GATIFLOXACIN
BMS-206584, CG-5501, AM-1155, Zymar, Bonoq, Gatiflo, AM-1155
(±)-1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Originally developed at Kyorin, gatifloxacin was first licensed to
Gruenenthal in Europe, and that company still maintains rights to the
oral and injectable formulations of the product. In October 1996, Kyorin
licensed gatifloxacin to BMS, granting the company development and
marketing rights in the U.S., Canada, Australia, Mexico, Brazil and
certain other markets. In 2006, rights to the compound were returned by
BMS. Subsequently, Senju and Kyorin signed a licensing agreement
regarding the development of ethical eye drops containing the
fluoroquinolone. In April 2000, Sumitomo Dainippon Pharma agreed to
comarket the oral formulation in Japan. In August of that year, Allergan
in-licensed gatifloxacin from Kyorin, gaining development and
commercialization rights to the drug in all territories except Japan,
Korea, China and Taiwan. The India-based Lupin Pharmaceuticals signed an
agreement in June 2004 with Allergan to promote the ophthalmic solution
of gatifloxacin in the pediatric specialty area in the U.S. PediaMed
Pharmaceuticals also holds rights to the drug. In 2009, Kyorin licensed
the drug candidate to Senju in China.
Gatifloxacin is the common name for
(±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic
acid (1), one of the most important broad-spectrum antibacterial
agents and a member of the fourth-generation fluoroquinolone
family.(1)Fluoroquinolones inhibit the enzyme DNA gyrase (topoisomerase
II), which is responsible for the supercoiling of the DNA double helix,
preventing the replication and repair of bacterial DNA and
RNA.(2) Gatifloxacin (1) reached the market in 1999 under the
brand name Tequin for the treatment of respiratory tract infections. The
drug is available as tablets and aqueous solutions for intravenous
therapy as well as eye drop formulation (Zymar).
To date, there are several processes described for the preparation
of gatifloxacin, which can be grouped into two main categories: direct
substitution of the 7-position fluorine atom of
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic
acid (2) by 2-methylpiperazine (Scheme 1),(3-5) and through
boron chelate-type intermediates to overcome the diminished reactivity
induced by the 8-methoxy group, which uses as starting material the
ethyl ester derivative 3 (Scheme 2).(6-9)
SCHEME1
- 1.
Mather, R.; Karenchak, L. M.; Romanowski, E. G.; Kowalski, R. P. Am. J. Ophthalmol.2002, 133 ( 4) 463
- 2.
Corey, E. J.; Czakó, B.; Kürti, L. Molecules and Medicine; Wiley: NJ, 2007; p 135.
- 3.
Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. 8-Alkoxyquinolonecarboxylic
acid and salts thereof excellent in the selective toxicity and process
of preparing the same EP 0 230 295 A3, 1987.
- 4.
Niddam-Hildesheim, V.; Dolitzky, B.-Z.; Pilarsky, G.; Steribaum, G. Synthesis of Gatifloxacin WO 2004/069825 A1, 2004.
- 5.
Ruzic, M; Relic, M; Tomsic, Z; Mirtek, M. Process for the
preparation of Gatifloxacin and regeneration of degradation products WO
2006/004561 A1, 2006.
- 6.
Iwata, M.; Kimura, T.; Fujiwara, Y.; Katsube, T. Quinoline-3-carboxylic
acid derivatives, their preparation and use EP 0 241 206 A2, 1987.
- 7.
Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.;
Garcheck, S. J.; Huband, M. D.; Sesnie,J. A.; Cohen, M. A.; Shapiro, M.
A. J. Med. Chem. 1995, 38, 4478
- 8.
Satyanarayana, C.; Ramanjaneyulu, G. S.; Kumar, I. V. S. Novel crystalline forms of Gatifloxacin WO 2005/009970 A1 2005.
- 9.
Takagi, N.; Fubasami, H.; Matsukobo, H.; (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture EP 0 464 823 A1, 1991.
………………………….
