method, namely, the reaction of 4-aminoisoquinoline with methyl vinyl ketone in the presence of As205 and concentrated sulfuric acid, was used to prepare 4-methylbenzo[c]-l,5-naphthyridine (1994AJC2129). 

The reactions of 3-(phenylcarbamoyl)coumarin 170 with ketones in the presence of ammonium acetate in ethanol at 20 C or in the absence of a solvent at 170 C yielded benzo[c][2,7]naphthyridines 171 (1985MI1). 

---