Aryl triazene compounds, their synthesis methods and applications in the preparation of anti-tumor drugs

Abstract

The present invention discloses an aryltriazene compound and its application in the preparation of anti-tumor drugs. The structure of the aryltriazene compound is shown in Formula I. The anti-cancer activity of the aryltriazene compound of the present invention is superior to that of the existing positive control drug dacarbazine; its safety index for tumor treatment is superior to that of dacarbazine; its cell permeability is superior to that of dacarbazine. The preparation method of the aryltriazene compound of the present invention has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economy and practicability. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of anti-tumor chemical drugs, and particularly relates to aryltriazene compounds, a synthesis method thereof, and applications in the preparation of anti-tumor drugs. Background Art

[0002] Alkylating agents are a type of cytotoxic drugs that can form carbocations or other reactive electrophilic groups in vivo, and then covalently bind to electron-rich groups (such as amino, mercapto, hydroxyl, carboxyl, phosphate groups, etc.) in biological macromolecules (such as DNA, RNA, enzymes, etc.) in cells, rendering them inactive or causing DNA molecules to break, resulting in the death of tumor cells. Alkylating agents were first applied clinically in 1942, mainly used for malignant lymphoma and chronic lymphocytic leukemia, and can also be used for malignant tumors, especially the superior vena cava syndrome caused by small cell lung cancer. Commonly used alkylating agents include cyclophosphamide, nitrogen mustard, thiotepa, lomustine, busulfan, dacarbazine, procarbazine, etc. Compared with other anti-tumor drugs, alkylating agents rarely produce drug resistance, and there is little cross-resistance, either between alkylating agents or between alkylating agents and non-alkylating agents, and the degree is relatively light. Myelosuppression and gastrointestinal reactions are common adverse reactions of this class of drugs.

[0003] Dacarbazine (MTIC), temozolomide (TMZ), etc. are all traditional triazene alkylating agents containing imidazole rings, mainly used for the treatment of cancers such as malignant melanoma, lymphoma, and lung cancer, but they all have serious toxic side effects such as gastrointestinal disorders, myelosuppression, and reproductive system damage, so their clinical use is mostly restricted; on the other hand, the imidazole ring has strong hydrophilic properties and poor cell membrane permeability, so alkylating agents containing imidazole rings are difficult to enter tumor cells and have poor bioavailability. To enhance the anti-tumor activity of triazene, reduce its toxic side effects, and improve its bioavailability, the present invention reports a class of novel aryltriazene alkylating agents. Summary of the Invention

[0004] In order to enhance the anti-tumor activity of triazene, reduce its toxic side effects, and improve its bioavailability, the purpose of the present invention is to provide aryltriazene compounds, a preparation method thereof, and applications in the preparation of anti-tumor drugs.

[0005] The purpose of the present invention is achieved by the following technical solutions:

[0006] An aryltriazene compound, the structure of which is shown in Formula I:

[0007]

[0008] Wherein Ar is 4-acylphenyl, and its structure is as follows:

[0009]

[0010] Among them, X is any one of the following structures:

[0011]

[0012] R is any one of the following structures:

[0013]

[0014] Among them, the Y group is H, halogen (F, Cl, Br, I), C1-C4 alkane, OCH n1 F n2 , NO2; for the OCH n1 F n2 , n1 and n2 are respectively 0-3, and the sum of n1 and n2 is 3;

[0015] The OCH n1 F n2 is preferably OCH3 or OCF3;

[0016] The Y group can be at any position on the aromatic ring, preferably at the para position of the aromatic ring;

[0017] Preferably, the aryltriazene compounds include the following specific compounds:

[0018]

[0019]

[0020] The compounds are respectively named A-CL-1, A-CL-2, A-CL-3, A-CL-4, A-CL-5, A-CL-6, A-CL-7, A-CL-8, A-CL-9, A-CL-10, A-CL-11, A-CL-12, A-CL-13, A-CL-14, A-CL-15, A-CL-16, A-CL-17, A-CL-18 and A-CL-19.

[0021] The preparation method of the aryltriazene compounds includes the following steps:

[0022] (1) Preparation of 4-carboxyphenyl diazonium salt

[0023] Dissolve p-aminobenzoic acid in a solvent, add an acid solution, control the temperature at 0~-10°C, and then slowly dropwise add 1~3 molar equivalents of sodium nitrite solution, and stir and react for 0.5~3 hours to obtain a 4-carboxyphenyl diazonium salt solution;

[0024] The synthesis route is as follows:

[0025]

[0026] In the above steps, the solvent is one of an acetonitrile-water mixture with a volume ratio of 2:1 or pure water; the acid is any one of hydrochloric acid or tetrafluoroboric acid;

[0027] (2) Preparation of 4-carboxyphenyltriazene

[0028] Dissolve 1-5 molar equivalents of secondary methylamine in an appropriate amount of water, add 3-10 molar equivalents of a base, control the temperature at 0 to -10 °C, and then slowly dropwise add the 4-carboxyphenyldiazonium salt solution prepared in (1). Stir and react at 0 to -10 °C for 1-5 hours. After the reaction is completed, adjust the pH to 2-3 with an acid, extract, and purify to obtain 4-carboxyphenyltriazene;

[0029] The synthesis route is as follows:

[0030]

[0031] The base is potassium carbonate or lithium carbonate; the acid is hydrochloric acid or sulfuric acid;

[0032] (3) Preparation of aryltriazene compounds

[0033] Dissolve 4-carboxyphenyltriazene and 1-5 molar equivalents of a condensation reagent in an appropriate amount of an organic solvent, place it in an ice bath, then add 1-5 molar equivalents of an organic base and 1-3 molar equivalents of N,N-diethylaminoethylamine. After stirring and reacting for 30 minutes, stir at room temperature for 24 hours. Quench with saturated brine, extract, and separate and purify to obtain aryltriazene compounds;

[0034] The synthesis route is as follows:

[0035]

[0036] The condensation reagent is composed of one or more of components A, B, or C;

[0037] Component A is 1-hydroxybenzotriazole (HOBT) and / or 3-hydroxypyridinetriazole (HABT);

[0038] Component B is N,N-diisopropylethylamine (DIPEA) and / or 2,2,6,6-tetramethylpiperidine;