WO 2005009970
http://www.google.com/patents/WO2005009970A1?cl=en
preparation of Gatifloxacin hemihydrate from Ethyl-1- Cyclopropyl-6,
7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate through
boron difluoride chelate. Ethyl-1-cyclopropyl- 6,
7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate is
reacted with aqueous hydrofluoroboric acid followed by condensation with
2-methyl piperazine in polar organic solvent resulting in an
intermediate l-Cyclopropyl-7- (3-methyl piperazin-1- yl).
-6-fluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylic acid boron
difluoride chelate. This intermediate may be further hydrolyzed to
yield Gatifloxacin. Gatifloxacin so obtained may needs purification to
yield high purity product. However to obtain directly high purity
Gatifloxacin it is desirable to isolate the intermediate by cooling to
low temperatures . Treating with an alcohol or mixture of alcohols
purifies this intermediate. The purified condensed chelate in aqueous
ethanol on hydrolysis with triethylamine followed by crystallization in
ethanol gives Gatifloxacin hemihydrate with high purity.
STAGE – I:
Ethyl l-cyclopropyl-6,7-difluoro-8-met oxy l-Cycloproρyl-6,
7-difluoro-8-methoxy -4-oxo-l, -dihydro-3-quinoline -4-oxo-l,
4-dihydro-3-quinoline carboxylate carboxylic acid boron difluoride
chelate
STAGE – II :
l-Cycloprop l-7- ( 3-methylpiperazin-l-yl.
6-fluoro~8-methoxy-4-oxo-l , 4-dihydro-3- carboxylicacid
borondifluoride chelate quinoline carboxylicacid borondifluoride chelate
STAGE -III :
l-Cyclopropyl-7- (3- ethylpiperaz.in-l-yl . GATIFLOXACIN
-6-fluoro-8-methoxy-4-oxo-l , 4-dihydro-3- quinoline carboxylicacid borondifluoride chelate
Example-I: Preparation of Gatifloxacin • with isolation of intermediate (boron difluoride chelate derivative)
Stage-1: Preparation of l-cyclopropyl-6, 7-di luoro-8-methoxy-4-oxo-
1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate.
Ethyl-l-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, -dihydro-3-
quinόline carboxylate (100g)is suspended in ,40%aq..hydrofluoroboric
acid -(1000 ml). Temperature of • the reaction mass is raised and
maintained at 95°C to 100°C for 5hrs followed by cooling to 30°C – 35°C.
Water (400 ml) is added and maintained at 25°C – 30°C for 2hrs .
Product is filtered, washed with water (500 ml) and dried at 40°C – 45°C
to constant weight. Dry weight of the product: 101.6 g (Yield: 95.8 %)
Stage-2: Preparation of 1- Cyclopropyl-7- (3-methylpiperazin-l-yl) –
6-fluoro-8-methoxy-4-oxo-l, -dihydro-3-quinoline carboxylic acid boron
difluoride chelate
100 g of Boron difluoride chelate derivative prepared as above in
stage-1 is suspended in acetonitrile (800 ml) , to that 2-methyl
piperazine (44.0 g, 1.5 mole equiv.) is added and mixed for 15 min to
obtain a clear solution. The reaction mass is maintained at 30°C – 35°C
for 12 hrs followed by cooling to -10°C to -5°C. The reaction mass is
maintained at -10°C to -5°C for 1 hr. The product is filtered and dried
at 45°C – 50°C to constant weight. Dry weight of the product: 116.0 g
(Yield: 93.9 %) .
The condensed chelate (100 g) prepared as above is suspended in
methanol (1500 ml), maintained at 40°C – 45°C for 30 min. The reaction
mass is gradually cooled, maintained for 1 hr at -5°C to 0°C. The
product is filtered, washed with methanol (50 ml) and dried at 45°C –
50°C to constant weight. Dry weight of the product: 80.0 g (Yield: 80.0
%)
Stage -3: Preparation of Gatifloxacin (Crude)
The pure condensed chelate (100.0 g) prepared as above in stage-2 is
suspended in 20% aq. ethanol (1000 ml) , the temperature is raised and
maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled,
filtered to remove insolubles, distilled under vacuum to remove solvent.
Fresh ethanol (200 ml) is added and solvent is removed under vacuum at
temperature below 50°C. Ethanol (200 ml) is added to the residue and
gradually cooled to -10°C to -5°C. The reaction mass is mixed at -10°C
to -5°C for 1 hr and then filtered. The wet cake is washed with ethanol
(25 ml) and dried at 45°C – 50°C to constant weight.
