Novel porphin compound and application thereof in field of medicine

Abstract

The invention relates to a novel porphin compound (I) and application thereof in the field of medicines. The compound has the following structure: # imgabs0 #, wherein n in-(CH2) n is 0-7; r1 and R2 are the same or different and can be independently-(CH2) mCOOH,-(CH2) mCO (CH2) nCOOH,-(CH2) mNHCO (CH2) nCOOH,-(CH2) mOH and-(CH2) mO (CH2O) mH, m is equal to 1-7, and n is equal to 1-3; r3 is-H,-F,-Cl,-Br,-I,-O (CH2) m Me,-(CH2) mCH3,-(CH2) mCH (CH3) 2,-(CH2) mO (CH2) mCH3,-(CH2) m (OCH2CH2) pCH3,-(CH2) mCO (CH2) mCH3, m = 0-7, p = 1-3, and q = 1-7; r < 4 > is-H,-Cl,-Br or-I. The compound has a remarkable photodynamic anti-tumor effect and can be used as a photodynamic therapeutic drug for diseases such as tumors, retina macular degeneration, actinic keratosis, nevus flammeus and condyloma acuminata.

Description

Technical Field

[0001] The present invention relates to photosensitizing drugs and photodynamic therapy, and in particular to a novel AB3-type porphin compound and its application in the medical field. Background Art

[0002] Photodynamic therapy (PDT), also known as photoradiation therapy, is an important treatment method developed in recent decades for both tumors and non-tumor diseases. The mechanism of action of PDT involves the photosensitizer, after entering the body, distributing itself to target tissues. Then, under irradiation with light of a specific wavelength, it produces reactive oxygen species, which kill the target tissues. Compared with conventional therapies, PDT has gained recognition among physicians and patients for its proven efficacy and minimal side effects, making it an important treatment option for various conditions, including tumors, macular degeneration, port-wine stains, and actinic keratosis.

[0003] Photosensitizers are a core element of photodynamic therapy. Because different diseases have distinct characteristics, such as lesion location and size, currently available photosensitizers do not meet the clinical needs of diverse conditions. There is a need to develop photosensitizers with diverse characteristics for clinical use (Ca. Cancer J. Clin., 2011, 61: 250-281; Nat. Rev. Cancer, 2003, 3, 380-387; Photochem. and Photobiol., 2020, 96, 517-523; Chem. Rev., 2015, 115, 10261-10306).

[0004] Meso-tetraphenylporphine (also known as meso-tetraphenylporphyrin, compound 1) is a photosensitizer with excellent singlet oxygen generation ability and a maximum absorption wavelength of 648 nm. Porphines with different phenyl substitutions at the meso position represent a novel class of compounds. Durantini et al. (J. Porphyr. Phthalocya., 2000, 4, 233-242) reported the preparation and UV-visible absorption characteristics of AB3-type porphin compounds. Yu Yuanbin et al. also reported the preparation of AB3-type porphin compounds (such as compound 2) in their patent (CN103694246A). However, these publications did not investigate the pharmacological activity of the prepared compounds. Zhang et al. reported compounds 1, 2, and 3. Photodynamic activity tests showed that compounds 1 and 3 had extremely weak antitumor activity, while compound 2 exhibited some antitumor activity (Chinese Chem. Lett., 2017, 28, 777-781). No positive control was included in the experiment. We systematically investigated the optical and pharmacological properties of the reported AB3-type porphin compounds and found that these compounds suffer from poor solubility, low cellular uptake in vivo, and low photodynamic activity in cells or animals, hindering their clinical application. To overcome these shortcomings, we further structurally modified these compounds. Results showed that the resulting compounds exhibited significantly improved biocompatibility and enhanced photodynamic antitumor activity.

[0005] Summary of the Invention

[0006] To address the shortcomings of existing AB3-type porphin compounds, such as poor solubility, low cellular uptake rate in the body, and low photodynamic activity at the cellular or animal level, the present invention has developed a new class of AB3-type porphin compounds by further structurally modifying the reported compounds. The compounds have significantly improved biocompatibility and significantly enhanced photodynamic anti-tumor effects.

