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Novel tetrapyrrole derivative and application thereof

A derivative, tetrapyrrole technology, applied in the field of new intermediate diphenyldihalogenated porphine tetrapyrrole derivatives, can solve the problems of complex composition, difficult preparation, poor water solubility and the like

Pending Publication Date: 2021-12-24
SHANGHAI XIANHUI MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In order to overcome the defects of complex composition, unstable structure, difficult preparation, high cost, easy aggregation, poor water solubility, strong skin phototoxicity and side effects in the existing photosensitive drugs, the present invention uses diphenyl dihalogenated porphine compound as an intermediary The phenyl group introduces a polar group as a hydrophilic group and an alkyl group as a hydrophobic group to improve the hydrophilicity of the compound and inhibit the aggregation ability of the compound; in addition, a halogen is introduced at the meso position of the compound to improve the generation ability of active free radicals And photodynamic biological activity, the new compound prepared has stable structure, good hydrophilicity, not easy to aggregate, simple preparation process, low production cost, strong photodynamic effect, and small skin phototoxic side effects. After a lot of creative work, a new compound was synthesized. A series of intermediary diphenyl dihalogenated porphines and amino acid condensate derivatives thereof complete the present invention

Method used

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  • Novel tetrapyrrole derivative and application thereof
  • Novel tetrapyrrole derivative and application thereof
  • Novel tetrapyrrole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] 5,15-bis[(3-methoxy-4-carboxymethoxy)phenyl]-10,20-dichloroporphine (I 1 )

[0127]

[0128] 2-(4-Formyl-2-methoxyphenoxy)ethyl acetate (643mg, 2.7mmol) and dipyrromethane (392mg, 2.7mmol) were dissolved in DCM (500mL), and added dropwise under nitrogen protection Trifluoroacetic acid (0.12mL, 1.7mmol), stirred at room temperature for 12 hours. Dichlorodicyanobenzoquinone DDQ (0.735 g, 3.24 mmol) and triethylamine (4 mL) were added and the reaction was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane as the eluent) to obtain a purple powder IV 1 (434.4mg, 44.3%). 1 H NMR (400MHz, CDCl 3 ): δppm 10.32 (s, 2H), 9.41 (d, J = 4.6Hz, 4H), 9.15 (d, J = 4.6Hz, 4H), 7.89 (d, J = 2.0Hz, 2H), 7.80 (dd, J=8.0,2.1Hz,2H),7.29(s,2H),5.05(s,4H),4.48(q,J=7.1Hz,4H),4.06(s,6H),1.47(t,J=7.1 Hz,6H),-3.06(s,2H).MS(MALDI-TOF):m / z=727.3[M+H] + .

[0129] 5,15-bis[(3-methoxy-4-etho...

Embodiment 2

[0132] 5,15-bis[(3-methoxy-4-hydroxyethoxy)phenyl]-10,20-dichloroporphine (I 13 )

[0133]

[0134] Reference compound I 1 The synthetic method prepared compound I 13 . 1 H NMR (400MHz, DMSO-d 6 ): δppm 8.86 (brs, 4H), 8.15 (d, J = 7.9Hz, 4H), 7.96 (d, J = 8.0Hz, 2H), 7.74 (d, J = 7.5Hz, 2H), 7.43 (d, J=7.8Hz, 2H), 4.97(t, J=5.6Hz, 2H), 4.25(d, J=5.2Hz, 4H), 3.97(s, 6H), 3.75-3.70(m, 4H), -2.73 (s,2H). 13 C NMR (101MHz, DMSO-d 6 ):δppm 151.12,150.91,145.65,145.44,145.01,144.71,144.40,143.71,140.60,132.93,131.96,131.14,130.53,130.00,124.20,122.05,120.78,118.74,115.34,114.86,114.13,109.39,70.25,60.89 , 56.83. HRMS (MALDI-TOF): calculated for C 38 h 32 Cl 2 N 4 o 6 [M+H] + , 710.17; found 711.3284.

