CINOXACIN
Synonym(s):1-Ethyl-1,4-dihydro-4-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid
- CAS NO.:28657-80-9
- Empirical Formula: C12H10N2O5
- Molecular Weight: 262.22
- MDL number: MFCD00056776
- EINECS: 249-133-8
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-05 11:59:05
What is CINOXACIN?
Absorption
Rapidly absorbed after oral administration. While concurrent food intake may delay the drug absorption, the total drug absorption is not affected.
Toxicity
Oral, subcutaneous, and intravenous LD50 in the rat is 3610 mg/kg, 1380 mg/kg, and 860 mg/kg, respectively. Oral, subcutaneous, and intravenous LD50 in the mouse is 2330 mg/kg, 900 mg/kg, and 850 mg/kg, respectively. Symptoms following an overdose of cinoxacin may include gastrointestinal effects such as anorexia, nausea, vomiting, epigastric distress, and diarrhea; the severity of the epigastric distress and diarrhea are dose-related. Headache, dizziness, insomnia, photophobia, tinnitus, and a tingling sensation have also been reported in some patients.
Originator
Cinobac,Lilly,UK,1979
The Uses of CINOXACIN
Cinoxacin is an antibacterial quinolone previously known for its use in the treatment of urinary tract infections.
Background
Synthetic antimicrobial related to oxolinic acid and nalidixic acid and used in urinary tract infections.
Indications
For the treatment of initial and recurrent urinary tract infections in adults caused by the following susceptible microorganisms: Escherichia coli, Proteus mirabilis, Proteus vulgaris, Klebsiella species (including K. pneumoniae), and Enterobacter species.
What are the applications of Application
Cinoxacin is an antibacterial quinolone
Definition
ChEBI: A member of the class of cinnolines that is 6,7-methylenedioxycinnolin-4(1H)-one bearing an ethyl group at position 1 and a carboxylic acid group at position 3. An analogue of oxolinic acid, it has similar antibacterial actions. It was formerly used for the treatment of urinary tract infections.
Manufacturing Process
About 23 g (0.095 mol) of 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3- carbonitrile were added to a mixture of 200 ml of concentrated hydrochloric acid and 200 ml of acetic acid. The resultant reaction mixture was heated under reflux for 18 hours, The excess acids were removed under vacuum, and the residue was taken up in 150 ml of a 5% sodium bicarbonate solution. The resultant solution was treated with 5 g of charcoal and filtered. The filtrate was made acidic by the addition of hydrochloric acid and the resulting precipitate was removed by filtration. 23 g, representing a yield of 91.6% of 1-ethyl-6,7-methylenedioxy-4(1H)-oxocinnoline-3-carboxylic acid as light tan crystals which melted at 261°C to 262°C with decomposition were recovered.
brand name
Cinobac (Lilly).
Therapeutic Function
Antibacterial
Antimicrobial activity
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.
Pharmaceutical Applications
A cinnoline derivative formulated for oral administration. It is active against most Enterobacteriaceae, but Ps. aeruginosa, Gram-positive bacteria and anaerobes are resistant.
It is well-absorbed when given orally. Administration with food reduces the peak concentration by about one-third, but the area under the concentration–time curve (AUC) remains unchanged. Concentrations in prostatic and bladder tissues reach 60% and 80%, respectively, of the simultaneous serum concentrations.
It is almost entirely eliminated in the urine, about 40–60% as unchanged drug and the rest as metabolites, most of which have no antibacterial activity. Urinary concentrations of active drug in the first 2 h after administration of a dose is 100–500 mg/L. Elimination is reduced by probenecid and by renal impairment, the half-life rising to about 12 h in endstage renal failure.
Adverse reactions that are common to the group are reported in 4–5% of patients; these are primarily gastrointestinal tract disturbances, but rashes occur in up to 3% and CNS disturbances in less than 1%. Use is restricted to uncomplicated urinary tract infection.
Pharmacokinetics
Cinoxacin is a synthetic antibacterial agent with in vitro activity against many gram-negative aerobic bacteria, particularly strains of the Enterobacteriaceae family. Cinoxacin inhibits bacterial deoxyribonucleic acid (DNA) synthesis, is bactericidal, and is active over the entire urinary pH range. Cross resistance with nalidixic acid has been demonstrated.
Clinical Use
1-Ethyl-1,4-dihydro-4-oxo[1,3]dioxolo[4,5g]cinnoline-3-carboxylic acid (Cinobac) is a close congener (isostere) ofoxolinic acid (no longer marketed in the United States) andhas antibacterial properties similar to those of nalidixic andoxolinic acids.
It is recommended for the treatment of urinary tract infectionscaused by strains of Gram-negative bacteria susceptibleto these agents. Early clinical studies indicate that thedrug possesses pharmacokinetic properties superior to thoseof either of its predecessors. Thus, following oral administration,higher urinary concentrations of cinoxacin thanof nalidixic acid or oxolinic acid are achieved. Cinoxacinappears to be more completely absorbed and less proteinbound than nalidixic acid.
Synthesis
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 diazotation 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-methylendioxycinnoline (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.
Metabolism
Hepatic, with approximately 30-40% metabolized to inactive metabolites.
Properties of CINOXACIN
Melting point: | 261-262° (dec) |
Boiling point: | 405.47°C (rough estimate) |
Density | 1.3545 (rough estimate) |
refractive index | 1.6660 (estimate) |
storage temp. | 2-8°C |
solubility | 1 M NaOH: soluble50mg/mL |
pka | pKa 5.38(H2O t=25.0 I=0.025) (Uncertain) |
form | solid |
color | White to Off-White |
Stability: | Hygroscopic |
CAS DataBase Reference | 28657-80-9(CAS DataBase Reference) |
Safety information for CINOXACIN
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 |
GHS Hazard Statements |
H302:Acute toxicity,oral H315:Skin corrosion/irritation H319:Serious eye damage/eye irritation H335:Specific target organ toxicity, single exposure;Respiratory tract irritation |
Precautionary Statement Codes |
P261:Avoid breathing dust/fume/gas/mist/vapours/spray. P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing. |
Computed Descriptors for CINOXACIN
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