[0007] The present invention is summarized as follows: A novel AB3-type porphyrin compound (I) is characterized by having the following structure:

[0008] in: -(CH2) n where n is 0 - 7; R 1 、R 2 The same or different and may independently be -(CH2) m COOH, -(CH2) m CO(CH2) nCOOH, -(CH2) m NHCO(CH2) n COOH, -(CH2) m OH, -(CH2) m O(CH2O) m H, m=1-7, n=1-3; R 3 -H, -F, -Cl, -Br, -I, -O(CH2) m Me, -(CH2) m CH3, -(CH2) m CH(CH3)2, -(CH2) m O(CH2) m CH3, -(CH2) m (OCH2CH2) p CH3, -(CH2) m CO(CH2) m CH3, m=0-7, p=1-3, q=1-7; R 4 They are -H, -Cl, -Br, and -I.

[0009] The AB3-type porphyrin compound (I) according to claim 1, comprising: 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I1); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I2); 5-[[4-(1-(2-oxo-4-carboxy)butylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I3); 5-[[4-(1-(dicarboxymethylene)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I4); 5-[[4-(1-(2-oxo-4-carboxy)butylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I5); 5-[[4-(1-(3-aza-4-oxo)carboxyhexylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I6); 5-[[4-(1-(1-carboxy)carboxyethylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I7); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I8); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I9); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 10 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 11 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 12 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 13 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 14 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 15 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 16 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 17); 5-[4-(2-oxo-2-(2-oxo-4-carboxyl)butylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 18 ); 5-[4-(2-oxo-2-(3-aza-4-oxo)carboxyhexylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 19 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I 20 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I 21 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 22 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 23 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 24 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 25 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 26 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 27 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrachloro-10,15,20-triphenylporphyrin (I 28 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetrachloro-10,15,20-triphenylporphyrin (I 29 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 30 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 31 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetraiodo-10,15,20-triphenylporphyrin (I 32 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetraiodo-10,15,20-triphenylporphyrin (I 33 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methoxy)phenylporphyrin (I 34 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tris(perfluorophenyl)porphyrin (I 35 ).

[0010] The novel AB3-type porphyrin compound (Formula I) described in claim 1 can be used as a photodynamic therapy drug for diseases such as tumors, retinal macular degeneration, actinic keratosis, port-wine stains, and condyloma acuminata. DETAILED DESCRIPTION

[0011] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0012] [Example 1] 5-[[4-(1-( N , N Synthesis of [1,2-dicarboxymethyl)amino]formyl]phenyl]-10,15,20-triphenylporphyrin (I1):

