TWI535690B - Hepatocellular cancer therapeutic agent precursor and its manufacturing method - Google Patents

Description

Liver cancer therapeutic agent label precursor and manufacturing method thereof

The invention relates to a label precursor and a manufacturing method thereof, in particular to a compound L-Nε-[2-(trityl)thioethyl]-Nα- which is used for the treatment of liver cancer and can be combined with a radioisotope. 8-heptadecenylcarbonyl-6-aza-5-oxy-9-(trityl)thio-1,5-nonanediamine (L-Nε-[2-(Triphenylmethyl)thioacetyl]- Nα-8-heptadecenylcarbonyl-6-aza-5-oxo-9-(triphenyl methyl)thio-1,5-nonanediamine) (hereinafter referred to as HOC-NODA), and L-Nε-[2-(tritylmethyl) Thioethyl]-Nα-5,6-diiodotetradecylcarbonyl-6-aza-5-oxy-9-(trityl)thio-1,5-nonanediamine ( L-Nε-[2-(Triphenylmethyl)thioacetyl]-Nα-5,6-diiodotetradecylcarbonyl-6-aza-5-oxo-9-(triphenylmethyl)thio-1,5-nonanediamine) (hereinafter referred to as TDI-NODA) .

Primary liver cancer (referred to as liver cancer) is one of the ten most common and serious malignant tumors in the world. It has 260,000 cases per year, accounting for 4% of malignant tumors. In recent years, the incidence rate is on the rise, causing human health. Great threat. Therefore, it is of great significance to improve the diagnosis and treatment level of liver cancer.

At present, the treatment methods for liver cancer are more commonly used, including: (1) surgical resection; (2) stop tube embolization; (3) local alcohol injection; (4) local acetic acid injection; (5) microwave coagulation; 6) cryotherapy; (7) chemotherapy; (8) radiation therapy; (9) immunotherapy; (10) supportive treatment and other ten treatments. According to the 2010 American Liver Disease Society guidelines for liver cancer treatment, early treatment has the best effect. Through surgical resection and tumor ablation treatment, there is still a chance to be cured. The 5-year survival rate is about 50%-75%. However, in the mid-term, which only accepts embolization, the 3-year survival rate is only 50%; while the late-year survival period is only 50% or less.

The average person talks about the color change of liver cancer, mainly the rapid growth of liver tumors, which makes the liver cancer patients usually diagnosed in the middle and late stages, and the treatment effect is relatively poor at the early stage. However, if the target drug can be applied to patients with advanced liver cancer, in addition to prolonging the survival period, the risk of death can be reduced and the quality of life of the patient can be relatively improved.

Lipiodol is an iodinated poppy seed oil that has a significant uptake of liver cancer tissue. It can selectively accumulate in the patient's liver cancer tissue. The ratio of libidol transcatheter hepatic artery perfusion as a diagnosis and treatment of liver cancer has an increasing tendency, and even small tumors can be detected. Based on libido, it can selectively stay in the patient's liver cancer tissue, so it can be used to carry some chemotherapeutic and radiotherapy drugs to achieve the target treatment purpose.

In recent years, target therapeutic drugs have been widely used in anticancer therapy. The principle of target therapy is to block the path of mutation, proliferation or spread involved in the progression of cancer cells, block the necessary path of cancer cell growth or repair, or deprive its nutrient source by inhibiting tumor angiogenesis. To achieve the purpose of inhibiting the growth of cancer cells, promoting cancer cell death, and preventing the spread of cancer cells. These drugs can attack specific kinases, molecules, or cancer cell surface antigens in cancer cells, and thus are more selective than traditional chemical treatments, and thus reduce the side effects caused by many anticancer drugs.

The radioisotope 铼-188 is a nuclear species of radiant beta (β max = 2.12 MeV) and gamma (Y = 155 keV) with a half-time of 16.9 hours. It can be obtained by a generator, is easy to obtain, and its radiation energy and half-life are suitable for the diagnosis and treatment of diseases. It is a medical isotope with potential for development, especially in the in vivo radiation therapy of tumors. Important performance. Therefore, libido containing 铼-188 is considered to be an effective therapeutic agent for radiation therapy of liver cancer in vivo.

Therefore, if a therapeutic agent precursor can be proposed to have a high solubility in libido and a property in which Libido can selectively stay in a patient's liver cancer tissue, it is possible to treat liver cancer. Providing tremendous benefits.

