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Novel pyropheophorbide a derivative, preparation method thereof and use thereof

A technology for pyropheophorbide and its derivatives, which is applied in the field of novel pyropheophorbide a derivatives and its preparation, can solve the problems of fast metabolism of taraporfin, difficulty in preparation, and easy oxidation of moporfin And other issues

Active Publication Date: 2019-01-25
陈志龙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs still have certain disadvantages, such as temoporfin is easily oxidized and has poor stability; taraporfin is metabolized too quickly and is difficult to prepare.

Method used

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  • Novel pyropheophorbide a derivative, preparation method thereof and use thereof
  • Novel pyropheophorbide a derivative, preparation method thereof and use thereof
  • Novel pyropheophorbide a derivative, preparation method thereof and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] 17 3 -The preparation method of [N-(2-oxo-4-carboxybutyl)] pyropheophytin (compound Ia-1) specifically comprises the following steps:

[0074]

[0075] Step 1): 17 3 -Synthesis of [N-(2-oxo-4-methoxycarbonylbutyl)]pyropheophytin

[0076] In a 50mL round bottom flask, pyropheophorbide a (2.0g, 3.75mmol), methyl 5-aminolevulinate hydrochloride (1.0g, 5.5mmol), HBTU (1.7g, 4.49mmol ) was dissolved in dichloromethane (100mL), then DIPEA (2.0mL) was added, and stirred at room temperature for 6h. Wash three times with water (100mL×3), combine the organic phase, anhydrous MgSO 4 Dry, filter, concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography, the eluent is dichloromethane:acetone (v / v=50:1), to obtain 17 3 -[N-(2-oxo-4-methoxycarbonylbutyl)]pyropheophytin (2.35g), yield 94.9%. 1 H NMR (400MHz, CDCl 3 )δppm: 9.48(s,1H),9.40(s,1H),8.62(s,1H),8.01(dd,J=18.2,11.7Hz,1H),6.31(d,J=17.8Hz,1H), 6.20(d, J=11.6Hz, 1H), 5.61(...

Embodiment 2

[0080] 3-(1-Methoxyethyl)-3-desvinyl-17 3 The preparation method of -[N-(2-oxo-4-carboxybutyl)] pyropheophytin (compound Ib-1) specifically comprises the following steps:

[0081]

[0082] Step 1): 3-(1-Methoxyethyl)-3-desvinyl-17 3 -Synthesis of [N-(2-oxo-4-methoxycarbonylbutyl)]pyropheophytin

[0083] to 17 3 -[N-(2-Oxo-4-methoxycarbonylbutyl)]pyropheophytin (132 mg, 0.2 mmol) was added with 5 mL of 30% HBr-AcOH solution, and stirred for 2 h. Slowly add 50mL of methanol and stir at room temperature for 4h. 100 mL of dichloromethane was added to the reaction solution, and the organic phase was washed with water three times. The organic phase was collected and washed with anhydrous MgSO 4 Dry, filter, collect the filtrate, remove the solvent under reduced pressure, and purify by silica gel column chromatography, the eluent is dichloromethane:acetone (v / v=50:1), to obtain 3-(1-methoxyethyl)- 3-Devinyl-17 3 -[N-(2-Oxo-4-methoxycarbonylbutyl)]pyropheophytin (91 mg), yie...

Embodiment 3

[0087] 17 3 - Preparation of [N-methyl-N-(2-oxo-4-carboxybutyl)] pyropheophytin (compound Ia-2)

[0088]

[0089] Using pyropheophytin-a and methyl 5-methylamino-4-oxopentanoate as raw materials, the method obtained with reference to Example 1:

[0090] 17 3 -[N-Methyl-N-(2-oxo-4-carboxybutyl)]pyropheophytin. 1 H NMR (400MHz, DMSO-d 6): δ ppm 12.33(s,1H),9.70(d,J=3.9Hz,1H),9.62(d,J=1.4Hz,1H),8.84(s,1H),5.98(dt,J=6.8, 3.9Hz, 1H), 5.19(s, 1H), 5.13(s, 1H), 4.57(dd, J=16.3, 7.9Hz, 1H), 4.33-4.21(m, 1H), 3.66(q, J=7.6 Hz, 3H), 3.54(s, 4H), 3.49(d, J=1.8Hz, 3H), 3.44(s, 2H), 3.21(s, 3H), 2.92-2.73(m, 8H), 2.69(s ,4H),2.47-2.39(m,6H),2.18(s,1H),2.04(dd,J=6.6,2.2Hz,3H),1.76(d,J=7.3Hz,3H),1.60(t, J=7.5Hz, 3H), 1.36(s, 4H), 0.19(s, 1H), -1.99(d, J=2.4Hz, 1H); ESI-MS m / z: 662.4[M+1] + .

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Abstract

The invention relates to a novel pyropheophorbide a derivative, a preparation method thereof and medical use. More specifically, the invention relates to a compound with a formula I as shown below, which is defined by the specification. The invention designs and prepares the pyropheophorbide a derivative which is single and stable in structure and simple and convenient in preparation method. The pyropheophorbide a derivative has very strong photodynamic activity, and can be used as a photodynamic drug for diagnosis and treatment of diseases such as tumor, macular degeneration, actinic keratosis, nevus flammeus and condyloma acuminata.

Description

technical field [0001] The invention belongs to the field of photosensitizing drugs and photodynamic therapy, and in particular relates to a novel pyropheophorbide-a derivative, a preparation method thereof and an application in the field of photodynamic therapy and diagnosis. Background technique [0002] As early as the 1930s, it was discovered that after feeding abalone livers to cats and mice and exposing them to sunlight, symptoms such as erythema, ulcers, and local necrosis would appear. This series of phenomena was later confirmed by Hashimoto (Japanese Journal of Medical Science & Biology. 1962, 15, 136-140) and others to be skin phototoxicity caused by the abalone toxin present in the abalone liver. Abalone toxins are derived from seaweed, which is the bait of abalone. It is pyropheophorbide-a, a product produced by the degradation of chlorophyll in seaweed after being swallowed by abalone. Active free radicals generated by abalone toxins and oxygen under the actio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22A61K41/00A61P17/00A61P17/12A61P27/02A61P31/20A61P35/00
CPCA61K41/0071A61P17/00A61P17/12A61P27/02A61P31/20A61P35/00C07D487/22
Inventor 陈志龙高迎华朱维严懿嘉陈聃烨
Owner 陈志龙
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