70458-96-7 Usage
Uses
1. Used in Medical Applications:
Norfloxacin is used as an antibacterial agent for treating infections caused by susceptible strains in various systems, including the urinary system, intestinal, respiratory system, surgery, gynecology, ENT, and dermatology. It is particularly effective against Escherichia coli, pneumobacillus, Aerobacter aerogenes, Aerobacter cloacae, Proteus, Salmonella, Shigella, Citrobacter, and Serratia. It is also used for the treatment of gonorrhea.
2. Used in Urinary Tract Infections and Prostatitis Treatment:
Norfloxacin is used as a fluorinated quinolone antibacterial agent in the clinical treatment of urinary tract infections and prostatitis. It has been shown to increase the expression of IL-10 and heme oxygenase 1 (HO-1) and decrease the expression of pro-inflammatory cytokines in neutrophils from cirrhotic subjects.
3. Used in Anticancer Applications:
When complexed with gold(III), norfloxacin binds to DNA and inhibits cellular proliferation in several cancer cell lines, making it a potential candidate for anticancer applications.
4. Used in Drug Delivery Systems:
Norfloxacin can be incorporated into novel drug delivery systems to enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for norfloxacin delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
5. Used in Veterinary Medicine:
Norfloxacin is also used in veterinary medicine to treat urinary tract and gynecological infections in animals. It has shown potent in vitro and in vivo activity against Pseudomonas, enteric gram-negative rods, and gram-positive cocci, including S. pseudintermedius, S. aureus, E. coli, Pasturella, and S. canis isolates from dogs.
Anti-infection drug
Norfloxacin is a quinolone-class anti-infective drug with high degree of antibacterial activity against Escherichia coli, Shigella, Salmonella, Proteus, Pseudomonas aeruginosa and other gram-negative bacteria as well as excellent antibacterial effect against Staphylococcus aureus, pneumococcus bacteria and other Gram-positive bacteria. Its major site of action is in the bacterial DNA gyrase, causing the rapid cracking of the bacteria DNA helix and rapidly inhibiting the bacterial growth and reproduction, finally killing the bacteria. Moreover, it has a strong penetration capability into the cell walls so that it has a stronger bactericidal effect with a small stimulation on the gastric mucosa.
It is clinically used for treating the susceptible strains caused infection diseases in urinary tract, intestinal, ENT, gynecology, surgery and dermatology with the major indications as follows:
1, genitourinary infections: simple and complicated urinary tract infections, bacterial prostatitis, gonococcal urinary tract infections and reproductive tract infections.
2, gastrointestinal tract infections.
3, typhoid and other Salmonella infections.
Norfloxacin is a concentration-dependent drug which means that the in vivo concentration of the drug is directly proportional to the in vivo efficacy of the drug. The higher the concentration is, the better effect is. As the food will slow down the absorption rate of norfloxacin in the human body, the plasma concentration in the case of taking it before meals (with empty stomach) is 2-3 fold of that in the case of taking it after a meal; therefore, taking it after the meal will greatly reduce the efficacy and may also lead to the drug resistance issue of the susceptible bacteria to the norfloxacin and other similar antimicrobial drugs.
The above information is edited by the lookchem of Dai Xiongfeng.
Production method
Nitration of o-dichlorobenzene or the chlorination of nitro chlorobenzene can both generate 3, 4-dichloro-nitrobenzene. It then undergoes reflux with potassium fluoride in dimethyl sulfoxide for being fluorinated to give 3-chloro-4-fluoro-nitrobenzene. In the presence of hydrochloric acid or aqueous acetic acid, it is further reduced by iron to 3-chloro-4-fluoro-aniline. 3-chloro-4-fluoro-aniline was then subject to reflux together with triethyl orthoformate and diethyl malonate (generate diethyl ethoxymethylenemalonate) in the presence of ammonium nitrate to give the condensation product with heating and cyclization in diphenyl ether or liquid paraffin to form the 7-chloro-6-fluoro-4-hydroxyquinoline-3-carboxylate with ethylation and further hydrolyzation to obtain the ethylated product. Finally, the ethylated product is condensed with piperazine to obtain norfloxacin. Its technology is relatively mature with a relative high yield being generally 40% to 65%. However, when introducing the piperazinyl group to the 7 position, the byproduct with the fluorine atom in 6 position can account for about 25%. It is hard for separation that can affect the yield. The overall yield calculated based on nitro chlorobenzene is above 8%.
Before the introduction of the pyrazine ring, 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-8-carboxylic acid ethyl ester should first react with fluoroboric acid or a boron trifluoride-diethyl ether or boron acetate to have the carbonyl group in 4 position form boron chelate. Further re-introduction of pyrazinyl can reduce the side reactions of the displacement of the position 7’s fluorine and can increase the yield by 15%, as well as improve the quality of the product.
