Novel coumarin and thiophene modified dipyrroloboron complexes and their use in medicine

Abstract

This invention relates to a class of novel coumarin-thiophene-modified dipyrroleboron complexes (I) and (II) and their applications in the pharmaceutical field. Wherein X is H, Cl, Br, or I; R... 1 With R 2 They may be the same or different and independent of -H, -OH, -O(CH2). m CH3,-O(CH2) p COOH,-O(CH2) n OH,-(OCH2CH2) n OH,-O(CH2) m CH(CH3)OH,-O(CH2) m C6H4OH,-O(CH2) p N[(CH2) p COOH]2,-O(CH2) p N[(CH2) n OH]2,-O(CH2) p O(CH2) m COOH,-O(CH2) p O(CH2) n OH,-O(CH2) p (OCH2CH2) q OH,-O(CH2) m CO(CH2) m COOH,-O(CH2) m CO(CH2) m OH or amino acid derivatives; R 3 For,; Z=O,S,Se; R 4 The possible values ​​are -H, -F, -Cl, -Br, -OH, -O(CH2). m CH3,-(CH2) m CH3,-C(CH3)3,-(CH2) m COOH; m=0-7, n=2-7, p=1-7, q=1-5. This invention relates to the field of photosensitizing drugs and photodynamic therapy (PDT), specifically to a class of novel coumarin-thiophene-modified dipyrroleborane complexes with advantages such as structural stability, high photodynamic activity, and ease of preparation. These compounds can be used as photosensitizing drugs or reagents for the diagnosis and treatment of diseases such as tumors, port-wine stains, and condyloma acuminata, and can also be used as fluorescent dyes and reagents in near-infrared fluorescence imaging and fluorescent labeling.

Description

Technical Field

[0001] This invention relates to the field of photosensitizing drugs and photodynamic therapy, specifically to a novel coumarin and thiophene-modified dipyrroleboron complex and its applications. Background Technology

[0002] The mechanism of photodynamic therapy is that after a photosensitizer enters the body, it is delivered to specific cells. Under irradiation with a laser of a specific wavelength, the photosensitizer transitions from the ground state (S0) to the excited state (S1), and then further transitions to the triplet excited state (T1) through intersystem crossing. The photosensitizer in the triplet state reacts with surrounding molecules to produce highly reactive free radicals (O2⁻•, •OH) or singlet oxygen (ROS), which kill target cells and lead to tumor necrosis or apoptosis. Jpn. J. Cancer Res. 2000, 91(5), 560–565 ; Oral Oncology. 2024, 9, 100129 This method has advantages over existing conventional tumor treatments, such as less invasiveness, fewer side effects, and faster recovery, and has great potential for development in the diagnosis and treatment of tumors.

[0003] Bipyrroleboryl complexes (BODIPY) are organic fluorescent dyes that have been extensively studied due to their excellent photophysical and photochemical properties. Current research primarily focuses on fluorescent molecules, with less emphasis on photodynamic therapy. The basic BODIPY molecule has a small core (compound 1), resulting in a short absorption wavelength (490 nm) and low emission intensity, which severely limits its application as a fluorescent probe. J. Am. Chem. Soc. , 127(35), 12162-12163; 2005). Vicente et al. prepared β The BODIPY dye molecule (compound 2) with a conjugated benzene ring increases the UV-Vis absorption and emission wavelengths to 630 nm and 650 nm, respectively, exhibiting strong fluorescence performance in cell fluorescence imaging but weak photodynamic activity. Chem. Eur. J. , 2012, 18, 3893-3905). In order to improve the singlet oxygen yield of BODIPY molecules, Samuel et al. chose to introduce thiophene-pyrrole BODIPY molecules to prepare compound 3, which has certain photodynamic effects and a maximum absorption wavelength of 610 nm ( Journal of Materials Chemistry B : 6(5), 753-762;2018). Our research group, including Cao Ning et al., prepared BODIPY molecules containing thiophene and thiophenepyrrole (compound 4). The maximum absorption wavelength of the compound reached 660 nm, and the photodynamic activity was significantly improved. European Journal of Medicinal Chemistry , 264 (2024), 116012).

