124858-35-1

Basic information

• Product Name: Nadifloxacin
• Synonyms: NDFX;Nadifiloxacin;NadifloxacinAPI;7-fluoro-8-(4-hydroxypiperidin-1-yl)-12-Methyl-4-oxo-1-azatricyclo[7.3.1.0^{5,13}]trideca-2,5(13),6,8-tetraene-3-carboxylic acid;9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid;NADIFLOXACIN;opc7251;(+/-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidino)-5-methyl-1-oxo-1h,5h-benzo[ij]quinolizine-2-carboxylic acid
• CAS NO: 124858-35-1
• Molecular Formula: C₁₉H₂₁FN₂O₄
• Molecular Weight: 360.38
• EINECS: 1533716-785-6
• Product Categories: ACUATIM;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 124858-35-1.mol

Chemical Properties

• Melting Point: 245-2470C (dec)
• Boiling Point: 624.891 °C at 760 mmHg
• Flash Point: 331.722 °C
• Appearance: off-white crystalline solid
• Density: 1.467 g/cm³
• Vapor Pressure: 1.77E-16mmHg at 25°C
• Refractive Index: 1.668
• Storage Temp.: -20?C Freezer
• Solubility: DMSO (Slightly), Methanol (Sparingly, Heated)
• PKA: 5.55±0.40(Predicted)
• Merck: 14,6345
• CAS DataBase Reference: Nadifloxacin(CAS DataBase Reference)
• NIST Chemistry Reference: Nadifloxacin(124858-35-1)
• EPA Substance Registry System: Nadifloxacin(124858-35-1)

Safety Data

• Hazardous Substances Data: 124858-35-1(Hazardous Substances Data)

Usage

Acne Treatment

Nadifloxacin(Nadibact Cream) from Japan Otsuka company developed the third generation quinolone antibacterial agents, The 1% ointment is used for the treatment of acne for the first time in the Japanese market in 1993 (known as acne, it is a common hair follicles, sebaceous glands, chronic inflammatory diseases, occurs in puberty), nadifloxacin is a novel DNA topoisomerase inhibitors, and also effective for G + bacteria, G-bacteria, anaerobes, but also produce b-lactamase bacteria and MRSA, effective against skin infections mainly Propionibacterium acnes bacteria about minimum inhibitory concentration is only 0.78mg/ml. currently used in the 1% ointment in the treatment of acne and folliculitis, high efficacy, efficiency up to 81.3%, side effects, only 56 cases have side effects from 3946 cases of patients, the ratio is about 1.42%.

Antibacterial Activity

Staphylococcus aureus, nadifloxacin minimum inhibitory concentration is the smallest of all eight kinds of antibiotics. When the concentration is 2mg/L, all clinical isolates are inhibited, while other antibacterial agents have been found more than 8mg/L MIC50 of resistant strains. Coagulase-negative staphylococci appear higher resistance. There are resistant strains of 4mg /L in Nadifloxacin but of over 8mg/L in the other seven antimicrobial drugs. It has strong antibacterial activity for propionibacterium acnes, nadifloxacin, penicillin, erythromycin, clindamycin and fusidic acid, in addition to the difloxacin and penicillin, it can produce resistance on the other antibacterial drugs. The results presented nadifloxacin Staphylococcus aureus and Propionibacterium have antibacterial activity, suggesting that effective treatment of acne infection. All subjects of quinolones against MSSA strains have antibacterial activity. Nadifloxacin, the strongest antibacterial activity (MIC90≤0.1mg/L), have strong antibacterial activity. The MIC90 is four times lower, compared with Tuosu difloxacin (Tosufloxacin) Division and Pakistan difloxacin (Sparfloxacin). Compared with MSSA, Nadifloxacin(Nadibact Cream) antibacterial activity is lower than against MRSA, but it is still the strongest of all the tested quinolone antibacterial. In the 5-year period, the MIC90 of Nadifloxacin(Nadibact Cream) was 1.56mg/L, while the MIC90 of other quinolones drugs is more than 12.5mg/L.

