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Tripterygium wilfordii lactone prodrugs having high aqueous solubility

A technology of inorganic esters and polar groups, applied in the field of triptolide prodrugs with high water solubility

Inactive Publication Date: 2001-10-10
法玛吉尼西斯公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dose standardization of suspensions is more problematic than solutions

Method used

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  • Tripterygium wilfordii lactone prodrugs having high aqueous solubility
  • Tripterygium wilfordii lactone prodrugs having high aqueous solubility
  • Tripterygium wilfordii lactone prodrugs having high aqueous solubility

Examples

Experimental program
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Embodiment 1

[0059] Example 1 Synthesis of 18-glutarylfuranoid triptolide analogs ( figure 1 ) and tromethamine salt (Figure 2B)

[0060] Triptolide (1 equiv) in anhydrous THF was added dropwise to a slight excess of NaH suspension in anhydrous THF at -78°C under an inert atmosphere. After about 0.5 hour, glutaraldehyde (1 equivalent or a slight excess) was added dropwise, and the mixture was stirred and allowed to come to room temperature over about 1 hour. The mixture was concentrated, dissolved in ether, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel.

[0061] To a stirred solution of 1 equivalent of glutaryl ester in THF was added a slight excess of tromethamine in methanol. The solution was concentrated, the salt was recovered and dried in vacuo.

Embodiment 2

[0063] Synthesis of triptolide analogs with lactone ring opening ( image 3 )

[0064] Triptolide, excess (2-hydroxyethyl)morpholine, and catalytic amount of DMAP (dimethylaminopyridine) are stirred in a polar aprotic solvent such as THF with moderate heating. The reaction was monitored by TLC. Once the reaction is complete, the reaction mixture is cooled and acetic anhydride is added to acetylate the 14- and 19-hydroxyl groups. The solvent was removed under reduced pressure, the residue was dissolved in ether, washed several times with water and sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. The product was purified by silica gel chromatography as required.

Embodiment 3

[0066] Synthesis of 12-tosyloxy-13-hydroxy triptolide ( Figure 5 )

[0067] The 14-hydroxyl group was first protected by converting it to a benzyl ether. In order to avoid the reaction of the acidic hydrogen of the conjugated lactone with basic reagents such as metal hydrides, this compound (1 equivalent) was mixed with BzBr (2.5 equivalents) on Ag 2 Reaction in DMF in the presence of O (2 equiv.) (see eg Mori et al.). The mixture was brought to room temperature with stirring and stirred for about 24 hours. The mixture was diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel, if necessary.

[0068] The resulting 14-O-benzyltriptolide was then heated with sodium hydroxide in aqueous THF to convert the 12,13-epoxide into a diol. The solution was concentrated and the residue was dissolved in ether and worked up as above.

[0069] The resulting diol (1 eq) was...

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PUM

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Abstract

Compounds useful in immunosuppressive and anti-inflammatory treatment are described. The compounds are hydrolyzable triptolide analogs with improved water solubility and generally lower toxicity than the parent compound.

Description

field of invention [0001] The present invention relates to compounds useful as immunosuppressants and anti-inflammatory agents. The compound has good water solubility and is converted into biologically active substances in the body. [0002] References Ferrier, R.J. Carbohydrate Chemistry, Kennedy, J.F., Ed., Clarendon Press, Oxford 10 (1990). Garver, L.C. et al., J. Am. Chem. Soc. 104:867 (1982). Gleichmann, E. et al., Immuno! . Today 5:324 (1984) Hormi, O.E.O. and Nasman, J.H., Syn. Commun. 16:69 (1986). Kocienski, P.J., Protecting Groups, Georg Thieme Verlag, Stuttgart (1994). Komgold, R. and Sprent, J., J. Exp. Med. 1-:1687 (1978). Kupchan, S.M. et al., J. Am. Chem. Soc. 94:7194 (1972). Kupchan, S.M. et al., US Patent 3,005,108 (1977). Lipsky, P.E. et al., US Patent 5,294,443 (1994). Ma, P-C. et al., J. Chin. Pharm. Sci 1:12 (1992). Mori, S. et al., Tetrahedron 47(27):5051-5070 (1991). Morris, R.E., Transplant Proc. 23(6):2722-2724 (1991). Morris, RE. et al., Tr...

Claims

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Application Information

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IPC IPC(8): A61K31/343A61K31/5377A61K31/661A61P29/00A61P37/06C07D303/17C07D303/31C07D493/14C07D493/22C07F9/655
CPCC07D493/14A61P29/00A61P37/06
Inventor J·H·马瑟
Owner 法玛吉尼西斯公司
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