[0004]

[0005] Currently, there are no marketed drugs containing dipyrrole boron complexes. Their main limitation lies in the short UV-Vis absorption wavelength of traditional BODIPY dye molecules, resulting in weak tissue penetration. Furthermore, their high hydrophobicity leads to non-specific adsorption and aggregation in vivo, causing poor biocompatibility and limiting their application in in vivo imaging and therapy. Therefore, significant structural modification and alteration of these compounds are necessary. To find superior BODIPY photosensitizers, after reviewing extensive literature, we conducted further structural modification and optimization, selecting coumarin derivatives with electron-donating groups as electron donors to obtain novel thiophene [3,2- b Thiophene-based BODIPY derivatives. Due to the introduction of coumarin derivative groups, these compounds exhibit a significant UV-Vis absorption region at 630-750 nm, resulting in significantly improved photodynamic activity. These compounds possess advantages such as structural stability, good hydrophilicity, and the ability to prevent aggregation, making them potential candidates for photodynamic therapy of diseases such as tumors, macular degeneration, actinic keratosis, port-wine stains, and condyloma acuminata.

[0006] The novel coumarin-thiophene-modified dipyrroleboron complex has high molar absorptivity, high fluorescence quantum yield and fluorescence lifetime, as well as good photothermal stability. Therefore, it can also play an application role in near-infrared fluorescent probes, cell imaging and tracing, protein and DNA labeling and other fields. Summary of the Invention

[0007] To overcome the shortcomings of existing photosensitizing drugs, such as short ultraviolet-visible absorption wavelength, weak absorption, and poor photodynamic activity, this invention designs and synthesizes a class of coumarin and thiophene-modified dipyrroleboron complexes. These compounds have strong photostability and are easy to prepare. This invention was completed after a great deal of creative work.

[0008] This invention relates to a novel coumarin-thiophene modified dipyrroleboron complex with high molar absorptivity, high photodynamic activity, and good hydrophilicity, and its applications.

[0009] The invention is summarized as follows: A new class of coumarin and thiophene-modified BODIPY derivatives have the following structures (I) and (II):

[0010] Where X is H, Cl, Br or I; R 1 With R 2 They may be the same or different and independent of -H, -OH, -O(CH2). m CH3, -O(CH2) pCOOH, -O(CH2) n OH,-(OCH2CH2) n OH, -O(CH2) m CH(CH3)OH, -O(CH2) m C6H4OH, -O(CH2) p N[(CH2) p COOH]2, -O(CH2) p N[(CH2) n OH]2, -O(CH2) p O(CH2) m COOH, -O(CH2) p O(CH2) n OH, -O(CH2) p (OCH2CH2) q OH, -O(CH2) p CO(CH2) q COOH, -O(CH2) p CO(CH2) q OH or amino acid derivatives; R 3 for , Z = O, S, Se; R 4 The possible values ​​are -H, -F, -Cl, -Br, -OH, and -O(CH2). m CH3, -(CH2) m CH3, -C(CH3)3, -(CH2) m COOH; m = 0-7, n = 2-7, p = 1-7, q = 1-5.

[0011] The amino acid derivatives mentioned above are: -O(CH2) m CONH(CH2) n COOH, -O(CH2) m CONHCH(CH3)COOH, -O(CH2) m CONH(CH2) n CO(CH2) p COOH, -O(CH2) m CONHCH[CH(CH3)2]COOH, -O(CH2) m CONHCH[CH2CH(CH3)2]COOH, -O(CH2)m CONHCH[CH(CH3)CH2CH3]COOH, -O(CH2) m CONHCH(CH2C6H5)COOH, -O(CH2) m CON[(CH2) n COOH]2, -O(CH2) m CONHCH(COOH)CH2COOH, m=1-7, n=1-7, p=1-5.