Embodiment 3

[0136] 5,15-bis[[3-methoxy-4-[2-oxo-2-(2-oxo-4-carboxy)butylamino]ethoxy]phenyl]-10,20-dichloro Porphin (I 26 )

[0137]

[0138] Reference compound I 1 The synthetic method prepared compound I 26 . 1 H NMR (400MHz, DMSO-d 6 ): δppm 12.55(s,2H),10.25(s,2H),9.58(d,J=4.5Hz,4H),8.99(brs,4H),7.73(s,2H),7.69(s,2H), 7.20(d, J=7.3Hz, 2H), 4.85(s, 4H), 4.28(d, J=4.6Hz, 4H), 3.85(s, 6H), 2.82-2.71(m, 8H), -2.73( s,2H). 13 C NMR (101MHz, DMSO-d 6):δppm 204.48,175.89,169.81,152.24,150.67,145.65,145.01,144.71,144.40,143.71,140.60,132.93(s),131.14,130.53,129.62,124.20,122.05,120.78,118.74,115.36,114.82,114.13, 109.39, 68.20, 56.83, 47.38, 37.95, 31.19. HRMS (MALDI-TOF): calculated for C 48 h 42 Cl 2 N 6 o 12 [M+H] + ,965.79; found 966.1093.

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Abstract

The invention relates to a novel intermediate di(disubstituted) phenyl dihalogenated porphin derivative which is stable in performance, good in hydrophilicity and not prone to aggregation and an application thereof. The compound has the following structures (I) and (II), wherein X is Cl, Br or I; A and Y are the same or different and are independently CH2 or O; R1 and R2 are different, R3 and R4 are the same or different, at least one of R3 and R4 contains a polar group, and R3 and R4 are independently alkyl groups, alkyl groups containing N or O atoms, alkyl groups containing carbonyl groups or alkyl groups containing amido bonds or alkyl carboxylic acid, alkyl alcohol, alkyl carboxylic acid containing N or O atoms, alkyl alcohol containing N or O atoms, alkyl carboxylic acid containing carbonyl groups, alkyl alcohol containing carbonyl groups, alkyl carboxylic acid containing amido bonds, and alkyl carboxylic acid containing carbonyl groups and amido bonds at the same time. The prepared intermediate dihalogenated diphenyl porphin photosensitizer has remarkable photodynamic activity, and can be used as a drug for photodynamic diagnosis and treatment of diseases such as tumors, retina macular degeneration, actinic keratosis, nevus flammeus and condyloma acuminata.

Description

technical field [0001] The invention relates to the field of photosensitizing drugs and photodynamic therapy, in particular to a new type of intermediary di(disubstituted) benzene with good stability, simple preparation process, good hydrophilicity, difficult aggregation, good photodynamic effect, and small skin phototoxicity and side effects. Dihalogenated porphine tetrapyrrole derivatives and their applications. Background technique [0002] Photodynamic therapy (PDT) is a promising new method for the diagnosis and treatment of tumors that is booming after traditional surgery, chemotherapy, and radiotherapy. The principle is that after the photosensitizer is intravenously injected into the human body, it can selectively accumulate or retain in the lesion (such as a malignant tumor). The photochemical reaction finally produces reactive oxygen species (such as singlet oxygen) to kill tumors or other pathological hyperplastic tissues. [0003] Photosensitizers, specific wav...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22A61K41/00A61K49/00A61P27/02A61P31/20A61P35/00
CPCC07D487/22A61K41/0071A61K49/0036A61P35/00A61P27/02A61P31/20
Inventor 陈志龙李慢一糜乐严懿嘉梁宏玉韩一平邱彦金辉鲍蕾蕾陈婷山妮妮坎敏敏首辛吴马大福特妮孔江颖陈聃烨吴晓锋邵志宇
Owner SHANGHAI XIANHUI MEDICAL TECH
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