Gemifioxacin CAS 175463-14-6

Introduction：Basic information about Gemifioxacin CAS 175463-14-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Gemifioxacin Basic information

• Product Name: Gemifioxacin
• Synonyms: gemifioxacin;GEMIFLOXACIN;7-(3-aminomethyl)-4-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-[1, 8]naphthyridine-3-carboxylic acid;7-[3-(Aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic Acid Mesilate;Gemifloxacin Mesilate;LB-20304 Mesilat;SB-265805 Mesilate;7-(3-Aminomethyl)-4-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1
• CAS: 175463-14-6
• MF: C18H20FN5O4
• MW: 389.38
• Product Categories: API;pharmaceutical intermediates
• Mol File: 175463-14-6.mol

Gemifioxacin Chemical Properties

• Melting point: 235-237°
• Boiling point: 638.9±65.0 °C(Predicted)
• density: 1?+-.0.1 g/cm3(Predicted)
• pka: 6.02±0.70(Predicted)
• InChI: InChI=1S/C18H20FN5O4/c1-28-22-14-8-23(6-9(14)5-20)17-13(19)4-11-15(25)12(18(26)27)7-24(10-2-3-10)16(11)21-17/h4,7,9-10H,2-3,5-6,8,20H2,1H3,(H,26,27)/b22-14+
• InChIKey: ZRCVYEYHRGVLOC-HYARGMPZSA-N
• SMILES: N1(C2CC2)C2C(=CC(F)=C(N3C/C(=N\OC)/C(CN)C3)N=2)C(=O)C(C(O)=O)=C1
• CAS DataBase Reference: 175463-14-6

Safety Information

• Hazardous Substances Data: 175463-14-6(Hazardous Substances Data)

Gemifioxacin Usage And Synthesis

Description

LG Life Sciences (formerly LG Chemical) has developedgemifloxacin (SB-265805, LB-20304a), a fluoronaphthyridoneactive against both Gram-positive and Gram-negativebacteria, including methicillin-resistant staphylococci, as atreatment for bacterial infection. By December 2002, thedrug had been approved in Korea.

Uses

Acyl Glucuronide - Gemifloxacin is a derivative of Gemifloxacin (G336000); a third generation fluorinated quinolone antibacterial.

Definition

ChEBI: A 1,4-dihydro-1,8-naphthyridine with a carboxy group at the 3-position, an oxo sustituent at the 4-position, a fluoro substituent at the 5-position and a substituted pyrrolin-1-yl group at the 7-position.

Antimicrobial activity

The broad antibacterial spectrum embraces most Gram-positive cocci (including high potency against Str. pneumoniae) and Gram-negative bacilli. It possesses a high affinity for pneumococcal topoisomerase IV. Activity against Gram-negative respiratory tract pathogens such as H. influenzae, Mor. catarrhalis, Ch. pneumoniae, L. pneumophila and Mycoplasma pneumonia is good. It is relatively inactive against Ps. aeruginosa and Enterococcus spp. Activity against Enterobacteriaceae is similar to that of moxifloxacin but it is less potent against anaerobes. Gemifloxacin is inactive against M. tuberculosis. Activity against Nocardia asteroides (MIC 0.5–1 mg/L) is better than that of other quinolones other than the investigational compound nemonoxacin .
Multistep resistance studies suggest that it is less likely than other quinolones to select for quinolone-resistant Str. pneumoniae strains. Because it inhibits both DNA gyrase and DNA topoisomerase IV enzyme systems at therapeutically relevant drug levels in Str. pneumoniae, single mutations in parC or gyrA result in only a small increase in the MIC. In Str. pneumoniae gyrA mutations arise at a lower rate (1.6 × 10?11) than mutations in parC. It seems to be unaffected clinically by quinolone efflux mechanisms in Str. pneumoniae. Low rates of resistance selection have also been reported in H. influenzae.

Pharmaceutical Applications

A fluoronaphthyridone derivative with a dual substituted pyrrolidine moiety at the C-7 position. It is formulated as the mesylate.