[0012] According to the present invention, a class of coumarin and thiophene-modified dipyrroleboron complexes (I) and (II) are characterized in that the class of compounds includes the following compounds: 13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I1); 13-[3-(7-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I2); 13-[3-(7-methoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I3); 13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I4); 13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I5); 13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2 H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I6); 13-[3-(7-carboxymethoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I7); 13-[3-(6-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I8) 3,9-Dibromo-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I9); 3,9-Diiodo-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 10 ); 3,9-Dibromo-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 11 ); 3,9-Diiodo-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H-chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 12 ); 3,9-Dibromo-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 13 ) 3,9-Diiodo-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 14 ) 3,9-Dibromo-13-[3-(7-carboxymethoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 15 ); 3,9-Diiodo-13-[3-(7-carboxymethoxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 16 ); 3,9-Diphenyl-13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2-g]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II1); 3,9-Diphenyl-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3-b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II2); 3,9-Diphenyl-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II3); 3,9-Diphenyl-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II4); 3,9-Diphenyl-13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II5).

[0013] Specific preparation scheme The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0014] 13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I1)

[0015] Compound II (200 mg, 1.12 mmol) and 3-formylcoumarin (97 mg, 0.56 mmol) were added to a single-necked flask, and DCM (30 mL) was added. Under argon atmosphere, 2 drops of trifluoroacetic acid were added dropwise, and the mixture was stirred at room temperature for 24 hours. Then, DDQ (127 mg, 0.56 mmol) was added, and stirring was continued for 30 minutes. Triethylamine (1.5 mL) and boron trifluoride diethyl ether solution (2 mL) were added sequentially, and stirring was continued for 3 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), extracted with dichloromethane (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The mixture was purified by column chromatography (DCM:PE = 1:1) to give a dark green solid I1 (68 mg, 21.6%). 1 H NMR (600 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.17 (d, J = 5.1 Hz, 2H), 7.86 (dd, J = 7.7, 1.6 Hz, 1H),7.81 – 7.74 (m, 1H), 7.61 – 7.56 (m, 5H), 7.48 (t, J = 7.5 Hz, 1H). 13 C NMR (151 MHz, DMSO-) d 6) δ 159.78, 154.51, 152.64, 150.05, 146.74, 139.94, 137.89,136.53, 135.19, 133.65, 129.83, 125.30, 123.45, 123.08, 122.40, 121.00,119.23, 116.82. 19 F NMR (565 MHz, DMSO- d 6) δ -146.73 (dd, J = 66.8, 32.0 Hz,2F). HRMS (ESI): m / z calcd for C 26 H 11 BF2N2O2S4Na [M + Na] + : 582.9663; found:582.9662.

[0016] 13-[3-(7-hydroxy-2-oxo-2-] H-chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I2)

[0017] Compound II (200 mg, 1.12 mmol) and 3-formyl-7-acetylcoumarin (130 mg, 0.56 mmol) were added to a single-necked flask, and DCM (30 mL) was added. Under argon atmosphere, 2 drops of trifluoroacetic acid were added dropwise, and the mixture was stirred at room temperature for 24 hours. Then, DDQ (127 mg, 0.56 mmol) was added, and the mixture was stirred for another 30 minutes. Triethylamine (1.5 mL) and boron trifluoride diethyl ether solution (2 mL) were added sequentially, and the mixture was stirred for another 3 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), extracted with dichloromethane (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The mixture was purified by column chromatography (DCM : PE = 1:1) to give a dark green solid (78 mg).

[0018] The solid (78 mg, 0.126 mmol) was added to a single-necked flask and dissolved in DCM / MeOH (v / v=3:1). Sodium methoxide (13.6 mg, 0.252 mmol) was added and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure and purified by column chromatography to obtain compound I2 (62 mg, 19.1%). 1 H NMR (600 MHz, DMSO- d 6) δ 10.93 (s, 1H), 8.42 (s, 1H), 8.15 (d, J =5.1 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 5.1 Hz, 2H), 7.53 (s,2H), 6.91 (dd, J = 8.3, 2.1 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H). 13 C NMR (151MHz, DMSO- d6) δ 163.17, 160.10, 156.65, 152.44, 149.80, 147.13, 140.00,137.66, 136.38, 136.17, 131.41, 123.40, 123.10, 122.33, 116.05, 114.20,111.77, 102.59. 19 F NMR (565 MHz, DMSO- d 6) δ -146.77 (dd, J = 64.0, 32.3 Hz,2F). HRMS (ESI): m / z calcd for C 26 H 10 BF2N2O3S4 [M – H] – : 574.9635; found:574.9641.