There are many studies regarding the synthesis of norfloxacin at home and abroad. But there have not been too many way for being used in industrial production. The improvement of its synthesis route can be mainly reflected in two aspects. First, improve the process of forming a ring; the second is doing sth on the introduction of piperazine group.
Toxicity grading
poisoning
Acute toxicity
intravenous-rat LD50: 245 mg/kg; Oral-Mouse LD50: 4000 mg/kg
Flammability and hazardous characteristics
it is combustible with combustion produces toxic fumes of nitrogen oxides and fluorides; Side effect when patients take it: musculoskeletal functional changes
Storage Characteristics
ventilation low-temperature and dry
Manufacturing Process
36 g (0.134 mol) of 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3carboxylic acid, 46 g of piperazine and 210 cm3 of pyridine were heated under reflux for 6 hours, while stirring. After the starting material had dissolved, a precipitate appeared after heating for about 2 hours 30 minutes. The major part of the solvent was removed by concentration in vacuo (15 mm Hg; 100°C). In order to remove the pyridine as completely as possible, the residue was taken up in 200 cm3of water and the concentration in vacuo was repeated.The residue, resuspended in 150 cm3 of water, was stirred. 150 cm3 of 2N NaOH were added thereto. The solution, which was slightly turbid, was treated with 5 g of animal charcoal and stirred for 30 minutes. After filtration, the pH was brought to 7.2 by adding acetic acid while stirring. The precipitate was filtered off, washed with water and dissolved in 250 cm3 of a 10% aqueous acetic acid. The acid solution (pH 4.4) was filtered and then brought to pH 7.2 by gradually added 2N NaOH.The suspension was heated to 90°C, while stirring. The crystals were separated and recrystallized from 280 cm3 of a mixture of DMF (1 volume) and ethanol (4 volumes). After drying in vacuo over phosphorus pentoxide, 29.5 g (yield 70%) of 1-ethyl-6-fluoro-4-oxo-7-piperazinyl-1,4dihydroquinoline-3-carboxylic acid, melting point 222°C, were obtained.
In air, this product is hygroscopic and gives a hemihydrate.
Therapeutic Function
Antibacterial
Antimicrobial activity
It is active against a wide range of Gram-negative bacteria, including Enterobacteriaceae and Campylobacter spp. Ps. aeruginosa, Acinetobacter, Serratia and Providencia spp. are weakly susceptible (and often resistant). It has no useful activity against anaerobes, Chlamydia, Mycoplasma and Mycobacterium spp.
Pharmaceutical Applications
A 6-fluoro, 7-piperazinyl quinoline available for oral administration and as an ophthalmic ointment.
Pharmacokinetics
Oral absorption: 50–70% Cmax 400 mg oral :1.5 mg/L after 1–1.5 h Plasma half-life :3–4 h Volume of distribution: 2.5–3.1 L/kg Plasma protein binding: 15%absorption and distribution Norfloxacin displays linear kinetics. There is no significant accumulation with the recommended dosage of 400 mg every 12 h. Food slightly delays but does not otherwise impair absorption. Antacids reduce absorption. It is widely distributed, but concentrations in tissues other than those of the urinary tract are low： levels in the prostate are around 2.5 mg/g.Metabolism and excretion Six or more inactive metabolites are produced. Around 30% of a dose appears as unchanged drug in the urine and <10% as metabolites, producing peak concentrations of microbiologically active drug of around 100–400 mg/L. Urinary recovery is halved by probenecid, with little effect on the plasma concentration. The apparent plasma elimination half-life increases with renal impairment, rising to around 8 h in the anuric patient. Some of the drug appears in the bile where concentrations three- to seven-fold greater than the simultaneous plasma levels are achieved, but this is not a significant route of elimination and hepatic impairment is without effect. Very variable quantities, averaging 30% of a dose, appear in the feces, producing concentrations of active agent of around 200–2000 mg/kg.
Clinical Use
Complicated and uncomplicated urinary tract infections (including prophylaxis in recurrent infections), prostatitis Uncomplicated gonorrhea Gastroenteritis caused by Salmonella, Shigella and Campylobacter spp., Vibrio cholerae Conjunctivitis (ophthalmic preparation)
Side effects
Untoward reactions are those common to the fluoroquinolones. Gastrointestinal tract disturbances, which are generally mild, have been reported in 2–4% of patients. CNS disturbances have largely been limited to headache, drowsiness and dizziness. Co-administration with theophylline results in increased plasma theophylline levels.
Safety Profile
Poison by intravenous route.Moderately toxic by other routes. Human systemic effectsby ingestion: musculoskeletal changes. An experimentalteratogen. Other experimental reproductive effects.Mutation data reported. When heated to decomposition itemits
Synthesis
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).
