26605-69-6

Geocillin,Roerig,US,1972

Carbenicillin indanyl sodium has been shown to reduce blood pressure in mammals and also has been used as a β-lactam antibiotic.

Has been shown to reduce blood pressure in mammals and also has been used as a β-lactam antibiotic.

ChEBI: Carindacillin sodium is an organic sodium salt. It contains a carindacillin(1-).

(A) Preparation of Phenylchlorocarbonyl Ketene: To phenylmalonic acid (20 g) in ethyl ether (100 ml) there is added phosphorus pentachloride (46 g). A vigorous reaction occurs. The reaction mixture is refluxed for 4 hours then the ether partially removed by heating on a steam bath. The reaction mixture becomes black when about half the ether is removed and the remaining ether is removed under reduced pressure (at 100 mm). The residue is distilled under vacuum and the fraction boiling at 75° to 90°C at 1.5 to 4 mm collected. The product, a yellow liquid, is redistilled at 74°C and 1.5 mm. It shows a strong peak in the infrared region of the spectrum at 4.69 mu. Repetition of this procedure but using 10 g of phenylmalonic acid instead of 20 g produces a less vigorous reaction on addition of the phosphorus pentachloride. The same product is obtained.
(B) Acylation of 6-Aminopenicillanic Acid: To a solution of the aryl halocarbonyl ketene (0.1 mol) in methylene chloride (sufficient to provide a clear solution and generally from about 5 to 10 ml per gram of ketene) there is added the proper alcohol R2OH (0.1 mol), in this case 5-indanyl alcohol. The reaction mixture is maintained under an atmosphere of nitrogen and stirred for a period of from 20 minutes to 3 hours, care being taken to exclude moisture. The temperature may range from about -70° to about - 20°C. The infrared spectrum of the mixture is then taken to determine and confirm the presence of the ketene ester. A solution of 6-aminopenicillanic acid-triethylamine salt (0.1 mol) in methylene chloride (50 ml) is added and the mixture stirred at -70° to -20°C for 10 minutes. The cooling bath is then removed and the reaction mixture stirred continuously and allowed to warm to room temperature.
Various isolation methods are then spelled out in US Patent 3,679,801.

Geocillin (Pfizer).

Antibacterial

Efforts to obtain orally active forms of carbenicillin led to theeventual release of the 5-indanyl ester carbenicillin indanyl,6-[2-phenyl-2-(5-indanyloxycarbonyl)acetamido]penicillanicacid (Geocillin), in 1972. Approximately 40% of theusual oral dose of indanyl carbenicillin is absorbed. After absorption,the ester is hydrolyzed rapidly by plasma and tissueesterases to yield carbenicillin. Thus, although the highlylipophilic and highly protein-bound ester has in vitro activitycomparable with that of carbenicillin, its activity in vivo isdue to carbenicillin. Indanyl carbenicillin thus provides anorally active alternative for the treatment of carbenicillinsensitivesystemic and urinary tract infections caused byPseudomonas spp., indole-positive Proteus spp., and selectedspecies of Gram-negative bacilli.
Clinical trials with indanyl carbenicillin revealed a relativelyhigh frequency of GI symptoms (nausea, occasionalvomiting, and diarrhea). It seems doubtful that the highdoses required for the treatment of serious systemic infectionscould be tolerated by most patients. Indanyl carbenicillinoccurs as the sodium salt, an off-white, bitter powderthat is freely soluble in water. It is stable in acid. It should beprotected from moisture to prevent hydrolysis of the ester.

Carbenicillin was used parenterally in the treatment of systemic Pseudomonas aeruginosa infections in small animals, usually in combination with an appropriate aminoglycoside agent, but in the USA the injectable is no longer available and most clinicians use ticarcillin or piperacillin in its place. Because the oral form is poorly absorbed and the drug has a rapid elimination half-life, oral therapy is only indicated for the treatment of susceptible urinary tract (and possibly prostate) infections as levels are too low in serum and other tissues for adequate therapy in other systemic Pseudomonas infections.