Anthryl-derived triphenyl quaternary phosphorus salt compound and application thereof

Abstract

The invention discloses an anthryl-derived triphenyl quaternary phosphonium salt compound and application thereof, and particularly relates to a compound shown as a formula I or pharmaceutically acceptable salt thereof, wherein variables of the compound are defined in the specification. The compound disclosed by the invention shows a good killing effect on various cancer cells. In addition, the compound provided by the invention has the advantages of cheap and easily available raw materials, remarkable anti-cancer effect and suitability for large-scale preparation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to an anthracene-derived triphenyl quaternary phosphonium salt compound and a preparation method thereof, a pharmaceutical composition comprising the compound, and use of the compound in preparing a drug for treating or preventing cancer. Background Art

[0002] Cancer has become a major threat to human life and health in the 21st century due to its high incidence, low cure rate and difficulty in detection. At present, the incidence and mortality of cancer in my country are increasing year by year. Therefore, the development of effective therapeutic drugs for cancer has become a top priority in the field of drug synthesis (CA Cancer J Cli. 2021, 71(3): 209-249.).

[0003] Mitochondria are unique organelles that exist in eukaryotic cells. They have a special structure and their own set of genetic material. Mitochondria are important sites for the tricarboxylic acid cycle, fatty acid oxidation, and amino acid degradation. Therefore, maintaining the integrity of mitochondrial structure and function is an important prerequisite for cells to maintain normal physiological activities. The proliferation of cancer cells requires energy from mitochondria. Therefore, mitochondria have become potential targets for the development of new anti-tumor drugs. Small molecule drugs targeting mitochondria are designed to affect the physiological activities of mitochondria and ultimately kill cancer cells (Cell. 2006, 126 (1): 177-89.).

[0004] In previous studies, the inventors' research group discovered a class of anthracene-substituted small molecules XI-011 ( Figure 1), which has significant inhibitory activity against a variety of cancer cells (Pharmacological Research, 2022, 177, 106128). Recently, through in-depth anti-cancer mechanism research, it was found that it has a strong activation effect on the P53 tumor suppressor gene and exhibits good anti-cancer activity (Int. J. Cancer, 2005, 115, 701–710.). In 2006, XI-011 was found to have the ability to bind to nucleic acids and inhibit DNA transcription (Antiviral Res. 2006, 69 (1): 9-23.). The anti-cancer mechanism of XI-011 was initially elucidated in 2011, that is, by inhibiting the expression of MDMX, thereby increasing the level of P53 to induce cell apoptosis, showing significant inhibitory activity against a variety of cancer cells such as breast cancer and cervical cancer (Neoplasia. 2011, 13 (7): 611-9.). Subsequent studies have shown that XI-011 was found not to act directly on MDMX or P53, but to inhibit MDMX and upregulate P53 levels by regulating the expression of MDMX. In 2023, XI-011 was found to act as a ligand for hnRNPA2B1, binding to the nucleotide binding domain, thereby inhibiting the transcription of MDMX (Pharmacological Research, 2023, 189: 106696.).

[0005] Based on previous studies, the inventors conducted further in-depth research and pioneered the design and synthesis of a new class of compounds for the treatment of cancer. These compounds have broad-spectrum anti-tumor activity and can effectively inhibit cervical cancer, gastric cancer, breast cancer and glioma cells, etc. They can inhibit the transcription of MDMX and target mitochondria, and have the advantages of simple preparation and low cost. Summary of the invention

[0006] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in:

[0009] R1 is selected from halogen and C 1-6 alkyl;

[0010] Ring A is selected from naphthyl, anthracenyl, phenanthrenyl and

[0011] L1 is selected from a direct bond and C 1-6 Alkylene;

[0012] X - represents a halogen ion;

[0013] n is 0, 1, 2 or 3;

[0014] m is 1, 2 or 3.

[0015] In some embodiments, R1 is selected from halogen and C 1-3 alkyl;

[0016] L1 is selected from a direct bond and a methylene group;

[0017] X - Represents Cl - or Br - ;

[0018] n is 0 or 1;

[0019] m is 1.

[0020] In some embodiments, Ring A is selected from naphthyl, anthracenyl and

[0021] In some embodiments, Selected from:

[0022]

[0023] In some embodiments, the compound of formula I is selected from the following compounds:

[0024]

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0026] In another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treatment or prevention, especially for use in treatment or prevention of cancer.

