Salts of sitafloxacin and pharmaceutical purposes thereof

A technology of sitafloxacin and hydrochloric acid, applied in the field of anti-infective drugs, can solve the problems of increasing production cost and difficulty, not having significant significance, and not solving the problems such as hygroscopic degradation of sitafloxacin

Active Publication Date: 2013-05-08
NANJING YOKO PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This can only reduce photodegradation to a certain extent, which is not significant, and it also increases the cost and difficulty of production
In addition, this only alleviates the problem of easy photolysis of sitafloxacin, but does not solve th

Method used

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  • Salts of sitafloxacin and pharmaceutical purposes thereof
  • Salts of sitafloxacin and pharmaceutical purposes thereof
  • Salts of sitafloxacin and pharmaceutical purposes thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The synthesis of embodiment 1 sitafloxacin

[0064] According to Synthesis and stereochemical structure-activity relationships of chiral7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents (J Med Chem 1994, 37, 20, 3344 .) The disclosed method synthesizes sitafloxacin.

[0065] 1 HNMR (DMSO-d 6 )δ

[0066] 0.43-0.46(m, 1H), 0.55-0.61(m, 2H), 0.79-0.83(m, 1H), 1.23(dm, 1H, J=27Hz), 3.06(t, 1H, J=5Hz), 3.25 -3.28(m, 1H), 3.35(d, 1H, J=7Hz), 3.83(d, 1H, J=7Hz), 3.92-3.96(m, 1H), 4.06-4.10(m, 1H), 4.50( dm, 1H, J = 64Hz), 7.74 (d, 1H, J = 14Hz), 8.47 (d, 1H, J = 2Hz) XRPD pattern shows crystals, and its X-ray powder diffraction pattern is at 2θ = 7.76°, 8.43° , 9.14°, 12.46°, 12.86°, 14.24°, 15.66°, 16.91°, 18.11°, 18.80°, 19.24°, 20.87°, 21.34°, 22.15°, 23.10°, 23.39°, 23.75°, 24.07°, 25.00 °, 25.70°, 26.22°, 26.71°, 27.07°, 28.04°, 29.04°, 29.62°, 30.48°, 31.22°, 31.73°, 32.57°, 33.22°, 33.82°°, 35.71°, 36.52°, 39.19° , the...

Embodiment 2

[0067] Preparation and characterization of embodiment 2 sitafloxacin hydrochloride

[0068] Weigh the obtained 100mg sitafloxacin (0.24mmol, 1eq), dissolve it in 15mL acetone, control the temperature at 30°C, stir until dissolved, add a hydrochloric acid solution containing 13.5mg hydrochloric acid (0.37mmol, 1.5eq) to the solution, stir reaction. After the reaction was finished, n-heptane was added to the reaction solution until the cloud point appeared. Reduce the temperature to room temperature at a rate of 5°C / min, filter, collect the solid, and dry under reduced pressure at 45°C overnight to obtain the obtained product. The obtained sitafloxacin hydrochloride was characterized by XRPD and DSC.

[0069] The melting point detected by DSC was 123.03°C.

Embodiment 3

[0070] Embodiment 3 Preparation and characterization of sitafloxacin tartrate crystal form I

[0071] Weigh 100mg of sitafloxacin (0.24mmol, 1eq), dissolve it in 15mL of acetone, control the temperature at 35°C, stir until dissolved, add a solution containing 43.2mg of tartaric acid (0.29mmol, 1.2eq) to the solution, and precipitate . Reduce the temperature to room temperature at a rate of 5°C / min, filter, collect the solid, and dry under reduced pressure at 45°C overnight to obtain the obtained product. The obtained sitafloxacin hydrochloride was characterized by XRPD and DSC.

[0072] The melting point detected by DSC was 193.32°C.

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PUM

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Abstract

The invention provides acid addition salts of sitafloxacin represented by the formula, crystal forms and preparation methods of the salts, and pharmaceutical compositions, preparations and pharmaceutical purposes of the salts, wherein A is described in the specification. Both stability and water-solubility of the salts of the sitafloxacin or the crystal forms are better than that of sitafloxacin free alkali; furthermore, the irritation is less than that of the sitafloxacin free alkali; and the compositions or preparations prepared from the salts are applied to clinical applications.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an acid addition salt of an anti-infective drug sitafloxacin, a crystal form of the salt and a preparation method, as well as the pharmaceutical composition, dosage form and pharmaceutical application of these salts. Background technique [0002] Sitafloxacin (sitafloxacin) is a broad-spectrum quinolone antibacterial drug developed by Daiichi Sankyo Co., Ltd. (Daiichi Sankyo). Bacteroids, Mycoplasma and Chlamydia all have strong antibacterial activity. It is clinically used as its monohydrate, oral tablets (50mg) and fine granules (100g, 10%) have been listed for the first time in Japan in June 2008, and the trade name is Gracevit, which is used for the treatment of severe refractory infectious diseases. disease. The drug has good oral absorption, bioavailability greater than 70%, and wide tissue distribution. The drug concentration in various tissues outside the ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4709A61P31/04
Inventor 晁阳叶海车晓明顾传虎包玉胜
Owner NANJING YOKO PHARMA GRP CO LTD
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