Pharmacokinetics

absorption and distribution
In oral escalating dose studies (single doses of 20–800 mg), Cmax ranged from 0.12 to 4.33 mg/L after an average of 1 h. Antacids significantly reduce the systemic availability and protein binding is relatively high. Excellent concentrations are achieved in serum as well as various tissues such as bronchial mucosa, epithelial lining fluid and alveolar macrophages. Absolute bioavailability of the 320 mg oral tablet is around 71%. Pharmacokinetics are not significantly altered when administered with a high fat meal.
Metabolism and excretion
The apparent elimination half-life ranges from 6 to 9 h, and 26–40% of administered doses are eliminated in urine. It is metabolized to a limited extent in the liver. Cytochrome P₄₅₀ enzymes do not play an important role in metabolism, and the metabolic activity of these enzymes is unaffected. Around 65% of the parent compound and its metabolites are eliminated in the feces and the remainder in the urine. The mean renal clearance after repeated doses of 320 mg is about 11.6 L/h, indicating active renal secretion. The mean apparent elimination half-life at steady state following administration of 320 mg to healthy subjects was approximately 7 h. No dosage adjustment is recommended in patients with mild, moderate or severe hepatic impairment. Clearance is reduced and plasma elimination is prolonged in patients with renal insufficiency, leading to an average increase in AUC values of c. 70%. Hemodialysis removes approximately 20–30% of an oral dose from plasma.

Clinical Use

Community-acquired pneumonia in adults
Acute exacerbations of chronic bronchitis in adults

Side effects

The most commonly reported side effects are diarrhea (3.6%), rash (2.8%) and nausea (2.7%). No evidence has emerged of a clinically significant prolongation in QTc interval. The phototoxicity potential is low and similar to that seen with ciprofloxacin. The overall incidence of drugrelated rash is 2.8%. The rash is most commonly mild, macropapular (occasionally urticarial), predominantly selflimiting, and mainly occurs in women under 40 years and in postmenopausal women on hormone replacement therapy after ≥10 days.

Synthesis

Oral gemifloxacin wasapproved by the FDA in April 2003. Two key intermediates,3-aminomethyl-4-methoxyiminopyrrolidine (105) and 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (108) were involved in the synthesisof gemifloxacin (XII). Michael addition of glycine ethylester hydrochloride (98) to acrylonitrile (99) in the presenceof KOH furnished cyanoester 100 in 48% yield. Protectionof the amino group and Dieckmann cyclization wereaccomplished in a one-pot process to furnish 4-cyano-1-(N-tbutoxycarbonyl)-pyrrolidine-3-one (101) in almostquantitative yield. The conversion of ketone 101 to alcohol102 was achieved via three reaction sequences in a one-potprocess in 83% yield. The hydroxy group was oxidized toketone 103 with pyridine-sulfur trioxide complex in DMSO.Treatment of ketone 103 with methoxyamine in the presenceof NaHCO3 provided methyloxime 104 in 88% yield.
Deprotection of the Boc groups in 104 by TFA affordedpyrrolidine 105 in 84% yield. Quinolone acid 108 wasemployed in the synthesis of ciprofloxacin and can bereadily prepared according to literature methods. Afour step sequence/one-pot process is depicted inScheme 12. Nicotinoyl acetate 106 was converted toenaminoester 107 by reaction with ethyl orthoformate andacetic anhydride, followed by reaction with the cyclopropylamine. 1,8-Naphthyridine 108 was obtained through baseassistedcyclization, followed by acid hydrolysis of the esterfunction via a one-pot process in 52% overall yield. Thecoupling reaction of quinolone 108 with pyrrolidine 105 wascarried out in CH3CN-H2O in the presence of benzaldehydeand triethylamine. The benzaldehyde served as an importantreagent to protect the primary amine selectively and thereforethe desired gemifloxacin derivative 109 was obtained in highyield and purity, otherwise a 10% by-product was observed. The deprotection and salt formation reactions werecarried out in one step by treatment of 109 withmethanesulfonic acid at 40-45oC in water. The gemifloxacinmesylate (XII) was collected by filtration upon cooling in95% yield.