Current applications involve novel derivatives of chlorine E6 and its pharmacologically recognized salts, as well as their preparations and uses.

Abstract

DEPCT6315 / 05 / 2562 This patent application relates to novel derivatives of chlorine E6 and its salts that have been Pharmaceutical acceptance, as well as its preparation and use, are matters of medicine. The amino acid derivative chlorine E6 ether comprises the general structural formulas I and optical. Its isomer, the process for its preparation, consists of the etherification of 3-vinyl in chlorine. RinE6 ether peptides are produced from 15-carboxyl ethyl and amino acid derivatives. Chlorin-E6 ether and its salts are pharmaceutically recognized and can be used as medicine. Antitumor activity by photodynamic means compared to the photosensitizer thalaporfin used in... A similar clinical trial previously conducted on the amino acid derivative chlorine E6 ether of this patent application has... Enhanced photodynamic antitumor activity and dark toxicity ratio. -High photosensitivity, a novel photodynamic antitumor drug prepared includes: Photodynamic anticancer drugs are used to treat non-vascular tumors. Severe photodynamic diseases such as macular degeneration and subdural hemorrhages can occur. Age-related skin conditions and a photodynamic treatment for genital warts. (chemical formula) (I) ----------------------------------------------------------- DEPCT63 Current applications involve novel derivatives of chlorine E6 and its pharmaceutically recognized salts. The science, as well as its preparation and medical applications, are related to the amino acid derivative chlorine E6E. The ther consists of a general structural formula I and its optical ishomer; the preparation process involves etherification. The peptide is produced from 15-carboxyethyl and amino acid derivatives in chlorine-E6 ether. Nochlorine E6 ether and its salts are pharmacologically recognized and can be used as antitumor drugs. The photodynamic method, when compared to the photosensitizer thalaporfin previously used in treatment, utilizes amino acid derivatives. The chlorine-E6 ether currently in use exhibits better photodynamic antitumor activity and a higher toxicity ratio. Dark-induced phototoxicity; a novel photodynamic antitumor drug prepared contains photodynamic antitumor drugs. Photodynamics is a drug used to treat benign vascular tumors such as macular degeneration. It is used for age-related macular degeneration and subcutaneous capillary hypertrophy, and as a treatment for genital warts. The photodynamic method. (chemical formula) (I) -----------------------------------------------------------

Description

A novel dihydroporphyrin E6 derivative and its pharmaceutically acceptable salt, its preparation method and applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a novel class of dihydroporphyrin photosensitizers—dihydroporphyrin e6 ether amino acid derivatives and their pharmaceutically acceptable salts, their preparation methods, and their applications in the preparation of antitumor drugs. Background Technology

[0002] Photodynamic therapy (PDT) is a novel cancer treatment technology developed in the early 1980s. Its treatment principle involves irradiating the lesion (tumor) tissue with a photosensitizer using a laser of a specific wavelength. The photosensitizer induces the generation of singlet oxygen (O2) in the tissue's matrix. 1 Reactive oxygen species (ROS) such as oxygen (O2) induce apoptosis or necrosis of tumor cells, thereby exerting a therapeutic effect on tumors. The specific wavelength refers to the maximum absorption wavelength of the photosensitizer in the red light region (>600nm). Because PDT (phototherapy with light) targets only the tumor tissue, it selectively destroys tumor cells while causing little or no damage to normal tissues or organs. It is a non-invasive treatment technology with advantages such as minimal side effects (no surgical trauma or pain, no vomiting, nausea, or immunosuppression caused by radiotherapy and chemotherapy), and the ability to be used repeatedly, alone or in combination with other treatments.

[0003] Light, oxygen in tissues, and photosensitizers are the three essential elements of phototherapy (PDT), with photosensitizers being the core. First-generation porphyrin photosensitizers, such as sodium porphyrin, have been successfully used in clinical tumor treatment with significant efficacy, but they also have obvious drawbacks: 1) The short maximum absorption wavelength in the red light region (630nm) results in insufficient laser penetration to kill tumors, and the low molar absorption coefficient (ε) leads to low photosensitivity; 2) They are multi-component porphyrin mixtures; 3) Slow in vivo clearance leads to high residual phototoxicity, requiring patients to avoid light for 4-8 weeks after treatment, causing significant psychological distress. Therefore, since the late 1990s, researchers have been developing second-generation photosensitizers, represented by dihydroporphyrin-based photosensitizers such as benzoporphyrin derivatives (BPD), chlorophyll a degradation derivatives, and chlorophyll dihydroporphyrin. Dihydroporphyrin photosensitizers have become a hot topic in photosensitizer research due to their single and well-defined structure, a maximum absorption wavelength in the red region (>600nm) shifted to 660-690nm compared to first-generation porphyrin photosensitizers (resulting in better tumor-killing depth and a molar absorption coefficient (ε) one order of magnitude higher), strong photosensitizing activity, rapid in vivo metabolism, and low residual phototoxicity. Reports on dihydroporphyrin photosensitizers are gradually increasing (e.g., Zhu Guohua, et al., 13).2 - N-(2-hydroxyethyl)-15 3 - N-(2-hydroxyethyl)-17 3 - methoxycarbonyl chlorin e6-13 1 ,15 2- Synthesis process and optical properties of diamides. Chemical Engineer, 2015, 235(4): 1-5; Fang Y, et al. Degradation of silkworm excrement chlorophyll and synthesis of dihydrogen porphyrin e6 ether derivatives. Organic Chemistry, 1995, 15(5): 493-498; Xiuhan Guo, et al. Synthesis of new chlorin derivatives containing maleimide functional group and their photodynamic activity evaluation. Bioorganic & Medicinal Chemistry Letters, 2015, 25(19): 4078-4081; Gushchina, O.I., et al. Synthesis of amide derivatives of chlorine e6 and investigation of their biological activity. Journal of Photochemistry and Photobiology B: Biology, 2015, 153: 76-81. Kwitniewski, M., et al. Diamino acid derivatives of PpIX as potential photosensitizers for photodynamic therapy of squamous cell carcinoma and prostate cancer: in vitro studies. Journal of Photochemistry and Photobiology B: Biology, 2009, 94, 214-222.; Serra, V.V., New porphyrin amino acid conjugates: synthesis and photodynamic effect in human epithelial cells. Bioorganic & Medicinal Chemistry, 2010, 18, 6170-6178.; Wang, H.M.; Porphyrin with amino acid moieties: a tumor photosensitizer. Chem. Biol. Interact. 2008, 172, 154-158; Smith, K.M., et al.Syntheses and cellular investigations of 17. 3 -,15 2 -,and 13 1 -amino acid derivatives of chlorin e6. Journal of Medicinal Chemistry, 2011, 54: 7464-7476; Yao Jianzhong et al. Synthesis of dihydroporphyrin f methyl ether and its photosensitizing power and tumor photobiological activity. Acta Pharmaceutica Sinica, 2000, 35(1): 63-66; 2001, 39(1): 1-4; Pandey, RK, et al. Chlorin and porphyrin derivatives as potential photosensitizers in photodynamic therapy. Photochemistry and Photobiology, 1991, 53(1): 65-72), Although most of the optimized products have good theoretical potential effects, most of the substances either have unsatisfactory activity data, high toxicity, too difficult synthesis, or too low yield, which makes them unsuitable for application.

[0004] Since 2000, several photosensitizers have been successfully applied clinically. Verteporfin was launched in 2000, temoporfin in 2001, and talaporfin in 2004. Additionally, pyrophoric acid α-hexyl ether [HPPH, trade name: Photochlor] has undergone Phase I and II clinical trials by Hisun Pharmaceuticals for the treatment of head and neck tumors. Despite this, the variety of drugs for treating tumors remains limited, offering patients limited choices, and there is significant room for improvement in their therapeutic efficacy and toxicity. Therefore, this invention aims to use dihydroporphyrin e6 as a raw material to modify and optimize its structure in order to develop a new class of highly efficient and low-toxicity dihydroporphyrin photosensitizers.