The dry weight of the Gatifloxacin is 83.3 g (Yield: 91.7 %)
Stage- 4: Purification of crude Gatifloxacin
Crude Gatifloxacin (100.0 g) prepared as above in stage-3 is
suspended in methanol (4000 ml), the temperature is raised and
maintained at 60°C to 65°C for 20 min. to get a clear solution.
Activated carbon (5 g) is added, maintained for 30 min and the solution
is filtered. The filtrate is concentrated to one third of its original
volume under vacuum at temperature below 40°C. The reaction mass is
gradually cooled and maintained at -10°C to -5°C for 2 hrs. The product
is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to
constant weight. The dry weight of the pure Gatifloxacin is 76.0 g
(Yield: 76.0 %)
Example-II: Preparation of Gatifloxacin without isolation of intermediate (boron difluoride chelate derivative)
Stage-1: Preparation of l-cyclopropyl-6, 7-difluoro-8-methoxy-4-
oxo-1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate.
Ethyll-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-
quinoline carboxylate (lOOg) is suspended in 40% aq. hydrofluoroboric
acid (1000 ml) . Temperature of the reaction mass is raised and
maintained at 95°C to 100°C for 5 hrs followed by cooling to 30°C –
35°C. 400 ml DM water is added, maintained at 25°C – 30°C for 2hrs . The
product is filtered, washed with DM water (500 ml) and dried at 40°C –
45°C to constant weight. The dry wt is 102.5 g (Yield: 96.6 %)
Stage – 2: Preparation of Gatifloxacin (Crude)
The boron difluoride chelate derivative (100 g) prepared as above in
stage-1 is suspended in acetonitrile (800 ml) , 2-methyl piperazine (44
g, 1.5 mole equiv.) is added and mixed for 15 min to obtain a clear
solution. The reaction mass is maintained at 30°C – 35°C for 12 hrs.
Removed the solvent by vacuum distillation. 20% Aq. ethanol (1000 ml) is
added, raised the temperature and maintained at 75°C to 80°C for 2 hrs.
The reaction mass is cooled, filtered to remove insolubles. The
filtrate is distilled under vacuum to remove solvent completely. Fresh
ethanol (250 ml) is added and distilled under vacuum at temperature
below 50°C. Fresh Ethanol (250 ml) is added to the residue and gradually
cooled to -10°C to -5°C. The reaction mass is maintained at -10°C to
-5°C for 1 hr and filtered. The wet cake is washed with ethanol (30 ml)
and dried at 45°C – 50°C to constant weight.
The dry weight of the Gatifloxacin is 73.5 g (Yield: 65.4 %)
Stage -3: Purification of crude Gatifloxacin
Crude Gatifloxacin (80.0 g) prepared as above in stage-2 is suspended
in methanol (2000 ml) , the temperature is raised and maintained at
60°C to 65°C for 20 min. to get a clear solution. The reaction mixture
is filtered. The filtrate is gradually cooled and maintained at -10°C to
-5°C for 2 hrs. The product is filtered, washed with methanol (50 ml)
and dried at 45°C – 50°C to constant weight.
The dry weight of the pure Gatifloxacin is 56.0 g (Yield: 70.0 %)
……………………….
WO 2005047260
http://www.google.co.in/patents/WO2005047260A1?cl=en
Gatifloxacin is the international common name of
l-cyclopropyl-6-fluoro-l, 4-dihydro-8-methoxy- 1-
(3-methyl-l-piperazinyl) -4-oxo-3-guinolin-carboxylic acid of formula
(I) , with application in medicine and known for its antibiotic
activity:
European patent application EP-A-230295 discloses a process for
obtaining gatifloxacin that consists on the reaction of compound (II)
with 2-
In this process the gatifloxacin is isolated in the form of a
hemihydrate after a laborious process of column chromatography and
recrystallisation in methanol, which contributes towards making the
final yield lower than 20% by weight. Moreover, in said process an
undesired by-product is formed, resulting from demethylation at position
8 of the ring. European patent application EP-A-241206 discloses a
process for preparing gatifloxacin, whose final steps are as follows:
(III) H ft N Me H DMSO
Gatifloxacin (I)
(IV) This process uses the intermediate compound (III) , which has
been prepared and isolated in a separate operation, while the
intermediate compound (IV) is also isolated before proceeding to its
conversion into gatifloxacin by treatment with ethanol in the presence
of triethylamine. The overall yield from these three steps is lower than
40%. These disadvantages — a synthesis involving several steps, low
yields, and the need to isolate the intermediate products — hinder the
production of gatifloxacin on an industrial scale. There is therefore a
need to provide a process for preparing gatifloxacin with a good
chemical yield, without the need to isolate the intermediate compounds
and that substantially avoids demethylation in position 8 of the ring.