[0027] On the other hand, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing cancer, preferably the cancer is selected from cervical cancer, gastric cancer, breast cancer and / or glioma.

[0028] In some embodiments, the cell line involved in the cancer is a cervical cancer cell line Hela, a gastric cancer cell line MKN45, a breast cancer cell line MCF-7 or a glioma cell line U87.

[0029] In a further aspect, the present invention provides methods for synthesizing compounds of formula I. General synthetic schemes for synthesizing compounds of the present invention are illustrated below.

[0030] In some embodiments, the present invention provides a method for preparing a compound of formula I, comprising the steps of:

[0031]

[0032] The compound of formula II is reacted with triphenylphosphine to produce the compound of formula I,

[0033] Where X - represents a halogen ion; X represents a halogen;

[0034] The remaining variables such as R1, Ring A, L1 and n are as defined above in Formula I.

[0035] It should be understood that the specific type of X in Formula II is - The corresponding.

[0036] For the reaction, appropriate reaction conditions are known to those skilled in the art or can be routinely determined, for example using the conditions shown in the examples. If not otherwise specified, the raw materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods below, methods similar to those given below, or methods known in the art. If necessary, the raw materials and intermediates in the synthetic reaction schemes can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc.

[0037] In some embodiments, the reaction is carried out in an organic solvent, preferably acetonitrile.

[0038] In some embodiments, the reaction is carried out at -15°C to 100°C, preferably at 0°C to 50°C, and more preferably at room temperature.

[0039] definition:

[0040] Unless otherwise specified, the various terms used in this specification and claims have the following meanings. In the case where a particular term or phrase is not particularly defined, it should not be considered to be uncertain or unclear, but should be properly understood according to the context of this article or the general meaning in the art.

[0041] The term "alkyl" as used herein means a fully saturated straight or branched aliphatic hydrocarbon group. Specifically, the alkyl group may have 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. Suitable C 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0042] When the alkyl groups defined above become divalent groups, i.e. have two single bonds connected to the other two groups, they are referred to as "alkylene" groups. Alkylene can have 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. Non-limiting examples of alkylene include methylene, ethylene, methylmethylene or propylene.

[0043] As used herein, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and / or iodine (I).

[0044] As used herein, the term "halide ion" refers to a fluoride ion (F - ), chloride ion (Cl - ), bromide ion (Br - ) and / or iodide ion (I - ).

[0045] As used herein, the term "direct bond" refers to a covalent bond directly connected to the relevant group. For example, when L1 is a direct bond, Formula I It can also be expressed as That is, the triphenylphosphine moiety is directly linked to the A ring.

[0046] It should be understood that when a bond is not attached to an atom but passes through a bond on a ring, it indicates that the bond can be attached to different positions on the ring, provided that the valence rules are followed. Can be expressed wait.

[0047] It should be understood that those skilled in the art will know that "Ph" in Formula I and the Example compounds refers to phenyl; "P" attached to L1 refers to phosphorus. Thus, It can also be expressed as

[0048] As used herein, the term "pharmaceutically acceptable" means molecular entities and compositions that are approved or approvable by relevant agencies in various countries, or listed in the generally recognized pharmacopoeia for use in animals, preferably humans, or that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.

[0049] As used herein, the term "pharmaceutically acceptable salt" means a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid. or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Those skilled in the art are aware of the general principles and techniques for preparing pharmaceutically acceptable salts, such as those described in Berge et al., Pharm ScL, 66, 1-19. (1977).

[0050] As used herein, the term "pharmaceutically acceptable excipient" refers to an additive other than the active ingredient in a pharmaceutical composition, which may also be referred to as an auxiliary material, which is pharmacologically inactive, compatible with other ingredients in the composition, and should be acceptable for administration to warm-blooded animals such as humans. It can be used as a carrier or medium in the administration form of the compound of the present invention, examples include but are not limited to cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc.

[0051] As used herein, "a compound of the present invention" includes a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof.

[0052] Application

[0053] The compounds and compositions of the present invention may be administered alone or in combination with one or more other therapeutic agents. The administration methods of the compounds and compositions include, but are not limited to, oral administration, rectal administration, parenteral administration or intravenous administration.

