2-phenylnaphthalene derivatives and their use in the preparation of an anti-hepatoma drug

Abstract

The application discloses a 2-phenyl naphthalene derivative and application thereof in preparation of an anti-hepatoma drug. The application provides some 2-phenyl naphthalene derivatives as human ribonucleotide reductase inhibitors, and the structure is shown as formula (I). Experiments prove that the 2-phenyl naphthalene derivative has obvious human ribonucleotide reductase inhibiting activity and effective anti-hepatoma effect, and provides a new selection for development and application of the anti-hepatoma drug based on inhibiting human ribonucleotide reductase activity.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis drugs, and in particular to a class of 2-phenylnaphthalene derivatives and applications thereof in the preparation of anti-liver cancer drugs. Background Art

[0002] Ribonucleotide reductase (RR) is a multiproteinase composed of two subunits: the large subunit RR1 and the small subunit RR2. RR is a crucial enzyme present in all organisms, catalyzing the rate-limiting step in the synthesis of deoxynucleoside triphosphates (dNTPs), converting ribonucleotide substrates into their respective deoxyribonucleotide forms. Because RR is the sole pathway for dNTP production, it plays a crucial role in maintaining the balance of intracellular nucleotide pools and the integrity of DNA synthesis. RR expression is elevated during the S phase of the cell cycle, when DNA synthesis occurs, making RR an important target for the treatment of proliferative diseases. Over the past two to three decades, drugs targeting RR have been extensively designed to treat bacterial and viral diseases, as well as various types of cancer. Most anticancer drugs targeting RR are nucleoside analogs that mimic RR's natural substrates. The most successful antimetabolite is gemcitabine, one of the few drugs clinically used for the treatment of pancreatic cancer. However, antimetabolites such as gemcitabine bind to numerous off-target enzymes involved in DNA synthesis and repair, leading to toxic side effects. Furthermore, gemcitabine irreversibly inhibits RR by alkylating cysteine ​​residues in the active region, which is partly responsible for the drug's low therapeutic index. Therefore, developing novel, highly effective, low-toxic, and safe RR-selective inhibitors for the treatment of RR-related cancers has significant social significance and promise.

[0003] Phenylnaphthalene derivatives are a class of compounds with diverse biological activities. R.E. Mussaud et al. discovered that 2-phenylnaphthalene derivatives can act as estrogen receptor (ER) modulators, thereby treating inflammatory diseases such as inflammatory bowel disease and Crohn's disease (Application No.: CN 02824736.1). J.E. Merrill discovered a class of phenylnaphthalene compounds with no affinity for either α- or β-ER, and applied them to the treatment of multiple sclerosis (Application No.: CN 200580045445.0). Rolf Hartmann et al. discovered that 2-phenylnaphthalene compounds can be used as 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-related diseases (Publication No.: US2010 / 0204234 Al). Furthermore, Shen Yuemao et al. discovered that a class of 2-phenylnaphthalene derivatives can be used in the development of anti-breast cancer drugs (Application No.: CN 201310125493.7). However, there are currently no reports of 2-phenylnaphthalene as a RR inhibitor, nor are there reports of this class of compounds being used to prepare anti-liver cancer drugs. It is necessary to explore the use of 2-phenylnaphthalene derivatives as new RR inhibitors and their application in the treatment of liver cancer, providing a solid experimental foundation for the further development of specific small molecule anti-liver cancer drugs targeting RR. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a new type of 2-phenylnaphthalene derivatives as human ribonucleotide reductase (hRR) inhibitors and the use of the 2-phenylnaphthalene derivatives in the preparation of anti-liver cancer drugs.

[0005] A class of 2-phenylnaphthalene derivatives, the structural formula of which is shown in formula (I):

[0006]

[0007] Where: R 1 For hydrogen, hydroxyl, methoxy,

[0008] R 2 For hydrogen, hydroxyl, methoxy,

[0009] R 3 is hydrogen, hydroxyl, methoxy;

[0010] R 4 is hydrogen, hydroxyl, methoxy;

[0011] R 5 is hydrogen, hydroxyl, methoxy;

[0012] Preferably, the present invention provides the following compound examples:

[0013]

[0014]

[0015] The compound of the present invention can be prepared by conventional methods. Preferably, it can be prepared by the following method: The preparation method of the 2-phenylnaphthalene derivative represented by formula (I) is as follows:

[0016]

[0017] The compounds of the present invention can be prepared into pharmaceutically acceptable salts, preferably hydrochlorides, sulfates, nitrates or phosphates.

[0018] The compound of the present invention can be used as a human ribonucleotide reductase inhibitor and has an effective anti-liver cancer effect.