The main object of the present invention is to provide a precursor of liver cancer therapeutic agent, which has a chemical structure with a ligand, can be combined with a complex of a radioisotope, and has a chemical structure with a specific functional group and is soluble. Libido, or further directly has the characteristics of libido, so that the combined radioisotope can stay in the liver cancer tissue of liver cancer patients, and is applied to the in vivo radiation therapy of liver cancer.

Another object of the present invention is to provide a method for producing a liver cancer therapeutic agent precursor precursor, which comprises preparing a compound structure by a series of chemical reactions to form a specific functional group to prepare the aforementioned compound HOC-NODA or TDI-NODA. Both can assist in the treatment of liver cancer, and the application is expected to be a novel therapeutic agent for liver cancer.

In order to achieve the above object, the present invention discloses a liver cancer therapeutic agent precursor and a method for producing the same, the liver cancer therapeutic agent precursor having a chemical structure: Wherein the functional group R is 8-heptadecenyl or 5,6-diiodotetradecyl.

Figure 1: It is a general structural diagram of the chemical structure of the precursor of liver cancer therapeutic agent in the present invention; Fig. 2 is a chemical structural diagram of the precursor of the liver cancer therapeutic agent HOC-NODA in the present invention; Fig. 3 is a chemical of the TDI-NODA precursor of the liver cancer therapeutic agent in the present invention. Structural diagram; Figure 4: It is a partial chemical reaction diagram of the precursor of the liver cancer therapeutic agent in the present invention; Fig. 5 is a precursor of the liver cancer therapeutic agent in the present invention. Part of the chemical reaction diagram; Figure 6 is a partial chemical reaction diagram of the precursor of the liver cancer therapeutic agent in the present invention; Figure 7 is a precursor of the liver cancer therapeutic agent in the present invention. Part of the chemical reaction pattern of the substance; Fig. 8 is a partial chemical reaction diagram of the precursor of the liver cancer therapeutic agent in the present invention; and Fig. 9 is a therapeutic agent for the liver cancer of the present invention. A partial chemical reaction diagram of the precursor of the label.

For a better understanding and understanding of the features and advantages of the present invention, the preferred embodiments and the detailed description are described as follows:

First, please refer to Fig. 1, which is a chemical structural formula of the precursor of the liver cancer therapeutic agent of the present invention; wherein R is two different functional groups. If R is 8-heptadecenyl, as shown in Fig. 2, the liver cancer therapeutic agent precursor is HOC-NODA. Whereas R is 5,6-diiodotetradecyl, as shown in Fig. 3, the liver cancer therapeutic agent precursor is TDI-NODA. The above two are based on the reactants to form a liver cancer therapeutic agent precursor with different functional groups, wherein the HOC-NODA is structurally and has a long-chain alkyl group on the one hand, which can increase its fat solubility and make a mismatch. The substance is easily soluble in libido and has the effect of increasing retention in liver cancer tissues; on the other hand, the structure of HOC-NODA can be bonded to ReO ³⁺ , which can be applied to the preparation of nucleoside medicines. TDI-NODA is already connected to the structure of Libido, which will increase its retention in liver cancer tissues, so it can be directly considered that it can be bonded to ReO ³⁺ without first dissolving it in libido. HOC-NODA is not the same. Both HOC-NODA and TDI-NODA can assist in the treatment of diseases. After combining with the above-mentioned 铼-188 ( ¹⁸⁸ Re) or another radioisotope such as 鎝-99m ( ^99m Tc), it forms a therapeutic marker for liver cancer. The substance is further applied as a nuclear medicine therapeutic agent for liver cancer.