The processes termed in English “one pot” are characterised in that the
synthesis is carried out in the same reaction vessel, without isolating
the intermediate compounds, and by means of successive addition of the
reacting compounds. The authors of the present invention have discovered
a simplified process for preparing gatifloxacin which does not require
isolation of the intermediate compounds .
Example 1: Preparing gatifloxacin from compound (II) 10 g (0.0339 moles, 1 equivalent) of compound
(II) is placed in a flask, 30 ml of acetonitryl (3 volumes) is added and this is heated to a temperature of 76-80° C.
Once reflux has been attained, and being the temperature maintained,
3.28 g (0.0203 moles, 0.6 equivalents) of hexamethyldisilazane (HMDS) is
added with a compensated adding funnel. Once addition is completed, the
reaction is maintained with stirring for 1 hour at a temperature of
76-80° C. Once this period has elapsed, the reaction mixture is cooled
to a temperature ranging between 0 and 15° C, and 5.78 g (0.0407 moles,
1.2 equivalents) of boron trifluoride ethyletherate is added while
keeping the temperature below 15° C. Once addition is completed, the
temperature is allowed to rise to 15- 25° C and it is kept under these
conditions for approximately 2 hours. The pH of the mixture is then
adjusted to an approximate value of 9 with triethylamine (approximately 2
ml) . To the resulting suspension is added a solution of 10.19 g
(0.1017 moles, 3 equivalents) of 2-methylpiperazine in 28 ml of
acetonitryl, while maintaining the temperature between 15 and 25° C. The
resulting amber solution is kept with stirring under these conditions
for approximately 3 hours . Once the reaction has been completed, the
solution is distilled at low pressure until a stirrable paste is
obtained. At this point 50 ml of methanol is added, the resulting
suspension is raised to a temperature of 63-67° C and is kept under
these conditions for approximately 5 hours . Once the reaction has been
completed, the mixture is cooled to a temperature of 25-35° C in a water
bath, and then at a temperature of 0-5° C in a water/ice bath for a
further 1 hour. The resulting precipitate is filtered, washed with cold
methanol (2 x 10 ml) and dried at 40° C in a vacuum oven to constant
weight. 10.70 g of crude gatifloxacin is obtained, having a water
content of 2.95% by weight. The yield of the process is 81.8%.
The crude product is crystallised in methanol by dissolving 20 g of
crude gatifloxacin in 1 1 of methanol (50 volumes) at a temperature of
63-67° C. Once all the product has been dissolved, the solution is left
to cool to a temperature of 30-40° C, and then to a temperature of 0-5° C
in a water/ice bath, maintaining it under these conditions for 1 hour.
The resulting suspension is filtered and the solid retained is washed
with 20 ml (1 volume) of cold methanol. The solid obtained is dried at
40° C in a vacuum oven to provide 18.65 g of gatifloxacin with a water
content of 2.36% by weight.
The overall yield from the compound (II) is 77.7%, with a purity
exceeding 99.8% as determined by HPLC chromatography. The content of
by-product resulting from demethylation in position 8 of the ring is
lower than 0.1% as determined by HPLC chromatography.