[0039] Component C is at least one of 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), ethyl chloroformate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-diisopropylcarbodiimide (DIC), benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), or 1-chloro-N,N,2-trimethylallylamine;

[0040] Preferably, the condensation reagent is a mixture of EDCI, HOBT and DIPEA;

[0041] The aryltriazene compounds of the present invention and their physiologically acceptable salts have anti-tumor activity and can be used to prepare anti-tumor drugs;

[0042] The tumors are malignant lymphoma, lung cancer, liver cancer, breast cancer, glioma or multiple myeloma;

[0043] The physiologically acceptable salts are tartrate, sulfate, hydrochloride;

[0044] The physiologically acceptable salts of the aryltriazene compounds are prepared by the following steps:

[0045] Dissolve the aryltriazene compound in an organic solvent containing 1.05 - 3.0 molar amounts of acid (HA), stir and react at -10°C to 40°C for 3 - 20 hours, separate the solid compound, wash it, and then redissolve the solid compound in water and freeze-dry to obtain the physiologically acceptable salt of the aryltriazene compound;

[0046] Preferably, the organic solvent is a mixed solution of methanol and dichloromethane with a volume ratio of 1:1.

[0047] The present invention has the following advantages and effects compared with the prior art:

[0048] 1. The anti-cancer activity of the aryltriazene compounds of the present invention is superior to that of the existing positive control drug dacarbazine; 2. The toxicity of the aryltriazene compounds of the present invention is lower than that of the positive control drug dacarbazine; 3. The small intestine absorption activity of the aryltriazene compounds of the present invention is superior to that of the positive control drug dacarbazine; 4. The preparation method of the aryltriazene compounds of the present invention has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economy and practicality. Detailed Embodiments

[0049] The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.

[0050] Example 1

[0051] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl)-3-methyl-3-cyclohexyltriazene (A-CL-1)

[0052] Comprising the following steps:

[0053] 1.1. Preparation of 4-carboxyphenyl diazonium salt

[0054] Weigh 1.0 g (7.3 mmol) of the drug p-aminobenzoic acid into a 100 ml reaction flask, add 20 ml of acetonitrile and 10 ml of water to dissolve it, and then add 3.5 ml of concentrated hydrochloric acid and place it in an ice bath. Dissolve 1.0 g (14.6 mmol) of sodium nitrite in a small amount of water, slowly drip it into the round-bottomed flask, and stir at 0 °C for 2 h to obtain 4-carboxyphenyl diazonium salt. Without separation and purification, directly put it into the next reaction.

[0055] 1.2. Preparation of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene

[0056] Add 2.8 mL (21.9 mmol) of N-methylcyclohexylamine, 3.02 g (21.9 mmol) of potassium carbonate and a small amount of water to a 100 ml round-bottomed flask, stir to dissolve, cool to 0 °C, and slowly drip the 4-carboxyphenyl diazonium salt solution prepared in 1.1 under stirring. After the addition is complete, react at 0 °C for 3 - 4 h, and track the reaction process by TLC plate spotting. After the reaction is completed, adjust the pH value to 2 - 3 with dilute hydrochloric acid, extract with ethyl acetate (4×50 ml), spin-dry the solvent, and recrystallize with ethanol to obtain 1.53 g of orange-red solid, with a yield of 80.3%. 1 H NMR(400MHz,DMSO-d6)δ:12.69(s,1H),7.90(d,J=8.6Hz,2H),7.39(d,J=8.6Hz,2H),3.78(tt,J=11.6,3.5Hz,1H),3.36(s,3H),1.92(d,J=11.1Hz,2H),1.81(d,J=13.2Hz,2H),1.67 - 1.54(m,3H),1.42 - 1.28(m,2H),1.18(tt,J=12.8,3.4Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ:167.2,154.5,130.5(2),126.6,119.9(2),64.4,40.3,33.2(2),31.1(2),25.0。

[0057] 1.3. Preparation of A-CL-1

[0058] Weigh 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene into a 50 ml reaction flask, add 228.0 mg (0.6 mmol) of HATU, dissolve it with redistilled DCM / DMF = 10 / 1 (V / V), place it in an ice bath, then add 0.3 mL of DIPEA (1.5 mmol) and 0.1 ml of N,N-diethylaminoethylamine (1.2 mmol), stir for 30 min and then transfer it to room temperature for reaction for 24 h. After the reaction is completed, add 50 mL of saturated brine to quench the reaction, extract with DCM (3×50 mL), combine the organic phases, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography (DCM / MeOH = 10 / 1, V / V, R f = 0.23) with gradient elution to obtain 153.0 mg of a yellow milky liquid with a yield of 85.1%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.72 (s, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 3.79 (t, J = 11.7 Hz, 1H), 3.57 (d, J = 5.7 Hz, 2H), 3.15 (s, 3H), 3.07 (s, 6H), 1.92 (d, J = 11.3 Hz, 2H), 1.83 (s, 2H), 1.61 (dd, J = 24.3, 12.3 Hz, 3H), 1.41 - 1.33 (m, 2H), 1.26 - 1.23 (m, 1H), 1.18 (d, J = 14.2 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6) δ: 166.7, 153.8, 130.3, 128.8 (2), 120.2 (2), 64.7, 50.8, 47.2 (2), 40.2, 35.3, 33.5 (2), 31.6 25.5, 25.4, 9.6 (2). All data confirm that the prepared compound is 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-cyclohexyltriazene (A-CL-1), and its structure is as follows:

[0059]

[0060] Example 2

[0061] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-phenyltriazene (A-CL-2).

[0062] It includes the following steps:

[0063] 2.1. Preparation of 4-carboxyphenyl diazonium salt

[0064] Change the feeding amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare according to the experimental method described in Step 1.1.

[0065] 2.2. Preparation of 1-(4-carboxyphenyl)-3-methyl-3-phenyltriazene

[0066] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate with 0.6 mL (6.0 mmol) of N-methylaniline and 0.8 g (6.0 mmol) of potassium carbonate respectively, and prepare according to the experimental method described in Step 1.2. 543.5 mg of yellow solid was obtained, with a yield of 72.9%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.00 (d, J = 8.6 Hz, 2H), 7.61 (dd, J = 11.8, 8.7 Hz, 4H), 7.49 - 7.44 (m, 2H), 7.22 (t, J = 7.3 Hz, 1H), 3.68 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ: 167.3, 153.6, 144.8, 131.1 (2), 129.8 (2), 126.1, 124.8, 121.4, 120.8, 118.0 (2), 33.5.