[0005] Summary of the Invention

[0006] This invention addresses the shortcomings of existing technologies by providing a novel dihydroporphyrin E6 derivative and its pharmaceutically acceptable salt, its preparation method, and its applications. The invention aims to find a class of photodynamic antitumor drugs with novel structure, strong antitumor activity, low toxicity, and high therapeutic index.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A chlorin e6 derivative and pharmaceutically acceptable salts thereof, the chlorin e6 derivative being a chlorin e6 ether amino acid derivative, the chlorin e6 ether amino acid derivative including a general structural formula I and optical isomers of the general structural formula I;

[0009]

[0010] In the above general structural formula I,

[0011] R1 represents H, lower alkyl, higher alkyl, (CH2) m OR3 or (CH2CH2O) k R4; wherein the higher alkyl is a straight chain or branched alkyl group containing 7-18 carbon atoms, R3 and R4 independently represent H, lower alkyl, m and k independently represent any integer between 2-6, and the lower alkyl in R1, R3 and R4 is a straight chain or branched alkyl group containing 1-6 carbon atoms;

[0012] R2 represents an amino acid residue.

[0013] Further preferably, R1 in the general structural formula I represents CH3, C3H7, C6H 13 , (CH2)2OCH3, (CH2)2OC3H7, (CH2)3OCH3, (CH2)4OCH3, (CH2CH2O)2CH3 or (CH2CH2O)3CH3.

[0014] Further preferably, R2 in the general structural formula I represents an aspartic acid, glutamic acid or lysine residue.

[0015] Further preferably, the chlorin e6 ether amino acid derivative and pharmaceutically acceptable salts thereof have the following structure: the general structural formula I can be any one of I1-I 27 , and the structures of R1 and R2 in I1-I 27 are as follows, respectively, and the preferred combinations of R1 substituents and R2 substituents are shown in Table 1:

[0016] Table 1: Partially preferred chlorin e6 ether amino acid derivatives I1-I 27

[0017]

[0018] wherein n represents "n-".

[0019] Further, the pharmaceutically acceptable salts of the chlorin e6 ether amino acid derivative are inorganic alkali metal salts of the chlorin e6 ether amino acid derivative, preferably sodium salts.

[0020] A preparation method of the chlorin e6 ether amino acid derivative, and the preparation method is as follows:

[0021] S11: chlorin e6 (Ⅴ) is used as raw material; the chlorin e6 can be directly purchased or obtained by using a literature method (Ma F, Yao JZ, et al. Optimization of synthesis process of photosensitizer chlorin e6 by orthogonal experimental design. Chinese Pharmaceutical Journal, 2005, 40(20): 1589-1591.).

[0022] S12: the 3-vinyl group in the chlorin e6 is subjected to addition reaction with hydrogen halide, and then the addition product is subjected to alcoholization reaction with alcohol (R1OH);

[0023] S13: the 15-ethyl carboxyl group in the chlorin e6 is subjected to peptide condensation reaction with amino acid, so as to obtain the chlorin e6 ether amino acid derivative I.

[0024] Further preferably, in step S13, the 15-ethyl carboxyl group in the chlorin e6 is reacted with 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) and various L-amino acid hydrochlorides (R2'NH2·HCl) which are protected by tert-butyl and non-α-amino tert-butyloxycarbonyl, so as to obtain the chlorin e6 ether amino acid derivative which is protected by carboxyl and amino, and then the chlorin e6 ether amino acid derivative which is protected by carboxyl and amino is subjected to tert-butyl / tert-butyloxycarbonyl removal, so as to obtain the target compound chlorin e6 ether amino acid derivative.

[0025] Further preferably, the preparation method of the chlorin e6 ether amino acid derivative is as follows:

[0026]

[0027] S1: the chlorin e6 (Ⅴ) is reacted with excessive 33% HBr glacial acetic acid solution at room temperature for 10-30 h, so as to obtain 3-(1-bromoethyl)-3-devinyl chlorin e6, which is compound Ⅳ;

[0028] S2: the compound Ⅳ is reacted with alcohol (R1OH) in the presence of excessive K2CO3, so as to obtain compound Ⅲ;

[0029] S3: the compound Ⅲ is reacted with 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) in dry or anhydrous N,N-dimethylformamide (DMF) at room temperature for 2-6 h, and then reacted with various L-amino acid hydrochlorides (R2'NH2·HCl) which are protected by tert-butyl and non-α-amino tert-butyloxycarbonyl in the presence of N,N-diisopropylamine (DIPEA), so as to obtain the chlorin e6 ether amino acid derivative Ⅱ which is protected by carboxyl and amino;

[0030] S4: Compound II is deprotected by trifluoroacetic acid (TFA) to remove the tert-butyl group / tert-butyloxycarbonyl group to obtain the target compound I, i.e. a chlorin e6 ether amino acid derivative.

[0031] Further preferably, the chlorin e6 described above can be prepared by acid-base degradation of chlorophyll a, which can be obtained from silkworm excrement or marine phytoplankton seaweed such as Spirulina and the like.

[0032] The content of chlorophyll a in silkworm excrement and seaweed such as Spirulina is about 0.75% and 1%-2% of the dry weight, respectively, and thus both are extremely rich and inexpensive chlorophyll resources. The preparation of chlorin e6 ether amino acid derivatives from silkworm excrement or seaweed can expand the medical applications of silkworm excrement or seaweed resources.

[0033] The reaction scheme for preparing chlorin e6 (V) from chlorophyll a (VII) is as follows:

[0034]

[0035] ① The crude chlorophyll a extract (paste-like chlorophyll) of silkworm excrement or seaweed available on the market is dissolved in ether, and stirred with an equal volume of concentrated hydrochloric acid at 0-5°C for 1 h to obtain pheophorbide a (VI);

[0036] ② Compound VI is rapidly refluxed in 25% potassium hydroxide in ethanol under nitrogen for 20 min to obtain V.

[0037] Further, the preparation method of the pharmaceutically acceptable salt of the chlorin e6 ether amino acid derivative is as follows: the chlorin e6 ether amino acid derivative is used to synthesize the inorganic alkali metal salt of the chlorin e6 ether amino acid derivative, specifically, the chlorin e6 ether amino acid derivative is reacted with the hydroxide of an inorganic alkali metal or an inorganic alkali metal to obtain the inorganic alkali metal salt of the chlorin e6 ether amino acid derivative, such as sodium hydroxide to obtain a sodium salt.

[0038] The chlorin e6 derivative and the pharmaceutically acceptable salt thereof are used for preparing a drug for treating tumors.

[0039] The chlorin e6 derivative and the pharmaceutically acceptable salt thereof are used for preparing a drug for treating benign vascular diseases, including macular degeneration and fresh port-wine stains.

[0040] The chlorin e6 derivative and the pharmaceutically acceptable salt thereof are used for preparing a drug for treating condyloma acuminatum.

[0041] The application provides a chlorin e6 derivative and a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and mainly has the following beneficial effects:

[0042] ①The original originality of the application lies in that no literature reports a new type of chlorin e6 ether amino acid derivative obtained by using chlorin e6 as a leading structure, simultaneously performing 3-vinyl etherification and 15-ethoxyl and amino acid peptide structure optimization design on the chlorin e6, improving the treatment effect by performing 3-vinyl etherification on the chlorin e6, and reducing the toxicity by introducing amino acid into the 15-acetyl group; specifically, the chlorin e6 ether amino acid derivative or the salt thereof has excellent photodynamic killing effect on human non-small cell lung cancer cells A549 and mouse melanoma cells B16-F10, and has the advantages of high efficiency and low toxicity, indicating that the compound can be used for preparing new photodynamic antitumor drugs.

