Grepafloxacin (trade name Raxar,

Glaxo Wellcome GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...

) was an oral broad-spectrum

fluoroquinolone A quinolone antibiotic is a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as wel ...

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

agent used to treat

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable d ...

s. Grepafloxacin was withdrawn worldwide from markets in 1999, due to its side effect of lengthening the

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

on the electrocardiogram, leading to cardiac events and

sudden death Sudden Death or Sudden death may refer to: Medical * Cardiac arrest, also known as sudden cardiac death, natural death from cardiac causes * Sudden cardiac death of athletes * Sudden infant death syndrome * Sudden unexpected death in epilepsy * ...

Clinical uses

Grepafloxacin was used for treating exacerbations of chronic bronchitis caused by susceptible bacteria (e.g. ''

Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacte ...

'', ''

Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They a ...

'', ''

Moraxella catarrhalis ''Moraxella catarrhalis'' is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system, and joints of humans. It causes the i ...

''), community-acquired pneumonia (including those, in addition to the above germs, caused by ''

Mycoplasma pneumoniae ''Mycoplasma pneumoniae'' is a very small bacterium in the class Mollicutes. It is a human pathogen that causes the disease mycoplasma pneumonia, a form of atypical bacterial pneumonia related to cold agglutinin disease. ''M. pneumoniae'' is c ...

'')

gonorrhea Gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium '' Neisseria gonorrhoeae''. Infection may involve the genitals, mouth, or rectum. Infected men may experience pain or burning with ...

and

non-gonococcal urethritis Nongonococcal urethritis (NGU) is an inflammation of the urethra that is not caused by gonorrheal infection. For treatment purposes, doctors usually classify infectious urethritis in two categories: gonococcal urethritis, caused by gonorrhea, ...

and

cervicitis Cervicitis is inflammation of the uterine cervix. Cervicitis in women has many features in common with urethritis in men and many cases are caused by sexually transmitted infections. Non-infectious causes of cervicitis can include intrauterin ...

(for example caused by ''

Chlamydia trachomatis ''Chlamydia trachomatis'' (), commonly known as chlamydia, is a bacterium that causes chlamydia, which can manifest in various ways, including: trachoma, lymphogranuloma venereum, nongonococcal urethritis, cervicitis, salpingitis, pelvic infl ...

'' or ''

Ureaplasma urealyticum ''Ureaplasma urealyticum'' is a bacterium belonging to the genus ''Ureaplasma'' and the family Mycoplasmataceae in the order Mycoplasmatales. This family consists of the genera ''Mycoplasma'' and ''Ureaplasma''. Its type strain is T960. There ar ...

'').

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

The scheme starts with the conversion of the carboxylic acid in (1) to its dimethyloxazoline derivative (3) by reaction with the

aminomethyl propanol Aminomethyl propanol is an organic compound with the formula H2NC(CH3)2CH2OH. It is colorless liquid that is classified as an alkanolamine. It is a useful buffer and a precursor to numerous other organic compounds. Synthesis Aminomethyl propano ...

(2).

Lithium diisopropylamide Lithium diisopropylamide (commonly abbreviated LDA) is a chemical compound with the molecular formula . It is used as a strong base and has been widely utilized due to its good solubility in non-polar organic solvents and non-nucleophilic nature ...

(LDA) then removes a proton from the 8 position; treatment of that anion with

trimethylsilyl iodide Trimethylsilyl iodide (iodotrimethylsilane or TMSI) is an organosilicon compound with the chemical formula (CH3)3SiI. It is a colorless, volatile liquid at room temperature. Preparation Trimethylsilyl iodide may be prepared by the oxidative cleav ...

leads to the silylated intermediate (4). A second round of LDA then generates a

carbanion In organic chemistry, a carbanion is an anion in which carbon is trivalent (forms three bonds) and bears a formal negative charge (in at least one significant resonance form). Formally, a carbanion is the conjugate base of a carbon acid: :R3CH ...

at the only open position; reaction with

methyl iodide Iodomethane, also called methyl iodide, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one ...

leads to the corresponding 5 methyl derivative (5). Treatment of that product with

cesium fluoride Caesium fluoride or cesium fluoride is an inorganic compound with the formula CsF and it is a hygroscopic white salt. Caesium fluoride can be used in organic synthesis as a source of the fluoride anion. Caesium also has the highest electropositivi ...

breaks the carbon–silicon bond, removing the silyl group; aqueous acid then hydrolyzes the

oxazoline Oxazoline is a five-membered heterocyclic organic compound with the formula . It is the parent of a family of compounds called oxazolines (emphasis on plural), which contain non-hydrogenic substituents on carbon and/or nitrogen. Oxazolines are the ...

to afford the free acid (6). This last intermediate is then taken on to the quinolone (9) by essentially the same scheme as that used to prepare

difloxacin Difloxacin (INN), marketed under the trade name Dicural, is a second-generation, synthetic fluoroquinolone antibiotic used in veterinary medicine. It has broad-spectrum, concentration dependent, bactericidal activity; however, its efficacy is n ...

, with the difference that the chain elongation is by means of Grignard reagent of

ethyl bromoacetate Ethyl bromoacetate is the chemical compound with the formula CH2BrCO2C2H5. It is the ethyl ester of bromoacetic acid and is prepared in two steps from acetic acid. It is a lachrymator and has a fruity, pungent odor. It is also a highly toxic alky ...

. Treatment of (9) with 2-methylpiperazine proceeds by reaction at the less hindered of the two amino groups;

saponification Saponification is a process of converting esters into soaps and alcohols by the action of aqueous alkali (for example, aqueous sodium hydroxide solutions). Soaps are salts of fatty acids, which in turn are carboxylic acids with long carbon chains ...

then affords grepafloxacin (10).

Stereochemistry

Grepafloxacin contains a stereocenter and consists of two enantiomers. This is a

racemate In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

, ie a 1: 1 mixture of (''R'')- and the (''S'')-forms:

References

{{QuinoloneAntiBiotics Fluoroquinolone antibiotics Withdrawn drugs Piperazines HERG blocker Cyclopropanes Carboxylic acids

Clinical uses

Synthesis

Stereochemistry

See also

References