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline: possibly increased risk of
convulsions, increased levels of aminophylline.
Analgesics: increased risk of convulsions with
NSAIDs.
Anticoagulants: anticoagulant effect of coumarins
enhanced.
Antimalarials: manufacturer of artemether with
lumefantrine advises avoid.
Ciclosporin: increased risk of nephrotoxicity.
Muscle relaxants: possibly increases tizanidine
concentration.
Theophylline: possibly increased risk of convulsions;
increased levels of theophylline.
Metabolism
Some metabolism occurs, possibly in the liver.
Norfloxacin is eliminated through metabolism, biliary
excretion and renal excretion. Renal excretion occurs by
both glomerular filtration and net tubular secretion. In
the first 24 hours, 33-48% of the drug is recovered in the
urine.
Norfloxacin exists in the urine as norfloxacin and six
active metabolites of lesser antimicrobial potency.
The parent compound accounts for over 70% of total
excretion. About 30% of an oral dose appears in the
faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 70458-96-7 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,0,4,5 and 8 respectively; the second part has 2 digits, 9 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 70458-96:
(7*7)+(6*0)+(5*4)+(4*5)+(3*8)+(2*9)+(1*6)=137
137 % 10 = 7
So 70458-96-7 is a valid CAS Registry Number.
InChI:InChI=1/C16H18FN3O3.C3H6O3/c1-2-19-9-11(16(22)23)15(21)10-7-12(17)14(8-13(10)19)20-5-3-18-4-6-20;1-2(4)3(5)6/h7-9,18H,2-6H2,1H3,(H,22,23);2,4H,1H3,(H,5,6)
70458-96-7Relevant articles and documents
Studies on Prodrugs. 10. Possible Mechanism of N-Dealkylation of N-Masked Norfloxacins Having Several Active Methylene Groups
Kondo, Hirosato,Sakamoto, Fumio,Inoue, Yoshimasa,Tsukamoto, Goro
, p. 679 - 682 (1989)
As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 deg C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice.It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the α carbon of the nitrogen atom.In in vivo experiments, N-masked NFLXs having acidic hydrogens on the α carbon to the nitrogen atom also liberated NFLX (2) after oral administration.
A norfloxacin, ciprofloxacin and enrofloxacin synthetic method
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Paragraph 0006; 0016-0027; 0040; 0041, (2019/07/10)
The present invention provides a norfloxacin, ciprofloxacin and enrofloxacin preparation method, which comprises the carboxylic acid and piperazine in the solvent under the catalytic action of the catalyst in the reaction step, the catalyst is AlBr3 , FeBr3 , ZnBr2 , CuBr2 Or SnBr4 , It has high yield, low cost and the advantage of energy saving and emission reduction.
Developing ciprofloxacin analogues against plant DNA gyrase: A novel herbicide mode of action
Wallace, Michael D.,Waraich, Nidda F.,Debowski, Aleksandra W.,Corral, Maxime G.,Maxwell, Anthony,Mylne, Joshua S.,Stubbs, Keith A.
, p. 1869 - 1872 (2018/02/23)
Ciprofloxacin has been shown to exhibit potent herbicidal activity through action against plant DNA gyrase, presenting a novel mode of action. Analogues of ciprofloxacin have been prepared with increased herbicidal activity and diminished antibacterial activity, compared to ciprofloxacin, as demonstrated using model systems.
A high-efficient environment friendly preparation method of quinolone ciprofloxacin drug (by machine translation)
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Paragraph 0026; 0029; 0030, (2019/01/04)
The invention discloses a high-efficient environmental protection quinolone ciprofloxacin preparation method of drug, is fluorobenzene formyl ethyl acetate, the original carboxylic acid triethyl amine compound as a raw material, the three raw materials into the reactor at a temperature of 90 - 150 °C reaction under 20 - 30 H prepare get quinolone basic parent ring, then adding piperazine, to aminocapronitrile as the solvent, the temperature of the reflux reaction 20 - 28 of H, continue adding 50% sodium hydroxide solution is carboxyl ester hydrolysis to obtain the target compound. The invention is simple in raw material market can buy price is cheap; multi-step reaction link together a pan operation intermediate does not need to separate operation, the reaction process is efficient labor-saving; the whole process of transformation efficiency is high, the final product does not need chromatographic treatment is simple washing can get the pure compound; safety in the course of reaction, after-treatment does not need the eluent separation only needs to ethyl acetate, petroleum ether and methanol washing and can be recycled can be pollution prevention; green reaction process, only ethanol by-product, the atom economy is high; quinolone compounds and high utility value, is important trovafloxacins antibacterial drug composition structure. (by machine translation)
ANTIBIOTIC RESISTANCE BREAKERS
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Page/Page column 100, (2019/01/05)
The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
Chemical synthesis method for norfloxacin
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, (2018/04/01)
The invention discloses a chemical synthesis method for norfloxacin. The chemical synthesis method comprises the following steps: (1) synthesis of a compound ethyl quinolinate: 3-ethylamino-2-(2,4-dichloro-5-fluorobenzoyl) ethyl acrylate is dissolved in DMF, potassium carbonate is added, the mixture is heated to 50-80 DEG C, reacts and stands overnight, a product is cooled and poured into cold water, produced solids are filtered, solids are washed with a large amount of water, and the product ethyl quinolinate is obtained; (2) synthesis of a compound quinolinic acid: ethyl quinolinate is dissolved in methanol, hydrochloric acid is added in a ratio being 1:1, reflux is performed for 2 h, white solids are precipitated and filtered, a filter product is washed with water and dried in a vacuum oven for 2 h, and the product quinolinic acid is obtained. The design is reasonable, and one novel norfloxacin synthesis method is selected and has good market application value.