[0019] 13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I4)

[0020] Compound I4 was prepared using the same synthetic method as compound I1.

[0021] 1 H NMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.15 (d, J = 5.2 Hz, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.61 – 7.52 (m, 4H), 7.17 (d, J = 2.3 Hz, 1H), 7.07(dd, J = 8.7, 2.4 Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 4.18 (t, J = 4.8 Hz, 2H), 3.78 (q, J = 4.9 Hz, 2H). 19F NMR (377 MHz, DMSO- d 6) δ -146.75 (dd, J =64.4, 29.7 Hz, 2F). HRMS (ESI): m / z calcd for C 28 H 15 BF2N2O4S4 [M] – : 619.9976;found: 619.9976.

[0022] 13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I5)

[0023] Compound I5 was prepared using the same synthetic method as compound I1.

[0024] 1 H NMR (400 MHz, DMSO- d 6) δ 8.45 (s, 1H), 8.14 (d, J = 5.1 Hz, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 5.2 Hz, 2H), 7.54 (s, 2H), 7.18 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 1H), 4.67 (t, J = 5.0 Hz, 1H), 4.28(t, J = 4.3 Hz, 2H), 3.83 – 3.76 (m, 2H), 3.52 (d, J = 4.4 Hz, 4H). 13 C NMR (151 MHz, DMSO-) d6) δ 163.34, 160.02, 156.53, 152.51, 149.88, 139.98, 137.73,136.42, 135.85, 131.02, 123.42, 123.10, 122.36, 117.16, 113.84, 112.83,101.55, 72.97, 69.11, 68.76, 60.69. 19 F NMR (565 MHz, DMSO- d 6) δ -146.75 (dd, J = 67.1, 32.4 Hz, 2F). HRMS (ESI): m / z Calculated for C 30 H 19 BF2N2O5S4 [M] – :664.0238; found: 664.0237.

[0025] 13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I6) Compound I7 was prepared using the same synthetic method as compound I1.

[0026] 1 H NMR (400 MHz, DMSO- d 6) δ 13.07 (brs, 1H), 8.46 (s, 1H), 8.16 (d, J = 5.2 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 6.4 Hz, 4H), 7.14 (s,1H), 7.08 (d, J = 8.8 Hz, 1H), 4.90 (s, 2H). 19 F NMR (377 MHz, DMSO- d 6) δ -146.75 (dd, J= 63.9, 31.9Hz, 2F). HRMS (ESI): m / z Calculated for C 28 H 12 BF2N2O5S4 [M – H] – : 632.9690; found: 632.9701. [Example 7] 13-[3-(6-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I8)

[0027] Compound I8 was prepared using the same method as compound I2.

[0028] 1 H NMR (600 MHz, DMSO- d 6) δ 10.92 (s, 1H), 8.32 (s, 1H), 8.13 (d, J =5.1 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 5.1 Hz, 2H), 7.52 (s,2H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H). 13 C NMR (151MHz, DMSO- d 6) δ 163.11, 160.10, 156.62, 152.42, 149.76, 147.12, 139.96,137.61, 136.36, 136.15, 131.40, 123.36, 123.05, 122.28, 116.01, 114.18,111.73, 102.51. 19 F NMR (565 MHz, DMSO- d 6) δ -146.76 (dd, J = 64.0, 32.2 Hz,2F). HRMS (ESI): m / zcalcd for C 26 H 10 BF2N2O3S4 [M – H] – : 574.9635; found: 574.9645. [Example 8] 3,9-Dibromo-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I9)

[0029] Compound a (200 mg, 1.12 mmol) and 3-formyl-7-acetylcoumarin (130 mg, 0.56 mmol) were added to a single-necked flask, and DCM (30 mL) was added. Under argon atmosphere, 2 drops of trifluoroacetic acid were added dropwise, and the mixture was stirred at room temperature for 24 hours. Then, DDQ (127 mg, 0.56 mmol) was added, and the mixture was stirred for another 30 minutes. Triethylamine (1.5 mL) and boron trifluoride diethyl ether solution (2 mL) were added sequentially, and the mixture was stirred for another 3 hours. The reaction was confirmed to be complete by TLC. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), extracted with dichloromethane (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The mixture was purified by column chromatography (DCM : PE = 1:1) to give a dark green solid (78 mg).