[0013] Methyl p-formylbenzoate (2.148 g, 13.1 mmol) and benzaldehyde (4.0 mL, 39.4 mmol) were added separately to refluxing propionic acid (425 mL). Pyrrole (7.1 mL, 52.6 mmol) was then slowly added. The reaction mixture was stirred at reflux for 1 h, and the reaction was monitored for completion by TLC. After the reaction mixture was cooled to 60°C, the propionic acid was removed under reduced pressure, and DCM (400 mL) was added for dissolution. The mixture was washed with H2O (300 mL x 3). The solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography to afford a purple-red solid, III1 (1.181 g, 13.4%). 1 H NMR (400 MHz, CDCl3): δ ppm 8.86 (d, J =7.2 Hz, 6H), 8.78 (d, J = 4.7 Hz, 2H), 8.44 (d, J = 8.0 Hz, 2H), 8.31 (d, J =8.1 Hz, 2H), 8.21 (d, J = 6.8 Hz, 6H), 7.76 (d, J = 7.4 Hz, 9H), 4.11 (s, 3H), -2.78 (s, 2H). Compound III1 (150 mg, 0.223 mmol) was dissolved in THF (20 mL), and KOH solution (2 mol / L, 10 mL) was added. The mixture was stirred under reflux for 6 h, and the reaction was complete by TLC. After the reaction solution was cooled to room temperature, the THF was removed under reduced pressure, and H₂O (10 mL) was added. The pH was adjusted to 5-6 with HCl solution (2 mol / L). The solution was filtered, washed with H₂O (10 mL x 3), and dried under vacuum to obtain IV1 (138 mg, 94%) as a purple-red solid. 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.84 (s,8H), 8.33 (d, J = 9.3 Hz, 4H), 8.23 (d, J = 6.2 Hz, 6H), 7.84 (d, J = 6.4 Hz,9H), -2.92 (s, 2H). Compound IV1 (100 mg, 0.14 mmol) was dissolved in DCM (10 mL), and HBTU (99 mg, 0.31 mmol) and DIPEA (0.2 mL, 0.84 mmol) were added sequentially. The reaction was stirred under nitrogen for 0.5 h, followed by dimethyl iminodiacetate hydrochloride (77 mg, 0.34 mmol). TLC was used to monitor the reaction until completion. The mixture was diluted with dichloromethane (20 mL) and washed sequentially with H2O (20 mL × 3) and saturated NaCl solution (20 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography to afford V1 (90 mg, 77.5%) as a purple-red solid. 1 HNMR (400 MHz, DMSO- d 6 ) δppm: 8.86 (d, J = 13.2 Hz, 8H), 8.30 (d, J = 7.7 Hz, 2H), 8.24 - 8.21 (m,6H), 7.83 (d, J = 7.1 Hz, 9H), 7.76 (d, J = 7.6 Hz, 2H), 4.52 (s, 2H), 4.43(s, 2H), 4.24 (dd, J= 7.2, 4.3 Hz, 4H), 1.34 - 1.25 (m, 6H), -2.91 (s, 2H). Compound V1 (80 mg, 0.10 mmol) was dissolved in THF (10 mL), followed by the addition of LiOH solution (1 mol / L, 4 mL). The reaction was stirred at room temperature for 4 h and monitored by TLC until completion. The mixture was diluted with water (10 mL) and the pH was adjusted to 5-6 with HCl solution (1 mol / L). The THF solvent was removed under reduced pressure, filtered, and dried in vacuo to yield a purple-red solid I1 (63 mg, 84.4%). 1 HNMR (600 MHz, DMSO- d 6): δ ppm 13.27 (s, 2H), 8.83 (s, 8H), 8.34 (d, J = 23.2Hz, 4H), 8.21 (d, J = 6.7 Hz, 6H), 7.84 - 7.80 (m, 9H), 4.21 (s, 4H), -2.91 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 167.99, 146.04 (s), 141.60, 135.21,135.00, 134.78, 128.58, 128.32, 127.47, 120.80, 120.64, 119.23, 40.52. HRMS(MALDI-TOF): m / z calcd for C 49 H 35 N5O5 [M+H] + , 774.2638; found, 774.1334.

[0014] [Example 2] 5-[[4-(1-( N,N Synthesis of [1,2-dicarboxyethyl)imino)formyl]phenyl]-10,15,20-triphenylporphyrin (I2):

[0015] Compound I2 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d6): δ ppm8.84 (s, 8H), 8.22 (s, 8H), 7.82 (s, 11H), 3.79 (s, 4H), 2.73 (s, 4H), -2.90 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 141.62, 134.70, 128.60, 127.50,30.90. HRMS (MALDI-TOF): m / z calcd for C 51 H 39 N5O5 [M+H] + ,802.2951; found,802.3712.

[0016] [Example 3] Synthesis of 5-[[4-(1-(2-oxo-4-carboxyl)butylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I3):

[0017] Compound I3 was prepared according to the synthetic method of compound I1. 1 H NMR (400 MHz, DMSO- d 6): δ ppm12.25 (s, 1H), 9.25 (s, 1H), 8.84 (s, 8H), 8.28 (d, J = 50.9 Hz, 10H), 7.82(s, 9H), 4.31 (s, 2H), 2.86 (s, 2H), 2.53 (s, 2H), -2.91 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6): δ ppm 205.70, 173.74, 166.44, 144.27, 141.13, 134.20, 133.32,129.47, 128.10, 127.01, 120.13, 118.96, 49.11, 34.22, 27.51. HRMS (MALDI-TOF): m / z calcd for C 50 H 37 N5O4 [M+H] + ,772.28; found, 772.2921.