[0067] 2.3. Preparation of A-CL-2

[0068] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene with 127.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-phenyltriazene, and prepare according to the experimental method described in Step 1.3. 132 mg of red solid was obtained, with a yield of 74.7%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.66 - 7.53 (m, 4H), 7.46 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 3.67 (s, 5H), 3.30 - 3.06 (m, 6H), 1.26 (s, 3H), 1.22 (s, 3H); 1313C NMR (101 MHz, DMSO-d6) δ: 166.6, 152.6, 144.9, 131.9, 129.8 (2), 129.0 (2), 124.7, 121.2 (2), 117.9 (2), 50.5, 47.1 (2), 34.8, 33.4, 9.3, 8.9. All data confirmed that the prepared compound was 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-phenyltriazene (A-CL-2), and its structure was as follows:

[0069]

[0070] Example 3

[0071] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-chloro)phenyltriazene (A-CL-3)

[0072] Comprising the following steps:

[0073] 3.1. Preparation of 4-carboxyphenyl diazonium salt

[0074] Change the feed amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare according to the experimental method described in step 1.1.

[0075] 3.2. Preparation of 1-(4-carboxy)phenyl-3-methyl-3-(4-chloro)phenyltriazene

[0076] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate with 0.7 mL (6.0 mmol) of N-methyl-4-chloroaniline and 0.8 g (6.0 mmol) of potassium carbonate respectively, and prepare according to the experimental method described in step 1.2. 539.2 mg of yellow powder solid was obtained, and the yield was 63.8%. 1 1H NMR (400 MHz, DMSO-d6) δ: 8.00 (d, J = 8.5 Hz, 2H), 7.62 (dd, J = 8.7, 4.1 Hz, 4H), 7.50 (d, J = 9.0 Hz, 2H), 3.66 (s, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 167.6, 153.2, 143.7, 131.0 (2), 129.6 (2), 128.7, 121.4 (2), 119.4 (2), 33.2.

[0077] 3.3. Preparation of A-CL-3

[0078] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene with 144.5 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-(4-chlorophenyl)triazene, and prepare according to the experimental method described in Step 1.3. Obtain 141.3 mg of an orange viscous liquid with a yield of 72.9%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.60 (dd, J = 8.8, 3.5 Hz, 4H), 7.48 (d, J = 9.0 Hz, 2H), 3.63 (s, 3H), 3.43 (dd, J = 12.4, 6.1 Hz, 2H), 2.74 (d, J = 24.1 Hz, 6H), 1.05 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6) δ: 166.2, 152.1, 143.8, 132.8, 129.6 (2), 128.8 (2), 128.5, 121.3 (2), 119.2 (2), 51.5, 47.2 (2), 37.0, 33.1, 11.3 (2). All data confirm that the prepared compound is 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-chlorophenyl)triazene (A-CL-3), and its structure is as follows:

[0079]

[0080] Example 4

[0081] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-methoxyphenyl)triazene (A-CL-4)

[0082] Comprising the following steps:

[0083] 4.1. Preparation of 4-carboxyphenyl diazonium salt

[0084] Change the feed amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare according to the experimental method described in Step 1.1.

[0085] 4.2. Preparation of 1-(4-carboxyphenyl)-3-methyl-3-(4-methoxyphenyl)triazene

[0086] 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate were replaced with 0.8 mL (6.0 mmol) of N-methyl-4-methoxyaniline and 0.8 g (6.0 mmol) of potassium carbonate, respectively, and the preparation was carried out according to the experimental method described in Step 1.2. 693.8 mg of yellow solid was obtained, with a yield of 83.4%. 1 H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H), 3.71 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ: 167.7, 157.0, 153.7, 138.5, 131.0 (2), 129.1, 121.1 (2), 119.9 (2), 115.0 (2), 55.9, 34.3.

[0087] 4.3 Preparation of A-CL-4

[0088] 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene was replaced with 142.7 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-(4-methoxyphenyl)triazene, and the preparation was carried out according to the experimental method described in Step 1.3. 136.5 mg of black solid was obtained, with a yield of 71.2%. 1 H NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 3.92 (dd, J = 10.1, 5.5 Hz, 2H), 3.85 (s, 3H), 3.67 (d, J = 3.0 Hz, 3H), 3.31 - 3.27 (m, 2H), 3.19 (q, J = 7.2 Hz, 4H), 1.42 (t, J = 7.2 Hz, 6H); 1313C NMR (101 MHz, CDCl3) δ: 167.7, 156.7, 153.3, 138.8, 130.2, 128.6 (2), 121.2 (2), 119.2 (2), 114.5 (2), 55.6, 53.3, 48.7 (2), 35.7, 33.6, 8.8 (2). All data confirmed that the prepared compound was 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-methoxyphenyl)triazene (A-CL-4), and its structure was as follows:

[0089]

[0090] Example 5

[0091] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-benzyltriazene (A-CL-5)

[0092] Comprising the following steps:

[0093] 5.1 Preparation of 4-carboxyphenyl diazonium salt

[0094] The feed amount of p-aminobenzoic acid was changed to (0.4 g, 3.0 mmol), and it was prepared according to the experimental method described in step 1.1.

[0095] 5.2 Preparation of 1-(4-carboxy)phenyl-3-methyl-3-benzyltriazene

[0096] 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate were respectively replaced with 0.7 mL (6.0 mmol) of N-methylbenzylamine and 0.8 g (6.0 mmol) of potassium carbonate, and it was prepared according to the experimental method described in step 1.2. 593.4 mg of yellow flocculent solid was obtained, and the yield was 75.5%. 1 1H NMR (400 MHz, DMSO-d6) δ: 7.93 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.3 Hz, 2H), 7.31 (d, J = 7.3 Hz, 3H), 5.03 (s, 2H), 3.12 (s, 3H); 13 13C NMR (101 MHz, DMSO-d6) δ: 167.8, 154.2, 137.2, 130.9 (2), 129.7 (2), 129.2, 129.0 (2), 128.3, 120.5 (2), 59.6, 35.2.