A norfloxacin, ciprofloxacin and enrofloxacin preparation method
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Paragraph 0113-0114, (2017/04/25)
The invention discloses a preparation method of norfloxacin, ciprofloxacin and enrofloxacin. The preparation method comprises the following steps: directly reacting 1-ethyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate or 1-cyclopropyl-6-fluoro-7-chlo-4-oxo-1,4-dihydro-quinoline-3-carboxylate with piperazine (or N-ethyl piperazine); and then, performing after-treatment to prepare a corresponding target product norfloxacin (or ciprofloxacin or enrofloxacin). The preparation method disclosed by the invention is short in reaction step, convenient to operate, less investment and beneficial to industrial production; consumption of piperazine (or N-ethyl piperazine) can be reduced by more than half; under the catalytic action, the reaction temperature is low, the byproducts are less, the yield is high and the cost is low; heavy use of inorganic acid and inorganic alkaline is avoided, so that the pollution is reduced.
Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2′→ SNAr→(Δ3,4-Δ2,3 shift)→oxidation sequence
Napoleon, John Victor,Kannoth Manheri, Muraleedharan
supporting information; experimental part, p. 3379 - 3388 (2011/11/30)
When subjected to tandem SN2-SNAr cyclization in the presence of alkyl or aralkyl amines, Baylis-Hillman acetates gave the corresponding 1,2-dihydroquinolines, which on simple exposure to light and oxygen afforded the corresponding 4- and 2-quinolones through sensitized oxidation or a 3,4-2,3 shift oxidation cascade. The mechanism of the oxidation step, the stabilities of the 1,2- and 1,4-dihydroquinolines in solution and in the solid state, and the synthetic elaboration of the key intermediates to known therapeutic agents are discussed. Georg Thieme Verlag Stuttgart · New York.
Diglyceride prodrug strategy for enhancing the bioavailability of norfloxacin
Dhaneshwar, Suneela,Tewari, Kunal,Joshi, Sonali,Godbole, Dhanashree,Ghosh, Pinaki
experimental part, p. 307 - 313 (2012/01/03)
Prodrug approach using diglyceride as a promoiety is a promising strategy to improve bioavailability of poorly absorbed drugs and the same was explored in the present work to improve oral bioavailability of norfloxacin; a second generation fluoroquinolone antibacterial. The prodrug was synthesized by standard procedures using dipalmitine as a carrier and the structure was confirmed by spectral analysis. Higher Log P indicated improved lipophilicity. The ester linkage between norfloxacin and dipalmitine would be susceptible to hydrolysis by lipases to release the parent drug and carrier in the body. In vivo kinetic studies in rats indicated 53% release of norfloxacin in plasma at the end of 8 h. The prodrug exhibited improved pharmacological profile than the parent compound at equimolar dose that indirectly indicated improved bioavailability.
Mechanism and synthesis of pharmacologically active quinolones from Morita-Baylis-Hillman adducts
Amarante, Giovanni W.,Benassi, Mario,Pascoal, Robert N.,Eberlin, Marcos N.,Coelho, Fernando
experimental part, p. 4370 - 4376 (2010/07/05)
The synthesis of quinolones from Morita-Baylis-Hillman (MBH) adducts is reported. The quinolone skeleton is formed via a TFA-mediated cyclization of the MBH adduct, and a mechanism study using ESI(+)-MS(/MS) has indicated the role played by TFA in this key reaction step. The total syntheses of Norfloxacin and a benzyl quinolone carboxylic acid (BQCA) derivative are described. Norfloxacin is a fluoroquinolonic antibacterial drug whereas BQCA is M1 receptor positive allosteric modulator and seem to provide access to new potential drugs for Alzheimer disease, pain, and sleep disorders. The syntheses of these two important quinolones exemplify the versatility and potentiality of the approach.
