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A class of 5-aminolevulinic acid derivatives and its preparation method and application

A technology of aminolevulinic acid and its derivatives, which is applied in the field of 5-aminolevulinic acid derivatives and its preparation, can solve the problems of limited cell absorption and high hydrophilicity, achieve strong photodynamic activity, improve fat solubility, and excellent The effect of pharmaceutical properties

Active Publication Date: 2018-09-25
DONGHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of 5-ALA is that its own hydrophilicity is too high, and it is a zwitterion under physiological pH conditions, which seriously affects its passage through the cell membrane and intercellular space, limiting its absorption by cells (J.Med.Chem., 2000, 43:4738-4746)

Method used

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  • A class of 5-aminolevulinic acid derivatives and its preparation method and application
  • A class of 5-aminolevulinic acid derivatives and its preparation method and application
  • A class of 5-aminolevulinic acid derivatives and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of methyl 5-((2'-tert-butyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoate:

[0024]

[0025] In a 50mL round bottom flask, mix 5-aminolevulinic acid methyl ester hydrochloride (1.0g, 5.5mmol), Boc-L-phenylalanine (1.46g, 5.5mmol), HBTU (1.7g, 4.49 mmol) was dissolved in DMF (10 mL), then DIPEA (2.0 mL, 11.5 mmol) was added, and the mixture was stirred at 24° C. for 6 h. Concentrate under reduced pressure to remove the solvent, and separate by silica gel column chromatography. The eluent is dichloromethane: methanol (v / v=50:1) to obtain a white solid 5-((2'-tert-butyloxycarbonylamino)- L-phenylpropionyl)amino-4-oxopentanoic acid methyl ester is 1.79 g, the yield is 83.2%. 1 H NMR(400MHz, CDCl 3 )δppm: 7.19 (s, 5H), 6.73 (s, 1H), 6.24 (s, 1H), 5.38 (t, J = 7.1 Hz, 1H), 4.12 (d, J = 12.5 Hz, 1H), 3.63 ( s, 3H), 3.60–3.47 (m, 2H), 3.11 (dd, J = 12.4, 7.0 Hz, 1H), 2.97 (dd, J = 12.3, 4.7, 1.4 Hz, 1H), 2.60 (dd, J = 12.3,4.7,1.4Hz,1H), 2.38(td,J=12.3,1.4...

Embodiment 2

[0027] Preparation of 5-((2'-tert-butyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoic acid n-hexyl ester:

[0028]

[0029] In a 50 mL round-bottom flask, mix 5-aminolevulinic acid n-hexyl ester hydrochloride (1.0g, 3.97mmol), Boc-L-phenylalanine (1.0g, 3.97mmol), HBTU (1.7g, 4.49 mmol) was dissolved in DMF (10 mL), DIPEA (1.5 mL, 8.6 mmol) was added, and the mixture was stirred at 24° C. for 6 h. Concentrate under reduced pressure to remove the solvent, and separate by silica gel column chromatography. The eluent is dichloromethane: methanol (v / v=100:1) to obtain a white solid 5-((2'-tert-butyloxycarbonylamino)- L-phenylpropionyl)amino-4-oxopentanoic acid n-hexyl ester 1.47g, the yield is 80.3%. 1 H NMR(400MHz, CDCl 3 )δppm: 7.19 (s, 5H), 6.73 (s, 1H), 6.24 (s, 1H), 5.33 (d, J = 12.5 Hz, 1H), 5.22 (t, J = 7.1 Hz, 1H), 3.97 ( dtd, J = 41.9, 12.2, 3.4 Hz, 2H), 3.71–3.59 (m, 2H), 3.09 (ddd, J = 24.4, 12.2, 6.8 Hz, 2H), 2.95 (dd, J = 12.4, 7.0 Hz, 1H), 2.79 (ddd, J = 40....

Embodiment 3

[0031] Preparation of 5-((2'-tert-butyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoic acid benzyl ester:

[0032]

[0033] In a 50mL round-bottom flask, mix 5-aminolevulinic acid benzyl ester hydrochloride (1.0g, 3.88mmol), Boc-L-phenylalanine (1.0g, 3.88mmol), HBTU (1.7g, 4.49 mmol) was dissolved in DMF (10 mL), then DIPEA (2.0 mL, 11.5 mmol) was added, and the mixture was stirred at 35° C. for 6 h. Concentrate under reduced pressure to remove the solvent, and separate by silica gel column chromatography. The eluent is dichloromethane: methanol (v / v=100:1) to obtain a white solid 5-((2'-tert-butyloxycarbonylamino)- L-phenylpropionyl)amino-4-oxopentanoic acid benzyl ester 1.82g, the yield is 75.6%; 1 H NMR(400MHz, CDCl 3 )δppm: 8.31(d,J=5.7Hz,1H),7.46-7.14(m,10H),7.04(d,J=8.6Hz,1H),5.08(s,2H), 4.20(s,1H), 3.97(dd,J=12.9,5.4Hz,2H),3.04–2.95(m,1H),2.76(d,J=10.8Hz,1H),2.72(d,J=7.9Hz,2H),2.56(d ,J=6.7Hz,2H),1.29(s,9H).ESI-MS m / z:469.2[M+H] + .

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Abstract

The invention relates to a 5-aminolevulinic acid derivative as well as a preparation method and application thereof. A structural formula is described in the specification. The preparation method comprises the following steps: dissolving a compound II and Boc-L-phenylalanine in an organic solvent, adding alkali and HBTU, stirring, carrying out reduced pressure concentration for removing the organic solvent, carrying out column chromatography, eluting and separating, so that the 5-aminolevulinic acid derivative is obtained. The 5-aminolevulinic acid derivative provided by the invention is applied to preparation of a photodynamic drug and is clear in structure; the preparation method is simple and convenient; and biological activity experimental results show that the 5-aminolevulinic acid derivative has good application prospects in the field of medicines.

Description

Technical field [0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a class of 5-aminolevulinic acid derivatives and their preparation methods and applications. Background technique [0002] Photodynamic therapy (PDT), also known as photoradiation therapy, refers to a new treatment method that produces photodynamic action to kill tumors or other pathological hyperplasia tissues under the irradiation of a certain wavelength of light after the drug enters the body. The photosensitizer , Irradiation light and oxygen constitute the three elements of the photodynamic effect. An important characteristic of photosensitizers is that they can preferentially accumulate in diseased tissues and produce specific biological effects, while having little or no impact on surrounding normal tissues. This feature makes PDT a very promising tumor treatment after surgery, chemotherapy, and radiotherapy. Therefore, photosensitizers are the key to the effect of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/06C07C271/22A61K41/00A61P35/00A61P9/10A61P17/12A61P31/20A61P17/00
CPCA61K41/0057C07B2200/07C07C269/06C07C271/22
Inventor 陈志龙高迎华朱维宋春宏塔比莎·娜姆琳达虞鑫海朱智甲单甜丽郭红哈迪亚·穆娜姆王力严懿嘉
Owner DONGHUA UNIV
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