The method for manufacturing a liver cancer therapeutic agent precursor precursor can refer to the chemical reaction formulas disclosed in the fourth to the ninth, respectively, and the step flow includes the steps: Step S1: Please refer to FIG. 4, using L-Nε -L-Nε-tert-butoxycarbonyllysine methyl ester and triphenylmethyl thio glycolic acid are subjected to amide amination to form L-Nε- Tri-butoxycarbonyl-Nα-[2-(triphenylmethyl)thioacetamido]-L-Nε-tert-butoxycarbonyl-Nα-[2-(triphenylmethyl)thioacetyl]lysine methyl ester (hereinafter referred to as compound 1); Step S2: Please refer to Figure 5 to hydrolyze the compound 1 to form L-Nε-t-butoxycarbonyl-Nα-[2-(tritylmethyl)thioethenyl] Leucine acid (L-Nε-tert-butoxycarbonyl-Nα-[2-(triphenylmethyl) thioacetyl] lysine) (hereinafter referred to as compound 2); Step S3: Please refer to Figure 6, using the compound 2 with [2-( Trimethylation of 2-(triphenylmethyl)thio]ethylamine to form L-Nε-tert-butoxycarbonyl-Nα-[2-(trityl)sulfide Ethyl]-6-aza-5-oxy -9-(trityl)thio-1,5-nonanediamine (L-Nε-tert-butoxycarbonyl-Nα-[2-(triphenylmethyl)) Thiaacetyl]-6-aza-5-oxo-9-(triphenyl methyl)thio-1,5-nonanediamine) (hereinafter referred to as compound 3); Step S4: Please refer to Figure 7, acidolysis of the compound 3 to form L -Nε-[2-(trityl)thioethenyl]-6-aza-5-oxy-9-(trityl)thio-1,5-nonanediamine (L-Nε -[2-(triphenylmethyl)thioacetyl]-6-aza-5-oxo-9-(triphenylmethyl)thio-1,5-nonanediamine) (hereinafter referred to as Compound 4); and Step S5: Please refer to Figures 8, 9 This compound 4 is subjected to a guanidine reaction with oleic acid or 6,7-diiodotetradecanoic acid to form HOC-NODA or TDI-NODA.

The HOC-NODA and TDI-NODA produced by the invention have a thiol protective structure, in view of the fact that the thiol is easily oxidized in a neutral or alkaline solution, and after being oxidized, it cannot be combined with 鎝-99m or 铼- Radioactive isotopes such as 188 form bonds and must be protected. There are many methods for protecting thiols. The present invention utilizes triphenylmethyl to protect two thiols in HOC-NODA and TDI-NODA, so that HOC-NODA and TDI-NODA can be stored at room temperature for a long time without Deterioration, this chemically stable property provides the convenience of HOC-NODA and TDI-NODA for convenient storage. Trityl advantage in that a weak bond energy of sulfur, heavy metals when present, sulfur - trityl (S-CPh ₃₎ of the bond is easily broken, thus forming the bonding of heavy metals and sulfur. Therefore, the present invention utilizes such a property that the trityl-protected thiol can be automatically detached when it is mismatched with hydrazine-99m or hydrazine-188 without removing the protecting group in advance.

Further, when the liver cancer therapeutic agent precursor precursor manufactured by the invention is applied, HOC-NODA and TDI-NODA are dissolved in trifluoroacetic acid, and an excess amount of triacetyl hexane is added to separate the thiol. The trityl group forms a solid which is insoluble in trifluoroacetic acid and can be removed by filtration or washed with n-hexane. The method is simple.

The following are the data and product analysis results of the present invention when actually synthesizing HOC-NODA and TDI-NODA.

Synthesis of Compound 1 : L-Nε-tert-butoxycarbonyllysine methyl ester hydrochloride (15.4 g, 51.7 mmol), tritylethyl ethane sulfide Alkyd (17.3 g, 51.7 mmol) as the reactant bis(cycloheximide)methane (1,3-dicyclohexylcarbodiimide) (16 g, 77.6 mmol) and N-hydroxysuccinimide (N-hydroxysuccinimide) 7.14 g, 62.0 mmol), and triethylamine (21.5 mL, 155.1 mmol) were dissolved in chloroform (250 mL) and heated at 50 ° C overnight for 24 hours. Solid was removed by suction filtration, the filtrate was evaporated to dryness under reduced pressure, acetone was added (150 mL) was dissolved the residue, filtered and the filtrate was evaporated to dryness under reduced pressure, using liquid chromatography _{(SiO 2, CHCl 3: EtOAc} = 4: 1) Separation and purification gave the solid product as Compound 1 (23.5 g, 79%).