PAPER
) through use of
boron chelate intermediates has been developed. The methodology involves
an initial activation step which accelerates the formation of the first
chelate under low-temperature conditions and prevents demethylation of
the starting material. To increase the overall yield and to avoid the
isolation and manipulation of the resulting intermediates, the process
has been designed to be carried out in one pot. As a result, we present
here an easy, scaleable and substantially impurity-free process to
obtain gatifloxacin (
Department of Research & Development, Química Sintética S.A.,
c/ Dulcinea s/n, 28805 Alcalá de Henares, and Department of Organic
Chemistry, University of Alcalá, 28871 Madrid, Alcalá de Henares, Spain
Org. Process Res. Dev., 2008, 12 (5), pp 900–903
DOI: 10.1021/op800042a
18
DSC analysis showed two endothermic peaks at 166.2 °C (T onset = 164.3 °C) and 190.0 °C (T onset
= 188.2 °C) and an exothermic one at 168.1 °C. The shape of this DSC
curve is characteristic of a monotropic transition between crystalline
forms
Water content by Karl Fischer 3.0%
(19) MS
m/
z 376 (M+ + H);
19
Although there are several hydrates described for gatifloxacin such
as, among others, the hemimydrate, sesquihydrate, and pentahydrate(Raghavan, K.
S.; Ranadive, S. A.;Gougoutas, J. Z.; Dimarco, J. D.; Parker, W.
L.; Dovich, M.; Neuman, A.Gatifloxacin pentahydrate. WO 2002/22126
A1, 2002) , the Gatifloxacin obtained by the present procedure does not
seem to form a stoichometric hydrate, but instead it retains moisture.
Thus, the product is usually
obtained with a Karl-Fischer value below 1% after drying, but it can
absorb moisture until a final content of about 3%. This water content
can vary between 2.0% and 3.5%, depending on the relative humidity of
the environment. DSC analysis revealed a broad endothermic signal with
minimum at 76 °C, while TGA analysis showed that the product loses all
the water below 80 °C.
No loss of weight is registered when
the product melts, and the weight is constant until the decomposition
of the material at about 200 °C. On the basis of these results, it can
be said that the water content of the gatifloxacin obtained by the
present process is retained moisture instead of water belonging to the
lattice. The shape of the derivative of the weight curve at the
beginning of the analysis shows that the sample has already lost part of
the moisture when the register starts. This is probably due to the
sample starting to lose weight when makes contact with the dry
atmosphere of the TGA oven that could explain the different values
obtained for water content of the analyzed sample by TGA (1.90%) and
Karl-Fischer (2.64%) methods.
1H NMR (DMSO-d6) δ 0.97 (d, J = 6.1 Hz, 3H), 1.04 (m, 2H), 1.15 (m, 2H), 2.75−2.94 (m, 4H) 3.14 (m, 1H), 3.30 (m, 2H), 3.74 (s, 3H), 4.15 (m, 1H), 7.70 (d, JH−F = 12.2 Hz, 1H), 8.67 (s, 1H).
13C NMR (DMSO-d6) δ 8.40, 8.42, 18.66, 40.28, 45.46, 50.17, 50.29 (d, JC−F = 3.44 Hz), 57.36 (d, JC−F = 3.74 Hz), 62.15, 106.0 (d, JC−F = 22.7 Hz), 106.04, 120.05 (d, JC−F = 8.6 Hz), 133.6 (d, JC−F = 1.1 Hz), 138.9 (d, JC−F = 11.9 Hz), 145.2 (d, JC−F = 5.87 Hz), 149.88, 155.06 (d, JC−F = 249.2 Hz), 165.56, 175.56 (d, JC−F = 3.3 Hz).
19F NMR (DMSO-d6) δ −120.4 (d, J = 12.2 Hz).
Anal. Calcd for C19H22N3O4F + 3.0% H2O; C, 58.95; H, 6.07; N, 10.85. Found: C, 58.90; H, 5.82; N, 10.90.
Side-effects and removal from the market
A
Canadian study published in the
New England Journal of Medicine in March 2006 claims Tequin can have significant
side effectsincluding
dysglycemia.
[2] An
editorial by Dr. Jerry Gurwitz in the same issue called for the
Food and Drug Administration (FDA) to consider giving Tequin a
black box warning.
[3] This
editorial followed distribution of a letter dated February 15 by
Bristol-Myers Squibb to health care providers indicating action taken
with the FDA to strengthen warnings for the medication.