[0030] The solid (78 mg, 0.126 mmol) was dissolved in 20 mL of dichloromethane in a single-necked flask. NBS (47.1 mg, 0.264 mmol) was added, and the mixture was stirred at room temperature for 10 h. The reaction was monitored by TLC until complete. The reaction was quenched with sodium thiosulfate solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain 90 mg of crude product for the next step. The crude product was dissolved in DCM / MeOH (v / v = 3:1) in a single-necked flask. Sodium methoxide (13.6 mg, 0.252 mmol) was added, and the mixture was stirred at room temperature for 20 min. The solvent was removed by vacuum removal, and column chromatography was used to purify compound I9 (45 mg, overall yield 10.9%). ¹H NMR (400 MHz, DMSO-) d 6) δ 10.94 (s, 1H), 8.42 (s, 1H), 7.85 (s, 2H), 7.68 (d, J= 8.7 Hz,1H), 7.58 (s, 2H), 6.90 (dd, J = 8.5, 2.3 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H). 19 FNMR (377 MHz, DMSO- d 6) δ -146.74 (dd, J = 64.6, 32.8 Hz, 2F). HRMS (ESI): m / z Calculated for C 26 H8BF2Br2N2O3S4[M – H] – : 732.7825; found 732.7850. [Example 9] 3,9-Diiodo-13-[3-(7-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 10 )

[0031] Compound I was prepared using the same synthetic method as compound I9. 10 . 1 H NMR (600 MHz, DMSO- d 6) δ 10.94(s, 1H), 8.42 (s, 1H), 7.89 (s, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.55 (s, 2H), 6.90 (dd, J = 8.5, 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 163.23, 159.96, 156.64, 152.43, 148.14, 147.17, 140.23, 136.30,136.00, 132.27, 131.43, 127.24, 122.65, 116.03, 114.22, 111.75, 102.58,90.28.19 F NMR (565 MHz, DMSO- d 6) δ -146.85 (dd, J = 66.0, 32.2 Hz, 2F). HRMS(ESI): m / z Calculated for C 26 H8BF2I2N2O3S4 [M] + : 827.7646; found 827.7651.

[0032] 3,9-Diphenyl-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II2)

[0033] Compound II2 was prepared using the same method as compound I2.

[0034] 1 H NMR (600 MHz, DMSO- d 6) δ 10.92 (s, 1H), 8.48 (s, 1H), 8.10 (s, 2H), 7.89 (d, J = 7.5 Hz, 4H), 7.75 (d, J = 8.7 Hz, 1H), 7.55 (s, 2H), 7.53 (t, J = 7.5 Hz, 4H), 7.47 (t, J = 7.2 Hz, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.6, 2.4 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 163.30, 160.01, 156.42,153.79, 153.20, 149.44, 140.47, 136.31, 133.52, 130.91, 129.90, 126.21,121.42, 119.70, 101.44. 19F NMR (565 MHz, DMSO- d 6) δ -145.85 (dd, J = 63.3,32.0 Hz, 2F). HRMS (ESI): m / z Calculated for C 38 H 19 BF2N2O5S4 [M] + : 728.0340;found: 728.0338.

[0035] [Example 11] 3,9-Diphenyl-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-Difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II4)

[0036] Compound II4 was prepared using the same method as compound I2.