Analytical data for Compound 1:

IR (KBr) 3337 (NH), 1742 and 1669 (CO) cm ^-1 . ¹ H NMR (CDCl ₃ ) 7.39-7.17 (m, 15 H, Ph), 6.51 (d, J = 7.5 Hz, 1 H, NHCH), 4.51 (br, 1 H, NHCH ₂ ), 4.30 (q, J = 6.0 Hz, 1 H, NCH), 3.69 (s, 3 H, OCH ₃ ), 3.06 (s, 2 H, CH ₂ S ), 3.02 (m, 2 H, CH ₂ N), 1.65 (m, 2 H, CHCH ₂ ), 1.50 (m, 2 H, CH ₂ CH ₂ NH), 1.40 (s, 9 H, C (CH _{3 ) 3} ), 1.68 (m, 2 H, CH ₂ CH ₂ CH). ¹³ C NMR (CDCl ₃ ) 172.23, 167.88 and 155.90 (CO), 143.95, 192.51, 128.09 and 127.0 (Ph), 77.18 (C (CH) ₃ ) ₃ ), 67.93 (CPh ₃ ), 52.27 and 52.15 (CH ₃ O and CH), 40.15 (CH ₂ NH), 36.06, 32.01, 29.47 and 22.29 (CH ₂ ), 28.37 (C(CH ₃ ) ₃ ) .

Synthesis of Compound 2: Compound 1 (23.54 g, 40.8 mmol) was dissolved in a methanol solution (400 mL) containing 10% potassium hydroxide, and potassium hydroxide as a catalyst was also exchanged for sodium methoxide; After stirring at room temperature for 30 minutes, it was cooled in an ice bath, and water (140 mL) was added to carry out a hydrolysis reaction, and concentrated hydrochloric acid was added dropwise until the pH of the solution was 6. The mixture was extracted with dichloromethane (3×100 mL).

Analytical data for Compound 2:

IR (KBr) 3348 (NH), 1714 and 1659 (CO) cm ^-1 . ¹ H NMR (DMSO-d ₆ ) 8.24 (d, J = 7.8 Hz, 1 H, NHCH), 7.43 - 7.28 (m, 15 H, Ph), 6.80 (br, 1 H, NHCH ₂ ), 4.12 (m, 1 H, CH), 2.92 (m, 4 H, CH ₂ S and CH ₂ NH), 1.69-1.20 (m, 6 H) , CH ₂ CH ₂ CH ₂ CH), 1.41 (s, 9 H, C(CH ₃ ) ₃ ). ¹³ C NMR (DMSO-d ₆ ) 173.28, 167.37 and 155.52 (CO), 144.08, 129.06, 128.05 and 126.76 , (Ph), 77.29 (C(CH ₃ ) ₃ ), 65.91 (CPh ₃ ), 52.10 (CH), 39.23, 35.74, 30.58, 29.05 and 22.68 (CH ₂ ), 28.23 (CH ₃ ).

Synthesis of Compound 3: Compound 2 (21.7 g, 38.6 mmol), [2-(trityl)thio]ethylamine (12.3 g, 38.6 mmol), as the reactant bis(cycloheximide) methane (12 g, 57.9 mmol) and N-hydroxybutaneimine (5.33 g, 46.3 mmol), and triethylamine (16 mL, 115.8 mmol) were dissolved in chloroform (200 mL) and heated at 50 ° C overnight. The reaction time was 24 hours. The mixture was suction filtered, the filtrate was taken, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (100 mL). The organic phase was evaporated to dryness under reduced pressure, and the residue was dissolved in acetone (100 mL), filtered, and evaporated. The filtrate was concentrated under reduced pressure and purified by liquid chromatography (SiO ₂ , CHCl ₃ : CH ₃ OH = 95; 5) to afford compound 3 (25.7 g, 77%).

Analytical data for Compound 3:

IR (neat) 3290 (NH), 1688 and 1642 (CO) cm ^-1 . ¹ H NMR (CDCl ₃ ) 7.40 - 7.16 (m, 30H, Ph), 6.36 (d, J = 7.8 Hz, 1 H, NHCH ), 6.05 (br, 1 H, NH(CH ₂ ) ₂ S), 4.55 (br, 1 H, NH(CH ₂ ) ₄ ), 4.02 (q, J = 7.2 Hz, 1 H, CHNH), 3.03 ( m, 6 H, CH ₂ CH ₂ S, COCH ₂ S and NHCH ₂ (CH ₂ ) ₃ ), 2.36 (t, J = 6.6 Hz, 2 H, CH ₂ CH ₂ S), 1.78-1.13 (m, 6H) , (CH ₂ ) ₃ CH), 1.42 (s, 9 H, C(CH ₃ ) ₃ ). ¹³ C NMR (CDCl ₃ ) 170.53, 168.20 and 155.87 (CO), 144.49, 143.87, 129.41, 128.06, 127.87, 126.96 and 126.69 (Ph), 77.13 (C(CH ₃ ) ₃ ), 67.86 and 66.72 (CPh ₃ ), 52.98 (CH), 40.06, 38.17, 36.0, 31.68, 31.55, 29.47 and 22.50 (CH ₂ ), 28.33 ( C (CH _{3) 3).}