[0018] [Example 4] Synthesis of 5-[[4-(1-(dicarboxymethylene)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I4):

[0019] Compound I4 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d 6): δ ppm8.84 (s, 8H), 8.34 (d, J = 2.8 Hz, 2H), 8.23 (d, J = 6.5 Hz, 6H), 7.84 (t, J= 8.2 Hz, 11H), 4.12 (d, J = 5.8 Hz, 1H), -2.91 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 171.91, 166.95, 141.62, 134.68, 128.59, 127.48, 126.39,120.61, 41.92. HRMS (MALDI-TOF): m / z calcd for C 48 H 33 N5O5 [M+H] + ,760.25; found,760.3913.

[0020] [Example 5] Synthesis of 5-[[4-(1-(2-oxo-4-carboxyl)butylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I5):

[0021] Compound I5 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d 6): δ ppm8.83 (d, J = 8.4 Hz, 8H), 8.32 (d, J = 8.4 Hz, 4H), 8.06 - 8.05 (m, 6H), 7.59- 7.57 (m, 6H), 4.30 (d, J = 5.9 Hz, 2H), 2.86 (t, J= 6.5 Hz, 2H), 2.64 (s,9H), 2.56 - 2.53 (m, 2H), -2.91 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm174.18, 138.74, 137.79, 134.58, 128.08, 126.39, 120.57, 34.71, 28.00, 21.50.HRMS (MALDI-TOF): m / z calcd for C 53 H 43 N5O4 [M+H] + ,814.33; found, 814.9786.

[0022] [Example 6] Synthesis of 5-[[4-(1-(3-aza-4-oxo)carboxyhexylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I6):

[0023] Compound I6 was prepared according to the synthetic method of compound I1. 1 H NMR (400 MHz, DMSO- d 6): δ ppm8.83 (s, 8H), 8.29 (s, 2H), 8.17 (s, 2H), 8.05 (d, J = 6.9 Hz, 6H), 7.59 (d, J = 7.0 Hz, 6H), 3.39 (s, 4H), 2.64 (s, 9H), 2.43 (d, J = 6.5 Hz, 4H), -2.93(s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 174.43, 171.91, 166.83, 138.73,137.79, 134.57, 128.07, 126.33, 120.56, 119.25, 38.92, 30.68, 29.75, 21.50.HRMS (MALDI-TOF): m / z calcd for C 54 H 46 N6O4 [M+H] +,843.36; found, 843.1185.

[0024] [Example 7] Synthesis of 5-[[4-(1-(1-carboxy)carboxyethylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I7):

[0025] Compound I7 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d 6): δ ppm12.59 (s, 2H), 8.86 (d, J = 20.3 Hz, 8H), 8.35 (s, 5H), 8.23 (d, J = 6.2 Hz,5H), 7.84 (d, J = 6.9 Hz, 9H), 4.62 (d, J = 5.2 Hz, 1H), 2.53 (s, 2H), -2.91(s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 141.62, 134.67, 128.58, 127.48,126.59, 120.61, 52.70, 31.13. HRMS (MALDI-TOF): m / z calcd for C 49 H 35 N5O5 [M+H] + ,774.26; found, 774.1334.

[0026] [Example 8] 5-[[4-(1-( N , N Synthesis of [1,2-dicarboxymethyl]amino]formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I8):

[0027] Compound I8 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d 6): δ ppm13.28 (s, 2H), 8.84 (s, 8H), 8.35 (d, J= 22.1 Hz, 4H), 8.08 (s, 6H), 7.62(s, 6H), 3.60 (s, 4H), 2.66 (s, 9H), -2.92 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6): δ ppm 139.79, 139.47, 139.02, 138.66, 137.33, 137.28, 137.22, 137.08,135.52, 134.71, 134.60, 134.33, 127.58, 127.51, 127.48, 127.40, 120.80,119.87, 118.55, 118.25, 66.50, 54.21, 21.59, 21.54. HRMS (MALDI-TOF): m / z calcd for C 52 H 41 N5O5 [M+H] + ,816.3108; found, 816.8924.

