Grepafloxacin

Grepafloxacin
Systematic (IUPAC) name
(RS)-1-cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)- 4-oxo-quinoline- 3-carboxylic acid
Clinical data
AHFS/Drugs.com Multum Consumer Information
Pharmacokinetic data
Protein binding 50%
Identifiers
CAS Number 119914-60-2 YesY
ATC code J01MA11
PubChem CID 72474
DrugBank DB00365 YesY
ChemSpider 65391 YesY
UNII L1M1U2HC31 YesY
KEGG C11368 YesY
ChEMBL CHEMBL583 YesY
Chemical data
Formula C19H22FN3O3
Molar mass 359.395 g/mol
Chirality 1 : 1 mixture (racemate)
  (verify)

Grepafloxacin hydrochloride (trade name Raxar, Glaxo Wellcome) was an oral broad-spectrum fluoroquinolone antibacterial agent used to treat bacterial infections. Grepafloxacin was withdrawn worldwide from markets in 1999,[1][2] owing to its side effect of lengthening the QT interval on the electrocardiogram, leading to cardiac events and sudden death.[3]

Clinical uses

Grepafloxacin was used for treating exacerbations of chronic bronchitis caused by susceptible bacteria (e.g. Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis),[4][5][6] community-acquired pneumonia (including those, in addition to the above germs, caused by Mycoplasma pneumoniae)[7][8] gonorrhea and non-gonococcal urethritis and cervicitis (for example caused by Chlamydia trachomatis or Ureaplasma urealyticum).[9][10]

Synthesis

The preparation of quinolones bearing a substituent at position 5 is complicated by the greater electrophilic character of the 8 position. One scheme for resolving the problem consists in blocking access to position 8 by first adding a readily removable group to that center.

Grepafloxacin synthesis:[11][12]

The scheme starts with the conversion of the carboxylic acid in (1) to its dimethyloxazoline derivative (3) by reaction with the dimethyl ethanolamine (2). Lithium diisopropylamide (LDA) then removes a proton from the 8 position; treatment of that anion with trimethylsilyl iodide leads to the silylated intermediate (4). A second round of LDA then generates a carbanion at the only open position; reaction with methyl iodide leads to the corresponding 5 methyl derivative (5). Treatment of that product with cesium fluoride breaks the carbon–silicon bond, removing the silyl group; aqueous acid then hydrolyzes the oxazoline to afford the free acid (6). This last intermediate is then taken on to the quinolone (9) [13] by essentially the same scheme as that used to prepare difloxacin, with the difference that the chain elongation is by means of Grignard reagent of Ethyl bromoacetate. Treatment of (9) with 2-methylpiperazine proceeds by reaction at the less hindered of the two amino groups; saponification then affords grepafloxacin (10).

See also

References

  1. ↑ "Glaxo Wellcome voluntary withdrawn Raxar (Grepafloxacin)" (PDF). Retrieved 2014-10-12.
  2. ↑ "Withdrawal of Product: RAXAR (grepafloxacin HCl) 600 mg Tablets, 400 mg Tablets, and 200 mg Tablets". U.S. Food and Drug Administration. Retrieved 2014-10-12.
  3. ↑ Sprandel, KA.; Rodvold, KA. (2003). "Safety and tolerability of fluoroquinolones.". Clin Cornerstone. Suppl 3: S29–36. PMID 14992418.
  4. ↑ Chodosh S, Lakshminarayan S, Swarz H, Breisch S (January 1998). "Efficacy and safety of a 10-day course of 400 or 600 milligrams of grepafloxacin once daily for treatment of acute bacterial exacerbations of chronic bronchitis: comparison with a 10-day course of 500 milligrams of ciprofloxacin twice daily". Antimicrob. Agents Chemother. 42 (1): 114–20. PMC 105465. PMID 9449270. Retrieved 2014-10-12.
  5. ↑ Langan CE, Cranfield R, Breisch S, Pettit R (December 1997). "Randomized, double-blind study of grepafloxacin versus amoxycillin in patients with acute bacterial exacerbations of chronic bronchitis". J. Antimicrob. Chemother. 40 Suppl A: 63–72. doi:10.1093/jac/40.suppl_1.63. PMID 9484875. Retrieved 2014-10-12.
  6. ↑ Langan CE, Zuck P, Vogel F, McIvor A, Peirzchala W, Smakal M, Staley H, Marr C (October 1999). "Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis". J. Antimicrob. Chemother. 44 (4): 515–23. doi:10.1093/jac/44.4.515. PMID 10588313. Retrieved 2014-10-12.
  7. ↑ O'Doherty B, Dutchman DA, Pettit R, Maroli A (December 1997). "Randomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia". J. Antimicrob. Chemother. 40 Suppl A: 73–81. doi:10.1093/jac/40.suppl_1.73. PMID 9484876. Retrieved 2014-10-12.
  8. ↑ Felmingham D (March 2000). "Respiratory pathogens: assessing resistance patterns in Europe and the potential role of grepafloxacin as treatment of patients with infections caused by these organisms". J. Antimicrob. Chemother. 45: 1–8. doi:10.1093/jac/45.suppl_2.1. PMID 10719006. Retrieved 2014-10-12.
  9. ↑ Ridgway GL, Salman H, Robbins MJ, Dencer C, Felmingham D (December 1997). "The in-vitro activity of grepafloxacin against Chlamydia spp., Mycoplasma spp., Ureaplasma urealyticum and Legionella spp". J. Antimicrob. Chemother. 40 Suppl A: 31–4. doi:10.1093/jac/40.suppl_1.31. PMID 9484871. Retrieved 2014-10-12.
  10. ↑ McCormack WM, Martin DH, Hook EW, Jones RB (1998). "Daily oral grepafloxacin vs. twice daily oral doxycycline in the treatment of Chlamydia trachomatis endocervical infection". Infect Dis Obstet Gynecol 6 (3): 109–15. doi:10.1155/S1064744998000210. PMC 1784789. PMID 9785106. Retrieved 2014-10-12.
  11. ↑ Hagen, S. E.; Domagala, J. M.; Heifetz, C. L.; Johnson, J. (1991). "Synthesis and biological activity of 5-alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic acids". Journal of Medicinal Chemistry 34 (3): 1155. doi:10.1021/jm00107a040.
  12. ↑ WO 8906649; eidem, U.S. Patent 4,920,120 (1989, 1990 both to Warner-Lambert).
  13. ↑ Hagen, S. E.; Domagala, J. M. (1990). "Synthesis of 5-methyl-4-oxo-quinolinecarboxylic acids". Journal of Heterocyclic Chemistry 27 (6): 1609. doi:10.1002/jhet.5570270616.
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