[0043] Compared with the second generation photosensitizer talaporfin used in the prior art, the chlorin e6 ether amino acid derivative or the salt thereof has the advantages of stronger photodynamic anticancer activity and higher dark toxicity-light toxicity ratio, and can be used for preparing new photodynamic anticancer drugs, drugs for photodynamic treatment of benign vascular diseases such as age-related macular degeneration (a kind of retinal microvascular proliferative disease) and fresh port wine stains (a kind of congenital skin microvascular malformation disease), and drugs for photodynamic treatment of condyloma acuminatum (human papilloma virus infection disease).

[0044] ②The chlorin e6 ether amino acid derivative or the pharmaceutically acceptable salt thereof is a new type of chlorin photosensitizer, and has the advantages of simple preparation method, low toxicity, wide raw material source, low requirement for equipment and mild conditions, and can be well applied to industrial production. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical scheme and advantages of the embodiments of the application clearer, the technical scheme of the application will be described clearly and completely in combination with specific embodiments of the application. Obviously, the described embodiments are some embodiments of the application, but not all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the application.

[0046] The reagents and raw materials used in the application are commercially available or can be prepared according to the literature method. The experimental methods in the following examples not specified in the specific conditions are usually carried out according to the conventional conditions or the conditions recommended by the manufacturer.

[0047] Preparation of chlorin e6 (V) from chlorophyllin a (VII)

[0048]

[0049] Silica gel H column chromatography of the crude product Ⅵ (15 g, containing Ⅵ about 8.25 g) after vacuum drying with P2O5, eluted with CHCl3 / MeOH (9 / 1, V / V) to give 4.6 g of black powder, which is the target compound chlorin e6 (Ⅴ), yield 55.4%. -1 2

[0050] The crude product Ⅵ (15 g, containing Ⅵ about 8.25 g) was added to 360 mL of 25% (w / v) potassium hydroxide ethanol solution, and refluxed rapidly for 20 min under nitrogen. The reaction was stopped, filtered, and the filtrate was diluted with 2 times amount of water, and adjusted to pH 5-6 with 10% sulfuric acid. After filtration and vacuum drying with P2O5, the target compound chlorin e6 (Ⅴ) was obtained by silica gel H column chromatography, yield 55.4%.

[0051] The following examples 1-27 are specific methods for synthesizing target compounds, chlorin e6 ether amino acid derivatives (Ⅰ) with different substituents from chlorin e6 (Ⅴ). The preparation flow chart is as follows:

[0052]

[0053] Example 1: Preparation of N-[3-(1-methoxy)ethyl-3-devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I1)

[0054] S1: Preparation of 3-(1-bromoethyl)-3-devinylchlorin e6 (Ⅳ)

[0055] Compound Ⅴ (5.0 g) was added to 200 mL of 33% HBr glacial acetic acid solution, and stirred at room temperature for 24 h. The glacial acetic acid and excess HBr were removed by evaporation under reduced pressure to obtain 5.6 g of dark green solid compound Ⅳ, which is 3-(1-bromoethyl)-3-devinylchlorin e6. It was directly used in the next reaction without purification.

[0056] S2: Preparation of 3-(1-methoxy)ethyl-3-devinylchlorin e6 (Ⅲ1)

[0057] Compound IV (1.12 g) was dissolved in 25 mL of anhydrous acetone, 2 g of K2CO3 and 2 mL of dry methanol were added, and the mixture was stirred and refluxed for 2 h, cooled to room temperature, 10 times the amount of water was added, the excess K2CO3 was neutralized with 10% H2SO4 and the pH was adjusted to 5-6, filtered, dried with P2O5 under vacuum, and then separated by silica gel H column chromatography to obtain 0.58 g of black powder III1, i.e. 3-(1-methoxy)ethyl-3-devinyl chlorin e6, with a yield of 55.0%.

[0058] The spectral data of 3-(1-methoxy)ethyl-3-devinyl chlorin e6 (III1) are as follows: MS (ESI + )m / z: 629.72 [M+H] + (100%).

[0059] S3: Preparation of N-[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 di-tert-butyl-L-aspartate (II1)

[0060] Compound III1 (135 mg, 0.215 mmol) was dissolved in 15 mL of dry DMF, EDCI (42 mg, 0.215 mmol) was added, and the mixture was stirred at room temperature for 5 h, then L-aspartic acid di-tert-butyl ester hydrochloride (73 mg, 0.258 mmol, 1.2 eq.) and DIPEA (86 μL, 0.516 mmol, 2.4 eq.) were added, and the reaction was continued at room temperature, TLC monitoring showed that the reaction was complete, then 4 times the amount of CH2Cl2 was added for dilution, and the reaction solution was sequentially washed with 5% citric acid (mass percentage), 5% NaHCO3 (mass concentration), water, and saturated brine, dried with anhydrous Na2SO4, and then the solvent was recovered under reduced pressure, and the black powder II11 was separated by flash chromatography to obtain 130 mg with a yield of 70.7%.

[0061] N-[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 di-tert-butyl-L-aspartate (II1) + )m / z: 856.52 [M+H] + (100%).

[0062] S4: Preparation of N-[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 di-tert-butyl-L-aspartate (II1)

[0063] Compound II1(50 mg, 0.0585 mmol) was dissolved in 5 mL dry CH2Cl2, 5 mL trifluoroacetic acid (TFA) was added, the reaction was stirred in ice bath, TLC was used to monitor the reaction, after the reaction was completed, the solvent was recovered under reduced pressure, and then separated by flash preparative chromatography to obtain black powder I136 mg, yield 82.9%.

[0064] N-[3-(1-methoxy) ethyl-3-devinyl dehydroporphyrin e6-15 2 The spectral data of N-[3-(1-methoxy) ethyl-3-devinyl dehydroporphyrin e6-15 + ]-L-aspartic acid (II1) are as follows: MS (ESI 2 )m / z: 744.64 (M+H, 100%).

[0065] Example 2: Preparation of N-[3-(1-n-propoxy) ethyl-3-devinyl dehydroporphyrin e6-15 2 ]-L-aspartic acid (II2)

[0066] S1: Preparation of 3-(1-bromoethyl)-3-devinyl dehydroporphyrin e6 (IV), which was prepared according to the method of step S1 in Example 1.

[0067] S2: Preparation of 3-(1-propoxy) ethyl-3-devinyl dehydroporphyrin e6 (III2): According to the method of step S2 in Example 1, compound IV (1.12 g) was reacted with 2 mL dry n-propyl alcohol to prepare 0.56 g black solid III2, yield 50.9%.

[0068] The spectral data of 3-(1-propoxy) ethyl-3-devinyl dehydroporphyrin e6 (III2) are as follows: MS (ESI + )m / z: 657.78 [M+H] + (100%).

[0069] S3: Preparation of N-[3-(1-n-propoxy) ethyl-3-devinyl dehydroporphyrin e6-15 2 ]-L-aspartic acid di-tert-butyl ester (II2)

[0070] According to the method of step S3 in Example 1, compound III2 (140 mg, 0.213 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride, and 2.4 equivalents of DIPEA in dry DMF to prepare black powder II2 125 mg, yield 66.3%.

[0071] N-[3-(1-n-propoxy) ethyl-3-devinyl dehydroporphyrin e6-15 2 ]-L-aspartic acid di-tert-butyl ester (II2) + )m / z: 884.63 [M+H]+ (100%).

