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Water-soluble prodrug of tamibarotene, and preparation method and applications thereof

A tamibarotene, water-soluble technology, applied in the fields of organic compound synthesis and medical application, can solve problems such as poor water solubility, inability to delay drug release, etc., and achieve the effect of good water solubility

Inactive Publication Date: 2012-12-12
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

N, N-dimethylethanolamine salt derivatives have good water solubility but cannot delay the release of drugs, N, N-dimethylethanolamine ester derivatives are expected to delay the release of drugs but their water solubility is poor

Method used

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  • Water-soluble prodrug of tamibarotene, and preparation method and applications thereof
  • Water-soluble prodrug of tamibarotene, and preparation method and applications thereof
  • Water-soluble prodrug of tamibarotene, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: Tamibarotene N, the preparation of N-dimethylethanolamine (DMEA) ester (carbodiimide method)

[0068] Tamibarotene (3.51g, 10mmol) was dissolved in 50ml of tetrahydrofuran, then DCC (3.09g, 15mmol) and HOBt (2.03g, 15mmol) were added, and the reaction was stirred at 0°C for 12 hours to generate Tamibar 1-Hydroxybenzotriazole active ester of rotin. Then DMEA (4.46g, 50mmol) was added, and the reaction was stirred at 0°C for 24h. The reaction solution was evaporated under reduced pressure to remove the solvent tetrahydrofuran (THF). After the residue was dissolved in a small amount of ethyl acetate, silica gel column chromatography was performed. The ester was used as the eluent for elution, and the eluent was rotary evaporated under reduced pressure to remove the solvent, and the DMEA ester of tamibarotene was prepared (white powder, yield 46.3%). mp 138.0-139.0°C. ESI-MS (m / z): 423.5 (M+H). 1 HNMR (DMSO-d 6 )δ: 1.238~1.251(m, 12H, 4×CH 3 ); 1.647(s, 4...

Embodiment 2

[0069] Embodiment 2: Tamibarotene N, the preparation of N-dimethylethanolamine (DMEA) ester (CDI method)

[0070] Tamibarotene (3.51 g, 10 mmol) was dissolved in 50 ml of tetrahydrofuran, then CDI (4.86 g, 30 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Then DMEA (4.46g, 50mmol) was added, and the reaction was stirred at room temperature for 24 hours. The reaction solution was evaporated under reduced pressure to remove the solvent THF, and the residue was dissolved with a small amount of ethyl acetate. The solvent was eluted, and the eluent was evaporated under reduced pressure to remove the solvent, and DMEA ester of tamibarotene (white powder, yield 75.9%) was prepared. mp 138.0-139.0°C.

Embodiment 3

[0071] Embodiment 3: Tamibarotene N, the preparation of N-dimethylethanolamine (DMEA) ester hydrochloride

[0072] Dissolve the DMEA ester of tamibarotene (4.23g, 10mmol) in 100ml of ethyl acetate, add 100ml of anhydrous HCl saturated ethyl acetate solution under stirring at room temperature, stir at room temperature for 1 hour, evaporate the solvent under reduced pressure, and then Add 200 ml of ethyl acetate to dissolve the residue, and evaporate the solvent under reduced pressure to obtain tamibarotene DMEA ester hydrochloride (white powder, yield 95.6%). mp 215.0-217.0°C. 1 HNMR (DMSO-d 6 )δ: 1.240~1.252(m, 12H, 4×CH 3 ); 1.636(s, 4H, 2×CH 2 ); 2.882(s, 6H, 2×CH 3 ); 3.546 (s, 2H, N-CH 2 ); 4.629 ~ 4.645 (t, J = 4.8Hz, 2H, O-CH 2 ); 7.293~7.308(d, J=9.0Hz, 1H, ArH); 7.575~7.589(m, 1H, ArH); 7.694~7.697(d, J=1.8Hz, 1H, ArH); 8.093~8.107(d , J=8.4Hz, 2H, 2×ArH); 8.194~8.208 (d, J=8.4Hz, 2H, 2×ArH); 10.114 (s, 1H, NH); 10.320 (s, 1H, HCl).

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Abstract

The invention provides a water-soluble prodrug of tamibarotene, and a preparation method and applications thereof and belongs to the technical fields of organic compound synthesis and medical applications. The water-soluble prodrug of tamibarotene has favorable water solubility and suitable drug crystal form, and therefore, is suitable to be used as a raw material for medical preparations and especially suitable for preparing injections. Particularly, the invention provides medical acceptable salts of tamibarotene DMEA ester, which have the general formula (I), wherein HA is HCl, H2SO4, HNO3,H3PO4, HOAc, paratoluenesulfonic acid, maleic acid, succinic acid, citric acid or L(+)-tartaric acid.

Description

technical field [0001] The invention relates to a water-soluble prodrug of tamibarotene, a preparation method and application thereof. It belongs to the technical field of organic compound synthesis and medical application. Background technique [0002] Tamibarotene (tamibarotene, 1), the chemical name is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] Benzoic acid is a new type of selective retinoic acid receptor alpha agonist developed by Japan Nippon Shinyaku Company, which was first launched in Japan in June 2005 (Drugs Fut 30:688-693, 2005). The drug is mainly used clinically for the treatment of various types of relapsed or refractory acute promyelocytic leukemia (APL) (Gan To Kagaku Ryoho 33:397-401, 2006). Compared with other drugs, it has the advantages of high curative effect, not easy to produce drug resistance, and small adverse reactions. The chemical structural formula of Tamibarotene is as follows (1): [0003] [0004] Tamibarotene is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/84C07C231/12A61K31/235A61P35/00A61P35/02
Inventor 徐文方边海勇齐永秀
Owner SHANDONG UNIV
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