[0054] The therapeutically effective amount will depend, inter alia, on the disease being treated, the severity of the disease, the age and relative health of the subject, the potency of the compound being administered, the mode of administration, and the desired treatment. In certain embodiments, the compounds of the invention may be administered in a daily dose of 0.01 to 500 mg / kg body weight, 0.01 to 100 mg / kg body weight, e.g., 0.1 to 10 mg / kg body weight.

[0055] Beneficial effects:

[0056] The compound of the present invention has a broad spectrum of anticancer activity, and exhibits significant killing effects on a variety of cancers, such as human cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell U87;

[0057] The compounds of the present invention can inhibit the transcription of MDMX and target mitochondria, thereby being effective against some drug-resistant tumors;

[0058] The compound of the present invention uses a commercially available compound as a substrate and can be prepared through a simple synthesis route (even through one or two steps of chemical reaction). It has the advantages of simple preparation conditions, easy separation, and applicability to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The accompanying drawings are used to provide a further understanding of the technical solution of the present invention and constitute a part of the specification. Together with the specific implementation methods of the present application, they are used to explain the technical solution of the present invention and do not constitute a limitation on the technical solution of the present invention.

[0060] Figure 1 The structure of XI-011 is shown.

[0061] Figure 2 , Figure 3 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 4 respectively.

[0062] Figure 4 , Figure 5 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 7 respectively.

[0063] Figure 6 , Figure 7 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 9 respectively.

[0064] Figure 8 , Fig. 9 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 11 respectively.

[0065] Fig.10 , Fig.11 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 13 respectively.

[0066] Fig.12 , Fig.13 These are the hydrogen and carbon nuclear magnetic resonance spectra of compound 15, respectively.

[0067] Fig.14 , Fig.15 They are the hydrogen and carbon nuclear magnetic resonance spectra of compound 17 respectively.

[0068] Fig.16 This is the half-inhibition graph of compound 4 on gastric cancer cell line MKN45.

[0069] Fig.17 This is the half inhibition graph of compound 7 on human cervical cancer cell line Hela.

[0070] Fig.18 This is the half-inhibition graph of compound 13 on breast cancer cell line MCF-7.

[0071] Fig.19 This is the half-inhibition graph of compound 13 on glioma cells U87. DETAILED DESCRIPTION

[0072] The technical solution of the present invention will be described clearly and completely below in conjunction with specific embodiments of the present invention. However, it should be understood that the protection scope of the present invention is not limited to these embodiments, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0073] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels, prepared according to methods in the prior art, or prepared according to methods similar to those disclosed in this application.

[0074] It should be understood that, without providing specific definition or description, the abbreviations herein have the meanings commonly understood by those skilled in the art.

[0075] Example 1 Preparation of Compound 4:

[0076]

[0077] Step 1. Under argon protection, commercially available anthraquinone 1 (50 mmol) was dissolved in 350 ml of dry tetrahydrofuran. After the obtained system was heated to 55 degrees Celsius, a tetrahydrofuran solution of methylmagnesium bromide (100 ml, 1.5 M / L, 150 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the reaction mixture was kept at 55 degrees Celsius, stirred and reacted for 3 hours. After the reaction was completed by TLC monitoring, 100 ml of water was added to the reaction system to quench the reaction. Extract with dichloromethane (3×80 ml), combine the organic phases, dry the organic layer with anhydrous sodium sulfate, and vacuum evaporate to remove the solvent. The obtained product was directly used in the next step without further purification.

[0078] Step 2. Compound 2 (10 mmol) was dissolved in 250 ml of tetrahydrofuran, and 50 ml of 48% hydrobromic acid aqueous solution was added to the reaction system, and the reaction was continued at room temperature for 1 hour. A large amount of light yellow crystals appeared in the system, and after filtration and drying, the target compound 3 was obtained with a crude yield of 69%.

[0079] Step 3. Dissolve compound 3 (5 mmol) in 20 ml of acetonitrile and add triphenylphosphine (7.5 mmol) to the solution. Continue the reaction at room temperature for 5 hours and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain yellow solid compound 4 with a yield of 81%.