[0037] 1 H NMR (600 MHz, DMSO- d 6) δ 8.49 (s, 1H), 8.10 (s, 2H), 7.88 (d, J =7.5 Hz, 4H), 7.77 (d, J = 8.7 Hz, 1H), 7.56 (s, 2H), 7.54 (t, J = 7.5 Hz, 4H), 7.47 (t, J = 7.2 Hz, 2H), 7.21 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 4.30 (t, J = 4.4 Hz, 2H), 3.84 – 3.81 (m, 2H), 3.54 (dq, J =8.2, 4.2 Hz, 4H). 13 C NMR (151 MHz, DMSO- d6) δ 163.33, 160.06, 156.54, 153.83,153.22, 149.46, 140.59, 136.37, 133.60, 131.01, 129.96, 126.27, 121.51,119.84, 101.54, 72.98, 69.11, 68.76, 60.69. 19 F NMR (565 MHz, DMSO- d 6) δ -145.55 (dd, J = 63.5, 32.0 Hz, 2F). HRMS (ESI): m / z Calculated for C 42 H 27 BF2N2O5S4 [M] + : 816.0864; found: 816.0867.

[0038] Photodynamic antiproliferative assay of photosensitizer on human esophageal cancer Eca-109 cells Test cells: human esophageal cancer cells Eca-109.

[0039] Light source: MDL-III-650 laser; SD2490 laser power meter.

[0040] Test compound: 13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I1); 13-[3-(7-hydroxy-2-oxo-2- H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I2); 13-[3-(7-(2-hydroxyethoxy)-2-oxo-2 H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I4); 13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2 H-chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I5); 13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2 H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I6); 13-[3-(7-carboxymethoxy-2-oxo-2- H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I7); 3,9-dibromo-13-[3-(7-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I8); 3,9-diiodo-13-[3-(7-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I9); 3,9-diphenyl-13-[3-(7-hydroxy)-2-oxo-2 H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene(II2)3,9-diphenyl-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2 H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II4); compound 4 and the control drug temopofen (provided by Shanghai Xianhui Pharmaceutical Technology Co., Ltd.).

[0041] Photodynamic antitumor cell proliferation experiment: Cells in the logarithmic growth phase were digested with trypsin, resuspended in complete culture medium, and seeded into 96-well plates at 100 µL per well. The plates were then incubated at 37°C with 5% CO2 for 24 hours. After incubation, the tested photosensitizer was added at a final concentration of 5 μM. Following 24 hours of incubation, the liquid in the wells was removed, and the cells were then subjected to laser irradiation (50 mW / cm²). 2 Wavelength 650 nm, light dose 4 J / cm 2 After treatment, the culture medium was added to a complete culture medium and incubated for further growth. MTT assay was performed the following day. The liquid in each well was discarded, and 20 μL of 5 mg / mL MTT solution was added. After reacting for 4 hours, the liquid was removed, and 150 µL of DMSO was added to dissolve the reaction product. The OD value was measured at 490 nm using a microplate reader. The experiment was repeated three times.

[0042] The experimental results are shown in Table 1. The results showed that the tested compounds had a certain inhibitory effect on human esophageal cancer cells. Among them, compounds I4, I5 and I6 had excellent photodynamic antitumor activity, which was significantly better than the control drug temopofen.

[0043] Table 1. Inhibitory effect of the new compound on the proliferation of Eca-109 human esophageal cancer cells. <![CDATA[I1]]> 62.5 4 <![CDATA[5.07 ± 2.78 **∆ ]]> <![CDATA[I2]]> 62.5 4 <![CDATA[84.53 ± 1.68 ***∆∆ ]]> <![CDATA[I4]]> 62.5 4 <![CDATA[54.09 ± 4.28 ***∆∆ ]]> <![CDATA[I5]]> 62.5 4 <![CDATA[87.30 ± 0.79 ***∆∆∆ ]]> <![CDATA[I6]]> 62.5 4 <![CDATA[75.70 ± 7.74 ***∆∆∆ ]]> <![CDATA[I7]]> 62.5 4 8.99 ± 2.55 <![CDATA[I8]]> 62.5 4 <![CDATA[49.36 ± 8.68 ***∆∆ ]]> <![CDATA[I9]]> 62.5 4 2.98 ± 2.00 <![CDATA[I 10 ]]> 62.5 4 5.04 ± 2.42 <![CDATA[II2]]> 62.5 4 5.06 ± 2.18 <![CDATA[II4]]> 62.5 4 9.51 ± 2.00 Temopofen 62.5 4 6.60 ± 3.23 Compound 4 62.5 4 29.23 ± 2.42 Blank control 0 4 0 Compared with the control drug temopofen,* p <0.05,** p <0.01, *** p <0.001 Compared with control drug compound 4, ∆ P <0.05, ∆∆ P <0.01, ∆∆∆ P <0.001.