[0097] 5.3 Preparation of A-CL-5

[0098] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene with 134.7 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-benzyltriazene, and prepare according to the experimental method described in Step 1.3. 132.2 mg of a red solid was obtained with a yield of 71.9%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.76 (s, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 6.4 Hz, 2H), 7.30 (d, J = 6.8 Hz, 3H), 5.02 (s, 2H), 3.54 (s, 2H), 3.10 (s, 3H), 2.96 (s, 6H), 1.15 (t, J = 6.5 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6) δ: 166.5, 153.2, 137.2, 131.0, 129.2 (2), 128.8 (2), 128.3 (2), 128.2, 120.4 (2), 59.5, 50.9, 49.1 (2), 47.2, 35.1, 10.1 (2). All data confirmed that the prepared compound was 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-benzyltriazene (A-CL-5), and its structure was as follows:

[0099]

[0100] Example 6

[0101] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene (A-CL-6)

[0102] Comprising the following steps:

[0103] 6.1. Preparation of 4-carboxyphenyl diazonium salt

[0104] Change the feed amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare according to the experimental method described in Step 1.1.

[0105] 6.2. Preparation of 1-(4-carboxyphenyl)-3-methyl-3-(4-chloro)benzyltriazene

[0106] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate with 0.6 mL (6.0 mmol) of N-methyl-4-chlorobenzylamine and 0.8 g (6.0 mmol) of potassium carbonate respectively, and prepare according to the experimental method described in Step 1.2. 603.4 mg of yellow solid was obtained with a yield of 83.2%. 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.4 Hz, 4H), 7.34 (d, J = 8.1 Hz, 2H), 5.03 (s, 2H), 3.12 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 167.7, 154.1, 136.4, 136.2, 130.9 (2), 130.3 (2), 129.2, 128.1 (2), 120.6 (2), 58.8, 35.2.

[0107] Preparation of 6.3.A-CL-6

[0108] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene with 144.5 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-(4-chloro)benzyltriazene, and prepare according to the experimental method described in Step 1.3. 152.3 mg of yellow viscous liquid was obtained with a yield of 75.9%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.83 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.7 Hz, 4H), 7.34 (d, J = 8.2 Hz, 2H), 5.01 (s, 2H), 3.61 (d, J = 5.8 Hz, 2H), 3.11 (s, 9H), 1.21 (t, J = 7.2 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ: 167.7, 153.4, 132.9, 132.6, 130.7, 130.3 (2), 129.0 (2), 128.6 (2), 120.7, 59.6, 53.3, 48.5 (2), 43.4, 35.7, 8.9 (2). All data confirm that the prepared compound is 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-chloro)benzyltriazene (A-CL-6), and its structure is as follows:

[0109]

[0110] Example 7

[0111] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-methoxy)benzyltriazene (A-CL-7)

[0112] Comprising the following steps:

[0113] 7.1. Preparation of 4-carboxyphenyl diazonium salt

[0114] Change the feeding amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare according to the experimental method described in step 1.1.

[0115] 7.2. Preparation of 1-(4-carboxy)phenyl-3-methyl-3-(4-methoxy)benzyltriazene

[0116] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate with 0.9 mL (6.0 mmol) of N-methyl-4-methoxybenzylamine and 0.8 g (6.0 mmol) of potassium carbonate respectively, and prepare according to the experimental method described in step 1.2. Obtain 726.9 mg of yellow powder solid, and the yield is 83.4%. 1 H NMR (400 MHz, DMSO-d6) δ: 7.93 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 4.95 (s, 2H), 3.74 (s, 3H), 3.09 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ: 167.7, 159.4, 154.3, 130.9 (2), 129.8 (2), 128.8, 127.8, 120.5 (2), 114.6 (2), 59.1, 55.6, 34.9.

[0117] 7.3. Preparation of A-CL-7

[0118] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxy)phenyl-3-methyl-3-cyclohexyltriazene with 149.7 mg (0.5 mmol) of 1-(4-carboxy)phenyl-3-methyl-3-(4-methoxy)benzyltriazene, and prepare according to the experimental method described in step 1.3. Obtain 145.3 mg of yellow viscous liquid, and the yield is 73.2%. 11H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 4.94 (s, 2H), 3.74 (s, 3H), 3.63 (s, 2H), 3.16 (s, 6H), 3.07 (s, 3H), 1.23 (t, J = 14.4 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ: 167.8, 159.3, 153.75, 129.5 (2), 129.3 (2), 128.6, 127.6, 120.6 (2), 114.2 (2), 59.2, 55.3, 53.1, 48.6 (2), 43.2, 35.6, 8.8 (2). All data confirmed that the prepared compound was 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-methoxy)benzyltriazene (A-CL-7), and its structure was as follows:

[0119]

[0120] Example 8

[0121] Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-trifluoromethoxy)benzyltriazene (A-CL-8)

[0122] It includes the following steps:

[0123] 8.1 Preparation of 4-carboxyphenyl diazonium salt

[0124] Change the feeding amount of p-aminobenzoic acid to (0.4 g, 3.0 mmol), and prepare it according to the experimental method described in step 1.1.

[0125] 8.2 Preparation of 1-(4-carboxy)phenyl-3-methyl-3-(4-trifluoromethoxy)benzyltriazene

[0126] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine and 3.02 g (21.9 mmol) of potassium carbonate with 1.0 mL (6.0 mmol) of N-methyl-4-trifluoromethoxybenzylamine and 0.8 g (6.0 mmol) of potassium carbonate respectively, and prepare it according to the experimental method described in step 1.2. 876.5 mg of yellow powder solid was obtained, and the yield was 82.7%. 1HNMR(400MHz, DMSO-d6) δ: 7.94 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 4.96 (s, 2H), 3.05 (s, 3H); 13 CNMR(101MHz, DMSO-d6) δ: 168.9, 154.7, 146.1, 131.6 (2), 130.5 (2), 129.8, 128.2, 127.3, 120.3 (2), 114.5 (2), 59.5, 35.3.

