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High water-soluble prodrug, and its preparing method and pharmaceutical use

A prodrug and water-soluble technology, applied in the field of prodrugs, can solve the problems of decreased water solubility and unsuitability for clinical application

Inactive Publication Date: 2005-12-21
赵洪
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the small molecule substance is very insoluble in water, or more than two such molecules need to be attached to PEG, the water solubility of the conjugated PEG will be greatly reduced, so it is not suitable for clinical application

Method used

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  • High water-soluble prodrug, and its preparing method and pharmaceutical use
  • High water-soluble prodrug, and its preparing method and pharmaceutical use
  • High water-soluble prodrug, and its preparing method and pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] Iminodiacetic acid (compound 1, 5 g, 37.57 mmol) was dissolved in dichloromethane solution (DCM, 100 mL), diisobutyl dicarbonate (9.02 g, 41.32 mmol) was added and the mixture was stirred at room temperature for 2 hours react. Afterwards, the mixture was extracted with 0.1N HCl (3×100 mL), and the organic layer was washed with magnesium sulfate (MgSO 4 ), filtered and evaporated to give compound 2 (7.88 g, 33.81 mmol, 90% yield). 1 H NMR (300MHz, CDCl 3 )δ11.0(s, 2H), 3.90(s, 4H), 1.40(s, 9H); 13 C NMR (75.4MHz, CDCl 3 ) δ 176.0, 156.3, 70.9, 54.2, 28.7.

Embodiment 2

[0154] In the solution of compound 2 (3.94g, 16.91mmol), add the solution containing 4-dimethylaminopyridine (DMAP, 4.13g, 33.81mmol), 20(S)-camptothecin-(S) A DCM solution of alanine TFA salt (8.76g, 16.91mmol) and 1-(3-dimethylaminopropane)-3-acetaldehyde carbodiimide hydroxide (EDC, 4.86g, 25.36mmol) ( 400mL). The mixture was stirred and warmed to room temperature for two hours. with 0.1M NaHCO 3 (3×200mL), 0.1N HCl (3×200mL) and water (200mL) washed the reactant, and the organic layer was washed with MgSO 4 Drying, filtration and evaporation afforded compound 3 (9.42 g, 15.21 mmol, 90%). 1 H NMR (300MHz, CDCl 3 )δ11.0(s, 1H), 8.06(d, 1H), 8.0(d, 1H), 7.65(m, 2H), 7.57(d, 1H), 7.42(d, 2H), 6.74(s, 1H ), 4.75(s, 2H), 4.60(m, 1H), 3.90(s, 2H), 3.85(s, 2H), 1.96(q, 2H), 1.40(s, 9H), 0.96(t, 3H) ; 13 C NMR (75.4MHz, CDCl 3 )δ 176.0, 172.0, 170.9, 160.9, 160.7, 156.3, 149.2, 145.9, 140.3, 134.5, 129.2, 128.7, 128.3, 127.3, 127.2, 126.6, 125.9, 105.8, 91.7, 70.9, 66.2, 5 ...

Embodiment 3

[0156] In the aqueous solution of compound 2 (3.94g, 16.91mmol), add cooling to 0 ℃ containing 4-dimethylaminopyridine (DMAP, 4.13g, 33.81mmol), and M hydroxysuccinimide (NHS, 3.89g , 33.82 mmol) and 1-(3-dimethylaminopropane)-3-e acetaldehyde carbodiimide hydroxide (EDC, 6.48 g, 33.82 mmol) in DCM (400 mL). The mixture was stirred and warmed to room temperature for two hours. The reaction was washed with 0.1N HCl (3×200 mL), and the organic layer was dried under reduced pressure (using MgSO 4 ), filtered and evaporated to give compound 4 (6.86 g, 16.06 mmol, 90%). 1 H NMR (300MHz, CDCl 3 )δ3.90(s, 4H), 2.73(t, 8H), 1.40(s, 9H); 13 C NMR (75.4MHz, CDCl 3 )δ 176.0, 168.5, 156.3, 70.9, 49.1, 28.7, 22.7.

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Abstract

The present invention discloses a high water-solubility precursor medicine, its preparation method and application in pharmaceutical technology. Said invention provides a general formula accorded with said precursor medicine. Said precursor medicine can be made up by using parent medicine and organic aid and making them undergo a certain reaction process. Said invention also provides the concrete steps of its preparation method, and said precursor medicine can be used for preparing several medicines, and has the advantages of high water-solubility, good effect and lower toxic side-effect.

Description

technical field [0001] The invention belongs to the field of prodrugs, in particular to a highly water-soluble prodrug, and also relates to a preparation method of the prodrug and its application in pharmacy. Background technique [0002] In recent years, in the process of creating new pharmaceutical preparations, it has been found that some drugs that do have good curative effects do not meet the requirements due to their physical and chemical properties (such as too little solubility, or even do not dissolve in general solvents, or even dissolve but reach Less than the required concentration, etc.) or the stability and absorption are not ideal, or have irritating, unpleasant smell, or have serious toxic and side effects, so that they cannot be used in clinical practice, or even eliminated. Sometimes it is necessary to prolong the action time of the drug, delay the time for the emergence of drug-resistant bacteria, or make targeted preparations, etc. In order to overcome t...

Claims

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Application Information

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IPC IPC(8): A61K47/59
Inventor 赵洪
Owner 赵洪
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