. CH3SO3H

8-{4-[2(S)-Amino-propionyloxy] piperidine-l-yl}-9-fluoro-5 (S)-methyl-ό, 7-dihydro-l- oxo-lH, 5H-benzo[i,j]quinolizine-2-carboxylic acid of structural Formula I can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections.

Formula I

U.S. Patent Nos. 6,750,224 and 7,247,642 describes optically pure S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, their processes of preparation and their pharmaceutical compositions.

PATENT

WO 2007102061

http://www.google.co.in/patents/WO2007102061A2?cl=en

Scheme 1

Experimental:

(S)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid was prepared as per procedure described in Chem. Pharm. Bull. 1996, 44(4), 642-645.

Example-l

Preparation of (2’S,5S)-9-fluoro-6,7-dihydro-8-(4-(N-tert-butoxycarbonyI-L-aIaninyl- oxy)-piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid:

Method-1 : To a mixture of N-tert-butoxycarbonyl-L-alanine (473 g) in dichloromethane (2 L), dicyclohexylcarbodiimide (515 g) dissolved in dichloromethane (2 L) was charged at -10 to 0 ⁰C to provide a turbid suspension. To the turbid suspension, 300 g of (S)-9-fluoro-6,7- dihydro-8-(4-hydroxy-piperidin- 1 -yl)-5-methyl- 1-oxo- lH,5H-benzo[i,j]quinolizine-2- carboxylic acid was added followed by 4-N,N-dimethylamino pyridine (58 g) and the reaction mixture was stirred at -10 to 5 °C temperature over a period of 2 h. Suspension was filtered and solid was washed with 500 ml of dichloromethane. The filtrate was washed with water. Filtrate was dried over anhydrous sodium sulfate. Dried organic layer was then concentrated to its half volume where upon solid was precipitated. The solid was filtered and washed with 300 ml of dichloromethane. Clear organic filtrate was concentrated to dryness to provided an oily mass. Oily mass was triturated with diethyl ether (4 L) to provide white solid. The solid was filtered under suction and washed with diethyl ether (1 L) to provide title compound in 415 g (94%) quantity.

Method-2: To a mixture of triethylamine (98.0 ml) and N-tert-butoxycarbonyl-L-alanine (110 g) in tetrahydrofuran (1050 ml) and N,N-dimethyl formamide (350 ml) mixture, was added 2,4,6-trichlorobenzoyl chloride (100 ml). The resultant mixture was stirred at a temperature -5 to 0 °C for 5 h. To the > reaction mixture 4-N,N-dimethylamino pyridine (24g) and (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid (70 g) was added. The reaction mixture was stirred for additional 7 h at -5 to 0 ⁰C temperature. The suspension was filtered at room temperature and the filtrate was extracted with ethyl acetate after addition of water. The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 85 g quantity.

Method-3: To a solution N-tert-butoxycarbonyl-L-alanine (7.9 g) in tetrahydrofuran (75 ml) and N,N-dimethyl formamide (25 ml) mixture at -10 to 0°C was added methanesulfonyl chloride (2.42 ml) dropwise. To the above solution triethylamine (8.7 ml) was added dropwise over 5 min. the reaction was stirred for 1.5 h maintaining the temperature between at -10 to 0 ⁰C. To the reaction mixture (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l- yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (5.01 g) and 4-N₅N- dimethylamino pyridine (1.70 g) was added. The reaction mixture was stirred for additional 1 h at -5 to 0 °C temperature. The suspension was filtered at room temperature and the filtrate was diluted with water (300 ml) and extracted with ethyl acetate (150 ml x 2). The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 6.38 g (86%) quantity.

Example-2

Preparation of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt:

To a mixture of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-N-tert-butoxycarbonyl-L-alaninyloxy- piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid (415 g) in acetone (4.5 L) was charged methanesulfonic acid (66 ml). Reaction mixture was stirred at 65-67 °C temperature for overnight. The suspension was filtered at 40-45 ⁰C. Solid was washed with acetone (1.5 L) followed by diethyl ether (1.5 L). Off white solid was dried under 40 to 45 mm vacuum at 55-60 °C temperature over the period of 3-4 h. Title compound was obtained as a free flowing off white material 383.0 g (93%).

For MF: C₂₃H₃₀FN₃O₈S, MS (ES+) m/z 432 (obtained as free base for MF: C₂₂H₂₆FN₃O₅);

M.P. 278.50 ⁰C by DSC

PATENT

A S-(-)-optically pure benzoquinolizine carboxylic acid, its derivatives, its pharmaceutically acceptable salts, derivatives, pseudopolymorphs, polymorphs or hydrates thereof of formula I,

Formula I

Patent

PATENT

The tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry^® and Eudragit^®. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 :

Table 1 provides the composition of batches of the present invention.

Table 1

Procedure: The compound of Formula I or pharmaceutically acceptable salts, esters or products thereof, lactose and croscannellose sodium were sifted and dry mixed in a rapid mixer granulator. The above mass was granulated by spraying aqueous solution of povidone. The granules were dried in a fluidized bed drier, sifted and oversize granules were milled in a Quadra mill. The resultant granules were mixed with talc, croscarmellose sodium, microcrystalline cellulose and sodium stearyl fumarate in a double cone blender. The lubricated granules were compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.

Table 2 provides the dissolution data for the compound of formula I or pharmaceutically acceptable salts, esters or products thereof tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 0.1 N hydrochloric acid (900 ml) was used as a medium. Table 2: Dissolution data

//////////////////////////////

^aChemical name: S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. ^bChemical name: S-(–)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3, 3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate. ^cChemical name: R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate.

31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.

Read more at:
http://economictimes.indiatimes.com/articleshow/41359481.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst

Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0

• C19-H21-F-N2-O4.C6-H14-N4-O2
• MW: 534.5855

• L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)

 WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate

(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate

 L-arginine salt of (S)-nadifloxacin

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232

CN 102532131, WO 2005023805, WO 2002009758, WO 2001085095, WO 2000068229

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WO2002009758A2 *	31 Jul 2001	7 Feb 2002	Satish B Bhawsar	Inhibitors of cellular efflux pumps of microbes
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Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.

 

///////////keywords  USFDA, Qualified Infectious Disease Product status, Wockhardt,  drugs,  WCK 2349, QIDP

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