[0072] S4: Preparation of N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I2)

[0073] Compound II2 (50 mg, 0.0566 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) according to the procedure of Example 1, Step S4 to give black powder I2 35 mg in 80.2% yield.

[0074] N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I2) gave the following spectral data: MS (ESI + )m / z: 772.66 [M+H] + (100%).

[0075] Example 3: Preparation of N-[3-(1-n-hexoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I3)

[0076] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) was prepared according to the procedure of Example 1, Step S1.

[0077] S2: Preparation of 3-(1-n-hexoxy)ethyl-3-devinyl chlorin e6 (III3): Compound IV (1.12 g) was reacted with 2 mL of dry n-hexanol according to the procedure of Example 1, Step S2 to give 0.48 g of black solid III3 in 41.0% yield.

[0078] Compound III3 gave the following spectral data: MS (ESI + )m / z: 699.68 [M+H] + (100%).

[0079] S3: Preparation of N-[3-(1-n-hexoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid di-tert-butyl ester (II3): Compound III3 (150 mg, 0.215 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF according to the procedure of Example 1, Step S3 to give black powder II3 120 mg in 60.4% yield.

[0080] Compound II3 gave the following spectral data: 1HNMR (600 MHz, CD3COCD3, δ, ppm): 10.01 (s, 1H), 9.87 (s, 1H), 9.05 (s, 1H), 7.09 (s, 1H), 6.09-6.03 (m, 1H), 5.50 (d, J = 18.4 Hz, 1H), 5.41 (d, J = 18.4 Hz, 1H), 4.70-4.66 (m, 2H), 4.63 (d, J = 5.1 Hz, 1H), 3.85 (q, J = 7.8 Hz, 2H), 3.77-3.72 (m, 1H), 3.65 (s, 3H), 3.64-3.59 (m, 1H), 3.50 (s, 3H), 3.32 (s, 3H), 2.78-2.63 (m, 4H), 2.39 (m, 2H), 2.11 (d, J = 6.8 Hz, 3H), 1.77 (d, J = 6.8 Hz, 3H), 1.73 (t, J = 7.6 Hz, 3H), 1.28 (s, 9H), 1.25 (s, 9H), 1.16-1.12 (m, 6H), 0.74 (t, J = 6.8 Hz, 3H), -1.37 (s, 1H), -1.58 (s, 1H); MS (ESI + )m / z: 926.55 [M+H] + (100%).

[0081] S4: Compound II3 (50 mg, 0.0541 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder, N-[3-(1-n-hexyloxy)ethyl-3-devinyl-dihydrophenoxazine e6-15 2 -L-aspartic acid (I3) 34 mg, yield 77.4%.

[0082] The spectral data of compound I3 are: UV-vis λ max (CH3OH, nm) (ε / M -1 cm -1 ): 396 (89500), 497 (10200), 653 (36900); 1H NMR (600 MHz, CH3OD, δ, ppm): 10.25 (s, 1H), 9.95 (s, 1H), 9.19 (s, 1H), 6.06-6.01 (m, 1H), 5.69 (d, J = 18.5 Hz, 1H), 5.47 (d, J = 18.5 Hz, 1H), 4.81-4.76 (m, 1H), 4.66-4.59 (m, 2H), 3.85 (q, J = 7.7 Hz, 2H), 3.80-3.75 (m, 1H), 3.62 (s, 3H), 3.60-3.56 (m, 1H), 3.49 (s, 3H), 3.35 (d, J = 4.6 Hz, 3H), 2.92 (s, 2H), 2.77-2.71 (m, 1H), 2.48-2.30 (m, 3H), 2.11 (d, J = 6.8 Hz, 3H), 1.76 (d, J = 6.8 Hz, 3H), 1.67 (t, J = 7.6 Hz, 3H), 1.22-1.08 (m, 6H), 0.70 (t, J = 7.0 Hz, 3H); MS (ESI + )m / z: 814.52 [M+H] + (100%).

[0083] Example 4: Preparation of N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 di-tert-butyl-L-aspartate (I4)

[0084] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) according to the method described in step S1 of Example 1.

[0085] S2: Compound IV (1.12 g) was reacted with 2 mL of dry ethylene glycol monomethyl ether to give 0.54 g of black solid 3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6 (III4) in a yield of 47.9% according to the method described in step S2 of Example 1.

[0086] Spectral data of compound III4: MS (ESI + )m / z: 673.72 [M+H] + (100%).

[0087] S3: Compound III4 (150 mg, 0.223 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of di-tert-butyl-L-aspartate hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15

[0088] MS (ESI + m / z: 900.54 [M+H] + (100%).

[0089] S4: Compound II4 (50 mg, 0.0556 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15

[0090] MS (ESI + m / z: 900.54 [M+H] + (100%).

[0091] Example 5: N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 Preparation of N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15

[0092] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) was carried out according to the procedure described in Step S1 of Example 1.

[0093] S2: Compound IV (1.12 g) was reacted with 2 mL of dry ethylene glycol mono-n-propyl ether to give 0.49 g of black solid 3-[1-(2-propoxy)ethoxy]ethyl-3-devinyl chlorin e6 (III5) according to the procedure described in Step S2 of Example 1.

[0094] MS (ESI + m / z: 900.54 [M+H] + (100%).

[0095] S3: Compound III5 (150 mg, 0.214 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15

[0096] MS (ESI) m / z: 928.68 [M+H] + MS (ESI) m / z: 928.68 [M+H] + (100%).

[0097] S4: Compound II5 (50 mg, 0.0539 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) according to the procedure of Example 1, step S4 to give N-[3-[l-(2- propyloxy)ethoxy]ethyl-3-devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I5) 33 mg, yield 75.1%.

[0098] MS (ESI) m / z: 928.68 [M+H] + MS (ESI) m / z: 928.68 [M+H] + (100%).

[0099] Example 6: Preparation of N-[3-[l-(3-methoxy)propoxy]ethyl-3- devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I6)

[0100] S1: Preparation of 3-(l-bromoethyl)-3-devinylchlorin e6 (IV) according to the procedure of Example 1, step S1.

[0101] S2: Compound IV (1.12 g) was reacted with 2 mL of dry 1,3-propanediol monomethyl ether according to the procedure of Example 1, step S2 to give 0.51 g of black solid 3-[l-(3-methoxy)propoxy]ethyl-3-devinylchlorin e6 (III6), yield 44.3%.

[0102] MS (ESI) m / z: 928.68 [M+H] + MS (ESI) m / z: 928.68 [M+H] + (100%).

[0103] S3: Compound III6 (150 mg, 0.219 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF according to the procedure of Example 1, step S3 to give N-[3-[l-(3-methoxy)propoxy]ethyl-3- devinylchlorin e6-15 2 -acyl]-L-aspartic acid di-tert-butyl ester (II6) 115 mg, yield 57.6%.

[0104] MS (ESI) m / z: 928.68 [M+H] +m / z: 914.58 [M + H] + (100%).

[0105] S4: Compound II6 (50 mg, 0.0548 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) according to the procedure of Example 1, Step S4 to give N-[3-[l-(3-methoxy)propoxy]ethyl-3- devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I6) 34 mg, yield 77.5%.

[0106] Spectroscopic data for compound I6: MS (ESI + m / z: 802.62 [M + H] + (100%).

[0107] Example 7: Preparation of N-[3-[l-(4-methoxy)butyloxy]ethyl-3-devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I7)

[0108] S1: Preparation of 3-(l-bromoethyl)-3-devinylchlorin e6 (IV) was carried out according to the procedure of Example 1, Step S1.

[0109] S2: Compound IV (1.12 g) was reacted with 2 mL of dry 1,4-butanediol monomethyl ether according to the procedure of Example 1, Step S2 to give 0.47 g of black solid 3-[l-(4- methoxy)butyloxy]ethyl-3-devinylchlorin e6 (III7), yield 40.0%.

