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A class of fat-soluble 5-aminolevulinic acid derivatives and preparation method and application thereof

A technology of aminolevulinic acid and derivatives, which is applied in the field of fat-soluble 5-aminolevulinic acid derivatives and their preparation, can solve the problems of high hydrophilicity, restricted cell absorption, etc., and achieves easy preparation and strong photodynamic activity. , the effect of enhancing fat solubility

Active Publication Date: 2018-08-14
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 fat-soluble 5-aminolevulinic acid derivatives and preparation method and application thereof
  • A class of fat-soluble 5-aminolevulinic acid derivatives and preparation method and application thereof
  • A class of fat-soluble 5-aminolevulinic acid derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Preparation of 5-((2'-benzyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoic acid methyl ester:

[0023]

[0024] In a 50mL round bottom flask, 5-aminolevulinic acid methyl ester hydrochloride (1.0g, 5.5mmol), Cbz-L-phenylalanine (1.64g, 5.5mmol) and HBTU (1.7g, 4.49 mmol) was dissolved in DMF (10 mL), and DIPEA (2.0 mL, 11.5 mmol) was added, and stirred at 24° C. for 6 h. Concentrated under reduced pressure to remove the solvent, separated by silica gel column chromatography, the eluent was dichloromethane:methanol (v / v=50:1), to obtain a white solid 5-((2'-benzyloxycarbonylamino)-L- Phenylpropionyl) amino-4-oxopentanoic acid methyl ester 1.95g, yield 83.2%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.34 (s, 3H), 7.38–7.27 (m, 2H), 7.19 (s, 5H), 6.73 (s, 1H), 6.24 (s, 1H), 5.87 (d, J = 12.3Hz, 1H ), 5.19(t, J=7.0Hz, 1H), 4.62(d, J=12.4Hz, 1H), 4.23(d, J=12.4Hz, 1H), 3.75–3.62(m, 2H), 3.63(s ,3H),3.31(dd,J=12.4,7.0Hz,1H),3.06–2.91(m,2H),2.46–2.37(m,1H),2.32(dt,J=12....

Embodiment 2

[0026] Preparation of 5-((2'-benzyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoic acid n-hexyl ester:

[0027]

[0028] In a 50mL round bottom flask, 5-aminolevulinic acid n-hexyl hydrochloride (1.0g, 3.97mmol), Cbz-L-phenylalanine (1.19g, 3.97mmol) and HBTU (1.7g, 4.49 mmol) was dissolved in DMF (10 mL), and DIPEA (1.5 mL, 8.6 mmol) was added, and stirred at 24° C. for 6 h. Concentrated under reduced pressure to remove the solvent, separated by silica gel column chromatography, the eluent was dichloromethane:methanol (v / v=100:1), to obtain a white solid 5-((2'-benzyloxycarbonylamino)-L- phenylpropionyl)amino-4-oxopentanoic acid n-hexyl 1.60g, yield 81.3%. 1 H NMR (400MHz, CDCl 3)δppm: 7.34 (s, 3H), 7.37–7.29 (m, 2H), 7.19 (s, 5H), 6.36 (d, J = 12.3Hz, 1H), 6.24 (s, 1H), 5.63 (d, J =12.4Hz,1H),5.52(t,J=7.0Hz,1H),4.77(d,J=12.2Hz,1H),4.08(td,J=12.4,2.3Hz,1H),4.01–3.91(m ,1H),3.64(ddd,J=12.3,9.8,2.1Hz,1H),3.42(d,J=12.4Hz,1H),3.17(dd,J=12.4,6.9Hz,1H),2.99–2.87( (...

Embodiment 3

[0030] Preparation of 5-((2'-benzyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoic acid benzyl ester:

[0031]

[0032] In a 50 mL round bottom flask, 5-aminolevulinic acid benzyl hydrochloride (1.0 g, 3.88 mmol), Cbz-L-phenylalanine (1.16 g, 3.88 mmol) and HBTU (1.7 g, 4.49 mmol) was dissolved in DMF (10 mL), and DIPEA (2.0 mL, 11.5 mmol) was added, and stirred at 25° C. for 6 h. Concentrated under reduced pressure to remove the solvent, separated by silica gel column chromatography, the eluent was dichloromethane:methanol (v / v=100:1), to obtain a white solid 5-((2'-benzyloxycarbonylamino)-L- Benzylpropionyl)amino-4-oxopentanoic acid benzyl ester 1.53g, yield 78.6%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.38–7.27(m,10H),7.19(s,5H),6.73(s,1H),6.40(d,J=12.4Hz,1H),6.24(s,1H),5.53(d,J =12.4Hz,1H),5.41(t,J=7.0Hz,1H),4.82(dd,J=30.4,12.4Hz,2H),4.40(d,J=12.5Hz,1H),3.55(d,J =12.3Hz,1H),3.47(dd,J=12.4,7.0Hz,1H),3.36(ddd,J=12.5,3.9,2.2Hz,1H),3.12(dd,J=12.4,7.0Hz,1H) ,2.68(ddd,...

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Abstract

The invention relates to a fat soluble 5-aminolevulinic acid derivative, as well as a preparation method and application thereof. The derivative has a structural formula as shown in the specification. The preparation method comprises the following steps: dissolving a compound II and Cbz-L-phenylalanine in an organic solvent; adding alkali and HBTU, and stirring; concentrating at reduced pressure to remove the organic solvent; and performing column chromatography eluting and separating to obtain the derivative. The derivative is applied to preparation of photodynamic medicines, and has stable chemical property, single structure and simple preparation. Bioactive experiment results indicate that the fat soluble 5-aminolevulinic acid derivative has an excellent application prospect.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a class of fat-soluble 5-aminolevulinic acid derivatives and a preparation method and application thereof. Background technique [0002] Photodynamic therapy (PDT) is a clinical treatment method that combines the application of photosensitizers and corresponding light sources to selectively destroy diseased tissues through photodynamic reactions. PDT was created in the 1970s. With the development and progress, it has gradually become one of the basic means of treating tumors. PDT is a new disease treatment method based on the interaction of light, photosensitizer and oxygen; the photosensitizer (photodynamic therapy drug) is injected into the human body, and after a certain period of time, the tumor site is irradiated with light of a specific wavelength. A series of photochemical and photobiological reactions, with the participation of molecular oxygen, produces singl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/06A61K41/00A61P35/00A61P9/10A61P17/12A61P31/20A61P17/00
CPCA61K41/0057C07B2200/07C07C269/06C07C271/22
Inventor 陈志龙朱维高迎华宋春宏鲁志彬塔比莎·娜姆林达虞鑫海朱智甲单甜丽郭红哈迪亚·穆娜姆王力
Owner DONGHUA UNIV
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