[0028] [Example 9] 5-[[4-(1-( N , N Synthesis of [1,2-dicarboxyethyl)amino]formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I9):

[0029] Compound I9 was prepared according to the synthetic method of compound I1. 1 H NMR (600 MHz, DMSO- d 6): δ ppm12.48 (s, 2H), 8.84 (s, 8H), 8.28 (d, J = 39.1 Hz, 4H), 8.08 (s, 6H), 7.61 (s, 6H), 3.80 (s, 4H), 2.66 (s, 4H), -2.91 (s, 2H). 13 C NMR (100 MHz, DMSO- d6): δ ppm 142.69, 142.32, 141.88, 141.61, 135.50, 134.69, 134.63, 134.37,127.72, 127.68, 127.49, 126.89, 126.77, 126.67, 120.86, 119.97, 118.64,118.34, 118.18, 66.46, 54.27. HRMS (MALDI-TOF): m / z calcd for C 54 H 45 N5O5 [M+H] + ,844.3421; found, 844.4312.

[0030] [Example 10] 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 16 ) synthesis:

[0031] Compound I was prepared according to the synthetic method of compound I1 16 . 1 H NMR (400 MHz, DMSO- d 6): δ ppm8.83 (s, 8H), 8.24 - 8.21 (m, 6H), 8.14 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 6.3Hz, 9H), 7.65 (d, J = 7.9 Hz, 2H), 4.37 (s, 2H), 4.10 (s, 2H), 4.01 (s, 2H), -2.92 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6): δ ppm δ 171.31, 141.22, 134.21,128.09, 126.99, 119.97, 31.12, 29.80, 28.97, 22.06, 13.93, 0.08. HRMS (MALDI-TOF): m / z calcd for C 50 H 37 N5O5 [M+H]+ ,788.2795; found, 788.2926.

[0032] [Example 11] 5-[4-(2-oxo-2-( N,N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 17 ) synthesis:

[0033] Compound I was prepared according to the synthetic method of compound I1 17 . 1 H NMR (600 MHz, DMSO- d 6): δ ppm8.85 (d, J = 18.8 Hz, 8H), 8.22 (d, J = 7.0 Hz, 6H), 8.16 (d, J = 7.7 Hz,2H), 7.83 (d, J = 7.4 Hz, 9H), 7.66 (d, J = 7.8 Hz, 2H), 4.12 (s, 2H), 3.81(t, J = 7.3 Hz, 2H), 3.60 (t, J = 7.3 Hz, 2H), 2.61 (dd, J = 15.0, 7.7 Hz, 4H), -2.91 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 170.83, 141.69, 134.68,128.56, 127.47, 120.47, 42.32, 29.45. HRMS (MALDI-TOF): m / z calcd for C 52 H 41 N5O5 [M+H] + ,816.3108; found, 816.4385.

[0034] [Example 12] 5-[4-(2-oxo-2-(2-oxo-4-carboxyl)butylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 18 ) synthesis:

[0035] Compound I was prepared according to the synthetic method of compound I1 18 . 1 H NMR (600 MHz, DMSO- d 6): δ ppm12.21 (s, 1H), 8.84 (d, J = 18.3 Hz, 8H), 8.23 – 8.21 (m, 6H), 8.16 (d, J =7.8 Hz, 2H), 7.83 (dd, J = 12.3, 4.8 Hz, 9H), 7.74 (d, J = 7.8 Hz, 2H), 4.15(d, J = 5.2 Hz, 2H), 3.89 (s, 2H), 2.75 (t, J = 6.2 Hz, 2H), 2.50 – 2.50 (m,2H), -2.90 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 174.16, 170.99, 141.69,139.75, 134.67, 128.55, 128.17, 127.46, 120.46, 49.16, 42.38, 34.64, 29.44,28.03, 22.54. HRMS (MALDI-TOF): m / z calcd for C 51 H 39 N5O4 [M+H] + ,786.3002;found, 786.8829.

[0036] [Example 13] 5-[4-(2-oxo-2-(3-aza-4-oxo)carboxyhexylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 19 ) synthesis:

[0037] Compound I was prepared according to the synthetic method of compound I1 19 . 1 H NMR (600 MHz, DMSO- d 6): δ ppm8.85 (d, J= 22.0 Hz, 8H), 8.22 (d, J = 6.5 Hz, 6H), 8.16 (d, J = 7.8 Hz,2H), 7.84 (dd, J = 9.3, 7.3 Hz, 9H), 7.71 (d, J = 7.8 Hz, 2H), 3.79 (s, 2H), 3.28 - 3.24 (m, 4H), 2.46 (t, J = 7.0 Hz, 2H), 2.37 (t, J = 7.0 Hz, 2H), -2.91 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6): δ ppm 170.79, 141.69, 134.68,128.56, 128.18, 127.47, 120.47, 42.77, 39.18, 38.92. HRMS (MALDI-TOF): m / z calcd for C 52 H 42 N6O4 [M+H] + ,815.3268; found, 815.2134.