[0110] Spectroscopic data for compound III7: MS (ESI + m / z: 701.62 [M + H] + (100%).

[0111] S3: Compound III7 (150 mg, 0.214 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF according to the procedure of Example 1, Step S3 to give N-[3-[l-(4-methoxy)butyloxy]ethyl-3- devinylchlorin e6-15 2 di-tert-butyl ester (II7) 112 mg, yield 56.4%.

[0112] Spectroscopic data for compound II7: MS (ESI + m / z: 928.66 [M + H] + (100%).

[0113] S4: Compound II7 (50 mg, 0.0539 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) according to the procedure of Example 1, step S4 to give N-[3-[l-(4-methoxy) butoxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I7) 32 mg, yield 72.8%.

[0114] Spectroscopic data of compound I7: MS (ESI + )m / z: 816.52 [M+H] + (100%).

[0115] Example 8: Preparation of N-[3-[l-(2-(2-methoxy)ethoxy)ethoxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (I8)

[0116] S1: Preparation of 3-(l-bromoethyl)-3-devinyl chlorin e6 (IV) was prepared according to the procedure of Example 1, step S1.

[0117] S2: Compound IV (1.12 g) was reacted with 2 mL of dry diethylene glycol monomethyl ether according to the procedure of Example 1, step S2 to give 0.49 g of black solid 3-[l-(2-(2-methoxy)ethoxy)ethoxy] ethyl-3-devinyl chlorin e6 (III8), yield 40.7%.

[0118] Spectroscopic data of compound III8: MS (ESI + )m / z: 717.59 [M+H] + (100%).

[0119] S3: Compound III8 (150 mg, 0.209 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF according to the procedure of Example 1, step S3 to give N-[3-[l-(2-(2-methoxy)ethoxy)ethoxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid di-tert-butyl ester (II8) 100 mg, yield 50.6%.

[0120] Spectroscopic data of compound II8: MS (ESI + )m / z: 944.52 [M+H] + (100%).

[0121] S4: Compound 18 (50 mg, 0.0530 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) according to the procedure of Step S4 of Example 1 to give N-[3-[1-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (18) 30 mg, yield 68.1%.

[0122] Spectroscopic data for compound 18: MS (ESI + )m / z: 832.60 [M+H] + (100%).

[0123] Example 9: Preparation of N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid (19)

[0124] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) was prepared according to the procedure of Step S1 of Example 1.

[0125] S2: Compound IV (1.12 g) was reacted with 2 mL of dry triethylene glycol monomethyl ether according to the procedure of Step S2 of Example 1 to give 0.42 g of black solid 3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6 (III9), yield 33.1%.

[0126] Spectroscopic data for compound III9: MS (ESI + )m / z: 761.66 [M+H] + (100%).

[0127] S3: Compound III9 (150 mg, 0.197 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-aspartic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF according to the procedure of Step S3 of Example 1 to give N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-aspartic acid di-tert-butyl ester (19) 90 mg, yield 46.2%.

[0128] Spectroscopic data for compound 19: MS (ESI + )m / z: 988.64 [M+H] + (100%).

[0129] S4: Following the procedure of Step S4 of Example 1, compound II 9 (50 mg, 0.0507 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3-devinylchlorin e6-15 2 -acyl]-L-aspartic acid (I 9) 30 mg, 67.7% yield.

[0130] Spectral data of compound I 9: MS (ESI + )m / z: 876.68 [M+H] + (100%).

[0131] Example 10: Preparation of N-[3-(1-methoxy)ethyl-3-devinylchlorin e6-15 2 -acyl]-L-glutamic acid (I 10 )

[0132] S1 : Following the procedure of Step S1 of Example 1, compound 3-(1- bromoethyl)-3-devinylchlorin e6 (IV) was prepared;

[0133] S2: Following the procedure of Step S2 of Example 1, compound III 1 was obtained;

[0134] S3: Following the procedure of Step S3 of Example 1, compound III 1 (150 mg, 0.239 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-(1-methoxy)ethyl-3-devinylchlorin e6-15 2 -acyl]-L-glutamic acid di-tert-butyl ester (II 10 ) 135 mg, 65.0% yield.

[0135] Spectral data of compound II 10 : MS (ESI + )m / z: 870.58 [M+H] + (100%).

[0136] S4: Following the procedure of Step S4 of Example 1, compound II 10 (50 mg, 0.0575 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give N-[3-(1-methoxy)ethyl-3-devinylchlorin e6-15 2 -acyl]-L-glutamic acid (I 10 ) 38 mg, 87.2% yield.

[0137] Compound I 10 MS (ESI + )m / z: 758.55 [M+H] + (100%).

[0138] Example 11: Preparation of N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 11 )

[0139] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) according to the procedure described in Step S1 of Example 1.

[0140] S2: According to the procedure described in Step S2 of Example 2, compound III2 was obtained.

[0141] S3: According to the procedure described in Step S3 of Example 1, compound III2 (150 mg, 0.229 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid di-tert-butyl ester (II 11 ) 126 mg, 61.4% yield.

[0142] Compound II 11 MS (ESI + )m / z: 898.62 [M+H] + (100%).

[0143] S4: According to the procedure described in Step S4 of Example 1, compound II 11 (50 mg, 0.0557 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 11 ) 36 mg, 82.3% yield.

[0144] Compound I 11 MS (ESI + )m / z: 786.57 [M+H] + (100%).

[0145] Example 12: Preparation of N-[3-(1-n-hexyloxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I12 Preparation of compound Ⅱ

[0146] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (Ⅳ) was the same as the preparation method of step S1 in example 1.

[0147] S2: The method was the same as step S2 in example 3, to obtain compound Ⅲ3.

[0148] S3: According to the method of step S3 in example 1, compound Ⅲ3 (150 mg, 0.215 mmol) was reacted with an equivalent of EDCI, 1.2 times of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 times of DIPEA in dry DMF to obtain black powder N-[3-(1-n-hexyloxy) ethyl-3-devinyl chlorin e6-15 2 di-tert-butyl ester (Ⅱ 12 )117 mg, yield 58.0%.

[0149] Compound Ⅱ 12 spectral data: 1 H NMR (600 MHz, CD3COCD3, δ, ppm): 10.02 (s, 1H), 9.88 (s, 1H), 9.05 (s, 1H), 7.15 (s, 1H), 6.07 (m, 1H), 5.52 (d, J = 18.4 Hz, 1H), 5.39 (d, J = 18.4 Hz, 1H), 4.72-4.62 (m, 2H), 4.43-4.37 (m, 1H), 3.85 (q, J = 7.8 Hz, 2H), 3.7-3.71 (m, 1H), 3.66 (s, 3H), 3.66-3.59 (m, 1H), 3.50 (s, 3H), 3.32 (s, 3H), 2.81-2.70 (m, 2H), 2.46-2.25 (m, 4H), 2.11 (d, J = 6.6 Hz, 3H), 1.76 (d, J = 7.0 Hz, 3H), 1.73 (t, J = 7.5 Hz, 3H), 1.34 (s, 9H), 1.25-1.18 (m, 15H), 0.74 (t, J = 6.4 Hz, 3H), -1.39 (s, 1H), -1.60 (s, 1H). MS (ESI + )m / z: 940.72 [M+H] + (100%).

[0150] S4: According to the method of step S4 in example 1, compound Ⅱ 12 (50 mg, 0.0532 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to obtain black powder N-[3-(1-n-hexyloxy) ethyl-3-devinyl chlorin e6-152 -acyl]-L-glutamic acid (I 12 ) 35 mg, 79.5% yield.