Pharmacokinetics

Following a single topical application of 10 g nadifloxacin 1% cream to normal human back skin, the highest plasma concentration was determined to be 107 ng/mL with an elimination half-life of 19.4 hours. Approximately 0.09% of the administered dose was excreted in the urine over 48 hours post-dosing. The plasma concentration reached a steady state on Day 5 of repeated administration study when nadifloxacin 1% cream was applied at 5 g twice daily to normal healthy individuals for a period of 7 days. The plasma concentration reached a peak of 4.1 ng/ml at 8 hours post-final dosing with an elimination half-life of 23.2 hours. The urinary excretion rate reached 0.16% on Day 7.

Drug resistance

Inoculant in 108CFU/ml 2-5 when generations have clindamycin drug resistance, the drug concentration of 16-25 generations increased from 0.03μg/ml to 0.25μg/ml. When inoculant is 106CFU/ml, 14-25 on behalf of the concentration of clindamycin increased from 0.02μg/ml to0.10μg/ml. Nadifloxacin group,s results is that the 18-25 make drug concentration generations increased from 0.3μg/ml to 2.00μg/ml when inoculants at 108CFU/ml,16-25 make drug concentration generations increased from 0.2μg/ml to 1.00μg/ml when inoculants at 106CFU/ml. Explaining how the resistance. The use of the drug, which is more than 5 times the drug concentration of sensitive bacteria, cannot inhibit the growth of drug resistant bacteria. The P.acne to clindamycin and nadifloxacin has drug resistance almost at the same rate. Application: One kind of quinolone antibacterial drugs, a broad spectrum antibiotic,Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa and other aerobic and Propionibacterium acnes, Bacteroides fragilis and other anaerobic bacteria We have good antibacterial activity. Its efficacy is better than conventional antibiotic tetracycline, erythromycin, and clindamycin.

References

https://en.wikipedia.org/wiki/Nadifloxacin https://www.pharmacygeoff.md/Nadibact_Cream_Nadifloxacin_1_w_w_10g_Tube_p_923.html

Originator

Otsuka (Japan)

Pharmaceutical Applications

A lipophilic tricyclic fluorobenzoquinoline with a 4- hydroxylpiperinyl moiety at the C-8 position, formulated as a cream for topical use. It is active against many Grampositive bacteria involved in skin infections, including Propionibacterium acnes (MIC 0.25–2.0 mg/L), and Staph. aureus (MIC 0.015–2 mg/L). It appears to inhibit the generation of reactive oxygen species by neutrophils. The sodium salt is used as a 1% cream for use in acne vulgaris and cutaneous staphylococcal infections.

InChI:InChI=1/C19H21FN2O4/c1-10-2-3-12-16-13(18(24)14(19(25)26)9-22(10)16)8-15(20)17(12)21-6-4-11(23)5-7-21/h8-11,23H,2-7H2,1H3,(H,25,26)

Synthetic route

4-HYDROXYPIPERIDINE (5382-16-1) + 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (77483-92-2) → nadifloxacin (124858-35-1)

Conditions	Yield
In N,N,N,N,N,N-hexamethylphosphoric triamide at 160℃; for 7h;	25%

6-fluoro-2-methyl-quinoline (1128-61-6) → nadifloxacin (124858-35-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 87 percent / Br2, Ag2SO4, cc H2SO4, / 1 h 2: 68 percent / H2, / PtO2, / acetic acid / Ambient temperature 3: 2.) PPA, 3.) cc HCl, / 1.) 150 deg C, 1 h, 2.) 150 deg C, 30 min, 3.) AcOH, H2O, reflux, 2 h, 4: 25 percent / hexamethylphosphoric acid triamide / 7 h / 160 °C View Scheme

5-bromo-6-fluoro-2-methylquinoline (80290-18-2) → nadifloxacin (124858-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 68 percent / H2, / PtO2, / acetic acid / Ambient temperature 2: 2.) PPA, 3.) cc HCl, / 1.) 150 deg C, 1 h, 2.) 150 deg C, 30 min, 3.) AcOH, H2O, reflux, 2 h, 3: 25 percent / hexamethylphosphoric acid triamide / 7 h / 160 °C View Scheme

