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Bexarotene conjugate, drug composition and application thereof

A technology of a composition and a conjugate, applied in the field of medicine, can solve the problems of affecting drug efficacy, obvious toxic and side effects, and less free drug content, and achieve good treatment and/or prevention of Alzheimer's disease, strong anti-tumor activity, Easy to ingest effect

Inactive Publication Date: 2017-05-17
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, bexarotene has poor water solubility, low bioavailability after oral administration, and obvious toxic and side effects, which limit the wide application of the drug in clinical practice.
In addition, bexarotene can be highly combined with plasma proteins (99%), resulting in very little free drug content in the blood circulation, which affects the efficacy of the drug.

Method used

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  • Bexarotene conjugate, drug composition and application thereof
  • Bexarotene conjugate, drug composition and application thereof
  • Bexarotene conjugate, drug composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The synthesis of bexarotene glycerol phosphatidylcholine (see the synthetic route figure 1 )

[0062] Weigh 2.9 mmol of bexarotene into a 50 ml one-necked flask, add 10 ml of chloroform and stir to fully dissolve. Add 1.2mmol CDI at room temperature and mix well, react for 1-2h, TLC (thin layer chromatography) detection and follow the reaction progress. Add 1.2 mmol of GPC to the reaction system, dropwise add 2.9 mmol of DBU, stir and mix evenly. The reaction was continued for 48 h at room temperature. After TLC showed that the reaction was complete, the product was purified by column chromatography to obtain bexarotene glycerol phosphatidylcholine as a white crystalline solid with a yield of 80%.

[0063] 1 H NMR (Bruker DPX 500MHz, CD 3 OH) δ7.96 (4H, d, J = 0.40Hz), 7.35 (4H, t, J = 0.40Hz), 7.14 (4H, m, J = 0.40Hz), 5.88 (2H, dd, J = 0.40Hz ),5.64(1H,m,J=0.40Hz),5.27(2H,dd,J=0.40Hz),4.75(1H,dd,J=0.40Hz),4.62(1H,dd,J=0.40Hz), 4.26(4H,m), 3.61(2H,t,J=0.40Hz), 3...

Embodiment 2

[0066] The synthesis of bexarotene hexylene glycol succinoylglycerol phosphatidylcholine (see the synthetic route figure 2 )

[0067] Weigh 1g (2.9mmol) of bexarotene into a 50ml one-necked flask, add 10ml of chloroform and stir to fully dissolve. Add 3 mmol DCC at room temperature and mix well, and react for 1-2 hours. Add 2.5 mmol hexanediol to the reaction system, drop 2.9 mmol DMAP, stir and mix evenly. The reaction was continued for 48 h at room temperature. The product was purified by column chromatography to obtain bexarotene hexanediol monoester as a white crystalline solid with a yield of 82%.

[0068] Weigh 1.6mmol bexarotene hexanediol monoester in a 100mL round bottom flask, add 20mL CH 2 Cl 2 Stir to dissolve completely. Will be fully dissolved in 10mL CH 2 Cl 2 Slowly add 10.0 mmol of succinic anhydride into the bexarotyl hexanediol monoester solution, and stir to make the reactants mix evenly. The reaction was carried out at room temperature for 3-4 ho...

Embodiment 3

[0072] Synthesis of bexarotene dithiodiethylene glycol ester succinoylglycerol phosphatidylcholine (see the synthetic route image 3 )

[0073] Weigh 1g (2.9mmol) of bexarotene into a 50ml one-necked flask, add 10ml of chloroform and stir to fully dissolve. Add 3 mmol DCC at room temperature and mix well, and react for 1-2 hours. Add 2.5 mmol of dithiodiethylene glycol into the reaction system, drop 2.9 mmol of DMAP, stir and mix evenly. The reaction was continued for 48 h at room temperature. The product was purified by column chromatography to obtain bexarotene hexanediol monoester as a white crystalline solid with a yield of 75%.

[0074] Weigh 1.5mmol of bexarotene dithiodiethylene glycol monoester into a 100mL round bottom flask, add 20mL CH2Cl2 and stir to dissolve it completely. Slowly add 10.0 mmol succinic anhydride fully dissolved in 10 mL CH2Cl2 to the bexarotene dithiodiethylene glycol monoester solution, and stir to mix the reactants evenly. React at room tem...

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Abstract

The invention discloses a bexarotene conjugate, a drug composition and application thereof. The drug composition comprises the bexarotene conjugate or a medicinal composition of the bexarotene conjugate and a pharmacodynamics acceptable carrier and is a liquid preparation, a solid preparation, a semi-solid preparation, a capsule preparation, a granule preparation, a gel preparation and an injection preparation. The drug composition is nano granules or lipidosome prepared by the bexarotene conjugate or the bexarotene conjugate and additives, and the particle size is 10 to 1000 nm. The bexarotene conjugate and the nano granules thereof can be used as liquid preparations, solid preparations, semi-solid preparations, sterilized preparations and sterile preparations, are low in toxicity and can be used for treating tumors and treating or preventing alzheimer diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to bexarotene conjugates, pharmaceutical compositions and the preparation thereof for the prevention or treatment of skin T-cell lymphoma, non-small cell lung cancer, breast cancer, prostate cancer antitumor drugs and Alzheimer's disease. application in disease medicine. Background technique [0002] Bexarotene is a new type of retinoid X receptor (RXR) selective activator, which can selectively bind to RXR subunits (RXRα, RXRβ, RXRγ), and can inhibit the hematopoietic system and squamous cells. Cell growth of malignant tumor cell lines, induction of programmed death of some malignant tumor cell lines, etc. Bexarotene inhibits the growth of many cancer cells, such as prostate cancer, breast cancer and lung cancer cells. It is a highly effective drug for preventing and treating cancer, and can reduce the toxicity of clinical medication. Bexarotene is especially effective in inhi...

Claims

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Application Information

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IPC IPC(8): A61K31/192A61K47/54A61P35/00A61P17/00A61P31/10A61P25/28A61K47/69C07F9/09
CPCA61K31/192C07F9/09
Inventor 李新松何瑞玉姚琛杜亚伟
Owner SOUTHEAST UNIV
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