[0019] The present invention also provides a pharmaceutical composition comprising an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof. The compound of the present invention can be prepared into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, gels, finely divided powders or aerosols or sprays for inhalation, sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral administration (including intravenous, intramuscular or infusion).

[0020] The active ingredient of the pharmaceutical composition of the present invention may be the compound of the present invention alone, or may be a combination of the compound and other anti-tumor compounds as the active ingredient.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] The compound of the present invention has obvious human ribonucleotide reductase inhibitory activity and effective anti-liver cancer effect, providing a new option for the development and application of anti-liver cancer drugs based on inhibiting human ribonucleotide reductase activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The purpose of this study was to determine the effects of 2-phenylnaphthalene derivatives on the cell cycle and apoptosis of different liver cancer cells using flow cytometry.

[0024] Figure 2 This is a nude mouse transplant tumor experiment. DETAILED DESCRIPTION

[0025] The compounds of the present invention

[0026] The specific implementation methods of the present invention are further described below in conjunction with examples, but the present invention is not limited to the scope of the examples.

[0027] Example 1 Preparation of 6-(3-methoxyphenyl)-2-naphthol (HP13)

[0028] 6-Bromo-2-naphthol (1 g, 4.48 mmol) and 3-methoxyphenylboronic acid (681 mg, 4.48 mmol) were dissolved in an appropriate amount of toluene. Tetrakis(triphenyl)phosphine palladium (518 mg, 0.448 mmol) and 1 ml of 2% Na2CO3 aqueous solution were added. The mixture was stirred at 80°C under N2 protection for 18 hours. After completion of the reaction, the toluene was removed by rotary evaporation under reduced pressure, and the mixture was extracted three times with ethyl acetate and water. The ethyl acetate layer was dried and loaded onto a column. Compound HP13 was purified by silica gel column chromatography to yield a white solid in a 40% yield. Melting point: 93.6-94.5°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.81(1H,s,6-OH),8.09(1H,s,H-1),7.84(1H,d,J=8.8Hz,H-8),7.77-7.70(2H,m,H-3 ,H-4),7.41-7.28(3H,m,H-2',H-5',H-6'),7.14-7.09(2H,m,H-5,H-7),6.94-6.91(1H,m,H-4'),3.843(3H,s,3'-OC H 3). 13 CNMR(100MHz,DMSO-d6)δ(ppm):159.7,155.5,141.7,134.1,133.9,129.9,129.8,127.8, 126.5,125.2,125.2,119.0,118.9,112.6,112.0,108.4,55.0.HRMS(ESI,m / z)calcd.forC 17 H 14 O2(MH) - 249.0921, found 249.0936.

[0029] Example 2 Preparation of 6-(3,4-dimethoxyphenyl)-2-naphthol (HP15)

[0030] Compound HP15 was synthesized similarly to HP13. Its physical and chemical properties are as follows: white solid, yield: 46%, melting point: 173.9-174.7°C. 1H NMR (400MHz, CDCl3) δ (ppm): 7.92 (1H, s, H-1), 7.80 (1H, d, J = 8.4Hz, H-8), 7.73 (1H, d, J = 8.4Hz, H-4), 7.67 (1H, dd, J1 = 8.4Hz, J2 = 1.6Hz, H-3), 7.2 6-7.23(1H,m,H-6'),7.22(1H,s,H-5),7.17(1H,s,H-2'),7.13(1H,dd,J 1=8.8Hz,J2=2.4Hz,H-7),6.98(1H,d,J=8.4Hz,H-5'),3.98(3H,s,3'-OC H 3),3.94(3H,s,4'-OC H 3). 13 C NMR (100MHz, CDCl3) δ (ppm): 153.4,149.1,148.4,136.2,134.2,133.5,130.0,129.1,126 .8,126.1,125.1,119.5,118.2,111.5,110.5,109.3,56.0×2.HRMS(ESI,m / z)calcd.forC 18 H 16 O3(MH) - 279.1027, found 279.1040.

[0031] Example 3 Preparation of 4-(2-naphthyl)phenol (HP24)

[0032] Compound HP24 was synthesized similarly to HP13. Its physical and chemical properties are as follows: pale yellow solid, yield: 66%, melting point: 163.1-163.8°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.63(1H,s,4'-OH),8.10(1H,s,H-1),7.93(2H,d,J=8.4Hz,H-4,H-5),7.89(1H,d,J=7.6Hz,H-8),7.78 (1H,dd,J1=8.8Hz,J2=1.6Hz,H-3),7.64(2H,d,J=8.8Hz,H-2',H-6'),7.52-7.45(2H,m,H-6,H-7),6.90(2H,d,J=8.4Hz,H-3',H-5'). 13C NMR(100MHz,DMSO-d6)δ(ppm):157.2,137.5,133.4,131.6,130.6,128.2,128.0× 2,127.9,127.4,126.2,125.5,124.8,123.8,115.8×2.HRMS(ESI,m / z)calcd.for C 16 H 12 O(MH) - 219.0815, found 219.0835.

