76470-66-1

Loracarbef is a synthetic C-5 “carba” analogue of cefaclor. The smaller methylene moiety (as compared to sulfur) would be expected to make loracarbef more reactive/potent, and this seems to be the case. It is more stable chemically, however, and this adds to its virtues.

Lorabid,Eli Lilly and Company

An antibiotic, a synthetic carbacephem analogue of cefaclor, and is more stable chemically.

ChEBI: A synthetic "carba" analogue of cefaclor, with carbon replacing sulfur at position 1. Used to treat a wide range of infections caused by both gram-positive and gram-negative bacteria.

Loracarbef was obtained by biochemical method.
a) Cultivation of a microorganism having an ability of optically selective acylation
As a seed strain, Pseudomonas melanogenum ATCC 17808 [Biological properties are described in Journal of the Agricultural Chemical Society of Japan 37, 71 (1963)] is used.
As the seed medium, an aqueous solution containing 1% polypepton, 1% yeast extract, 0.5% meat extract, 0.5% sodium glutamate and 0.25% sodium chloride and adjusted to a pH of 7.0 with 5 N NaOH is used. One loopful of the seed strain is inoculated into 10 ml the seed medium and culturing is carried out at of 30°C for 24 hours. The whole amount of the seed medium is put into 300 ml of the culture medium in a 2 L Erlenmeyer flask and culturing is carried out at a temperature of 30°C. The composition of the culture medium is the same as that of the seed medium.
b) Preparation of cell suspension
After culturing for 24 hours, cell bodies are recovered from the culture broth by centrifugation and washed 2 times with 50 ml of 0.9% saline solution. The cells are suspended in a concentration of 20 mg/ml by dry weight in 1/30 M phosphate buffer (pH 6.5).
c) Preparation of a substrate solution
200 mg of the trifluoroacetate of ()-cis-7-amino-3-chloro-1-azabicyclo[4,2,0] oct-2-en-8-on-2-carboxylic acid (obtained by the method described in JPUPA No. 87791/80) and 800 mg of the hydrochloride of D-phenylglycine methylester are added in 9 ml of 1/30 M potassium phosphate buffer (pH6.5). 5 N KOH is added in a small portion and the mixture is again adjusted to a pH of 6.5 to dissolve two starting compounds. Finally, deionized water is added to make 10 ml of a solution.
d) Enzyme reaction
In this step, 10 ml of the disrupted cell suspension is added to 10 ml of the substrate solution and enzyme reaction is carried out at a temperature of 30°C for 2 hours. The reaction is monitored by high speed liquid chromatography. Elution is carried out with 7% methanol - 0.2 M KH2PO4 solution. Reaction reaches maximum in a yield of 90% to the starting compound in 2 hours.
After the completion of reaction, cell bodies are removed from the reaction solution by centrifugation. The supernatant is concentrated under reduced pressure and charged on a column with 100 ml of Diaion HP-10. After adding 200 ml of deionized water, elution is carried out with 25% aqueous methanol solution. Then, the fractions containing the desired compound are concentrated under reduced pressure to make a 5 ml of concentrate. The concentrate is charged on a column packed with 130 ml of Sephadex-LH20 and elution is carried out with a solvent of water and methanol (50:50). The desired product is eluted in 55 ml to 75 ml of fractions. The fractions are concentrated under reduced pressure and lyophilized to obtain 78 mg (6R,7S)-7-(R)-phenylglycinamido-3-chloro-1-azabicyclo[4,2,0]oct-2-en-8-on- 2-carboxylic acid of a white powder [α]D21 = -75.8° (c = 0.4, H2O), melting point 300°C or more (browning).

Lorabid (King).

Antibiotic

An oral carbacephem, with carbon replacing sulfur in the fused ring structure. Its structure and properties are otherwise closely related to those of cefaclor, but it has improved chemical stability. Activity and stability to β-lactamases correspond closely to those of cefaclor.
It is almost completely absorbed by the oral route, but food delays absorption. A 500 mg oral dose achieves a serum concentration of around 16 mg/L after 1.3 h. Adequate concentrations are achieved for the treatment of upper respiratory tract infection. Sputum concentrations have been found to be around 2% of the corresponding plasma level. The plasma half-life is about 1 h and protein binding is 25%. Most of the dose is excreted unchanged in the urine, 60% within 12 h. The elimination half-life is increased in patients with impaired renal function. Probenecid delays excretion.
Diarrhea is the most prominent side effect, occurring in about 4% of patients. Other gastrointestinal upsets are also reported. It has been used for the oral treatment of upper respiratory tract infection, skin and soft-tissue infections, and uncomplicated urinary tract infection caused by sensitive organisms, but is not widely available.

Loracarbef (Lorabid) is the first of a series of carbacephemsprepared by total synthesis to be introduced. Carbacephemsare isosteres of the cephalosporin (or △ 3-cephem) antibioticsin which the 1-sulfur atom has been replaced by a methylene(CH2) group. Loracarbef is isosteric with cefaclor and hassimilar pharmacokinetic and microbiological properties.Thus, the antibacterial spectrum of activity resembles thatof cefaclor, but it has somewhat greater potency againstH. influenzae and M. catarrhalis, including β-lactamase–producing strains. Unlike cefaclor, which undergoes degradationin human serum, loracarbef is chemically stable inplasma. It is absorbed well orally. Oral absorption is delayedby food. The half-life in plasma is about 1 hour.

Diarrhea is the most common adverse effect with loracarbef and, along with certain other adverse effects, is seen more frequently with children, so this lessens enthusiasm for the drug in patients younger than 12 years.