5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (79085-71-5) → nadifloxacin (124858-35-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.) PPA, 3.) cc HCl, / 1.) 150 deg C, 1 h, 2.) 150 deg C, 30 min, 3.) AcOH, H2O, reflux, 2 h, 2: 25 percent / hexamethylphosphoric acid triamide / 7 h / 160 °C View Scheme

nadifloxacin (124858-35-1) + methyl iodide (74-88-4) → methyl-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H-benzoquinolizine-2-carboxylate (129672-74-8)

Conditions	Yield
With potassium hydroxide In N,N,N,N,N,N-hexamethylphosphoric triamide; ethanol at 60℃; for 1.5h;	91%

4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluoroaniline (1201939-89-0) + nadifloxacin (124858-35-1) → N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;	70%

nadifloxacin (124858-35-1) + acetic acid (64-19-7) → 8-(4-acetoxy-1-piperidyl)-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoquinolizine-2-carboxylic acid (81962-90-5)

Conditions	Yield
With sulfuric acid In dichloromethane for 5h; Heating;	57%

nadifloxacin (124858-35-1) + 6-(S-tritylmercapto)hexanoic acid (80441-55-0) → C44H45FN2O5S (1398623-75-0)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 22℃; for 13h; Inert atmosphere;	24%

nadifloxacin (124858-35-1) → 9-fluoro-6,7-dihydro-5-methyl-8-(4-sulfoxy-1-piperidyl)-1-oxo-1H,5H-benzoquinolizine-2-carboxylic acid (130539-79-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / 85percent potassium hydroxide / hexamethylphosphoric acid triamide; ethanol / 1.5 h / 60 °C 2: 1) chlorosulfonic acid / 1) 50-55 deg C, 30 min, 2a) 50-55 deg C, 6 h, 2b) r.t., overnight 3: 38 percent / 0.1N KOH / methanol View Scheme

nadifloxacin (124858-35-1) → pyridinium 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-2-methoxycarbonyl-5-methyl-1-oxo-1H,5H-benzoquinolizine sulfate (130539-78-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / 85percent potassium hydroxide / hexamethylphosphoric acid triamide; ethanol / 1.5 h / 60 °C 2: 1) chlorosulfonic acid / 1) 50-55 deg C, 30 min, 2a) 50-55 deg C, 6 h, 2b) r.t., overnight View Scheme

L-arginine (74-79-3) + nadifloxacin (124858-35-1) → RS-(+/-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt (627891-20-7)

D-arginine (157-06-2) + nadifloxacin (124858-35-1) → RS-(+/-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid D-arginine salt

nadifloxacin (124858-35-1) → R-(+)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid + S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (154357-42-3)

Conditions	Yield
With Lux-cellulose-2 (cellulose tris(3-chloro-4-methyl phenyl carbamate)) column In ethanol; hexane; acetic acid; diethylamine at 35℃; Solvent; Temperature; Resolution of racemate;

Upstream product

• 79085-71-5 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline 
• 80290-18-2 5-bromo-6-fluoro-2-methylquinoline 
• 1128-61-6 6-fluoro-2-methyl-quinoline 
• 5382-16-1 4-HYDROXYPIPERIDINE 
• 77483-92-2 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid 

Downstream Products

• 81962-84-7 R-(+)-9-fluoro-8-(4-hydroxypiperidin-1-yl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 
• 154357-42-3 S-(-)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 
• 1398623-75-0 C₄₄H₄₅FN₂O₅S 

Relevant articles and documents

Pyrroloquinoline and benzoquinolizine compounds and antimicrobial compositions

A benzoheterocyclic compound of the formula (I) STR1 wherein R1, R2, R3 and n are as defined, and its pharmaceutically acceptable salts, processes for preparing same and antibacterial composition containing the benzoheterocyclic compound as an active ingredient and a pharmaceutically acceptable carrier are disclosed.