[0127] 8.3. Preparation of A-CL-8

[0128] Replace 130.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-cyclohexyltriazene with 176.6 mg (0.5 mmol) of 1-(4-carboxyphenyl)-3-methyl-3-(4-trifluoromethoxy)benzyltriazene, and prepare according to the experimental method described in step 1.3. 166.1 mg of yellow viscous liquid was obtained, with a yield of 73.6%. 1 H NMR(400MHz, DMSO-d6) δ: 8.85 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 4.93 (s, 2H), 3.64 (m, 2H), 3.15 (m, 6H), 3.05 (s, 3H), 1.24 (t, J = 14.3 Hz, 6H); 13 CNMR(101MHz, CDCl3) δ: 167.8, 158.7, 152.3, 131.2 (2), 130.8, 129.7, 128.9 (2), 127.6, 120.8 (2), 114.3 (2), 59.2, 53.5, 49.3 (2), 43.3, 35.7, 8.7 (2). All data confirm that the prepared compound is 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3-methyl-3-(4-trifluoromethoxy)benzyltriazene (A-CL-8), and its structure is as follows:

[0129]

[0130] Example 9

[0131] 9.1. Preparation of 1-(4-(N-isopropylamino)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-9) includes the following steps:

[0132] 9.1.1. Preparation of 4-carboxyphenyl diazonium salt

[0133] Prepared according to the experimental method described in Step 1.1

[0134] 9.1.2. Preparation of 1-(4-carboxyphenyl)-3,3-dimethyltriazene

[0135] Replace 2.8 mL (21.9 mmol) of N-methylcyclohexylamine with 2.99 g (21.9 mmol) of 33% aqueous dimethylamine solution, and prepare according to the experimental method described in Step 1.2. Recrystallize from ethanol to obtain 1.26 g of orange-yellow solid, with a yield of 89.4%. 1 H NMR (400 MHz, DMSO-d6) δ: 7.90 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 3.52 (s, 3H), 3.18 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 167.8, 154.0, 130.4(2), 126.8, 119.8(2), 43.0, 35.9.

[0136] 9.1.3. Preparation of 1-(4-(N-isopropylaminocarbonyl)phenyl)-3,3-dimethyltriazene (A-CL-9)

[0137] Weigh 193.2 mg (1.0 mmol) of the compound 1-(4-carboxyphenyl)-3,3-dimethyltriazene into a 50 mL reaction flask, add 287.6 mg (1.5 mmol) of EDCI and 202.6 mg (1.5 mmol) of HOBT, dissolve with redistilled DCM / DMF = 10 / 1 (V / V), place it in an ice bath, then add 0.5 ml of DIPEA (3.0 mmol). After reacting at 0 °C for 1 h, add 0.1 mL (1.2 mmol) of isopropylamine and stir for 30 min, then transfer to room temperature and continue to react for 24 h. After the reaction is completed, quench with 50 mL of saturated brine, extract with DCM (3 × 50 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, remove DMF with an oil pump, and the crude product can obtain 183.4 mg of white flocculent crystals after standing, with a yield of 78.3%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.12 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.10 (dd, J = 14.2, 6.6 Hz, 1H), 3.51 (s, 3H), 3.16 (s, 3H), 1.16 (d, J = 6.6 Hz, 6H); 1313C NMR (101 MHz, DMSO-d6) δ: 165.0, 152.5, 131.0 (2), 128.2 (2), 119.5, 42.9, 40.9, 35.9, 22.4 (2). All data confirmed that the prepared compound was 1-(4-(N-isopropylcarbamoyl)phenyl)-3,3-dimethyltriazene (A-CL-9), and its structure was as follows:

[0138]

[0139] 9.2. Preparation of 1-(4-(N-(2-dimethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-10)

[0140] It includes the following steps:

[0141] 9.2.1. Preparation of 4-carboxyphenyldiazonium salt

[0142] Prepared according to the experimental method described in step 1.1.

[0143] 9.2.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0144] Prepared according to the experimental method described in step 9.1.2.

[0145] 9.2.3. Preparation of 1-(4-(N-(2-dimethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-10)

[0146] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.13 mL (1.2 mmol) of N,N-dimethylethylenediamine, and prepare according to the method described in step 9.1.3. Silica gel column chromatography (DCM / MeOH = 30 / 1, V / V, R f = 0.41) gradient elution for separation and purification to obtain 209.3 mg of white solid, with a yield of 79.4%. 1 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (t, J = 5.6 Hz, 1H), 7.86 (m, 2H), 7.43 (m, 2H), 3.59 (dd, J = 11.7, 5.8 Hz, 2H), 3.53 (s, 3H), 3.25 (t, J = 6.0 Hz, 2H), 3.18 (s, 3H), 2.85 (s, 6H); 13CNMR (101 MHz, DMSO-d6) δ: 167.1, 153.4, 130.4 (2), 120.1 (2), 56.7, 43.5 (2), 43.1 (2), 36.5. All data confirm that the prepared compound is 1-(4-(N-(2-dimethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-10), and its structure is as follows:

[0147]

[0148] 9.3. Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-11)

[0149] It includes the following steps:

[0150] 9.3.1. Preparation of 4-carboxyphenyl diazonium salt

[0151] Prepared according to the experimental method described in Step 1.1.

[0152] 9.3.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0153] Prepared according to the experimental method described in Step 9.1.2.

[0154] 9.3.3. Preparation of 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-11)

[0155] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.17 mL (1.2 mmol) of N,N-diethylaminoethylamine, and prepare according to the method described in Step 9.1.3. The crude product is separated and purified by gradient elution on a silica gel column (DCM / MeOH = 25 / 1, V / V, R f = 0.23), and 245.2 mg of orange milky liquid is obtained with a yield of 84.2%. 1 H NMR (400 MHz, DMSO-d6) δ: 8.43 (t, J = 5.6 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 3.50 (s, 3H), 3.35 (dd, J = 13.7, 6.1 Hz, 2H), 3.15 (s, 3H), 2.66–2.54 (m, 6H), 0.99 (t, J = 7.1 Hz, 6H); 1313C NMR (101 MHz, DMSO-d6) δ: 166.4, 153.1, 131.1, 128.6 (2), 120.1 (2), 51.7, 47.2 (2), 43.3, 37.4, 36.3, 11.8 (2). All data confirmed that the prepared compound was 1-(4-(N-(2-(diethylamino)ethyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-11), and its structure was as follows:

[0156]

[0157] 9.4. Preparation of 1-(4-(N-(3-(dimethylamino)propyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-12)

[0158] It includes the following steps:

[0159] 9.4.1. Preparation of 4-carboxyphenyl diazonium salt

[0160] Prepared according to the experimental method described in step 1.1.

[0161] 9.4.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0162] Prepared according to the experimental method described in step 9.1.2.