Synthesis of Compound 4: Compound 3 (25.7 g, 29.7 mmol) was dissolved in anhydrous tetrahydrofuran (800 mL), and hydrogen chloride gas was used as a reagent to carry out acid hydrolysis. After being saturated, the mixture was stirred at room temperature for 1 hour. The mixture was suction filtered, and the solid was taken and washed with diethyl ether (100 mL). After dissolving in dichloromethane, the organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate (100 mL). Separation and purification, to give the product compound 4 (16.5g, 73%) The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, using liquid chromatography _{(30:: CH 3 OH =} 70 CHCl 3 SiO 2,).

Analytical data for Compound 4:

IR (neat) 3287 (NH), 1644 (CO) cm ^-1 . ¹ H NMR (CDCl ₃ ) 7.41 - 7.17 (m, 30 H, Ph), 6.52 (d, J = 7.8 Hz, NHCH), 6.45 ( t, J = 5.4 Hz, 1 H, NHCH ₂ ), 4.07 (q, J = 7.5 Hz, 1 H, CHNH), 3.01 (m, 4 H, CH ₂ CH ₂ S and CH ₂ S), 2.63 (t , J = 6.6 Hz, 2 H, CH ₂ NH ₂ ), 2.37 (m, 2 H, CH ₂ CH ₂ S), 1.92 (br, 2 H, NH ₂ ), 1.67-1.18 (m, 6 H, ( CH ₂ ) ₃ CH). ¹³ C NMR (CDCl ₃ ) 170.71 and 168.20 (CO), 144.57, 143.94, 129.47, 128.09, 127.92, 126.99 and 126.74 (Ph), 67.85 and 66.74 (CPh ₃ ), 53.07 (CH) , 41.44, 38.23, 36.13, 32.46, 32.01, 31.65 and 22.49 (CH ₂ ).

Formation of 6,7-diiodotetradecanoic acid: taking libido (12.8 g, 23.9 mmol) dissolved in a methanol solution (400 mL) containing 10% potassium hydroxide, or a hydroxide as a catalyst Potassium was replaced by sodium methoxide; it was then stirred at room temperature for 3 hours, concentrated, and then hydrolyzed by adding 20 mL of methanol and 20 mL of water, placed in an ice bath, and concentrated hydrochloric acid was added until the pH of the solution was 6. The mixture was extracted with dichloromethane (3×100 mL).

Analytical data of 6,7-diiodotetradecanoic acid:

IR (neat) 2950 (OH) , 1620 (CO) cm -1. 1 H NMR (CD 3 OD) 4.17-4.15 (m, H, (CHI) 2), 2.20 (t, 2H, C H 2 COOH) , 2.06-1.28 (m, 10 H, CH ₂ ), 0.94-0.90 (m, 3 H, CH ₃ ). ¹³ C NMR (CD ₃ OD) 179.32 (CO), 40.36 and 40.29, (CHI) ₂ ), 35.99 ( C H ₂ COOH), 29.41, 29.38, 29.31, 29.22, 29.19, 29.12, 28.89, 25.65, 22.27 (CH ₂ ), 13.07 (CH ₃ ).

Synthesis of HOC-NODA: Compound 4 (1.14 g, 1.49 mmol), oleic acid (0.48 mL, 1.49 mmol), hexane (cycloheximide) methane (0.46 g, 2.24 mmol) and N-hydroxyl Dibutylimine (0.20 g, 1.79 mmol), and triethylamine (0.62 mL, 4.47 mmol) were dissolved in chloroform (100 mL) and heated at 50 ° C overnight for 24 hours. The organic layer was concentrated under reduced pressure, and the residue was dissolved in acetone (100 mL). The filtrate was concentrated under reduced pressure and purified by liquid chromatography (SiO ₂ , CHCl ₃ : CH ₃ OH = 95: 5) to give the product as HOC-NODA (1.15 g, 75%).