[0080] Compound 4: 1 H NMR(500MHz, CDCl3)δ:7.88(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),7.51-7.48(m,3H),7.30-7 .28(m,12H),7.12(t,J=8.5Hz,2H),6.92(t,J=7.5Hz,2H),5.69(d,J=13.5Hz,2H),2.72(s,3H); 13 C NMR(125MHz, CDCl3)δ:134.67,134.65,134.20,134.12,132.40,132.34,130.21,130.17,129.69,129.59,129.19,12 9.16,125.53,124.93,124.63,124.43,124.41,117.70,117.03,116.31,116.23,25.32,24.95,14.32.ESI-HRMScalcd for C 34 H 28 P([M-Br - ] + )467.1924, found 467.1917.

[0081] Example 2 Preparation of Compound 7:

[0082]

[0083] Step 1. Add triphenylphosphine (15 mmol) to a round-bottom flask containing 20 ml of acetonitrile and seal the bottle mouth. After it is fully dissolved, bubble nitrogen into the obtained solution for 2 minutes, and then use nitrogen protection. Add liquid bromine to the reaction system at room temperature. Quickly add commercially available 9-anthrol 5 (10 mmol) to the reaction system and react at room temperature for 1 hour. After the reaction is completed, filter the solution at 0 degrees Celsius. Dissolve the filtered solid in 1,4-dioxane and perform vacuum rotary evaporation to remove excess bromine. The obtained solid is then placed in chloroform and recrystallized twice, and the obtained golden solid is compound 6 with a yield of 76%.

[0084] Step 2. Dissolve compound 6 (5 mmol) in 20 ml of acetonitrile and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain yellow solid compound 7 with a yield of 75%.

[0085] Compound 7: 1 H NMR(400MHz, Methanol-d4)δ:8.64(d,J=3.6Hz,1H),8.06(d,J=8.0Hz,2H),7.89(d,J=9.2Hz,2H),7.83-7.78(m,3H) ,7.60-7.54(m,8H),7.52-7.51(m,3H),7.49(m,1),7.39(t,J=6.4Hz,2H),7.22-7.17(m,2H),5.93(d,J=14.2Hz,2H). 13 C NMR(100MHz, CDCl3)δ=134.91,134.88,134.48,134.39,134.25,132.24,132.14,132.06,131.17,131.11,131.06,131.02, 129.98,129.85,129.00,128.68,128.56,127.33,126.57,125.10,124.08,124.05,118.24,117.40,25.82,25.35; ESI-HRMS calcd for C 33 H 25 BrP([M-Br - ] + )531.0872,found531.0862

[0086] Example 3 Preparation of Compound 9:

[0087]

[0088] Step 1. Dissolve commercially available 9-bromomethylanthracene (5 mmol) in 20 ml of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. The residue is washed with V 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain yellow solid compound 9 with a yield of 82%.

[0089] Compound 9: 1 H NMR(400MHz, DMSO-d6)δ:8.71(d,J=3.6Hz,1H),8.07(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.79(t,J=9.2Hz, 3H),7.58-7.53(m,7H),7.51-7.45(m,6H),7.39(t,J=6.5Hz,2H),7.13(t,J=6.5Hz,2H),6.11(d,J=14.6Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ:134.95,134.33,134.23,130.82,130.78,129.81,129.69,128.95,125.92,125.13,124.24,117.97,117.04.ESI-HRMS calcd for C 33 H 26 P([M-Br - ] + )453.1767,found453.1758.

[0090] Example 4 Preparation of Compound 11:

[0091]

[0092] Step 1. Dissolve commercially available 4-methyl-1-bromomethylnaphthalene (5 mmol) in 20 ml of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. The residue is washed with V 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain a white solid compound 11 with a yield of 82%.

[0093] Compound 11: 1H NMR(500MHz, CDCl3)δ:7.72-7.61(m,10H),7.51(m,5H),7.47-7.45(m,1H),7.35(d,J=8.6Hz,1H),7.25 (t,J=7.7Hz,1H),7.21(t,J=7.7Hz,1H),7.01(t,J=7.7Hz,1H),5.72(s,1H),5.69(s,1H),3.46(s,2H). 13 C NMR(100MHz, CDCl3)δ:135.08,135.05,134.38,134.28,133.54,132.33,130.56,130.23,130.11, 129.42,129.37,128.66,126.44,125.81,125.42,123.14,118.11,117.2,27.85,27.38.ESI-HRMS calcd forC 30 H 26 P([M-Br - ] + )417.1767, found 417.1760.