[0163] 9.4.3. Preparation of 1-(4-(N-(3-(dimethylamino)propyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-12)

[0164] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.15 mL (1.2 mmol) of 3-dimethylaminopropylamine, and prepare according to the method described in step 9.1.3. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 25 / 1, V / V, R f = 0.32) gradient elution to obtain 229.30 mg of yellow powder solid, with a yield of 82.7%. 1 1H NMR (400 MHz, DMSO-d6) δ: 8.43 (t, J = 5.5 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 3.51 (s, 3H), 3.27 (dd, J = 12.8, 6.9 Hz, 2H), 3.17 (s, 3H), 2.26 (t, J = 7.1 Hz, 2H), 2.14 (s, 6H), 1.65 (s, 2H); 1313C NMR (101 MHz, DMSO-d6) δ: 166.2, 153.0, 131.3, 128.5 (2), 120.1 (2), 57.4, 45.6 (2), 43.4 (2), 38.2, 27.6. All data confirm that the prepared compound is 1-(4-(N-(3-(dimethylamino)propyl)carbamoyl)phenyl)-3,3-dimethyltriazene (A-CL-12), and its structure is as follows:

[0165]

[0166] 9.5. Preparation of 1-(4-(N-(3-(diethylamino)propyl)carbamoyl)phenyl)-3,3-dimethyltriazene (A-CL-13)

[0167] It includes the following steps:

[0168] 9.5.1. Preparation of 4-carboxyphenyl diazonium salt

[0169] Prepared according to the experimental method described in Step 1.1.

[0170] 9.5.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0171] Prepared according to the experimental method described in Step 9.1.2.

[0172] 9.5.3. Preparation of 1-(4-(N-(3-(diethylamino)propyl)carbamoyl)phenyl)-3,3-dimethyltriazene (A-CL-13)

[0173] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.18 mL (1.2 mmol) of 3-diethylaminopropylamine, and prepare according to the method described in Step 9.1.3. The crude product was separated and purified by gradient elution on a silica gel column (DCM / MeOH = 45 / 1, V / V, R f = 0.54) to obtain 214.8 mg of an orange-yellow oily solid with a yield of 84.3%. 1 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (t, J = 5.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 3.52 (s, 3H), 3.12 (dd, J = 20.2, 12.9 Hz, 9H), 1.94–1.82 (m, 2H), 1.25 (dd, J = 7.9, 4.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 6H); 13CNMR (101 MHz, DMSO-d6) δ: 166.9, 153.5, 153.3, 130.8, 128.7 (2), 120.1 (2), 55.3, 49.4 (2), 46.9, 43.4, 36.9, 24.3, 9.1 (2). All data confirm that the prepared compound is 1-(4-(N-(3-(diethylamino)propyl)carbamoyl)phenyl-3,3-dimethyltriazene (A-CL-13), and its structure is as follows:

[0174]

[0175] 9.6. Preparation of 1-(4-(O-(2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-14)

[0176] It includes the following steps:

[0177] 9.6.1. Preparation of 4-carboxyphenyl diazonium salt

[0178] Prepared according to the experimental method described in Step 1.1.

[0179] 9.6.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0180] Prepared according to the experimental method described in Step 9.1.2.

[0181] 9.6.3. Preparation of 1-(4-(O-(2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-14)

[0182] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.12 mL (1.2 mmol) of N,N-dimethylethanolamine, and prepare according to the method described in Step 9.1.3. The crude product is separated and purified by gradient elution on a silica gel column (DCM / MeOH = 30 / 1, V / V, R f = 0.43) to obtain 198.3 mg of pink granular solid, and the yield is 82.7%. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 4.48 - 4.40 (m, 2H), 3.54 (s, 4H), 3.20 (s, 3H), 3.09 - 3.03 (m, 2H), 2.55 (s, 6H); 1313C NMR (101 MHz, DMSO-d6) δ 165.9, 154.9, 131.0 (2), 125.9, 120.4 (2), 61.6, 57.2, 44.9 (2), 43.6 (2), 36.5. All data confirm that the prepared compound is 1-(4-(O-(2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-14), and its structure is as follows:

[0183]

[0184] 9.7. Preparation of 1-(4-(O-(2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-15)

[0185] It includes the following steps:

[0186] 9.7.1. Preparation of 4-carboxyphenyl diazonium salt

[0187] Prepared according to the experimental method described in Step 1.1.

[0188] 9.7.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0189] Prepared according to the experimental method described in Step 9.1.2.

[0190] 9.7.3. Preparation of 1-(4-(O-(2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-15)

[0191] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.16 mL (1.2 mmol) of N,N-diethylethanolamine, and prepare according to the method described in Step 9.1.3. The crude product is separated and purified by gradient elution on a silica gel column (DCM / MeOH = 50 / 1, V / V, R f = 0.33) to obtain 203.1 mg of an orange-yellow viscous solid with a yield of 82.9%. 1 1H NMR (400 MHz, DMSO-d6) δ: 7.97 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.4 Hz, 2H), 4.49 (s, 2H), 3.55 (s, 3H), 3.11 (s, 9H), 1.19 (s, 6H); 13CNMR (101 MHz, DMSO-d6) δ: 165.7, 155.1, 131.1 (2), 125.5, 120.5 (2), 59.7, 50.4 (2), 47.8, 43.6, 36.6, 9.3 (2). All data confirm that the prepared compound is 1-(4-(O-(2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-15), and its structure is as follows:

[0192]

[0193] 9.8. Preparation of 1-(4-(O-(3-dimethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-16)

[0194] It includes the following steps:

[0195] 9.8.1. Preparation of 4-carboxyphenyl diazonium salt

[0196] Prepared according to the experimental method described in Step 1.1.

[0197] 9.8.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0198] Prepared according to the experimental method described in Step 9.1.2.

