5-aminolevulinic acid/3-hydroxypyridone conjugate and its preparation method and use

A technology of aminolevulinic acid and hydroxypyridine, which can be used in pharmaceutical combinations, medical preparations containing active ingredients, and production of bulk chemicals, etc. Strong phototoxic effect

Active Publication Date: 2018-12-11
ZHEJIANG GONGSHANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The accumulation of PpIX in cells is not only related to the concentration of ALA, but another key factor is the activity of ferrous chelatase, which can catalyze the chelation of ferrous ions by PpIX produced by ALA, making it into a light-free ferrous ion. Active heme, resulting in decreased drug activity

Method used

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  • 5-aminolevulinic acid/3-hydroxypyridone conjugate and its preparation method and use
  • 5-aminolevulinic acid/3-hydroxypyridone conjugate and its preparation method and use
  • 5-aminolevulinic acid/3-hydroxypyridone conjugate and its preparation method and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1, the preparation method of compound 1, carry out the following steps successively:

[0046] A, the synthesis of compound 6

[0047] Benzylation of ethyl maltol: ethyl maltol - compound 5 (84g, 0.4mol) was dissolved in methanol (300mL), NaOH solution (26.4g dissolved in 80mL H 2 O). The mixture was heated to boiling, and benzyl bromide (85.6 mL, 0.72 mol) was added dropwise over 2 hours. Dissolved and continued heating at 60-65°C overnight (12h). NaBr was removed by filtration, the filtrate was concentrated to about 1 / 3 of the original volume with a rotary evaporator), dichloromethane (400 mL) was added, and 5% (mass %) NaOH solution (3 × 250 mL), H 2 O (2×300mL) washed with anhydrous Na 2 SO 4 dry. After filtration, the obtained filtrate was evaporated to remove the solvent (mainly dichloromethane, including methanol), added diethyl ether (100 mL), and placed in a 4°C refrigerator. The product (compound 6, ie, benzyl-protected ethyl maltol) was preci...

Embodiment 2

[0077] Embodiment 2, the preparation method of compound 2a, carry out the following steps successively:

[0078] A. Synthesis of Compound 10:

[0079] Benzyl-protected ethyl maltol—a mixture of compound 9 (10g, 43.4mmol), selenium dioxide (14.5g, 130.4mmol) and bromobenzene (50mL) was vigorously stirred at 135-140°C for 4h. After cooling and filtering, the filtrate was evaporated to dryness, and the residue was chromatographically purified on a silica gel column (with about 600 g of 200-300 mesh silica gel inside) (ethyl acetate / cyclohexane, 2:1) to obtain a brown oil --- Compound 10 ( 4.6g, 43%). 1 H NMR (CDCl 3 ,400MHz): δ1.23(d,J=6.7Hz,3H,CH 3 ), 4.85(q, J=6.7Hz, 1H, CH), 5.22(d, J=2.0Hz, 2H, CH 2 ), 6.46(d, J=5.6Hz, 1H, C5-H in pyridone), 7.37(m, 5H, Ph), 7.71(d, J=5.6Hz, 1H, C6-H in pyridone).ESI -MS:m / z 247([M+H] + ).

[0080] B. Synthesis of Compound 11:

[0081] Compound 10 (4.0g, 16.2mmol) was dissolved in dichloromethane (50mL), and 50% KOH (5.45g, 48.6mmol) ...

Embodiment 3

[0091] Embodiment 3, the preparation method of compound 3a, carry out the following steps successively:

[0092] A. Synthesis of Compound 17:

[0093] Compound 16 (0.94g, 3.82mmol) and N-hydroxysuccinimide (0.485g, 4.2mmol) were dissolved in tetrahydrofuran (20ml), stirred at room temperature for 30min, DCC (0.866g, 4.2mmol) was added, and stirred for 5h. A solution of methylamine in tetrahydrofuran (2M, 4.58mmol) was added and stirred overnight at room temperature. Filtration, the filtrate was concentrated, and purified by silica gel column chromatography (containing about 150 g of 200-300 mesh silica gel) (ethyl acetate / methanol 9:1) to obtain product 17 (0.85 g, 86%). 1 H NMR (CDCl 3 ,400MHz)δ2.78(d,J=5.0Hz,3H,CH 3 ),5.39(s,2H,CH 2 ), 6.49(d, J=5.6Hz, 1H, C5-H in pyridone), 7.40(m, 5H, Ph), 7.70(br, 1H, NH), 7.84(d, J=5.6Hz, 1H, C6-H in pyridone).ESI-MS: m / z260([M+H] + ).

[0094] Note: Compound 16 was synthesized according to literature method (Xie, Y.Y.; Liu, M.S.;...

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Abstract

The invention discloses conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one. The conjugates are conjugates of 5-aminolevulinic acid and an iron chelating agent, i.e., 3-hydroxyl pyrid-4-one and are ALA-HPO conjugates 1 to 4 separately. The invention further simultaneously discloses a preparation method for the conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one and use of the conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one. The conjugates can be used for preparing photodynamic therapy drugs and can also be used for preparing drugs for treating skin cancer, lung cancer or verruca acuminata.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and relates to a class of 5-aminolevulinic acid (ALA)-iron chelator conjugates, a preparation method and application thereof—as a photodynamic therapy drug. Background technique [0002] Photodynamic therapy (PDT) is a new technology for selective treatment of (vascular) proliferative lesions that came out in the late 1970s, and has become one of the most active research fields in the world's tumor prevention and treatment science. 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 singlet oxygen and / or free radicals, oxidatively destroys various biological ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/69C07D213/81A61K41/00A61P35/00A61P31/20
CPCY02P20/55
Inventor 周涛思南·贝托罗伯特·海德亚力山大·麦克罗伯特
Owner ZHEJIANG GONGSHANG UNIVERSITY
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