[0151] Compound I 12 UV-vis λ max (CH3OH, nm) (ε / M -1 cm -1 ): 397 (87100), 497 (9200), 653 (33100). 1 HNMR (600 MHz, CH3OD, δ, ppm): 10.30 (s, 1H), 9.95 (s, 1H), 9.26 (s, 1H), 6.04-5.98 (m, 1H), 5.73 (d, J = 17.7 Hz, 1H), 5.45 (d, J = 17.7 Hz, 1H), 4.67-4.62 (m, 2H), 4.50-4.47 (m, 1H), 3.81-3.73 (m, 3H), 3.59 (s, 3H), 3.57-3.55 (m, 1H), 3.48 (s, 3H), 3.30 (s, 3H), 2.76-2.70 (m, 1H), 2.45-2.28 (m, 3H), 2.28-2.17 (m, 2H), 2.07 (d, J = 6.7 Hz, 3H), 1.76 (d, 3H), 1.60 (t, J = 7.6 Hz, 3H), 1.20-1.03 (m, 6H), 0.69 (t, J = 7.0 Hz, 3H). MS (ESI + )m / z: 828.62 [M+H] + (100%).

[0152] Example 13: N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 13 ) Preparation

[0153] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) according to the preparation method of step S1 in Example 1.

[0154] S2: According to the method of step S2 in Example 4, compound III 4 was obtained.

[0155] S3: According to the method of step S3 in Example 1, compound III 4 (150 mg, 0.223 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-152 [-acyl]-L-glutamic acid di-tert-butyl ester (II) 13 120mg, yield 58.9%.

[0156] Compound II 13 Spectral data: MS(ESI) + m / z: 914.56 [M+H] + (100%).

[0157] S4: Following the method in step S4 of Example 1, compound II 13 (50 mg, 0.0548 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to produce a black powder N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyldihydroporphyrin e6-15. 2 [-acyl]-L-glutamic acid (I 13 34mg, yield 77.5%.

[0158] Compound I 13 Spectral data: MS(ESI) + m / z: 802.65 [M+H] + (100%).

[0159] Example 14: N-[3-[1-(2-propoxy)ethoxy]ethyl-3-desinyldihydroporphyrin e6-15 2 [-acyl]-L-glutamic acid (I 14 Preparation of )

[0160] S1: The preparation of 3-(1-bromoethyl)-3-devinyldihydroporphyrin e6(Ⅳ) is the same as the preparation method of step S1 in Example 1;

[0161] S2: Using the same method as step S2 in Example 5, compound III5 was obtained;

[0162] S3: Following the method in step S3 of Example 1, compound III5 (150 mg, 0.214 mmol) was reacted in dry DMF with an equimolar amount of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride, and 2.4 equivalents of DIPEA to prepare a black powder N-[3-[1-(2-propoxy)ethoxy]ethyl-3-devinyldihydroporphyrin e6-15 2 [-acyl]-L-glutamic acid di-tert-butyl ester (II) 14 102mg, yield 50.6%.

[0163] Compound II 14 Spectral data: MS(ESI) + m / z: 942.66 [M+H] +(100%).

[0164] S4: As in Example 1, Step S4, compound II 14 (50 mg, 0.0531 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder N-[3-[1-(2-propoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 14 ) 32 mg, yield 72.6%.

[0165] Compound I 14 spectral data: MS (ESI + )m / z: 830.62 [M+H] + (100%).

[0166] Example 15: Preparation of N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 15 )

[0167] S1 : Preparation of 3-(1 -bromoethyl)-3-devinyl chlorin e6 (IV) as in Example 1, Step S1 ;

[0168] S2: As in Example 6, Step S2, compound III 6 was obtained;

[0169] S3: As in Example 1, Step S3, compound III 6 (150 mg, 0.219 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid di-tert-butyl ester (II 15 ) 107 mg, yield 52.8%.

[0170] Compound II 15 spectral data: MS (ESI + )m / z: 928.62 [M+H] + (100%).

[0171] S4: As in Example 1, Step S4, compound II 15 (50 mg, 0.0539 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-152 N-[3-[1-(4-methoxy)butyloxy]ethyl-3- dehydrodivinylchlorin e e6-15 15 )33mg, yield 75.1%.

[0172] Compound I 15 MS (ESI + )m / z: 816.71 [M+H] + (100%).

[0173] Example 16: N-[3-[1-(4-methoxy)butyloxy]ethyl-3- dehydrodivinylchlorin e e6-15 2 di-tert-butyl ester (I 16 ) of preparation

[0174] S1: Preparation of 3-(1-bromoethyl)-3-dehydrodivinylchlorin e e6 (IV) according to the procedure described in step S1 of Example 1.

[0175] S2: According to the procedure described in step S2 of Example 7, compound III 7 was obtained.

[0176] S3: According to the procedure described in step S3 of Example 1, compound III 7 (150 mg, 0.214 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-[1-(4-methoxy)butyloxy]ethyl-3- dehydrodivinylchlorin e e6-15 2 di-tert-butyl ester (II 16 )103mg, yield 51.1%.

[0177] Compound II 16 MS (ESI + )m / z: 942.68 [M+H] + (100%).

[0178] S4: According to the procedure described in step S4 of Example 1, compound II 16 (50 mg, 0.0531 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give N-[3-[1-(4-methoxy)butyloxy]ethyl-3- dehydrodivinylchlorin e e6-15 2 di-tert-butyl ester (I 16 )31mg, yield 70.4%.

[0179] Compound I 16 MS (ESI + )m / z: 830.59 [M+H]+ (100%).

[0180] Example 17: Preparation of N-[3-[l-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 17 )

[0181] S1: Preparation of 3-(l-bromoethyl)-3-devinyl chlorin e6 (IV) according to the procedure described in step S1 of Example 1.

[0182] S2: According to the procedure described in step S2 of Example 8, compound III 8 was obtained.

[0183] S3: According to the procedure described in step S3 of Example 1, compound III 8 (150 mg, 0.209 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-[l-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid di-tert-butyl ester (II 17 ) 93 mg, 46.4% yield.

[0184] Compound II 17 spectral data: MS (ESI + )m / z: 958.54 [M+H] + (100%).

[0185] S4: According to the procedure described in step S4 of Example 1, compound II 17 (50 mg, 0.0522 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give N-[3-[l-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 17 ) 30 mg, 68.0% yield.

[0186] Compound I 17 spectral data: MS (ESI + )m / z: 846.74 [M+H] + (100%).

[0187] Example 18: Preparation of N-[3-[l-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I18 Preparation of N-[3-[1-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15

[0188] S1 : Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) by the same method as in Step S1 of Example 1 ;

[0189] S2: By the same method as in Step S2 of Example 9 to give compound III 9;

[0190] S3: By the same method as in Step S3 of Example 1, compound III 9 (150 mg, 0.197 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of L-glutamic acid di-tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-[1-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-L-glutamic acid di-tert-butyl ester (II 18 ) 85 mg in 43.0% yield.

[0191] Compound II 18 spectral data: MS (ESI + )m / z: 1002.72 [M+H] + (100%).

[0192] S4: By the same method as in Step S4 of Example 1, compound II 18 (50 mg, 0.050 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give black powder N-[3-[1-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-L-glutamic acid (I 18 ) 30 mg in 67.6% yield.

[0193] Compound I 18 spectral data: MS (ESI + )m / z: 890.68 [M+H] + (100%).