[4] Subsequently
it was reported on May 1, 2006 that Bristol-Myers Squibb would stop
manufacture of Tequin, end sales of the drug after existing stockpiles
were exhausted, and return all rights to Kyorin.
[5]
Union Health and Family Welfare Ministry of India on 18 March 2011
banned the manufacture, sale and distribution of Gatifloxacin as it
caused certain adverse side effects
[6]
Contraindications
Diabetes[7]
Availability
Gatifloxacin is currently available only in the US and Canada as an ophthalmic solution.
In China it is sold in tablet as well as in eye drop formulations.
Ophthalmic anti-infectives are generally well tolerated. The
concentration of the drug observed following oral administration of
400 mg gatifloxacin systemically is approximately 800 times higher than
that of the 0.5% Gatifloxacin eye drop. Given as an eye drop,
Gatifloxacin Ophthalmic Solution 0.3% & 0.5% cause very low systemic
exposures. Therefore, the systemic exposures resulting from the
gatifloxacin ophthalmic solution are not likely to pose any risk for
systemic toxicities.
- The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with
CuCN and N-methyl-2-pyrrolidone at 150 C gives
2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with
concentrated H2SO4 yields the benzamide (III) The hydrolysis of (III)
with H2SO4 -. water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic
acid (IV), which by reaction with SOCl2 is converted into the acyl
chloride (V). The condensation of (V) with diethyl malonate by means of
magnesium ethoxide in toluene affords diethyl 2-
(2,4,5-trifluoro-3-methoxybenzoyl) malonate (VI), which by treatment
with p-toluenesulfonic acid in refluxing water gives ethyl 2-
(2,4,5-trifluoro-3-methoxybenzoyl) acetate (VII). The condensation of
(VII) with triethyl orthoformate in refluxing acetic anhydride yields
3-ethoxy -2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylic acid ethyl ester
(VIII), which is treated with cyclopropylamine (IX) to afford the
corresponding cyclopropylamino derivative (X). The cyclization of (X) by
means of NaF in refluxing DMF gives
1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to
yield the corresponding free acid (XII). Finally, this compound is
condensed with 2-methylpiperazine (XIII) in hot DMSO.
 |
|
Title: Gatifloxacin
CAS Registry Number: 112811-59-3
CAS Name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid
Trademarks: Tequin (BMS); Zymar (Allergan)
Molecular Formula: C19H22FN3O4
Molecular Weight: 375.39
Percent Composition: C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.05%
Literature References: Fluorinated quinolone antibacterial. Prepn: K. Masuzawa et al., EP 230295; eidem, US 4980470 (1987, 1990 both to Kyorin); J. P. Sanchez et al., J. Med. Chem. 38, 4478 (1995); of the sesquihydrate: T. Matsumoto et al., US5880283 (1999 to Kyorin). In vitro antibacterial activity: A. Bauernfeind, J. Antimicrob. Chemother. 40, 639 (1997); H. Fukuda et al., Antimicrob. Agents Chemother. 42, 1917 (1998). Clinical pharmacokinetics: M. Nakashima et al., ibid. 39, 2635 (1995). Clinical study in urinary tract infection: H. Nito, 10th Mediterranean Congr. Chemother. 1996, 327; in respiratory tract infection: S. Sethi, Expert Opin. Pharmacother. 4, 1847 (2003).
Properties: Pale yellow prisms from methanol as hemihydrate, mp 162°.
Melting point: mp 162°
Derivative Type: Sesquihydrate
CAS Registry Number: 180200-66-2
Manufacturers’ Codes: AM-1155
Molecular Formula: C19H22FN3O4.1½H2O
Molecular Weight: 384.40
Percent Composition: C 59.37%, H 6.03%, F 4.94%, N 10.93%, O 18.73%
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Synthetic); Quinolones and Analogs
|
References
- Burka JM, Bower KS, Vanroekel RC, Stutzman RD, Kuzmowych CP, Howard RS (July 2005). “The
effect of fourth-generation fluoroquinolones gatifloxacin and
moxifloxacin on epithelial healing following photorefractive
keratectomy”. Am. J. Ophthalmol. 140 (1): 83–7. doi:10.1016/j.ajo.2005.02.037.PMID 15953577.
