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Elogated and multiple spacers in activatible prodrugs

A compound and alkyl technology, applied in the field of drug prodrugs, can solve problems such as reducing tumor cell drug resistance

Inactive Publication Date: 2004-07-07
SYNTARGA BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the dose is high enough, it can kill all tumor cells, thereby reducing the development of tumor cell drug resistance

Method used

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  • Elogated and multiple spacers in activatible prodrugs
  • Elogated and multiple spacers in activatible prodrugs
  • Elogated and multiple spacers in activatible prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Synthesis of 2′-[4-nitrocinnamyl carbonate]-paclitaxel 1.

[0115] To a solution of 200 mg (1.12 mmol, 4.8 eq) of 4-nitrocinnamyl alcohol in dry dichloromethane / tetrahydrofuran under an argon atmosphere were added pyridine (94 μl, 5.0 eq) and 4-nitrophenyl Chloroformate (236 mg, 5.0 equiv). The reaction mixture was stirred at room temperature for 12 hours. The mixture was cooled to 0° C. and a catalytic amount of DMAP, a few drops of triethylamine and 200 mg of paclitaxel (1.0 eq.) were added. The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated and the residual solid was dissolved in dichloromethane. The organic layer was washed thoroughly with saturated sodium bicarbonate solution, 0.5N potassium bisulfate and brine, and dried over anhydrous sodium sulfate. After solvent evaporation, the residual yellow oil was purified by column chromatography (ethyl acetate-hexane; 1:1) to afford 144 mg of 1 (58%). M.P.151℃;

[0116] ...

Embodiment 2

[0118] Principles of 1,8-elimination: chemical reduction of nitrocinnamyl carbonate 1

[0119] 36 mg of 2'-[4-nitrocinnamyl carbonate]-paclitaxel 1 was dissolved in 8 ml methanol and 2 ml acetic acid. A catalytic amount of zinc dust was added and the resulting red mixture was stirred for 12 hours. Dichloromethane was added and the organic layer was washed with saturated sodium bicarbonate, 0.5N potassium bisulfate, brine and water, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residual yellow film was purified by column chromatography (ethyl acetate-hexane; 2:1) to obtain 28 mg of paclitaxel (via 300 MHz 1 H-NMR confirmed) and 4 mg of unreacted starting compound. When the compound was stirred under the same conditions in the absence of zinc powder, no paclitaxel was formed, suggesting that reduction of the nitro group by zinc resulted in the release of paclitaxel.

Embodiment 3

[0121] Synthesis of Aloc-D-Ala-Phe-Lys(Aloc)-OH 9

[0122] Step a: Synthesis of Fmoc-Phe-Lys(Boc)-OBu 4

[0123] To a solution of 2.50 g of Fmoc-Phe-ONSu 2 (ONSu=N-hydroxysuccinimide) (5.16 mmol) in dry dichloromethane at 0 °C in an argon atmosphere was added 0.791 ml of triethylamine (1.1 eq. .) and 1.92 g H-Lys(Boc)-OBu.HCl3 (1.1 eq.). The reaction mixture was stirred at room temperature for 5 hours, then dichloromethane was added and the organic layer was washed with the following solution: 10% citric acid, saturated sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting white solid 4 (3.08 g, 89%) was used directly without further purification. M.P.93℃; 1 H-NMR (300MHz, CDCl 3 ): δ1.10-1.90 (m, 24H, 6CH 2 -Lys and 18 tert-butyl), 3.06 (m, 2H, N-CH2 -Lys and benzyl), 4.19 (t, 1H, Fmoc), 4.25-4.55 (m, 4H, 2 Fmoc and 2 Hα), 7.19-7.78 (m, 13H, aromatic) ppm; MS (FAB) m / e 672(M+H) + , 694(M+Na) + ;C 3...

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PUM

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Abstract

This invention is directed to prodrugs that can be activated at the preferred site of action in order to selectively deliver the corresponding therapeutic parent drugs to target cells or to the target site. This invention will therefore primarily but not exclusively relate to tumor cells as target cells. More specifically the prodrugs are compounds of the formula V-(W)k-(X)1-A-Z, wherein: V is a specifier; (W)k-(X)1-A is an elongated self-elimination spacer system; W and X are each a 1,(4+2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)m wherein: Y is a 1,(4+2n) electronic cascade spacer, or a group of formula U being a cyclisation elimination spacer; Z is a therapeutic drug; k, 1 and m are integers from 0 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), with the provisos that: - when A is (Y)m: k+1+m >= 1, and if k+1+m = 1; - when A is U: k+1 > / = 1.

Description

technical field [0001] The present invention relates to prodrugs which can be activated at a preferred site of action and which can be used to selectively deliver a corresponding therapeutic or diagnostic parent moiety to a target cell or site. Thus, the present invention relates primarily, but not exclusively, to tumor cells as target cells. Background technique [0002] The lack of selectivity of chemotherapeutic agents is a major problem in cancer treatment. Because the compounds used in cancer chemotherapy are highly toxic, they often have serious side effects. In order to suppress these side effects (such as toxicity to the gastrointestinal tract and bone marrow), dose limitation is often required, which in turn makes it impossible to achieve drug concentrations that can completely eradicate tumors. In addition, tumors can become resistant to anticancer agents after prolonged treatment. In modern drug development, the targeting of cytotoxic drugs ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/50A61K31/337A61K38/00A61K47/16A61K47/30A61K47/42A61K47/48A61P29/00A61P31/04A61P31/12A61P35/00A61P43/00C07D305/14C07K4/00C07K14/47
CPCA61K47/48761A61K47/48361A61K47/48715B82Y5/00A61K47/48338A61K47/65A61K47/6889A61K47/67A61K47/6899A61P29/00A61P31/04A61P31/12A61P35/00A61P43/00
Inventor 弗朗西斯库斯·马里纳斯·亨德里克斯·德-赫罗特帕特里克·亨利·博伊斯克尔约翰内斯·威廉·舍雷恩迪克·德-福斯莱昂纳德斯·威廉默斯·阿德里安·范-贝尔科姆古斯科·弗雷德里克·比舍安托瓦妮特·欧根妮·泽伦拉尔夫·库库克卡斯滕·阿尔布雷赫特
Owner SYNTARGA BV
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