Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Grepafloxacin: Difference between pages

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc}}

| verifiedrevid = 461123703

| IUPAC_name = (''RS'')-1-Cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxo-quinoline-3-carboxylic acid

| chirality = [[Racemic mixture]]

| routes_of_administration =

| elimination_half-life =

| CAS_number_Ref = {{cascite|correct|??}}

| C=19 | H=22 | F=1 | N=3 | O=3

'''Grepafloxacin''' (trade name '''Raxar''', [[Glaxo Wellcome]]) was an oral broad-spectrum [[fluoroquinolone]] [[antibacterial]] agent used to treat [[bacteria]]l [[infection]]s. Grepafloxacin was withdrawn worldwide from markets in 1999,<ref name="urlwww.fda.gov">{{cite web |url=https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3634b1a_tab5a.pdf |title= Glaxo Wellcome voluntary withdrawn Raxar (Grepafloxacin) |website= [[Food and Drug Administration]] |access-date=2014-10-12}}</ref><ref name="urlLetter -Raxar">{{cite web |url=https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3634b1a_tab5b.htm |title=Withdrawal of Product: RAXAR (grepafloxacin HCl) 600 mg Tablets, 400 mg Tablets, and 200 mg Tablets |work= U.S. Food and Drug Administration |access-date=2014-10-12}}</ref> due to the drug's potential to cause [[long qt syndrome|a potentially fatal cardiac arrhythmia]].<ref>{{cite journal | vauthors = Sprandel KA, Rodvold KA | title = Safety and tolerability of fluoroquinolones | journal = Clinical Cornerstone | volume = Suppl 3 | pages = S29–S36 | year = 2003 | pmid = 14992418 | doi = 10.1016/s1098-3597(03)90027-5 }}</ref>

== Clinical uses ==

Grepafloxacin was used for treating exacerbations of chronic bronchitis caused by susceptible bacteria (e.g. ''[[Haemophilus influenzae]]'', ''[[Streptococcus pneumoniae]]'', ''[[Moraxella catarrhalis]]''),<ref name="pmid9449270">{{cite journal | vauthors = Chodosh S, Lakshminarayan S, Swarz H, Breisch S | title = 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 | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 1 | pages = 114–120 | date = January 1998 | pmid = 9449270 | pmc = 105465 | doi = 10.1128/AAC.42.1.114 }}</ref><ref name="pmid9484875">{{cite journal | vauthors = Langan CE, Cranfield R, Breisch S, Pettit R | title = Randomized, double-blind study of grepafloxacin versus amoxycillin in patients with acute bacterial exacerbations of chronic bronchitis | journal = The Journal of Antimicrobial Chemotherapy | volume = 40 Suppl A | pages = 63–72 | date = December 1997 | pmid = 9484875 | doi = 10.1093/jac/40.suppl_1.63 | doi-access = free }}</ref><ref name="pmid10588313">{{cite journal | vauthors = Langan CE, Zuck P, Vogel F, McIvor A, Peirzchala W, Smakal M, Staley H, Marr C | display-authors = 6 | title = Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis | journal = The Journal of Antimicrobial Chemotherapy | volume = 44 | issue = 4 | pages = 515–523 | date = October 1999 | pmid = 10588313 | doi = 10.1093/jac/44.4.515 | doi-access = free }}</ref> community-acquired pneumonia (including those, in addition to the above germs, caused by ''[[Mycoplasma pneumoniae]]'')<ref name="pmid9484876">{{cite journal | vauthors = O'Doherty B, Dutchman DA, Pettit R, Maroli A | title = Randomized, double-blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia | journal = The Journal of Antimicrobial Chemotherapy | volume = 40 Suppl A | pages = 73–81 | date = December 1997 | pmid = 9484876 | doi = 10.1093/jac/40.suppl_1.73 | doi-access = }}</ref><ref name="pmid10719006">{{cite journal | vauthors = Felmingham D | title = Respiratory pathogens: assessing resistance patterns in Europe and the potential role of grepafloxacin as treatment of patients with infections caused by these organisms | journal = The Journal of Antimicrobial Chemotherapy | volume = 45 | issue = 90002 | pages = 1–8 | date = March 2000 | pmid = 10719006 | doi = 10.1093/jac/45.suppl_2.1 | doi-access = }}</ref> [[gonorrhea]] and [[non-gonococcal urethritis]] and [[cervicitis]] (for example caused by ''[[Chlamydia trachomatis]]'' or ''[[Ureaplasma urealyticum]]'').<ref name="pmid9484871">{{cite journal | vauthors = Ridgway GL, Salman H, Robbins MJ, Dencer C, Felmingham D | title = The in-vitro activity of grepafloxacin against Chlamydia spp., Mycoplasma spp., Ureaplasma urealyticum and Legionella spp | journal = The Journal of Antimicrobial Chemotherapy | volume = 40 Suppl A | pages = 31–34 | date = December 1997 | pmid = 9484871 | doi = 10.1093/jac/40.suppl_1.31 | doi-access = free }}</ref><ref name="pmid9785106">{{cite journal | vauthors = McCormack WM, Martin DH, Hook EW, Jones RB | title = Daily oral grepafloxacin vs. twice daily oral doxycycline in the treatment of Chlamydia trachomatis endocervical infection | journal = Infectious Diseases in Obstetrics and Gynecology | volume = 6 | issue = 3 | pages = 109–115 | year = 1998 | pmid = 9785106 | pmc = 1784789 | doi = 10.1155/S1064744998000210 | doi-access = free }}</ref>

