CN102372679A - Febuxostat water-soluble derivative and preparation method thereof - Google Patents
Febuxostat water-soluble derivative and preparation method thereof Download PDFInfo
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- CN102372679A CN102372679A CN2010102649066A CN201010264906A CN102372679A CN 102372679 A CN102372679 A CN 102372679A CN 2010102649066 A CN2010102649066 A CN 2010102649066A CN 201010264906 A CN201010264906 A CN 201010264906A CN 102372679 A CN102372679 A CN 102372679A
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Abstract
The invention provides a febuxostat water-soluble derivative expressed by a general formula I, wherein M represents choline, lysine, arginine, diethylamine, triethylamine, diethanol amine and triethanolamine. The lysine or arginine can be selected from an L configuration, a D configuration or a DL configuration.
Description
Technical field
The present invention relates to a kind of TMX-67 soluble derivative and preparation method thereof.
Technical background
TMX-67, chemical name: 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid is mainly used in the treatment of hyperuricemia.
TMX-67 is almost insoluble in water, causes the stripping of TMX-67 oral prepns difficult especially, in preparation process, needs earlier TMX-67 is carried out the ultra micro efflorescence, has increased the complicacy of preparation process and the production cost of preparation.
In the molecular structure of TMX-67, there is an exposed carboxyl, be easy to and various organic bases salifies, improve its solubleness in water.
Summary of the invention
The present invention provides the soluble derivative of the TMX-67 shown in a kind of general formula I.
Wherein, M represents choline, Methionin, l-arginine, diethylamine, triethylamine, diethylolamine, trolamine.Methionin or l-arginine can be L configuration, D configuration or DL configuration.
The present invention also provides the preparation method of these compounds, the alkali that can use the M representative directly in and TMX-67, the crystallization means through routine are separated out the product crystallization then.
Embodiment
Can further describe the present invention through following embodiment, yet invention of the present invention is not limited to following embodiment, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjustment also should be thought and belong to scope of the present invention.
The preparation of embodiment 1 TMX-67 choline salt (I1)
TMX-67 5.0g is suspended in the 30ml methyl alcohol, adds the methanol solution of 6.7g25% choline, be dissolved into light yellow transparent solution very soon; Add the 100ml ether, be stirred to a large amount of solids and separated out, filter; Ether is washed, and 45 ℃ of vacuum-dryings get white needle-like crystals 5.2g.ESI-MS：339.2(M+Na
+)。Ultimate analysis: C (59.83%), H (7.41%), N (9.97%), S (7.61%); Calculated value: C (59.65%), H (7.32%), N (10.06%), S (7.82%).
The preparation of embodiment 2 TMX-67 Methionins (I2)
TMX-67 5.0g is suspended in the 35ml methyl alcohol, and adding 2.9 gram L-Methionins stir and make dissolving, add the 80ml ether, have been stirred to a large amount of solids and have separated out, and filter, and ether is washed, and 45 ℃ of vacuum-dryings get white crystal 5.6g.ESI-MS：339.3(M+Na
+)。Ultimate analysis: C (57.12%), H (6.54%), N (12.11%), S (6.93%); Calculated value: C (57.26%), H (6.59%), N (11.95%), S (6.84%).
The preparation of embodiment 3 TMX-67 triethylamine salts (I3)
TMX-67 5.0g is suspended in the 30ml methyl alcohol, adds the 1.6g triethylamine, be dissolved into clear solution very soon, add the 65ml ether, be stirred to a large amount of solids and separated out, filter, ether is washed, and 45 ℃ of vacuum-dryings get white needle-like crystals 3.8g.ESI-MS：339.2(M+Na
+)。Ultimate analysis: C (63.28%), H (7.48%), N (10.06%), S (7.68%); Calculated value: C (63.02%), H (7.63%), N (10.17%), S (7.85%).
The preparation of embodiment 4 TMX-67 triethanolamine salts (I4)
TMX-67 5.0g is suspended in the 30ml methyl alcohol, adds the 2.35g trolamine, be dissolved into clear solution very soon, add the 100ml ether, be stirred to a large amount of solids and separated out, filter, ether is washed, and 45 ℃ of vacuum-dryings get white needle-like crystals 4.6g.ESI-MS：339.1(M+Na
+)。Ultimate analysis: C (56.76%), H (6.71%), N (9.03%), S (6.89%); Calculated value: C (56.85%), H (6.57%), N (9.12%), S (6.72%).
The experiment of embodiment 5 water solubilities
| Medicine name | Water-soluble |
| TMX-67 choline salt (I1) | Yi Rong |
| TMX-67 Methionin (I2) | Dissolving |
| TMX-67 triethylamine salt (I3) | Dissolving |
| TMX-67 triethanolamine salt (I4) | Dissolving |
Embodiment 6: pharmacological evaluation
Experimental technique:
Test is divided into groups and dosage: 70 rats are divided at random: blank group, model group, TMX-67 control group, TMX-67 choline salt group, TMX-67 Methionin group, TMX-67 triethylamine salt group, TMX-67 triethanolamine salt group.Every group each 10.Every day is with 10mlkg-1 capacity gastric infusion .1 time, successive administration 4d.Dosage is 0.04gkg-1 blank group, model group: irritate stomach with the volume pure water.