[0033] Example 4 Preparation of 4-(6-methoxynaphthalen-2-yl)phenol (HP26)

[0034] Compound HP26 was synthesized similarly to HP13. Its physical and chemical properties are as follows: pale yellow solid, yield: 55%, melting point: 209.4-210.1°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.55(1H,s,4'-OH),8.02(1H,s,H-1),7.84(2H,dd,J1=8.8Hz,J2=3.2Hz,H-4,H-8),7.72(1H,dd,J1=8.4Hz,J2=1.6Hz,H-3) ,7.60(2H,d,J=8.4Hz,H-2',H-6'),7.31(1H,d,J=2.4Hz,H-5),7.16(1H,dd,J 1=8.8Hz,J2=2.4Hz,H-7),6.88(2H,d,J=8.4Hz,H-3',H-5'),3.87(3H,s,6-OC H 3). 13 CNMR(100MHz,DMSO-d6)δ(ppm):157.0,156.9,135.2,132.9,130.8,129.4,128.8,12 7.7×2,127.1,125.2,123.8,118.7,115.7×2,105.6,55.1.HRMS(ESI,m / z)calcd.for C 17 H 14 O2(MH) - 249.0921,found 249.0927.

[0035] Example 5 Preparation of 6-(3-hydroxyphenyl)-2-naphthol (HP27)

[0036] Compound HP27 was synthesized similarly to HP13. Its physical and chemical properties are as follows: white solid, yield: 58%, melting point: 175.7-176.5°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.80(1H,s,3'-OH),9.53(1H,s,6-OH),8.00(1H,s,H-1),7.83(1H,d,J=8.8Hz,H-8),7.74(1H,d,J=8.4Hz,H-4),7.6 5(1H,dd,J1=8.0Hz,J2=1.6Hz,H-3),7.26(1H,t,J=8.0Hz,H-5'),7.17-7. 09(4H,m,H-5,H-7,H-2',H-6'),6.76(1H,dd,J1=7.6Hz,J2=1.6Hz,H-4'). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.8,155.4,141.6,134.4,133.8,129.8,129.7,127. 9,126.5,125.1,124.9,118.9,117.4,114.0,113.3,108.4.HRMS(ESI,m / z)calcd.for C 16 H 12 O2(MH) - 235.0765,found 235.0785.

[0037] Example 6 Preparation of 6-(4-hydroxyphenyl)-2-naphthol (HP28)

[0038] Compound HP28 was synthesized similarly to HP13. Its physical and chemical properties are as follows: white solid, yield: 55%. Melting point: 224.8-225.5°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.70(1H,s,4'-OH),9.53(1H,s,6-OH),7.95(1H, s,H-1),7.78(1H,d,J=8.8Hz,H-8),7.71(1H,d,J=8.8Hz,H-4),7.64(1H,dd,J1= 8.8Hz,J2=1.6Hz,H-3),7.57(2H,d,J=8.4Hz,H-2',H-6'),7.11(1H,d,J=2.4Hz, H-5),7.08(1H,dd,J1=8.4Hz,J2=2.4Hz,H-7),6.86(2H,d,J=8.8Hz,H-3',H-5'). 13C NMR(100MHz,DMSO-d6)δ(ppm):156.8,155.0,134.4,133.2,131.0,129.4,128.0, 127.6×2,126.4,125.0,123.8,118.8,115.7×2,108.4.HRMS(ESI,m / z)calcd.for C 16 H 12 O2(MH) - 235.0765, found 235.0783.

[0039] Example 7 Preparation of 7-(4-hydroxyphenyl)-2-naphthol (HP30)

[0040] Compound HP30 was synthesized similarly to HP13. Its physical and chemical properties are as follows: white solid, yield: 56%, melting point: 174.2-174.9°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.73(1H,s,4'-OH),9.58(1H,s,7-OH),7.86(1H, s,H-1),7.78(1H,d,J=8.4Hz,H-4),7.73(1H,d,J=8.8Hz,H-5),7.60(2H,d,J=8. 4Hz,H-2',H-6'),7.50(1H,dd,J1=8.4Hz,J2=1.6Hz,H-3),7.16(1H,d,J=2.0Hz, H-8),7.04(1H,dd,J1=8.8Hz,J2=1.6Hz,H-6),6.88(2H,d,J=8.0Hz,H-3',H-5'). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.1,155.5,137.7,135.0,130.9,128.9,128.0, 127.9×2,126.4,122.2,121.6,118.2,115.7×2,108.8.HRMS(ESI,m / z)calcd.for C 16 H 12 O2(MH) - 235.0765, found 235.0783.