[0038] [Example 14] 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 28 ) synthesis;

[0039] Compound I was prepared according to the synthetic method of compound I1 28 . 1 HNMR (400 MHz, DMSO- d 6 ) δ ppm:12.94 (s, 2H), 9.07 - 8.45 (m, 4H), 8.16-8.11 (m, 6H), 7.89 - 7.30 (m, 13H), 4.34 (d, J = 15.5 Hz, 2H), 3.64 - 3.57 (m, 2H), -2.95 (s, 2H). 13C NMR (151 MHz, DMSO- d 6): δ ppm171.65, 142.35, 133.57, 129.14, 128.45, 120.26, 41.02.HRMS (MALDI-TOF): m / z calcd for C 49 H 31 Br4N5O5 [M+2] + ,1090.9018; found,1090.8967.

[0040] [Example 15] 5-[[4-(1-( N,N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methoxy)phenylporphyrin (I 34 ) synthesis:

[0041] Compound I was prepared according to the synthetic method of compound I1 34 . 1 H NMR (600 MHz, DMSO- d 6): δ ppm13.28 (s, 2H), 8.84 (s, 8H), 8.35 (d, J = 22.1 Hz, 4H), 8.08 (s, 6H), 7.62(s, 6H), 3.60 (s, 4H), 3.32 (s, 9H), -2.92 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6): δ ppm 139.71, 139.42, 139.02, 138.66, 137.46, 137.28, 137.12, 137.08,135.56, 134.74, 134.62, 134.38, 127.58, 127.52, 127.46, 127.41, 120.80,119.89, 118.52, 118.25, 66.52, 54.21, 54.11. HRMS (MALDI-TOF): m / z calcd for C 52 H 41 N5O8[M+H] + , 864.2995; found, 864.2898.

[0042] [Example 16] 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tris(perfluorophenyl)porphyrin (I 35 ) synthesis:

[0043] Compound I was prepared according to the synthetic method of compound I1 35 . 1 H NMR (600 MHz, DMSO- d 6): δ ppm13.28 (s, 2H), 8.08 (d, 2H), 7.96 (d, J = 7.8 Hz, 2H), 7.81 (d, J = 7.8 Hz,2H), 7.34 (d, J = 5.8 Hz, 2H), 7.28 (d, J = 5.8 Hz, 2H), 7.62 (d, 2H), 3.60 (s, 4H), -2.82 (s, 2H). 13 C NMR (100 MHz, DMSO- d 6): δ ppm174.21, 169.60,146.68, 146.65,143.38 143.22, 142.53, 134.65, 134.40, 132.59, 130.21, 127.86,127.13, 120,18, 119.71, 107.78, 53.32, 53.18. HRMS (MALDI-TOF): m / z calcd for C 49 H 20 F 15 N5O5 [M+H] + ,1044.1225; found, 1044.1286.

[0044] [Example 17] Photodynamic antiproliferation experiment of photosensitizer on human esophageal cancer Eca-109 cells Test cells: human esophageal cancer cell line Eca-109.

[0045] Light source: MDL-III-650 laser; SD2490 laser power meter.