[0094] Example 5 Preparation of Compound 13:

[0095]

[0096] Step 1. Dissolve commercially available 5-bromo-10,11-dihydro-5H-dibenzo[a,d][7]cycloheptene (5 mmol) in 20 ml of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, and then monitor the reaction by TLC.

[0097] After the reaction is completed, acetonitrile is removed by vacuum rotary evaporation. 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain white solid compound 13 with a yield of 78%.

[0098] Compound 13: 1 H NMR (500MHz, CDCl3) δ = 7.75 (t, J = 8.1Hz, 3H), 7.66–7.45 (m, 8H), 7.28 (d, J = 7.2Hz, 6H), 7.25 –7.20(m,3H),7.10(d,J=7.7Hz,2H),7.04–6.95(m,2H),3.47(s,1H),2.71(d,J=2.7Hz,4H). 13C NMR(125MHz, CDCl3)δ=141.71,141.66,135.22,135.19,135.07,134.98,133.91,133.85,131.08,131.06,130 .24,130.12,129.74,129.70,129.68,129.62,127.50,127.47,118.25,117.46,54.83,54.49,32.99;ESI-HRMS calcdfor C 33 H 28 P([M-Br - ] + )455.1923, found 455.1921.

[0099] Example 6 Preparation of Compound 15:

[0100]

[0101] Step 1. Dissolve commercially available 2-bromomethylnaphthalene (5 mmol) in 20 ml of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. The residue is washed with V 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain white solid compound 15 with a yield of 71%.

[0102] Compound 15: 1 H NMR (500MHz, CDCl3) δ: 7.77-7.70 (m, 9H), 7.68 (d, J = 8.7Hz, 1H), 7.62-7.55 (m, 6H), 7. 52(d,J=8.0Hz,3H),7.44-7.35(m,2H),7.14(d,J=8.5Hz,1H),5.52(d,J=14.5Hz,2H). 13 C NMR (100MHz, CDCl3) δ: 135.07, 135.04, 134.59, 134.50, 131.35, 131.28, 130.28, 130.16, 128. 69,128.50,128.47,127.96,127.65,126.65,126.47,118.36,117.51,31.31,30.85.ESI-HRMS calcd for C 29 H 24 P([M-Br - ] + )403.1610,found 403.02.

[0103] Example 7 Preparation of Compound 17:

[0104]

[0105] Step 1. Dissolve commercially available 1-bromomethylnaphthalene (5 mmol) in 20 ml of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, and monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by vacuum rotary evaporation. The residue is washed with V 二氯甲烷 / V 甲醇 =10:1 passed through a silica gel column to obtain white solid compound 17 with a yield of 86%.

[0106] Compound 17: 1 H NMR(500MHz, CDCl3)δ:7.72-7.61(m,10H),7.51(m,5H),7.47-7.45(m,1H),7.35(d,J=8.6Hz,1H),7.25 (t,J=7.7Hz,1H),7.21(t,J=7.7Hz,1H),7.01(t,J=7.7Hz,1H),5.72(s,1H),5.69(s,1H),3.46(s,2H). 13 C NMR(100MHz, CDCl3)δ:135.08,135.05,134.38,134.28,133.54,132.33,130.56,130.23,130.11, 129.42,129.37,128.66,126.44,125.81,125.42,123.14,118.11,117.23,27.85,27.38.ESI-HRMS calcd forC 29 H 24 P([M-Br - ] + )403.1610,found403.04.

[0107] Example 8 Pharmacological Test

[0108] The inhibitory activity of compounds 4, 7, 9, 11, 13, 15, and 17 against human cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87 (the above four cell lines are all from the cell bank of the Institute of Basic Research, Chinese Academy of Medical Sciences) was evaluated.

[0109] The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method was used to determine the half inhibitory concentration (IC50) of the compounds on four human tumor cell lines: Hela, MKN45, MCF-7, and U87. 50 ).

[0110] Detection principle: MTT can penetrate the cell membrane and enter the cell. The succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to blue-purple needle-shaped formazan crystals that are insoluble in water and deposited in the cells. The crystals can be dissolved by dimethyl sulfoxide (DMSO). The absorbance measurement can reflect the cell survival rate.

[0111] The half inhibitory concentration (IC 50 ) is defined as the drug concentration when 50% of the tumor cells survive. According to the measured optical density (OD value), a standard curve of cell growth inhibition rate is prepared, and then the corresponding drug concentration is obtained on the curve.