- Park-Wyllie, Laura Y.; David N. Juurlink;
Alexander Kopp; Baiju R. Shah; Therese A. Stukel; Carmine Stumpo; Linda
Dresser; Donald E. Low; Muhammad M. Mamdani (March 2006).“Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults”. The New England Journal of Medicine 354 (13): 1352–1361. doi:10.1056/NEJMoa055191. PMID 16510739. Retrieved 2006-05-01. Note: publication date 30 March; available on-line 1 March
- Gurwitz, Jerry H. (March 2006). “Serious Adverse Drug Effects — Seeing the Trees through the Forest”. The New England Journal of Medicine 354 (13): 1413–1415.doi:10.1056/NEJMe068051. PMID 16510740. Retrieved2006-05-01.
- Lewis-Hall, Freda (February 15, 2006). “Dear Healthcare Provider:” (PDF). Bristol-Myers Squibb. Retrieved May 1, 2006.
- Schmid, Randolph E. (May 1, 2006). “Drug Company Taking Tequin Off Market”. Associated Press. Archived from the original on November 25, 2007. Retrieved 2006-05-01.[dead link]
- “Two drugs banned”. The Hindu (Chennai, India). 19 March 2011.
- Peggy Peck (2 May 2006). “Bristol-Myers Squibb Hangs No Sale Sign on Tequin”. Med Page Today. Retrieved 24 February2009.
| EP0610958A2 * |
20 Jul 1989 |
17 Aug 1994 |
Ube Industries, Ltd. |
Intermediates in the preparation of 4-oxoquinoline-3-carboxylic acid derivatives |
| ES2077490A1 * |
|
|
|
Title not available |
| Citing Patent |
Filing date |
Publication date |
Applicant |
Title |
| WO2008126384A1 |
31 Mar 2008 |
23 Oct 2008 |
Daiichi Sankyo Co Ltd |
Method for producing quinolone carboxylic acid derivative |
| CN101659654B |
28 Aug 2008 |
6 Nov 2013 |
四川科伦药物研究有限公司 |
2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof |
| CN102351843A * |
18 Aug 2011 |
15 Feb 2012 |
张家口市格瑞高新技术有限公司 |
Synthesis method of 2-methyl piperazine lomefloxacin |
| EP1832587A1 * |
2 Mar 2007 |
12 Sep 2007 |
Quimica Sintetica, S.A. |
Method for preparing moxifloxacin and moxifloxacin hydrochloride |
| US7365201 |
2 Mar 2006 |
29 Apr 2008 |
Apotex Pharmachem Inc. |
Process for the preparation of the boron difluoride chelate of quinolone-3-carboxylic acid |
| US7875722 |
30 Sep 2009 |
25 Jan 2011 |
Daiichi Sankyo Company, Limited |
Method for producing quinolone carboxylic acid derivative |
| EP0464823A1 * |
Jul 4, 1991 |
Jan 8, 1992 |
Kyorin Pharmaceutical Co., Ltd. |
(6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for
their manufacture |
| US4997943 * |
Mar 31, 1987 |
Mar 5, 1991 |
Sankyo Company Limited |
Quinoline-3-carboxylic acid derivatives |
| Citing Patent |
Filing date |
Publication date |
Applicant |
Title |
| CN101659654B |
Aug 28, 2008 |
Nov 6, 2013 |
四川科伦药物研究有限公司 |
2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof |
| CN102351843A * |
Aug 18, 2011 |
Feb 15, 2012 |
张家口市格瑞高新技术有限公司 |
Synthesis method of 2-methyl piperazine lomefloxacin |
* Cited by examiner
TAKE A TOUR
TAKE A TOUR
Amritsar, punjab, India
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Amritsar is one of the largest cities of the Punjab state in India.
The city origin lies in the village of Tung, and was named after the
lake founded by the fourth Sikh …
GOLDEN TEMPLE
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Tandoori chicken at Surjit Food Plaza. amritsar
The Jallianwalla Bagh in 1919, months after the massacre
Mealtime at the Golden Temple Amritsar
Golden Temple – Harmandir Sahib: Free food for everyone
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Maharaja Ranjit Singh’s Ram Bagh Gardens
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tandoori chicken