[0046] Test compound: 5-[[4-(1-( N,N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I1); 5-[[4-(1-( N,N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I2); 5-[[4-(1-(2-oxo-4-carboxyl)butylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I3); 5-[[4-(1-(dicarboxymethylene)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I4); 5-[[4-(1-(2-oxo-4-carboxyl)butylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I5); ) butylamino) formyl] phenyl] -10,15,20-tri(4-methyl) phenylporphyrin (I5); 5-[[4-(1-(3-aza-4-oxo) carboxyhexylamino) formyl] phenyl] -10,15,20-tri(4-methyl) phenylporphyrin (I6); 5-[[4-(1-(1-carboxy) carboxyethylamino) formyl] phenyl] -10,15,20-triphenylporphyrin (I7); 5-[[4-(1-( N,N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I8); 5-[[4-(1-( N,N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I9); 5-[4-(2-oxo-2-( N,N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 16 ); 5-[4-(2-oxo-2-( N,N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 17 ); 5-[4-(2-oxo-2-(2-oxo-4-carboxyl)butylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 18 ); 5-[4-(2-oxo-2-(3-aza-4-oxo)carboxyhexylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 19 );5-[[4-(1-( N,N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 28 );5-[[4-(1-( N,N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methoxy)phenylporphyrin (I 34 );5-[[4-(1-( N,N-dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tris(perfluorophenyl)porphyrin (I 35 ); Control compound 1, control compound 2, control compound 3 and control drug hemoporfin (provided by Shanghai Xianhui Pharmaceutical Technology Co., Ltd.).

[0047] Photodynamic therapy against tumor cell proliferation: The cells in the logarithmic growth phase were digested with trypsin and resuspended in complete medium to form a cell suspension. The suspension was inoculated into 96-well plates with 100 μL per well and cultured in a 37°C 5% CO2 incubator. After 24 hours of incubation, the tested photosensitizer was added for incubation at a final drug concentration of 5 μM. After 24 hours of drug incubation, the liquid in the wells was removed and the cells were irradiated with laser light (power 20 mW / cm 2 , wavelength 650 nm, light dose 8 J / cm 2 ), after treatment, complete culture medium was added and cultured in an incubator. The MTT assay was performed the next day. The liquid in the wells was discarded, 20 μL of 5 mg / mL MTT solution was added to each well, the liquid was removed after 4 hours of reaction, 150 μL of DMSO was added to dissolve the reaction product, and the OD value was detected at 570 nm by a microplate reader. The experiment was repeated three times. The experimental results are shown in Table 1. The results show that the tested AB3-type porphyrin compounds all had a certain inhibitory effect on human esophageal cancer cells, among which compounds I1, I2, I7, I8, and I 17 , I 28 , I 34 and I 35 The photodynamic anti-tumor activity is relatively excellent, and is significantly better than control compound 1, control compound 2, control compound 3 and control drug hemoporfin.

[0048] Table 1 Inhibitory effect of new compounds on the proliferation of Eca-109 human esophageal cancer cells Compound Drug concentration (μM) <![CDATA[Light dose (J / cm 2 )]]> Inhibition rate (%) <![CDATA[I1]]> 4 8 <![CDATA[86.42 ± 2.06 ***, ∆∆∆ ]]> <![CDATA[I2]]> 4 8 <![CDATA[88.07 ± 1.63 ***, ∆∆∆ ]]> <![CDATA[I3]]> 4 8 <![CDATA[85.64 ± 2.48 ***, ∆∆ ]]> <![CDATA[I4]]> 4 8 <![CDATA[84.22 ± 2.22 ***, ∆∆ ]]> <![CDATA[I5]]> 4 8 <![CDATA[85.13 ± 2.60 ***, ∆∆ ]]> <![CDATA[I6]]> 4 8 <![CDATA[79.46 ± 2.89 ***, ∆∆ ]]> <![CDATA[I7]]> 4 8 <![CDATA[90.38 ± 2.00 ***, ∆∆∆ <!-- 13 -->]]> <![CDATA[I8]]> 4 8 <![CDATA[86.64 ± 2.81 ***, ∆∆ ]]> <![CDATA[I9]]> 4 8 <![CDATA[84.22 ± 2.22 ***, ∆∆ ]]> <![CDATA[I 16 ]]> 4 8 <![CDATA[85.79 ± 2.08 ***, ∆∆ ]]> <![CDATA[I 17 ]]> 4 8 <![CDATA[86.94 ± 2.76 ***, ∆∆ ]]> <![CDATA[I 18 ]]> 4 8 <![CDATA[85.77 ± 2.45 ***, ∆∆ ]]> <![CDATA[I 19 ]]> 4 8 <![CDATA[84.07 ± 2.37 ***, ∆∆ ]]> <![CDATA[I 28 ]]> 4 8 <![CDATA[95.40 ± 2.23 ***, ∆∆ ]]> <![CDATA[I 34 ]]> 4 8 <![CDATA[88.37 ± 2.36 ***, ∆∆ ]]> <![CDATA[I 35 ]]> 4 8 <![CDATA[87.63 ± 2.17 ***, ∆∆ ]]> Control compound 1 4 8 10.03 ± 1.65 Control compound 2 4 8 25.82 ± 2.13 Control compound 3 4 8 11.34 ± 1.48 Heimporfen 4 8 41.92 ± 2.74 Blank control 0 0 0 Compared with the control drug hemoporfin,* p <0.05,** p <0.01,*** p <0.001; Compared with the antitumor effects of control compounds 1 and 2, ∆ p <0.05, ∆∆ p <0.01, ∆∆∆ p <0.001.

