Cinoxacin, Azolinic acid: Cinoxacin, 1-ethyl-1,4-dihydro-4-oxo[1,3]-dioxolo[4,5-g] cinnolin-3-carboxylic acid (33.2.14), is synthesized by a different scheme starting with 2-amino-4,5-methylendioxyacetophenone (33.2.10), which is synthesized by reducing 4,5-methylendioxy-2-nitroacetophenone with hydrogen over a platinum catalyst. In diazo-tation conditions, this undergoes spontaneous heterocyclization to 4-hydroxy-6, 7-methylendioxycinnoline (33.2.11) obviously due to the presence of a significant amount of the enol form of acetophenone (33.2.10) under the reaction conditions. The resulting cinnoline (33.2.11) then undergoes bromination by molecular bromine in the presence of potassium acetate, giving 3-bromo-4-hydroxy-6,7-methylendioxycinnoline (32.2.12). Upon reacting this with univalent copper cyanide in dimethylformamide, the bromine atom is replaced with a cyano group, forming the 3-cyano-4-hydroxy-6,7-methylen-dioxycinnoline (33.2.13). The resulting product is alkylated at the first position by ethyl iodide using sodium hydride as a base, and the cyano group is hydrolyzed to a carboxyl group using a mixture of hydrochloric and acetic acids, giving the desired cinoxacin [68,69].
This drug is effective with respect to Gram-negative microorganisms and is used for the same indications as nalidixic and oxolinic acids. Synonyms of this drug are cinobactin, nossacin, uronorm, and others.
Norfloxacin: Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolincarboxylic acid (33.2.18), is the first representative of a series of fluorinated quinolones as well as the first drug of the quinolone derivatives used in medicine that contains a piperazine substituent. The method of synthesis is basically the same as that suggested for synthesizing nalidixic and oxolinic acids.
Reacting 3-chloro-4-fluoroaniline and ethyl ethoxymethylenmalonate gives the substitution product (33.2.15), which upon heating in diphenyl ester cyclizes into ethyl ester of 6-fluoro-7-chloro-1,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.16). Direct treatment of the product with ethyl iodide in the presence of triethylamine and subsequent hydrolysis with a base gives 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-3-quinolin-4-on-carboxylic acid (33.2.17). Reacting this with piperazine gives norfloxacin (33.2.18) [70-75].
Norfloxacin possesses a broad spectrum of bactericidal action. It is highly active with respect to most Gram-negative and a few Gram-positive microorganisms. Anaerobic bacteria are not sensitive to this drug, while enterococci and akinetobacter are not very sensitive. It is used for bacterial infections of the urinary tract, prostate gland, gastrointestinal tract, gonorrhea, and traveler's diarrhea. Synonyms of this drug are noroxin, barazan, fulgram, bacidal, and others.
Ciprofloxacin: Ciprofloxacin, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piper-azinyl)-3-quinolincarboxylic acid (33.2.19), is synthesized in a completely analogous scheme, except that instead of using ethyl iodide in the alkylation stage, cyclopropyl bromide is used [76-78].
Ciprofloxacin possesses a broad spectrum of antimicrobial action. It is highly effective against Gram-negative microorganisms, such as blue-pus bacillus, hemophilic and colon bacillus, shigella, salmonella, meningococci, gonococci, and a few forms of enterococci. It is also active with respect to many strains of staphylococci, camphylobacter, legionella, mycoplasma, chlamydia, and mycobacteria. Ureaplasma urealyticum, Clostridium difficile, and Nocardia asteroids are resistant to it. It is used for infections of the urinary tract, respiratory tract, biliary tract, infective-inflammatory diseases of the abdominal cavity and organs, pelvis minor, bones, joints, and skin.
Ciprofloxacin is also effective for bacterial prostatitis, noncomplicated gonorrhea, osteomyelitis, and pulmonary infections. It is effective in treating acute infectious diarrhea, including traveler's diarrhea and enteritis. Side effects are rarely seen when taking this drug. Synonyms of this drug are ciproquin, ciprolet, cipropan, ciproxan, ciprocinal, and many others.
Enoxacin: Enoxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naph-thiridin-3-carboxylic acid (33.2.24), only differs from norfloxacin in that the carbon atom in position 8 of norfloxacin is replaced with a nitrogen atom, i.e. this drug belongs to the napthiridine series and not the quinolone series. It is synthesized from 2,6-dichloro-3-nitropyridine, which is reacted with N-ethoxycarbonylpiperazine, and which leads to substitution of the chlorine atom at the second position of the pyridine ring to give (33.2.20). Subsequent replacement of the chlorine atom at position C6 with an amino group (using ammonia), acylation of the resulting amino group with acetic anhydride, and finally, reduction of the nitro group at position C3 of the pyridine ring with hydrogen gives 6-amino-3-acetylamino-2-(4-ethoxycarbonylpiperazinyl)pyridine (33.2.21). In order to introduce a fluorine atom at position C3, a Schiemann reaction is carried out. To do this, the free amino group is diazotated with amyl nitrite, and the resulting diazonium salt is treated with tetra-fluoroboric acid. The resulting diazonium tetrafluoroborate undergoes pyrolysis to give 3-fluoro-6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)pyridine. Finally, removing the o
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