Triglyceride prodrug based on lymphatic mediated transport and preparation method thereof

A prodrug and pharmaceutical technology, applied in the field of medicine, can solve the problems of few researches and systematic discussions without researches

Active Publication Date: 2019-06-07
SHENYANG PHARMA UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many prodrug designs with triglyceride as the backbone, but so far no research has systematically discussed the relationship between the structure of the prodrug and the affinity of pancreatic lipase, and the impact of its affinity on the oral absorption of the prodrug; Triglycerides have been explored as vehicles for lymphatic delivery of antineoplastic drugs, but there are few studies on oral triglyceride prodrugs against solid tumors

Method used

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  • Triglyceride prodrug based on lymphatic mediated transport and preparation method thereof
  • Triglyceride prodrug based on lymphatic mediated transport and preparation method thereof
  • Triglyceride prodrug based on lymphatic mediated transport and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0079] Example 1 Preparation of docetaxel-C5-triglyceride prodrug (DTX-5C-TG)

[0080] The structure is as follows

[0081]

[0082] Dissolve 10.25g (40mmol) of palmitic acid in 100ml of anhydrous dioxane, add 3 drops of N,N-dimethylformamide, add 4.9g (41mmol) of thionyl chloride dropwise, and vacuumize under nitrogen protection after dropping. Reflux at 110°C for 4h, and concentrate the reaction solution under reduced pressure to obtain a pale yellow oil. Dissolve 1.75g ​​(20mmol) of 1,3-dihydroxyacetone in 100ml of anhydrous dichloromethane, add 5ml (40mmol) of triethylamine, quickly add the above oily substance dropwise under ice bath, vacuumize nitrogen protection after dropping, at room temperature React overnight. The reaction solution was concentrated, washed twice with distilled water, the aqueous layer was extracted with chloroform, the organic layer was washed once with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent ...

example 2

[0085] Example 2 Preparation of docetaxel-C5(Et)-triglyceride prodrug (DTX-5C(Et)-TG)

[0086] The structure is as follows

[0087]

[0088] The preparation method of 1,3-dipalmitin is the same as example 1. Dissolve 1.5g (6.33mmol) of L-glutamic acid-γ-Benyl ester in 10ml of acetic acid, add 10ml of water, stir in ice bath for 20min, add 3.45g (50mmol) of sodium nitrite, react in ice bath for 2h, and react overnight at room temperature . The reaction solution was extracted with ethyl acetate, the organic layer was washed once with water, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 2. 1 g of compound 1 was redissolved in 30 ml of anhydrous dichloromethane, 100 mg (0.8 mmol) of DMAP was added, and 0.6 g (5.88 mmol) of acetic anhydride was added dropwise. After the dropping, the mixture was vacuumed under nitrogen protection and reacted overnight at room temperature. The solvent w...

example 3

[0090] Example 3 Preparation of docetaxel-C5(Piv)-triglyceride prodrug (DTX-5C-(Piv)-TG)

[0091] The structure is as follows

[0092]

[0093] The preparation method of 1,3-dipalmitin is the same as example 1. Dissolve 1.5g (6.33mmol) of L-glutamic acid-γ-Benyl ester in 10ml of acetic acid, add 10ml of water, stir in ice bath for 20min, add 3.45g (50mmol) of sodium nitrite, react in ice bath for 2h, and react overnight at room temperature . The reaction solution was extracted with ethyl acetate, the organic layer was washed once with water, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 2. 1 g of compound 1 was redissolved in 30 ml of anhydrous dichloromethane, and 100 mg of (0.8mmol) DMAP, 770mg (6.28mmol) of pivaloyl chloride was added dropwise, and after the dropwise evacuation under nitrogen protection, the reaction was carried out overnight at room temperature. The solvent ...

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Abstract

The invention belongs to the technical field of medicines, and relates to a triglyceride prodrug based on lymphatic mediated transport, in particular to a triglyceride prodrug with different linkagesand based on lymphatic mediated transport and preparation and application of the triglyceride prodrug in drug delivery. The present invention provides the prodrug with different connecting keys and asynthesis method thereof. The structure of the prodrug is as follows, and X, R1, R2, n and m are described in the claims and specifications. According to the prodrug provided by the invention, the digestion and absorption mechanism of glycerol in the gastrointestinal tract is simulated by using the structure of triglycerides, the lymphatic transport of drugs is promoted, the first-pass effect is avoided, and the prodrug has targeting property and can obviously enhance or improve the bioavailability of drugs.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to a triglyceride prodrug based on lymphatic mediated transport, in particular to a triglyceride prodrug with different linking chains of lymph mediated transport and its preparation and application in drug delivery. Background technique: [0002] Oral administration is the most convenient way of administration and has many advantages, including low treatment cost and high patient compliance. However, there are also many problems at the same time. Some drugs have poor water solubility and poor intestinal membrane permeability. Road toxicity is also a major drawback of oral drug delivery. These limiting factors are a great challenge for the development of oral drug delivery. [0003] The lymphatic system plays an important role in nutrient uptake, immune response, lipid homeostasis, and tumor metastasis. Therefore, drug lymphatic transport is an effective way to improve the pharmac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61P35/00A61P3/06A61P29/00A61K31/337A61K47/54
CPCA61K31/337A61P35/00C07D305/14A61K47/543A61K9/0053
Inventor 孙进何仲贵田楚彤
Owner SHENYANG PHARMA UNIVERSITY
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