==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.

[[File:Grepafloxacin synthesis.svg|thumb|center|700px|Grepafloxacin synthesis:<ref>{{cite journal | vauthors = Hagen SE, Domagala JM, Heifetz CL, Johnson J | title = Synthesis and biological activity of 5-alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic acids | journal = Journal of Medicinal Chemistry | volume = 34 | issue = 3 | pages = 1155–1161 | date = March 1991 | pmid = 2002456 | doi = 10.1021/jm00107a040 }}</ref><ref>{{Cite patent|country=WO|number=8906649}}; eidem, {{US patent|4920120}} (1989, 1990 both to Warner-Lambert).</ref>]]

The scheme starts with the conversion of the carboxylic acid in ('''1''') to its dimethyloxazoline derivative ('''3''') by reaction with the [[aminomethyl propanol]] ('''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''') <ref>{{Cite journal | doi = 10.1002/jhet.5570270616| title = Synthesis of 5-methyl-4-oxo-quinolinecarboxylic acids| journal = Journal of Heterocyclic Chemistry| volume = 27| issue = 6| pages = 1609–1616| year = 1990| vauthors = Hagen SE, Domagala JM }}</ref> 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''').

== Stereochemistry ==

Grepafloxacin contains a stereocenter and consists of two enantiomers. This is a [[racemate]], ie a 1: 1 mixture of (''R'')- and the (''S'')-forms:

{| class="wikitable" style="text-align:center"

|- class="hintergrundfarbe6"

! colspan="2"| Enantiomers of grepafloxacin

|-

| [[File:(R)-Grepafloxacin Structural Formula V1.svg|250 px]]<br />(''R'')-grepafloxacin<br /><small> CAS number: 146761-68-4</small>

| [[File:(S)-Grepafloxacin Structural Formula V1.svg|250 px]]<br />(''S'')-grepafloxacin<br /><small> CAS number: 146761-69-5</small>

|}

== See also ==

*[[Quinolone antibiotics]]

== References ==

{{Reflist}}

{{QuinoloneAntiBiotics}}

[[Category:Fluoroquinolone antibiotics]]

[[Category:Withdrawn drugs]]

[[Category:Piperazines]]

[[Category:Cyclopropanes]]

[[Category:Carboxylic acids]]

[[Category:Potassium channel blockers]]