[0199] 9.8.3. Preparation of 1-(4-(O-(3-dimethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-16)

[0200] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.14 mL (1.2 mmol) of 3-dimethylaminopropanol, and prepare according to the method described in Step 9.1.3. The crude product is separated and purified by gradient elution on a silica gel column (DCM / MeOH = 70 / 1, V / V, R f = 0.47) to obtain 191.2 mg of a pale yellow viscous solid, with a yield of 82.4%. 1 H NMR (400 MHz, DMSO-d6) δ: 7.95 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 4.31 (t, J = 6.2 Hz, 2H), 3.55 (s, 3H), 3.20 (s, 3H), 3.12 - 3.06 (m, 2H), 2.71 (s, 6H), 2.11 - 2.01 (m, 2H); 1313C NMR (101 MHz, DMSO-d6) δ: 165.9, 154.9, 131.0, 125.9 (2), 120.4 (2), 62.2, 54.2 (2), 43.6, 42.4, 36.6, 23.9. All data confirmed that the prepared compound was 1-(4-(O-(3-dimethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-16), and its structure was as follows:

[0201]

[0202] 9.9. Preparation of 1-(4-(O-(3-diethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-17)

[0203] It includes the following steps:

[0204] 9.9.1. Preparation of 4-carboxyphenyl diazonium salt

[0205] Prepared according to the experimental method described in Step 1.1.

[0206] 9.9.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0207] Prepared according to the experimental method described in Step 9.1.2.

[0208] 9.9.3. Preparation of 1-(4-(O-(3-diethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-17)

[0209] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.17 mL (1.2 mmol) of 3-diethylaminopropanol, and prepare according to the method described in Step 9.1.3. The crude product was separated and purified by gradient elution on a silica gel column (DCM / MeOH = 45 / 1, V / V, R f = 0.53) to obtain 254.9 mg of an orange milky liquid with a yield of 83.2%. 1 1H NMR (300 MHz, DMSO-d6) δ: 7.96 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H), 3.55 (s, 3H), 3.17 (dt, J = 14.5, 6.6 Hz, 9H), 2.17 - 2.01 (m, 2H), 1.20 (d, J = 14.5 Hz, 6H); 1313C NMR (101 MHz, DMSO-d6) δ: 166.1, 154.9, 130.9 (2), 125.8, 120.5 (2), 62.1, 48.6, 47.0, 43.6 (2), 36.6 (2), 23.6, 9.1 (2). All data confirm that the prepared compound is 1-(4-(O-(3-diethylamino)propyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-17), and its structure is as follows:

[0210]

[0211] 9.10. Preparation of 1-(4-(O-(1-methyl-2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-18)

[0212] Comprising the following steps:

[0213] 9.10.1. Preparation of 4-carboxyphenyl diazonium salt

[0214] Prepared according to the experimental method described in Step 1.1.

[0215] 9.10.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0216] Prepared according to the experimental method described in Step 9.1.2.

[0217] 9.10.3. Preparation of 1-(4-(O-(1-methyl-2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-18)

[0218] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.13 mL (1.2 mmol) of 1-dimethylamino-2-propanol, and prepare according to the method described in Step 9.1.3. The crude product was separated and purified by gradient elution on a silica gel column (DCM / MeOH = 70 / 1, V / V, R f = 0.45) to obtain 202.2 mg of a pale yellow solid with a yield of 87.0%. 1 1H NMR (400 MHz, DMSO-d6) δ: 7.91 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 5.19 (dd, J = 11.7, 6.5 Hz, 1H), 3.54 (s, 3H), 3.19 (s, 3H), 2.59 (dd, J = 12.8, 7.5 Hz, 1H), 2.38 (dd, J = 12.9, 4.4 Hz, 1H), 2.21 (s, 6H), 1.27 (d, J = 6.3 Hz, 3H); 1313C NMR (101 MHz, DMSO-d6) δ: 165.5, 154.7, 130.8 (2), 126.5, 120.4 (2), 69.0, 64.0, 55.4, 46.1 (2), 43.6, 36.6, 18.8. All data confirmed that the prepared compound was 1-(4-(O-(1-methyl-2-dimethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-18), and its structure was as follows:

[0219]

[0220] 9.11. Preparation of 1-(4-(O-(1-methyl-2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-19)

[0221] It includes the following steps:

[0222] 9.11.1. Preparation of 4-carboxyphenyl diazonium salt

[0223] Prepared according to the experimental method described in step 1.1.

[0224] 9.11.2. Preparation of 1-(4-carboxy)phenyl-3,3-dimethyltriazene

[0225] Prepared according to the experimental method described in step 9.1.2.

[0226] 9.11.3. Preparation of 1-(4-(O-(1-methyl-2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-19)

[0227] Replace 0.1 mL (1.2 mmol) of isopropylamine with 0.18 mL (1.2 mmol) of 1-diethylamino-2-propanol, and prepare according to the method described in step 9.1.3. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 30 / 1, V / V, R f = 0.44) gradient elution to obtain 213.4 mg of a white viscous solid with a yield of 83.5%. 1 1H NMR (400 MHz, DMSO-d6) δ: 7.97 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.42 - 5.28 (m, 1H), 3.55 (s, 4H), 3.20 (s, 8H), 1.35 (d, J = 6.3 Hz, 3H), 1.24 (t, J = 6.7 Hz, 6H); 1313C NMR (101 MHz, DMSO-d6) δ: 165.4, 155.0, 131.1 (2), 125.9, 120.4 (2), 54.1, 42.3, 38.7 (2), 36.2, 31.2, 18.5, 17.2, 12.9. All data confirmed that the prepared compound was 1-(4-(O-(1-methyl-2-diethylamino)ethyl)oxycarbonyl)phenyl-3,3-dimethyltriazene (A-CL-19), and its structure was as follows:

[0228]

[0229] Example 10

[0230] Proliferation Inhibition Experiment of Aryl Triazene Compounds on Tumor Cells

[0231] Experimental Method: Cells in the logarithmic growth phase (human hepatocellular carcinoma cells (HepG-2), rat glioma cells (C6), human colon cancer cells (SW620), human prostate cancer cells (PC-3), mouse melanoma cells (B16), human lung cancer cells (A549), all purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences) were respectively added with an appropriate amount of RPMI 1640 culture medium (containing 10% fetal bovine serum and 100 U / mL penicillin), and the cell concentration was adjusted to 5×10 5 cells / mL. The tumor cell suspension of 100 μL was inoculated into a 96-well culture plate. After being placed in a 5% CO2 incubator and cultured at 37 °C for 24 h, the prepared test drug was added (the control group did not add the drug), and after continuing to culture for 48 h, 30 μL of 5 mg / mL MTT solution was added to each well, and it was incubated at 37 °C for 4 h. The supernatant was discarded, and 100 μL of DMSO was added to each well to dissolve the formed formazan. The OD value was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) instrument (Thermo product).