[0041] Example 8 Preparation of 6-(4-hydroxyphenyl)naphthalen-2-yl dimethylcarbamate (HP31)

[0042] Step ①: Dissolve 6-bromonaphthalene-2-ol (200 mg, 0.89 mmol) in dry chloroform (15 mL), then add triethylamine (1 mL). Add dimethylcarbamoyl chloride (412 μL, 4.48 mmol) dropwise to the solution under ice-cooling conditions. The reaction mixture is then stirred at 60°C overnight. After the reaction is complete, the solvent is removed, and the residue is extracted twice with ethyl acetate and water. The organic layer is then collected, dried over anhydrous magnesium sulfate, and concentrated. Finally, silica gel column chromatography (eluent: PE / EA = 8 / 1) affords the intermediate 6-bromonaphthalene-2-yl dimethylcarbamate (235 mg, yellow powder, yield: 89%).

[0043] Step 2: Dissolve the intermediate 6-bromonaphthalen-2-yl dimethylcarbamate (100 mg, 0.34 mmol), (4-hydroxyphenyl)boronic acid (469 mg, 0.34 mmol), and tetrakistriphenylphosphine palladium (393 mg, 0.034 mmol) in toluene (10 mL). Add 2% aqueous Na2CO3 (1 mL) to the solution. Place the mixture under a nitrogen atmosphere and stir at 80°C for 10 hours. After removing the toluene, the residue was extracted, dried, and purified to yield the product HP31 (52 mg). The physical and chemical properties of compound HP31 are as follows: pale yellow solid, yield: 50%, melting point: 230.7-231.5°C. 1 HNMR(400MHz,DMSO-d6)δ(ppm):9.61(1H,s,4'-OH),8.12(1H,s,H-1),7.95(1 H,d,J=9.2Hz,H-4),7.92(1H,d,J=8.8Hz,H-8),7.79(1H,dd,J1=8.8Hz,J2=1. 6Hz,H-3),7.64(2H,d,J=8.8Hz,H-2',H-6'),7.63(1H,s,H-5),7.29(1H,dd,J 1=8.8Hz,J2=1.6Hz,H-7),6.89(2H,d,J=8.0Hz,H-3',H-5'),3.09(3H,s,-N(C H 3)2),2.94(3H,s,-N(C H 3)2). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.2,154.1,148.7,137.1,131.9,131.0,130.4,129.0,12 7.9×2,127.8,125.4,123.7,122.2,118.0,115.7×2,36.3,36.1.HRMS(ESI,m / z)calcd.for C 19 H17 NO3(MH) - 306.1136,found306.1144.

[0044] Example 9 Preparation of 7-(4-hydroxyphenyl)naphthalen-2-yl dimethylcarbamate (HP32)

[0045] Compound HP32 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 52%, melting point: 201.2°C-201.9°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm):9.63(1H,s,4'-OH),8.06(1H,s,H-1),7.96(1H, d,J=8.8Hz,H-5),7.91(1H,d,J=8.8Hz,H-4),7.75(1H,dd,J1=8.8Hz,J2=1.6Hz ,H-3),7.63(2H,d,J=8.8Hz,H-2',H-6'),7.38-7.36(1H,m,H-8),7.25(1H,dd, J1=8.8Hz, J2=2.0Hz,H-6),6.90(2H,d,J=8.4Hz,H-3',H-5'),3.10(3H,s,-N(C H 3)2),2.95(3H,s,-N(C H 3)2). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.3,154.1,149.2,134.3,133.8,131.5,130.4,129.3,12 8.6,128.0×2,124.4,123.4,121.5,118.4,115.8×2,36.3,36.1.HRMS(ESI,m / z)calcd.for C 19 H 17 NO3(MH) - 306.1136,found306.1141.

[0046] Example 10 Preparation of 4-(6-(3-morpholinopropoxy)naphthalen-2-yl)phenol (HP33)

[0047] Compound HP33 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 36%, melting point: 195.8-196.4°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.57(1H,s,4'-OH),8.01(1H,s,H-1),7.85-7.82(2H,m,H-4,H-8),7.71(1H,dd,J1=8.8Hz,J2=1.6Hz,H-3),7.59(2H,d, J=8.4Hz,H-2',H-6'),7.30(1H,d,J=2.4Hz,H-5),7.15(1H,dd,J1=9.2Hz,J 2=2.4Hz,H-7),6.87(2H,d,J=8.8Hz,H-3',H-5'),4.11(2H,t,J=6.4Hz,-OC H 2CH2CH2-morpholinyl),3.57(4H,t,J=4.4Hz,-N(CH2C H 2)2O),2.46(2H,t,J=6.4Hz,-OCH2CH2C H 2-morpholinyl),2.38(4H,br,-N(C H 2CH2)2O),1.97-1.90(2H,m,-OCH2C H 2CH2-morpholinyl). 13 C NMR(100MHz,DMSO-d6)δ(ppm):156.9,156.3,135.2,132.9,130.8,129.4,128.7,127.7×2,127.1, 125.1,123.7,118.9,115.7×2,106.3,66.1×2,65.8,54.8,53.3×2,25.8.HRMS(ESI,m / z)calcd.for C 23 H 25 NO3(MH) - 362.1762,found362.1770.

