Nalidixic acid

14-Hydroxydihydronormorphinone Cyclobutane carboxylic acid chloride Lithium aluminum hydride 

To a slurry of 110.5 g of 14-hydroxydihydronormorphinone in 2.5 liters of methylene chloride and 280 ml of triethylamine was added a solution of 106 g of cyclobutanecarboxylic acid chloride in 500 ml of methylene chloride. The temperature of the reaction mixture was maintained at 20°C to 25°C during the addition. After 5 minutes the reaction mixture was brought to reflux and heated for 5 hours. 

It was then cooled, washed with water, dried over sodium sulfate and evaporated to dryness. The residue was crystallized from benzene and pentane to give 138.5 g of the dicyciobutane-carbonyl derivative, melting point about 112°C (dec.). 

The dicyclobutanecarbonyl derivative (136.7 g) was dissolved in 200 ml of tetrahydrofuran and added dropwise to a suspension of 34.2 g of lithium aluminum hydride in 1 liters of tetrahydrofuran. The temperature of the mixture rose to reflux during the addition. Reflux was maintained for 2 hours after the addition was completed. After cooling, 110 ml of ethyl acetate was added dropwise, followed by 30 ml of water, followed by a solution of 53 g of ammonium chloride in 125 ml of water. The resulting mixture was filtered and the inorganic precipitate was washed with methanol. Evaporation of the combined filtrates gave 66 g of N-cyclobutylmethyl-14-hydroxydihydronormorphinone, melting point 229 to 231°C. 

Chemical Name 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Common Name — 

Blumberg, H., Pachter, IJ. and Matossian, Z. U.S. Patent 3,332,950 July 25,1967 assigned to Endo Laboratories, Inc. 

Trade Name Manufacturer Country Year Introduced 

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The antibacterial agent nalidixic acid [389-08-2] (37) is formed by reaction of 2-ainino-6-methylpyridine [1824-81 -3] with an alkoxymethylenemalonic ester to form the 1,8-naphthyridine carboxyUc ester followed by alkylation and ester hydrolysis (37). 

The greatest medicinal interest in pyridopyrimidines has been in another type of antibacterial derivative, the analogues of nalidixic acid, piromidic (68) (71CPB1426) and pipemidic (69) acids (75JMC74). 

Derivatives of nalidixic acid (69a-69d), containing an amino or acetyl-amino substituent at position 7 and an alkyl group at N-1, were successfully nitrated to give (70a-70d). However, in all cases hydrolysis of the amino and acetylamino group was observed (79YZ155 80CPB235). 

Treatment of ethyl 4-chloro-7-diethylamino-6-nitro-l,8-naphthyridine 3-carboxylate (104) with the amines RH [R = N(CH2)s NH(CH2)N(C2Hs)2] gives the corresponding 4-amino derivatives [105, R = N(CH2)s, 74% and 105, R = NH(CH2)N(C2Hs)2, 50%]. With diethylamine the 7-chloro-6-nitro derivative of nalidixic acid (i.e., 106) yields the 7-diethylamino compound 107 (62%) (79YZ155). 

Anti-mycobacterium avium activity in vitro of 3-carboxy-7-methyl-6-nitro-l-ethyl-l,8-naphthyridin-4(lH)-one (6-nitro derivative of nalidixic acid) was demonstrated (93MI1). 

Because of the number of citations, only selected imidazoquinolines are described, and biological activity is mentioned only briefly. The largest increase in the number of citations was caused by the discovery of the antibacterial properties of nalidixic acid type drugs. Efforts to prepare the bioisosters, for example of oxolinic acid, intensified in the early 1970s, and the discovery of the carcinogenic properties of 2-aminoimidazoquinolines followed in the early 1980s. These azoloquinolines can be considered as benzene-separated deazapurines. 

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2-amino-6-methylpyridine (36) proceeds directly to the naphthyri-dine (38) the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. W-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). 

Ethoxymethyleneethyl malonate Floctafenine Nalidixic acid Pipemidic acid Piromidic acid Rosoxacin... 

Gallamine triethiodide Ibuprofen Nalidixic acid Oxetorone fumarate Oxolinic acid Piroheptine Rosoxacin Tridihexethyl iodide Ethyl 4-iodobutyrate Meptazinol... 

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