Claims

1. A novel class of coumarin-thiophene-modified dipyrroleboron complexes and their applications. Their characteristics are... It has the following structures (I) and (II):

2. Where X is H, Cl, Br, or I; R 1 With R 2 They may be the same or different and independent of -H, -OH, -O(CH2). m CH3, -O(CH2) p COOH, -O(CH2) n OH, -(OCH2CH2) n OH, -O(CH2) m CH(CH3)OH, -O(CH2) m C6H4OH, -O(CH2) p N[(CH2) p COOH]2, -O(CH2) p N[(CH2) n OH]2, -O(CH2) p O(CH2) m COOH, -O(CH2) p O(CH2) n OH, -O(CH2) p (OCH2CH2) q OH,-O(CH2) m CO(CH2) m COOH, -O(CH2) m CO(CH2) m OH or amino acid derivatives; R 3 for , ;Z=O, S, Se; R 4 The possible values ​​are -H, -F, -Cl, -Br, -OH, and -O(CH2). m CH3, -(CH2) m CH3, -C(CH3)3, -(CH2) m COOH; m = 0-7, n = 2-7, p = 1-7, q = 1-5.

3. The amino acid derivative mentioned in claim 1 is: -O(CH2) m CONH(CH2) n COOH, -O(CH2) m CONHCH(CH3)COOH, -O(CH2) m CONH(CH2) n CO(CH2) p COOH, -O(CH2) m CONHCH[CH(CH3)2]COOH, -O(CH2) m CONHCH[CH2CH(CH3)2]COOH, -O(CH2) m CONHCH[CH(CH3)CH2CH3]COOH, -O(CH2) m CONHCH(CH2C6H5)COOH, -O(CH2) m CON[(CH2) n COOH]2,-O(CH2) m CONHCH(COOH)CH2COOH, m=1-7, n=1-7, p=1-5。 4. The novel coumarin and thiophene-modified dipyrroleboron complexes (I) and (II) according to claim 1, characterized in that... This class of compounds includes the following compounds: 13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2-g]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I1); 13-[3-(7-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I2); 13-[3-(7-methoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I3); 13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I4); 13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I5); 13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I6); 13-[3-(7-carboxymethoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I7); 13-[3-(6-hydroxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I8); 3,9-Dibromo-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (I9); 3,9-Diiodo-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 10 ); 3,9-Dibromo-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 11 ); 3,9-Diiodo-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 12 ); 3,9-Dibromo-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 13 ) 3,9-Diiodo-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 14 ) 3,9-Dibromo-13-[3-(7-carboxymethoxy-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 15 ); 3,9-Diiodo-13-[3-(7-carboxymethoxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenpateene (I 16 ); 3,9-Diphenyl-13-[3-(2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2-g]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II1); 3,9-Diphenyl-13-[3-(7-hydroxy-2-oxo-2-]] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II2); 3,9-Diphenyl-13-[3-(7-(2-hydroxyethoxy)-2-oxo-2-] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II3); 3,9-Diphenyl-13-[3-(7-(2-(2-hydroxyethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II4); 3,9-Diphenyl-13-[3-(7-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-2-oxo-2] H -chromene)]-Di[thiophene[2',3':4,5]thiophene][2,3- b ]-[3,2- g ]-6,6-difluoro-6-boron-3a,4a-diaza-s-indenotetraene (II5).

5. The novel coumarin and thiophene-modified dipyrroleboron complexes (I) and (II) according to claim 1 can be used to prepare drugs for treating diseases such as tumors, macular degeneration, actinic keratosis, port-wine stains, and condyloma acuminata; they can also be used as near-infrared fluorescent dyes in near-infrared fluorescence imaging, fluorescent labeling, or optoelectronic materials.

Images