[0048] Example 11 Preparation of 4-(7-(3-morpholinopropoxy)naphthalen-2-yl)phenol (HP34)

[0049] Compound HP34 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 66%, melting point: 148.3-149.1°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.61(1H,s,4'-OH),7.98(1H,s,H-1),7.84(1H,d,J=8.4Hz,H-5),7.78(1H,d,J=9.2Hz,H-4),7.62-7.57(3H,m,H -3,H-2',H-6'),7.33(1H,d,J=2.0Hz,H-8),7.10(1H,dd,J1=8.8Hz,J2=2.4Hz,H-6),6.89(2H,d,J=8.4Hz,H-3',H-5'),4.11(2H,t,J=6.4Hz,-OC H 2CH2CH2-morpholinyl),3.57(4H,t,J=4.4Hz,-N(CH2C H 2)2O),2.45(2H,t,J=7.2Hz,-OCH2CH2C H 2-morpholinyl),2.36(4H,br,-N(C H 2CH2)2O),1.96-1.90(2H,m,-OCH2C H 2CH2-morpholinyl). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.2,156.7,137.9,134.7,130.8,128.9,127.9×3,127.1,122 .9,122.4,118.2,115.7×2,106.8,66.1×2,65.7,54.8,53.3×2,25.8.HRMS(ESI,m / z)calcd.for C 23 H 25 NO3(MH) - 362.1762,found362.1775.

[0050] Example 12 Preparation of 3-((6-(4-hydroxyphenyl)naphthalen-2-yl)oxy)propane-1,2-diol (HP35)

[0051] Compound HP35 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 55%, melting point: 210.2-210.9°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.55(1H,s,4'-OH),8.01(1H,s,H-1),7.86-7 .82(2H,m,H-4,H-8),7.71(1H,dd,J1=8.8Hz,J2=1.6Hz,H-3),7.60(2H,d,J= 8.8Hz,H-2',H-6'),7.31(1H,d,J=2.0Hz,H-5),7.17(1H,dd,J1=8.8Hz,J2=2 .4Hz,H-7),6.87(2H,d,J=8.4Hz,H-3',H-5'),5.03(1H,d,J=5.2Hz,-OCH2CH( OH )CH2OH),4.73(1H,t,J=5.6Hz,-OCH2CH(OH)CH2 OH ),4.14-3.96(2H,m,-OC H 2CH(OH)CH2OH),3.89-3.85(1H,m,-OCH2C H (OH)CH2OH),3.50(2H,t,J=5.6Hz,-OCH2CH(OH)C H 2OH). 13 C NMR(100MHz,DMSO-d6)δ(ppm):156.9,156.4,135.2,132.9,130.8,129.4,128.7,127.7×2, 127.1,125.1,123.7,119.0,115.7×2,106.3,69.9,69.6,62.7.HRMS(ESI,m / z)calcd.forC 19 H 18 O4(MH) - 309.1132, found 309.1144.

[0052] Example 13 Preparation of 3-((7-(4-hydroxyphenyl)naphthalen-2-yl)oxy)propane-1,2-diol (HP36)

[0053] Compound HP36 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 51%, melting point: 147.8-148.6°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.62(1H,s,4'-OH),7.98(1H,s,H-1),7.85(1H,d,J=8.4Hz,H-5),7.80(1H,d,J=9.2Hz,H-4),7.61-7.59(3H,m,H-3, H-2',H-6'),7.34(1H,d,J=2.0Hz,H-8),7.12(1H,dd,J1=8.8Hz,J2=2.4Hz,H-6),6.88(2H,d,J=8.8Hz,H-3',H-5'),5.04(1H,d,J=5.2Hz,-OCH2CH( OH )CH2OH),4.74(1H,t,J=5.6Hz,-OCH2CH(OH)CH2 OH ),4.14-3.96(2H,m,-OC H 2CH(OH)CH2OH),3.89-3.85(1H,m,-OCH2C H (OH)CH2OH),3.50(2H,t,J=5.6Hz,-OCH2CH(OH)C H 2OH). 13 C NMR(100MHz,DMSO-d6)δ(ppm):157.1,156.9,137.9,134.7,133.1,130.8,128.6×2,127.9 ,127.1,122.9,122.4,118.3,115.7×2,106.8,69.8,69.6,62.7.HRMS(ESI,m / z)calcd.for C 19 H 18 O4(MH) - 309.1132, found 309.1147.