[0194] Example 19: Preparation of N α -[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 19 )

[0195] S1 : Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) by the same method as in Step S1 of Example 1 ;

[0196] S2: The same method as step S2 of example 1, compound III 1 (150 mg, 0.239 mmol) was reacted with an equivalent of EDCI, 1.2 equivalent of N

[0197] S3: The same method as step S3 of example 1, compound III 1 (150 mg, 0.239 mmol) was reacted with an equivalent of EDCI, 1.2 equivalent of N ε -tert-butyloxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 equivalent of DIPEA to give black powder N α -[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-N ε -tert-butyloxycarbonyl-L-lysine tert-butyl ester (II 19 ) 138 mg, yield 63.4%.

[0198] Compound II 19 MS (ESI + )m / z: 913.56 [M+H] + (100%).

[0199] S4: The same method as step S4 of example 1, compound II 19 (50 mg, 0.0548 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder N α -[3-(1-methoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 19 ) 33 mg, yield 79.6%.

[0200] Compound I 19 MS (ESI + )m / z: 757.58 [M+H] + (100%).

[0201] Example 20: Preparation of N-[3-(1-n-propoxy)ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 20 )

[0202] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV), the same method as step S1 of example 1;

[0203] S2: The same method as step S2 of example 2, compound III 2 was obtained;

[0204] S3: Following the procedure of Example 1, Step S3, compound III 2 (150 mg, 0.229 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N- hydroxysuccinimide, and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-(1-n- propoxy)ethyl-3-devinylchlorin e6-15 ε - acyl]-L-lysine (I 2 - acyl]-L-lysine (I ε - acyl]-L-lysine (I 20 ) 130 mg, 60.5% yield.

[0205] Compound II 20 Compound II + m / z: 941.60 [M+H] + (100%).

[0206] S4: Following the procedure of Example 1, Step S4, compound II 20 (50 mg, 0.0532 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give black powder N-[3-(1-n- propoxy)ethyl-3-devinylchlorin e6-15 2 - acyl]-L-lysine (I 20 ) 30 mg, 71.9% yield.

[0207] Compound I 20 Compound I + m / z: 785.62 [M+H] + (100%).

[0208] Example 21: Preparation of N-[3-(1-n-hexyloxy)ethyl-3-devinylchlorin e6-15 2 - acyl]-L-lysine (I 21 ) 30 mg, 71.9% yield.

[0209] S1: Preparation of 3-(1-bromoethyl)-3-devinylchlorin e6 (IV) following the procedure of Example 1, Step S1;

[0210] S2: Following the procedure of Example 3, Step S2, compound III 3 was obtained;

[0211] S3: Following the procedure of Example 1, Step S3, compound III 3 (150 mg, 0.215 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N- hydroxysuccinimide, and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-(1-n- propoxy)ethyl-3-devinylchlorin e6-15 ε- tert-butoxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 eq DIPEA gave N-[3-(1-n-hexyloxy)ethyl-3-devinyl chlorin e6-15 2 - acyl]-N ε - tert-butoxycarbonyl-L-lysine tert-butyl ester (II 21 ) 116 mg, yield 55.0%.

[0212] Compound II 21 UV-vis λ 1 (CH3OH, nm) (ε / M + cm + ): 395 (67600), 497 (6300), 652 (23500).

[0213] Compound I 21 UV-vis λ 2 (CH3OH, nm) (ε / M 21 cm 21 ): 395 (67600), 497 (6300), 652 (23500).

[0214] Compound I 21 UV-vis λ max (CH3OH, nm) (ε / M -1 cm -1 ): 395 (67600), 497 (6300), 652 (23500).1 H NMR (600 MHz, CH3OD, δ, ppm): 10.45 (s, 1H), 10.07 (s, 1H), 9.38 (s, 1H), 6.06 (m, 1H), 5.90 (d, J = 17.9 Hz, 1H), 5.43 (d, J = 17.9 Hz, 1H), 4.74-4.70 (m, 1H), 4.58-4.52 (m, 2H), 3.90-3.80 (m, 3H), 3.63 (s, 3H), 3.60-3.56 (m, 1H), 3.52 (s, 3H), 3.37 (s, 3H), 3.05 (d, J = 6.1 Hz, 2H), 2.81-2.74 (m, 1H), 2.50-2.28 (m, 3H), 2.09 (d, J = 6.7 Hz, 3H), 2.00-1.87 (m, 2H), 1.75 (d, J = 7.5 Hz, 3H), 1.62 (d, J = 7.5 Hz, 3H), 1.51-1.32 (m, 4H), 1.21-1.06 (m, 6H), 0.71 (d, J = 7.0 Hz, 3H). MS (ESI + )m / z: 827.64 [M+H] + (100%).

[0215] Example 22: Preparation of N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 22 )

[0216] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) according to the method described in step S1 of Example 1.

[0217] S2: According to the method described in step S2 of Example 4, compound III 4 was obtained.

[0218] S3: According to the method described in step S3 of Example 1, compound III 4 (150 mg, 0.223 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester (II 22 ) 120 mg, yield 56.2%.

[0219] Compound II 22 MS (ESI+ m / z: 957.52 [M + H] + (100%).

[0220] S4: As in Example 1, step S4, compound II 22 (50 mg, 0.0523 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give black powder N-[3-[1-(2-methoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 22 ) 26 mg, yield 62.1%.

[0221] Compound I 22 MS (ESI + m / z: 801.62 [M + H] + (100%).

[0222] Example 23: Preparation of N-[3-[1-(2-propoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 23 )

[0223] S1 : Preparation of 3-(1 -bromoethyl)-3-devinyl chlorin e6 (IV) as in Example 1, step S1 ;

[0224] S2: As in Example 5, step S2, compound III 5 was obtained;

[0225] S3: As in Example 1, step S3, compound III 5 (150 mg, 0.214 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to give black powder N-[3-[1-(2-propoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester (II 23 ) 105 mg, yield 49.8%.

[0226] Compound II 23 MS (ESI + m / z: 985.54 [M + H] + (100%).

[0227] S4: As in Example 1, step S4, compound II 23(50 mg, 0.0508 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give black powder N-[3-[1-(2-propoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 23 ) 24 mg, yield 57.0%.

[0228] Compound I 23 spectral data: MS (ESI + )m / z: 829.65 [M+H] + (100%).

[0229] Example 24: Preparation of N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 2 -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 24 ) 24 mg, yield 57.0%.

[0230] S1 : Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) was carried out according to the procedure described in step S1 of Example 1 ;

[0231] S2: According to the procedure described in step S2 of Example 6, compound III 6 was obtained;

[0232] S3: According to the procedure described in step S3 of Example 1, compound III 6 (150 mg, 0.219 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N ε -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 2 -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 ε -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 24 ) 24 mg, yield 57.0%.

[0233] Compound II 24 spectral data: MS (ESI + )m / z: 971.52 [M+H] + (100%).

[0234] S4: According to the procedure described in step S4 of Example 1, compound II 24 (50 mg, 0.0515 mmol) was reacted with CH2Cl2-TFA (1 :1, v / v) to give black powder N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-15 2 -N-[3-[1-(3-methoxy)propoxy]ethyl-3-devinyl chlorin e6-1524 Yield 59.6%.

[0235] Compound I 24 Data of spectrum: MS (ESI + )m / z: 815.66 [M+H] + (100%).

[0236] Example 25: Preparation of N-[3-[1-(4-methoxy) butyloxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 25 )

[0237] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV), the same as the preparation method of step S1 in Example 1;

[0238] S2: The same as the method of step S2 in Example 7, to obtain compound III 7;

[0239] S3: According to the method of step S3 in Example 1, compound III 7 (150 mg, 0.214 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA in dry DMF to obtain black powder N-[3-[1-(4-methoxy) butyloxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester (II 25 ) 105 mg, yield 49.8%.

[0240] Compound II 25 Data of spectrum: MS (ESI + )m / z: 985.58 [M+H] + (100%).