Behind each treated animal last administration 1h, all the other 6 treated animal Intraperitoneal injection of hypoxanthine 100mg/kg body weight are irritated stomach simultaneously and are given nicotinic acid 80mg/kg body weight except that the blank group.The isometric saline water of blank treated animal abdominal injection is irritated stomach and is given with the volume pure water.Injection back 30min, each treated animal is through abdominal aortic blood, and the centrifugal 15min of 3000r/min gets serum, presses the operation of blood uric acid testing cassete specification sheets, surveys the blood urine acid number.
Experimental result:
Compare with the blank group, model group animal TMX-67 value obviously raises, prompting modeling success.TMX-67 control group, the various salt groups of TMX-67 and model group are relatively; The blood urine acid number obviously reduces; Show that TMX-67 is that the medicine of activeconstituents can obviously reduce the serum uric acid level of hyperuricemia rat, and the effect of the reduction TMX-67 of the various salt of TMX-67 to obviously be superior to the action effect of TMX-67.
Influence
to hyperuricemia rat serum uric acid level
Claims (2)
1. the TMX-67 soluble derivative shown in the general formula I:
Wherein, M represents choline, Methionin, l-arginine, diethylamine, triethylamine, diethylolamine, trolamine.Methionin or l-arginine can be L configuration, D configuration or DL configuration.
2. the preparation method of the said compound of claim 1: the alkali that can use the M representative directly in and TMX-67,
Crystallization means through routine are separated out the product crystallization then.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010102649066A CN102372679A (en) | 2010-08-27 | 2010-08-27 | Febuxostat water-soluble derivative and preparation method thereof |
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| CN2010102649066A CN102372679A (en) | 2010-08-27 | 2010-08-27 | Febuxostat water-soluble derivative and preparation method thereof |
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| CN102372679A true CN102372679A (en) | 2012-03-14 |
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| CN2010102649066A Pending CN102372679A (en) | 2010-08-27 | 2010-08-27 | Febuxostat water-soluble derivative and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177308A (en) * | 2014-07-31 | 2014-12-03 | 浙江中医药大学 | Three novel febuxostat medicament eutectic crystals and preparation method thereof |
| US20160038595A1 (en) * | 2013-03-15 | 2016-02-11 | Davidoff ALLEN | Xanthine oxidase inhibitor formulations |
| WO2016104960A3 (en) * | 2014-12-22 | 2016-09-15 | 제이투에이치바이오텍 (주) | Crystalline febuxostat pidolate salt and method for preparing same |
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| CN1954814A (en) * | 2005-10-26 | 2007-05-02 | 重庆医药工业研究院有限责任公司 | Medical composite with co-action for treating gout and its preparation method |
| CN101646440A (en) * | 2007-01-19 | 2010-02-10 | 武田制药北美公司 | Methods for preventing or reducing the number of gout flares using xanthine oxidoreductase inhibitors and anti-inflammatory agents |
| CN101658520A (en) * | 2008-08-26 | 2010-03-03 | 天津泰普药品科技发展有限公司 | Medicinal composition for treating hyperuricemia |
| CN101677999A (en) * | 2006-11-13 | 2010-03-24 | 塔普医药产品公司 | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
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2010
- 2010-08-27 CN CN2010102649066A patent/CN102372679A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1954814A (en) * | 2005-10-26 | 2007-05-02 | 重庆医药工业研究院有限责任公司 | Medical composite with co-action for treating gout and its preparation method |
| CN101677999A (en) * | 2006-11-13 | 2010-03-24 | 塔普医药产品公司 | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| CN101646440A (en) * | 2007-01-19 | 2010-02-10 | 武田制药北美公司 | Methods for preventing or reducing the number of gout flares using xanthine oxidoreductase inhibitors and anti-inflammatory agents |
| CN101658520A (en) * | 2008-08-26 | 2010-03-03 | 天津泰普药品科技发展有限公司 | Medicinal composition for treating hyperuricemia |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160038595A1 (en) * | 2013-03-15 | 2016-02-11 | Davidoff ALLEN | Xanthine oxidase inhibitor formulations |
| US11406713B2 (en) * | 2013-03-15 | 2022-08-09 | Xortx Therapeutics, Inc. | Xanthine oxidase inhibitor formulations |
| CN104177308A (en) * | 2014-07-31 | 2014-12-03 | 浙江中医药大学 | Three novel febuxostat medicament eutectic crystals and preparation method thereof |
| WO2016104960A3 (en) * | 2014-12-22 | 2016-09-15 | 제이투에이치바이오텍 (주) | Crystalline febuxostat pidolate salt and method for preparing same |
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Application publication date: 20120314 |