[0054] Example 14 Preparation of 4-(6-(3-(4-methylpiperazin-1-yl)propoxy)naphthalen-2-yl)phenol (HP37)

[0055] Compound HP37 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 36%, melting point: 161.5-162.3°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.57(1H,s,4'-OH),8.01(1H,s,H-1),7.85-7.81(2H,m,H-4,H-8),7.71(1H,dd,J1=8.8Hz,J2=1.6Hz,H-3),7.59(2H,d, J=8.4Hz,H-2',H-6'),7.29(1H,d,J=2.0Hz,H-5),7.14(1H,dd,J1=8.8Hz,J 2=2.4Hz,H-7),6.87(2H,d,J=8.8Hz,H-3',H-5'),4.10(2H,t,J=5.6Hz,-OC H 2CH2CH2-piperazinyl),2.45(2H,t,J=6.8Hz,-OCH2CH2C H 2-piperazinyl),2.37(8H,br,-OCH2CH2CH2N(C H 2C H 2)2NCH3),2.16(3H,s,-NC H 3),1.94-1.90(2H,m,-OCH2C H 2CH2-piperazinyl). 13 C NMR(100MHz,DMSO-d6)δ(ppm):156.9,156.3,135.2,132.9,130.8,129.4,128.7,127.7×2,127.1,125 .1,123.7,119.0,115.7×2,106.3,65.8,54.6×2,54.3,52.5×2,45.5,26.1.HRMS(ESI,m / z)calcd.for C 24 H 28 N2O2(MH) - 375.2078,found375.2088.

[0056] Example 15 Preparation of 4-(7-(3-(4-methylpiperazin-1-yl)propoxy)naphthalen-2-yl)phenol (HP38)

[0057] Compound HP38 was synthesized similarly to HP31. Its physical and chemical properties are as follows: pale yellow solid, yield: 44%, melting point: 158.1-158.8°C. 1H NMR (400MHz, DMSO-d6) δ (ppm): 7.98 (1H, s, H-1), 7.84 (1H, d, J = 8.4Hz, H-5), 7.79 (1H, d, J = 8.8Hz, H-4), 7.61 (2H, d, J = 8.8Hz, H-2', H-6'), 7. 59(1H,d,J=8.0Hz,H-3),7.33(1H,s,H-8),7.10(1H,d,J1=8.8Hz,J2=2.0Hz,H-6),6.88(2H,d,J=8.8Hz,H-3',H-5'),4.11(2H,t,J=6.4Hz,-OC H 2CH2CH2-piperazinyl),2.46(2H,t,J=7.2Hz,-OCH2CH2C H 2-piperazinyl),2.37(8H,br,-OCH2CH2CH2N(C H 2C H 2)2NCH3),2.17(3H,s,-NC H 3), 1.94 (2H, t, J = 6.4 Hz, -OCH2C H 2CH2-piperazinyl),1.90(1H,s,4'-OH). 13 CNMR(100MHz,DMSO-d6)δ(ppm):157.2,156.7,137.9,134.7,130.7,128.9,127.9×2,127.1,122.9, 122.4,118.2,115.7×2,106.7×2,65.8,54.6×2,54.3,52.5×2,45.5,26.1.HRMS(ESI,m / z)calcd.for C 24 H 28 N2O2(M+H) + 377.2224, found 377.2215.

[0058] Example 16 Preparation of 6-(4-hydroxyphenyl)naphthalen-2-yl acrylate (HP39)

[0059] Step ①: 6-bromonaphthalene-2-ol (1.0 g, 4.48 mmol), (4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)boric acid (995 mg, 4.48 mmol), Pd(PPh 3 ) 4 (52 mg, 0.045 mmol) and anhydrous potassium carbonate (929 mg, 6.72 mmol) were dissolved in THF / H 2 O (20 mL, v / v, 2 / 1). After completion of the reaction, THF was removed, and the residue was extracted, dried, concentrated, and purified by silica gel column chromatography (eluent: PE / EA=8 / 1) to give the intermediate 6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)naphthalene-2-ol (white powder, 432 mg, yield: 30%).

