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Novel chlorin e4 derivative, pharmaceutically acceptable salt thereof, and preparation methods and application of novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof

A chlorin and derivative technology, applied in the field of medicine, can solve problems such as poor stability of chlorin, and achieve the effects of excellent photodynamic killing effect, reducing dark toxicity, and high dark poison/phototoxicity ratio.

Active Publication Date: 2021-10-22
THE NAVAL MEDICAL UNIV OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the stability of chlorin e6 is poor due to the structure of a free ethyl carboxyl group at the 15-position

Method used

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  • Novel chlorin e4 derivative, pharmaceutically acceptable salt thereof, and preparation methods and application of novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof
  • Novel chlorin e4 derivative, pharmaceutically acceptable salt thereof, and preparation methods and application of novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof
  • Novel chlorin e4 derivative, pharmaceutically acceptable salt thereof, and preparation methods and application of novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: N-(chlorine e 4 -17 3 -acyl)-L-aspartic acid (I 1 ) preparation

[0071] Compound V (0.1g, 0.181mmol, 1.0equiv) was dissolved in 10mL of dry DMF, HATU (0.076g, 0.199mmol, 1.1equiv), L-aspartic acid di-tert-butyl hydrochloride (0.061g , 0.217mmol, 1.2equiv) and DIPEA (0.068g, 0.543mmol, 3.0equiv), stirred at room temperature for 12h. After the reaction was complete, 100 mL of ethyl acetate was added to dilute the reaction solution, washed three times with saturated NaCl water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 2 Cl 2 :CH 3 OH:HCO 2 Under the condition of H=40:1:0.1–30:1:0.1, purify with flash preparative column chromatography to obtain black powdery compound N-(chlorin e 4 -17 3 -acyl)-L-aspartic acid di-tert-butyl ester (II-1 1 ). The above II-1 1 Dissolve in 5 mL of dry dichloromethane, add 2 mL of trifluoroacetic acid (TFA), and stir at room temperature for 2 h. Add a lot of NaHCO 3 The ...

Embodiment 2

[0072] Embodiment 2: N-(chlorine e 4 -17 3 -acyl)-L-glutamic acid (I 2 ) preparation

[0073] According to the method of Example 1, compound V (0.1g, 0.181mmol, 1.0equiv) was mixed with 1.1 equivalents of HATU, 1.2 equivalents of L-di-tert-butyl glutamate hydrochloride and 3 times equivalents in dry DMF. Equivalent DIPEA makes N-(chlorine e 4 -17 3 -Acyl)-L-glutamic acid di-tert-butyl ester (II-1 2 ), then compound II-1 2 Dissolve in 5 mL of dry dichloromethane, add 2 mL of trifluoroacetic acid (TFA), stir at room temperature for 2 h, and obtain black powder compound I 2 0.093 g, yield 73.6%. HPLC purity: 99.3%. 1 H-NMR (600MHz, Acetone-d 6 ,ppm)δ10.19(s,1H),9.93(s,1H),9.39(s,1H),8.20(dd,J=17.8,11.4Hz,1H),6.37(d,J=17.9Hz,1H ),6.20(d,J=11.4Hz,1H),4.71–4.65(m,2H),4.21(t,J=6.6Hz,2H),3.91(s,3H),3.89(s,3H),3.61 (s, 3H), 3.50 (s, 3H), 3.34 (s, 3H), 2.28–2.19 (m, 4H), 1.83 (d, J=7.3Hz, 4H), 1.31 (s, 3H). MS (ESI + )m / z:682.57(M+H) + (100%).

Embodiment 3

[0074] Example 3: N α -(chlorin e 4 -17 3 -acyl)-L-lysine methyl ester (I 3 ) preparation

[0075] According to the method of Example 1, compound V (0.1g, 0.181mmol, 1.0equiv) was mixed with 1.1 equivalents of HATU and 1.2 equivalents of N in dry DMF. ε N α -(chlorin e 4 -17 3 -acyl)-N ε -tert-butoxycarbonyl-L-lysine methyl ester (II-1 3 ), then compound II-1 3 Dissolve in 5 mL of dry dichloromethane, add 2 mL of trifluoroacetic acid (TFA), stir at room temperature for 2 h, and obtain black powder compound I 3 0.088g, yield 69.3%. 1 H-NMR (600MHz, Acetone-d 6 ,ppm)δ9.79(s,1H),9.78(s,1H),9.10(s,1H),8.33(dd,J=11.7Hz,10.4Hz,1H),6.47(d,J=11.7Hz, 1H), 6.19(d, J=10.2Hz, 1H), 4.64(s, 2H), 4.08(s, 3H), 3.96(s, 3H), 3.71(t, 3H), 3.59(s, 3H), 3.37 (s, 3H), 1.99 (m, 4H), 1.82 (d, 4H), 1.74 (d, 4H), 1.10 (s, 3H). MS (ESI + )m / z:695.55(M+H) + (100%).

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Abstract

The invention belongs to the technical field of medicines, and relates to a novel chlorin e4 derivative and pharmaceutically acceptable salts thereof, and preparation methods and application of the novel chlorin e4 derivative and thepharmaceutically acceptable salt thereof. The chlorin e4 derivative comprises a structure shown as a general formula I and an optical isomer contained in the structural general formula I; according to the preparation method, 17-propionyl or 13-formyl in chlorin e4 and amino acid are subjected to peptide formation and / or 3-vinyl etherification. The chlorin e4 derivative and the pharmaceutically acceptable salt thereof can be applied as a photodynamic antitumor drug. Compared with the existing similar photosensitizer talaporfin which is clinically applied, the chlorin e4 derivative disclosed by the invention has the advantages of strong photodynamic antitumor activity, high dark toxicity-light toxicity ratio and the like; the derivative can be used for preparing novel photodynamic antitumor drugs including photodynamic cancer treatment drugs, drugs for photodynamic treatment of benign vascular diseases such as age-related macular degeneration and nevus flammeus and drugs for photodynamic treatment of condyloma acuminata.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a novel chlorin-based photosensitizer—chlorin e 4 Derivatives and their pharmaceutically acceptable salts, preparation methods and their use in the preparation of anti-tumor and other drugs. Background technique [0002] Photodynamic therapy (PDT) is a new tumor treatment technology developed in the late 1970s. The basis of the treatment is as follows: first, the patient injects a drug called photosensitizer (PS) intravenously, and after it is distributed and accumulated in the tumor site, the lesion is irradiated with a light source (Light source) that matches the maximum absorption wavelength of the photosensitizer. , to induce a series of photochemical reactions in the photosensitizer, prompting it to transition from the ground state (GroundSinglet State) to the excited state (Excited Singlet State), and then to the triplet state (ExcitedTriplet State) through intersystem cr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22A61K41/00A61P35/00A61P27/02A61P9/00A61P17/00A61P31/20
CPCC07D487/22A61K41/0071A61P35/00A61P27/02A61P9/00A61P17/00A61P31/20Y02P20/55
Inventor 姚建忠张星杰黄飞缪震元盛春泉
Owner THE NAVAL MEDICAL UNIV OF PLA
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