[0232] The cell growth inhibition rate was calculated according to the following formula:

[0233]

[0234] A curve was plotted with the sample concentration as the abscissa and the cell growth inhibition rate as the ordinate. According to the cell growth inhibition curve, the half-maximal inhibitory concentration IC 50 value was calculated.

[0235] Experimental Results: As can be seen from Table 1, the positive control drug dacarbazine (Dcb) only showed good proliferation inhibitory activity against B16, but the IC 50The value was still greater than 200 μM, being 259.5 ± 11.2 μM; while the aryltriazene compounds tested showed better cell proliferation inhibitory activity against all the tumor cell lines tested than the positive control drug Dcb. In particular, compound A-CL-2 showed excellent inhibitory activity against C6 and PC-3, with its IC 50 value less than 10 μM; A-CL-3 showed excellent proliferation inhibitory activity against C6, SW620, PC-3 and B16, with its IC 50 value less than 10 μM.

[0236] The results in Table 1 revealed that the structures of X and R had an impact on their antitumor activities. When X was 2-diethylaminoethylamino, the corresponding compounds had better antitumor activities; when R was an aryl group, they showed better antitumor activities than the corresponding arylmethyl groups.

[0237] Table 1. IC 50 a values (μM) of the target compounds against different tumor cells after 48 h

[0238]

[0239] a The IC 50 values were the averages of 4 independent experiments.

[0240] Example 11

[0241] Safety investigation experiment of aryltriazene compounds

[0242] Experimental method: According to the experimental method described in Example 9, the half-inhibitory constants (IC 50 ) of dacarbazine, A-CL-2, A-CL-3, A-CL-4 and A-CL-6 against human normal liver cells (LO2), human liver cancer cells (HepG-2), rat glioma cells (C6), human colon cancer cells (SW620), human prostate cancer cells (PC-3), mouse melanoma cells (B16), and human lung cancer cells (A549) were measured respectively. Their safety indices (SI) were calculated respectively. The safety index was defined as:

[0243] SI = IC 50 (LO2) / IC 50 (tumor cells)

[0244] Experimental results: The results are shown in Table 2. The positive control drug dacarbazine has high safety for B16 cells, and its SI value is 2.0; A-CL-2 has good safety for C6, SW620 and PC-3, and its SI values are all greater than 2.0; A-CL-3 has good safety for SW620, PC-3 and B16, and its SI values are all greater than 2.0; A-CL-4 has good safety for HepG-2, C6, SW620 and B16, and its SI values are all greater than 2.0; A-CL-6 shows high safety for all the investigated tumor cells, and its SI values are all greater than 2.0; It can be seen that the compounds of the present invention all show good safety and show strong cytotoxicity to tumor cells.

[0245] Table 2. Safety index (SI) of the target compound on different tumor cells

[0246]

[0247] Example 12

[0248] Experiment on the lipophilic and hydrophilic properties of aryltriazene compounds

[0249] Experimental method: a) Establish the detection standard curve of each sample to be tested. Dissolve Dcb, A-CL-2, A-CL-3, A-CL-4 and A-CL-4 in enzymatic hydrolysis buffer (50 mM Tris-HCl, 1.0 M NaCl, pH 7.4) respectively, and set 5 concentration gradients of 0.012725, 0.006363, 0.003181, 0.001591, 0.000795 μg / ml respectively. Draw the standard curve with the peak area as the ordinate and the drug concentration as the abscissa. This experiment is repeated 3 times; b) n-octanol saturated with aqueous solution and aqueous solution saturated with n-octanol. After mixing n-octanol and water in equal proportions, stir for 24 h to saturate the two phases with each other. After standing and separating the layers, the two phases are separated and stored separately for later use; b) Weigh 10 mg of the sample to be tested accurately, place it in a 10 mL volumetric flask, add n-octanol saturated with aqueous solution to dissolve the sample and dilute it to the scale. Accurately pipette 8 mL from it into a 25 mL volumetric flask, and add 8 mL of aqueous solution saturated with n-octanol. After shaking the 25 mL volumetric flask for 3 h, stand and separate the aqueous phase and the oil phase, filter through a 0.22 μm filter membrane, inject 10 μl each time, and use HPLC to measure the peak area, substitute it into the standard curve equation, and calculate the content of the sample to be tested in each phase.

[0250] Calculation formula of oil-water distribution coefficient:

[0251] Experimental results: The results are shown in Table 3. The LgP value of the positive control drug Dcb is 0.3, which is less than 1, indicating that Dcb has high solubility in water, low passive diffusion permeability, poor absorption and brain permeability, and high renal clearance. The LgP value of the compound of the present invention is between 3.0 and 4.0, indicating that such compounds have good permeability, increased binding to metabolic enzymes, and high metabolic degree.

[0252] Table 3. Hydrophilic-lipophilic balance of the target compounds

[0253]

[0254] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. An aryltriazene compound, characterized in that The structure is as shown in Formula I: wherein Ar is 4-acylphenyl, and its structure is as follows: wherein X is any one of the following structures: R is any one of the following structures: wherein the Y group is halogen, C1-C4 alkane, OCH n1 F n2 , NO2; The described OCH n1 F n2 , where n1 and n2 are each 0 - 3, and the sum of n1 and n2 is 3.

2. The aryltriazene compound according to claim 1, wherein: The OCH described above n1 F n2 is OCH3 or OCF3.

3. The aryltriazene compound according to claim 1, characterized in that: The Y group is in the para position of the aromatic ring.

4. The aryltriazene compound according to claim 1, wherein Specific compounds selected from the following:

5. Use of the aryltriazene compound according to any one of claims 1-3 and / or its physiologically acceptable salt in the preparation of an anti-tumor drug, characterized in that: The tumor is liver cancer, glioma, colon cancer, prostate cancer, melanoma or lung cancer.

6. Use of the aryltriazene compound and / or its physiologically acceptable salt in the preparation of an anti-tumor drug, characterized in that: The aryltriazene compound is selected from the following specific compounds: The tumor is liver cancer, glioma, colon cancer, prostate cancer, melanoma or lung cancer.

7. The application according to claim 5 or 6, characterized in that: The physiologically acceptable salt is tartrate, sulfate, hydrochloride.

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