[0241] S4: According to the method of step S4 in Example 1, compound II 25 (50 mg, 0.0508 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to obtain black powder N-[3-[1-(4-methoxy) butyloxy] ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 25 ) 23 mg, yield 54.7%.

[0242] Compound I 25 Data of spectrum: MS (ESI + )m / z: 829.68 [M+H]​+ (100%).

[0243] Example 26: N-[3-[1-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-desvinyldihydroporphyrin e6-15 2 [-acyl]-L-lysine (I 26 Preparation of )

[0244] S1: The preparation of 3-(1-bromoethyl)-3-devinyldihydroporphyrin e6(Ⅳ) is the same as the preparation method of step S1 in Example 1;

[0245] S2: Using the same method as step S2 in Example 8, compound III8 was obtained;

[0246] S3: Following the method in step S3 of Example 1, compound III8 (150 mg, 0.209 mmol) was reacted in dry DMF with an equivalent amount of EDCI and 1.2 equivalent amounts of N. ε -tert-butyloxycarbonyl-L-lysine tert-butyl ester hydrochloride was reacted with 2.4 equivalents of DIPEA to prepare a black powder N-[3-[1-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-desvinyldihydroporphyrin e6-15 2 -acyl]-N ε -tert-Butyloxycarbonyl-L-lysine tert-butyl ester (II) 26 95mg, yield 45.3%.

[0247] Compound II 26 Spectral data: MS(ESI) + m / z: 1001.54 [M+H] + (100%).

[0248] S4: Following the method in step S4 of Example 1, compound II 26 (50 mg, 0.05 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to produce a black powder N-[3-[1-(2-(2-methoxy)ethoxy)ethoxy]ethyl-3-desvinyldihydroporphyrin e6-15. 2 [-acyl]-L-lysine (I 26 22mg, yield 52.1%.

[0249] Compound I 26 Spectral data: MS(ESI) + m / z: 845.64 [M+H] + (100%).

[0250] Example 27: Preparation of N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-L-lysine (I 27 )

[0251] S1: Preparation of 3-(1-bromoethyl)-3-devinyl chlorin e6 (IV) according to the procedure described in step S1 of Example 1.

[0252] S2: According to the procedure described in step S2 of Example 9, compound III 9 was obtained.

[0253] S3: According to the procedure described in step S3 of Example 1, compound III 9 (150 mg, 0.197 mmol) was reacted with an equivalent of EDCI, 1.2 equivalents of N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester hydrochloride and 2.4 equivalents of DIPEA to give N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3- devinyl chlorin e6-15 2 -acyl]-N ε -tert-butoxycarbonyl-L-lysine tert-butyl ester (II 27 ) 86 mg, 41.7% yield.

[0254] Compound II 27 MS (ESI + )m / z: 1045.56 [M+H] + (100%).

[0255] S4: According to the procedure described in step S4 of Example 1, compound II 27 (50 mg, 0.0479 mmol) was reacted with CH2Cl2-TFA (1:1, v / v) to give N-[3-[1-(2-(2-(2-methoxy)ethoxy)ethoxy)ethoxy]ethyl-3-devinyl chlorin e6-15 2 -acyl]-L-lysine (I 27 ) 20 mg, 47.0% yield.

[0256] Compound I 27 MS (ESI + )m / z: 889.58 [M+H] + (100%).

[0257] Example 28: In vitro PDT anti-tumor activity test of the partial chlorin e6 ether amino acid derivatives

[0258] 1. Materials

[0259] Cell lines: human non-small cell lung cancer cell A549 and mouse melanoma cell B16-F10 were selected, which were provided by Shanghai Cell Bank of Chinese Academy of Sciences.

[0260] The laser light source was a 660nm semiconductor laser therapeutic instrument developed by Shanghai Bofei Biomedicine Company, and the maximum output power was 2W.

[0261] 2. Method

[0262] 1) Tumor cell lines: human non-small cell lung cancer cell (A549) and mouse melanoma cell (B16-F10) culture: the frozen cells were taken out from liquid nitrogen and immediately placed in a 42℃ water bath to quickly dissolve the cells, and then the culture solution containing fresh calf serum was replaced [RPMI 1640 or DMEM + 10% (v / v) FBS + 10% (v / v) + 1% (v / v) double-antibiotic (penicillin + streptomycin)], and cultured in a 37℃ CO2 incubator, and the culture solution was replaced every other day.

[0263] 2) Preparation of drug solution: the tested compound and the positive control drug talaporfin were dissolved in an appropriate amount of 0.1M NaOH, and then 0.1M HCl was added to adjust the pH to 7.4, and physiological saline was added to prepare a drug storage solution with an appropriate concentration.

[0264] 3) Determination of dark toxicity and PDT killing effect of the tested compound and the positive control drug on two kinds of tumor cells: 96-well plates were added with 100μL of cell suspension with a concentration of 5×10 3 / mL, and cultured in a 37℃, 5% CO2 incubator for 24h, then the cell culture solution was removed, and fresh culture solution containing different concentrations of sample solution was added, three replicate wells were set, and incubated at 37℃ and 5% CO2 (volume concentration) for 24h, then fresh culture solution was replaced, and no light was added (dark toxicity) or irradiated with 660nm wavelength laser (light dose 8J / cm 2 )(phototoxicity), and continued to culture for 24h. The drug-containing cell culture solution was removed, fresh culture solution was replaced, and 200μL of culture solution containing 10% (v / v) CCK-8 (Dojindo Laboratories, Japan) was added to each well, and continued to culture for 1.5h, then the absorbance value of each well at 450nm was determined by an enzyme marker (Tecan, Switzerland).

[0265] 3. Results

[0266] The dark toxicity and PDT killing effect of part of the preferred target compounds on tumor cells in vitro are shown in Table 2.

[0267] Table 2 Half inhibitory concentration IC of part of the target compounds on tumor cells50 (μM)

[0268]

[0269]

[0270] The results of Table 2 show that all the tested compounds have excellent PDT anti-cancer activity against both tumor cell lines under the light dose of 8 J / cm 2 The activity (phototoxicity) and the ratio of dark toxicity to phototoxicity (therapeutic index) of all the tested compounds are significantly better than that of talaporfin, a similar photosensitizer, indicating that the toxicity and activity of the new compounds have been more effectively separated compared with talaporfin, and have a better therapeutic index.

[0271] The preliminary structure-activity relationship shows that: ① the PDT anti-cancer activity of the tested target compounds increases with the increase of the carbon chain of the ether bond, and the activity of the amino acid derivatives of dihydrophenyl e6 n-hexyl ether (I3, I 12 and I 21 ) is the best; ② when the methylene unit of the ether carbon chain is replaced by an oxygen atom, the activity decreases, for example, the phototoxicity of the two tumor cell lines: I7 16 12 , I 25 21 ; ③ the type of amino acid also has a certain influence on the activity and dark toxicity, and aspartic acid is the best, that is, the aspartic acid derivative of dihydrophenyl e6 n-hexyl ether I3 has the highest PDT anti-cancer activity and the ratio of dark toxicity to phototoxicity, and the PDT anti-cancer activity against human non-small cell lung cancer cells A549 and mouse melanoma cells B16-F10 is 13.63 times and 12.07 times that of talaporfin, respectively, and the ratio of dark toxicity to phototoxicity against the two tumor cells is 14.04 times and 13.64 times that of talaporfin, respectively.

[0272] Therefore, the dihydrophenyl e6 ether amino acid derivatives in the present application are very likely to become another anti-tumor drug with better treatment effect and lower toxicity after talaporfin.

[0273] Finally, it should be noted that the above-described embodiments are only used to illustrate the technical solutions of the present application, and are not limiting; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that the technical solutions recorded in the foregoing embodiments can still be modified, or some or all of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.​​