Claims

1. The present invention relates to a novel porphin compound and its application, which has the following characteristics (I):

2. Among them: -(CH2) n where n is 0 - 7; R 1 、R 2 The same or different and may independently be -(CH2) m COOH, -(CH2) m CO(CH2) n COOH, -(CH2) m NHCO(CH2) n COOH, -(CH2) m OH, -(CH2) m O(CH2O) m H, m=1-7, n=1-3; R 3 is -H, -F, -Cl, -Br, -I, -O(CH2) m Me, -(CH2) m CH3, -(CH2) m CH(CH3)2, -(CH2) m O(CH2) m CH3, -(CH2) m (OCH2CH2) p CH3, -(CH2) m CO(CH2) m CH3, m = 0 - 7, p = 1 - 3, q = 1 - 7; R 4 is -H, -Cl, -Br, -I.

3. The AB3-type porphyrin compound (I) according to claim 1, comprising: 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I1); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I2); 5-[[4-(1-(2-oxo-4-carboxy)butylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I3); 5-[[4-(1-(dicarboxymethylene)amino)formyl]phenyl]-10,15,20-triphenylporphyrin (I4); 5-[[4-(1-(2-oxo-4-carboxy)butylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I5); 5-[[4-(1-(3-aza-4-oxo)carboxyhexylamino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I6); 5-[[4-(1-(1-carboxy)carboxyethylamino)formyl]phenyl]-10,15,20-triphenylporphyrin (I7); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I8); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I9); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 10 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 11 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 12 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 13 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 14 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 15 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 16 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-triphenylporphyrin (I 17 ); 5-[4-(2-oxo-2-(2-oxo-4-carboxyl)butylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 18 ); 5-[4-(2-oxo-2-(3-aza-4-oxo)carboxyhexylamino)ethylphenyl]-10,15,20-triphenylporphyrin (I 19 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I 20 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-methyl)phenylporphyrin (I 21 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 22 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-fluoro)phenylporphyrin (I 23 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 24 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-chloro)phenylporphyrin (I 25 ); 5-[4-(2-oxo-2-( N , N -dicarboxymethyl)amino)ethylphenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 26 ); 5-[4-(2-oxo-2-( N , N -dicarboxyethyl)amino)ethylphenyl]-10,15,20-tri(4-bromo)phenylporphyrin (I 27 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrachloro-10,15,20-triphenylporphyrin (I 28 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetrachloro-10,15,20-triphenylporphyrin (I 29 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 30 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetrabromo-10,15,20-triphenylporphyrin (I 31 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-7,8,17,18-tetraiodo-10,15,20-triphenylporphyrin (I 32 ); 5-[[4-(1-( N , N -dicarboxyethyl)amino)formyl]phenyl]-7,8,17,18-tetraiodo-10,15,20-triphenylporphyrin (I 33 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tri(4-methoxy)phenylporphyrin (I 34 ); 5-[[4-(1-( N , N -dicarboxymethyl)amino)formyl]phenyl]-10,15,20-tris(perfluorophenyl)porphyrin (I 35 ).

4. The novel AB3-type porphyrin compound (Formula I) according to claim 1 can be used as a photodynamic therapy drug for diseases such as tumors, macular degeneration, actinic keratosis, port-wine stains, and condyloma acuminata.

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