[0060] Step 2: Dissolve the intermediate 6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)naphthalen-2-ol (300 mg, 0.93 mmol) and triethylamine (390 μL, 2.81 mmol) in THF (15 mL). Then, slowly add acryloyl chloride (114 μL, 1.40 mmol) over 5 minutes at a temperature below 5°C. The reaction mixture is then warmed to room temperature and stirred for 6 hours until complete. The solvent is then removed, and the mixture is extracted twice with EA / H2O (30 mL, v / v, 1 / 1). The organic layer is collected, dried, concentrated, and purified by silica gel column chromatography (eluent: PE / EA = 15 / 1) to yield the intermediate 6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)naphthalen-2-yl acrylate (white powder, 301 mg, yield: 86%).

[0061] Step 3: Dissolve the intermediate 6-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)naphthalen-2-yl acrylate (300 mg, 0.26 mmol) and 1N HCl (2 mL) in anhydrous ethanol (15 mL), and stir the mixture at room temperature for 2 hours. Extract the mixture twice with EA / H₂O (30 mL, v / v, 1 / 1). The organic layer is collected, dried, concentrated, and purified by silica gel column chromatography (eluent: PE / EA = 6 / 1) to obtain the product HP39 (220 mg). The physical and chemical properties of compound HP39 are as follows: pale yellow solid, yield: 48%, melting point: 157.9-158.8°C. 1H NMR(400MHz,DMSO-d6)δ(ppm):9.62(1H,s,4'-OH),8.15(1H,s,H-1),8.01(1H,d, J=9.2Hz,H-4),7.95(1H,d,J=8.8Hz,H-8),7.82(1H,dd,J1=8.8Hz,J2=1.6Hz,H-3) ,7.72(1H,d,J=1.6Hz,H-5),7.65(2H,d,J=8.4Hz,H-2',H-6'),7.35(1H,d,J1=8.8 Hz,J2=2.4Hz,H-7),6.90(2H,d,J=8.8Hz,H-3',H-5'),6.61-6.44(2H,m,-OCOCH=C H 2),6.20-6.17(1H,m,-OCOC H =CH2). 13 C NMR(100MHz,DMSO-d6)δ(ppm):164.3,157.3,147.6,137.5,133.7,131.9,131.4,130.3,129 .4,128.0×2,127.9,127.6,125.6,123.8,121.7,118.2,115.8×2.HRMS(ESI,m / z)calcd.for C 19 H 14 O3(MH) - 289.0870,found 289.0884.

[0062] Example 17 Preparation of 7-(4-hydroxyphenyl)naphthalen-2-yl acrylate (HP40)

[0063] Compound HP40 was synthesized similarly to HP39. Its physical and chemical properties are as follows: pale yellow solid, yield: 51%, melting point: 188.6-189.4°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1H NMR(400MHz,DMSO-d6)δ(ppm):9.64(1H,s,4'-OH),8.10(1H,s,H-1),7.99(1H,d, J=8.0Hz,H-5),7.97(1H,d,J=8.4Hz,H-4),7.79(1H,d,J1=8.8Hz,J2=1.6Hz,H-3), 7.74(1H,d,J=1.6Hz,H-8),7.64(2H,d,J=8.4Hz,H-2',H-6'),7.31(1H,d,J1=8.8 Hz,J2=2.0Hz,H-6),6.90(2H,d,J=8.8Hz,H-3',H-5'),6.62-6.44(2H,m,-OCOCH=C H 2),6.21-6.18(1H,m,-OCOC H =CH2). 13 C NMR(100MHz,DMSO-d6)δ(ppm):164.3,157.4,148.2,138.3,133.8,133.7,130.3,129.7,129 .0,128.2,128.1×2,127.6,124.8,123.5,120.9,118.5,115.8×2.HRMS(ESI,m / z)calcd.forC 19 H 14 O3(MH) - 289.0870,found 289.0885.

[0064] Experimental Example 18 Human Ribonucleotide Reductase Inhibitory Activity of 2-Phenylnaphthalene Derivatives

[0065] The purpose of this experiment was to determine the in vitro inhibitory activity of the compounds of the present invention against hRR enzyme. The hRR enzyme activity assay used liquid chromatography to analyze the changes in CDP and its product, dCDP, during the catalytic reaction between hRR and the compound. RR activity was calculated using the following formula: RR activity = dCDP / (CDP + dCDP) × 100%. The results are shown in Table 1.

[0066] Table 1. Inhibitory activity of 2-phenylnaphthalene derivatives on hRR enzyme

[0067]

[0068] The experimental results showed that 2-phenylnaphthalene derivatives had strong inhibitory activity against hRR enzyme.