[0112] The determination method is as follows:

[0113] 1. Seed the cells in a 96-well plate at a density of 2000 cells / well and culture them in a CO2 incubator for 24 hours;

[0114] 2. Serially dilute the test compound (stock solution 10 mM) to 10 μM-5 μM-2.5 μM-1.25 μM-0.625 μM-0.3125 μM-0.15625 μM;

[0115] 3. Set up three sets of parallel wells for each concentration, add the test compound into the seeded cells respectively, and continue to culture for 72 hours;

[0116] 4. Take out the 96-well plate, add 20 μl of MTT solution to each well, and incubate in the incubator for 2 hours;

[0117] 5. Discard the upper layer of liquid, add 150 μl DMSO to each well, shake for 15 minutes, and wait for the formazan to completely dissolve;

[0118] 6. Measure the absorbance at 570 nm.

[0119] Three parallel experiments were performed, and the experimental results were averaged. The measured IC 50 See Table 1 for values.

[0120] Table 1

[0121]

[0122] Pharmacological tests showed that the compounds of the present invention exhibited significant anti-tumor activity against a variety of cancer cell lines. Among them, the IC values ​​of compound 13 against human cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87 were 2.34, 2.32, and 2.37, respectively. 50 The values ​​reach IC 50 The values ​​were 3.498±0.567μM, 4.568±0.464μM, 0.900±0.137μM and 2.620±0.284μM respectively. Compound 13 changed the rigid planar core structure of the anthracene or naphthalene ring and replaced it with a flexible dibenzocycloheptane structure. Compared with other compounds, it has significant inhibitory ability against four cell lines, and its activity against breast cancer MCF-7 cell line is increased by about 2 times.

[0123] Without being bound by any theory, the anticancer mechanism of anthracene-derived triphenyl quaternary phosphonium salts is believed to be that triphenyl quaternary phosphonium salts have strong lipophilicity and can interact with the hydrophobic region of the mitochondrial membrane, thereby being enriched in the mitochondria. Mitochondria are important organs for cell metabolism and energy supply, and are also an important energy source for the malignant growth of cancer cells. While targeting mitochondria, anthracene-derived triphenyl quaternary phosphonium salts also have the ability to inhibit DNA, ultimately inhibiting the transcription of mitochondrial DNA, affecting the normal physiological activities of mitochondria, and causing apoptosis of cancer cells, making compounds 4, 7, 9, 11, 13, 15, and 17 show good inhibitory activity against human cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell U87.

[0124] The above embodiments describe the preferred embodiments of the present invention in detail, but the present invention is not limited to the above embodiments and embodiments. Within the scope of the concept of the present invention, the technical solution of the present invention can be subjected to a variety of equivalent transformations, and these transformations all belong to the protection scope of the present invention. In order to avoid unnecessary repetition, the present invention will not further describe the possible combinations of various features, steps and / or elements; as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in: R1 is selected from halogen and C 1-6 alkyl; Ring A is selected from naphthyl, anthracenyl, phenanthrenyl and L1 is selected from a direct bond and C 1-6 Alkylene; X - represents a halogen ion; n is 0, 1, 2 or 3; m is 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halogen and C 1-3 alkyl; L1 is selected from a direct bond and a methylene group; X - Represents Cl - or Br - ; n is 0 or 1; m is 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from naphthyl, anthracenyl and 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Selected from:

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is selected from the following compounds:

6. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and optionally a pharmaceutically acceptable excipient.

7. Use of a compound of formula I according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 in the preparation of a medicament for treating or preventing cancer, preferably the cancer is selected from cervical cancer, gastric cancer, breast cancer and / or glioma; More preferably, the cancer involves the following cell lines: cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7 or glioma cell U87.

8. A method for preparing a compound of formula I according to any one of claims 1 to 5, comprising the steps of: The compound of formula II is reacted with triphenylphosphine to produce the compound of formula I, Where X - represents a halogen ion; X represents a halogen; wherein R1, Ring A, L1 and n are as defined for the compound of formula I in any one of claims 1 to 5.

9. The method according to claim 8, wherein the reaction is carried out in an organic solvent, preferably acetonitrile.

10. The method according to claim 8 or 9, wherein the reaction is carried out at -15°C to 100°C, preferably at 0°C to 50°C, more preferably at room temperature.

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