[0069] Experimental Example 19: Inhibitory Effect of 2-Phenylnaphthalene Derivatives on the Proliferation of Different Hepatocellular Carcinoma Cells

[0070] The purpose of this experiment was to detect the in vitro antiproliferative activity of the invented compounds against different liver cancer cells. Using the MTT method, cells in the logarithmic growth phase were seeded at a density of 3,000 cells per well in a 96-well tissue culture plate, and 100 μL of cell stock solution was added to each well. The next day, 7-9 concentration gradients of compound dissolved in 100 μL of complete culture medium at 2× the desired concentration were added to each well of the 96-well plate. Three replicates were set up and incubated for 72 hours. Then, 20 μL of 5 mg / mL MTT solution was added to each well, and incubation continued at 37°C for another 4 hours. The supernatant was removed, and 200 μL of DMSO was added to each well, and incubated at 37°C for 20 minutes. The absorbance at a wavelength of 490 nm was measured using a microplate reader. The structures are shown in Table 2.

[0071] Table 2. Inhibitory effects of 2-phenylnaphthalene derivatives on the proliferation of different liver cancer cells

[0072]

[0073] Note: ND means no cell inhibition was detected.

[0074] The experimental results showed that compounds HP28, HP34, HP35, HP37, HP38, and HP39 had significant anti-proliferative activity against a variety of tumor cells, including HepG2, HepG2.2.15, Huh-7 and Hep3B liver cancer cell lines.

[0075] Experimental Example 20 Determination of the Effects of 2-Phenylnaphthalene Derivatives HP28 and HP39 on Cell Cycle and Apoptosis of Hepatocellular Carcinoma Cells

[0076] The purpose of this experiment is to detect the effects of the inventive compounds on the cell cycle and apoptosis of different liver cancer cells in vitro. In this experiment, cells in the logarithmic growth phase were seeded in 6-well plates and treated with HP28 and HP39 for 24 hours or 48 hours, respectively. For cycle analysis, cells were fixed with 70% ethanol at -20°C overnight, washed with PBS the next day, centrifuged, and stained with propidium iodide (PI) for 30 minutes. For apoptosis analysis, culture medium and cells were collected and stained with Annexin V-FITC and PI for 10 minutes. Samples were measured by flow cytometry.

[0077] The experimental results show that ( Figure 1 ), HP28 and HP39 induced S phase arrest and cell apoptosis in HCC cells in a dose-dependent manner.

[0078] Experimental Example 21 In vivo antitumor study of 2-phenylnaphthalene derivatives HP28 and HP39

[0079] The purpose of this experiment is to detect the in vivo anti-tumor effect of the invented compounds. This experiment uses a transplanted tumor model of liver cancer cells to test the in vivo anti-tumor activity of compounds HP28 and HP39. The cell line used is Huh-7. The experimental method is to subcutaneously inoculate 1×10^7 Huh-7 cells on the right side of four-week-old male nude mice (nu / nu). When the tumor volume reaches 100mm^3, the tumor-bearing nude mice are randomly divided into six groups and intraperitoneally injected for 14 consecutive days. The groups are as follows: control group (5% DMSO, 8% Tween 80, 87% saline), HP28 (50 or 100 mg / kg / day) or HP39 (20 or 40 mg / kg / day). The tumor volume is measured according to the formula 0.5×width^2×length. After the treatment, tumor and tissue samples are collected for analysis. Tumor inhibition rate: >80% at the highest concentration; observation indicators: body weight of nude mice, subcutaneous transplanted tumor volume, and the health status of nude mice, such as mental state, diet and survival, are observed.

[0080] The experimental results show that ( Figure 2 Compounds HP28 and HP39 demonstrated significant in vivo growth inhibitory activity against Huh-7 cells, with significant tumor growth inhibition observed at doses of 100 mg / kg / day for HP28 and 40 mg / kg / day for HP39. No adverse reactions, such as weight loss, rash, or diarrhea, were observed in nude mice during administration, demonstrating that compounds HP28 and HP39 exhibited low toxicity within the dose range tested.

Claims

1. A 2-phenylnaphthalene derivative, characterized in that: The structure of the compound is shown in formula (I): ； （I）， Where: R 1 is hydrogen, R 2 for or ; Or, R 1 for or , R 2 is hydrogen; R 3 is hydrogen, hydroxy or methoxy; R 4 is hydrogen, hydroxy or methoxy; R 5 is hydrogen, hydroxy or methoxy.

2. The 2-phenylnaphthalene derivative according to claim 1, wherein: Its structural formula is as follows: ； HP33 HP34 ； HP37 HP38.

3. The pharmaceutically acceptable salt of a 2-phenylnaphthalene derivative according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is hydrochloride, sulfate, nitrate or phosphate.

4. Use of the 2-phenylnaphthalene derivative according to claim 1 or 2 in the preparation of human ribonucleotide reductase inhibitors.

5. Use of a 2-phenylnaphthalene derivative in the preparation of an anti-liver cancer drug, characterized in that: The 2-phenylnaphthalene derivative has the following structure: ； HP34 HP37 HP38.

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