Analytical data of compound HOC-NODA:

IR (neat) 3285 (NH), 1640 (CO) cm ^-1 . ¹ H NMR (CDCl ₃ ) 7.40-7.16 (m, 30 H, Ph), 6.48 (d, NHCH), 6.27 (t, 1 H, NHCH ₂ ), 5.73 (q, 1 H, CHNH), 5.33 (q, 2H, COCH ₂ ), 4.08 (q, 1 H, CHNH), 3.15 (q, 2 H, CH ₂ NH), 3.02 (m, 4 H,CH ₂ CH ₂ S and CH ₂ S), 2.36 (m,2 H,CH ₂ CH ₂ S),2.11-1.88 (m,8 H,COCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ ), 1.70-1.55 (m, 6H, CHCH ₂ CH ₂ CH ₂ CH ₂ and CH ₂ CH ₂ CH=CH), 1.44 (m, 2H, CHCH ₂ CH ₂ CH ₂ CH ₂ ), 1.27-1.06 (m , 16H, CH ₂ ), 0.88 (m, 3 H, CH ₃ ). ¹³ C NMR (CDCl ₃ ) 173.31, 170.76 and 168.44 (CO), 144.60, 143.97, 129.21, 128.15, 127.97, 127.06 and 126.79 (Ph) , 67.91 and 66.79 (CPh ₃ ), 52.91 (CH), 38.86, 38.33, 36.78, 36.17, 33.96, 31.90, 31.77, 31.67, 29.77, 29.75, 29.52, 29.32, 29.19, 28.90, 27.23, 27.20, 25.81, 25.65, 24.96, 22.68 and 22.52 (CH ₂ ), 14.13 (CH ₃ ).

Synthesis of TDI-NODA: Compound 4 (1.08 g, 1.41 mmol), 6,7-diiodotetradecanoic acid (0.72 g, 1.41 mmol), as the reactant bis(cycloheximide)methane (0.44 g) , 2.12 mmol) and N-hydroxybutanediimide (0.20 g, 1.70 mmol), and triethylamine (0.59 mL, 4.24 mmol) were dissolved in chloroform (100 mL) and heated at 50 ° C overnight. The time is 24 hours. The organic layer was concentrated under reduced pressure, and the residue was dissolved in acetone (100 mL). The filtrate was concentrated under reduced pressure and purified by liquid chromatography (SiO ₂ , CHCl ₃ : CH ₃ OH = 95:5) to give the product as TDI-NODA (1.39 g, 79%).

Analytical data of compound TDI-NODA:

IR (neat) 3280 (NH), 1650 (CO) cm ^-1 . ¹ H NMR (CDCl ₃ ) 7.40-7.19 (m, 30 H, Ph), 6.47 (d, N H CH), 6.24 (t, 1 H, N H CH ₂ ), 5.71 (q, 1 H, CH N H), 4.07 (q, 1 H, C H NH), 3.17 (q, 2 H, C H ₂ NH), 3.02-2.80 (m) , 4 H, C H ₂ CH ₂ S and CH ₂ S), 2.60-2.52 (m, 2H, (CHI) ₂ ), 2.38-2.34 (m, 2 H, CH ₂ C H ₂ S), 2.11-2.06 (m, 4 H, COC H ₂ C H ₂ CH ₂ CH ₂ ), 1.95-1.63 (m, 8H, CHC H ₂ C H ₂ CH ₂ CH ₂ CH ₂ CH ₂ and COCH ₂ CH ₂ C H ₂ C H ₂ ), 1.59-1.37 (m, 6H, CHCH ₂ CH ₂ C H ₂ C H ₂ C H ₂ CH ₂ ), 1.28-1.09 (m, 14H, CH ₂ ), 0.89-0.86 (m, 3 H, CH ₃ ). ¹³ C NMR (CDCl3) 173.26, 170.74 and 168.43 (CO), 144.59, 143.96, 129.51, 128.16, 127.98, 127.07 and 126.80 (Ph), 67.92 and 66.79 (CPh ₃ ), 52.90 (CH), 49.03, 40.83, 39.89, 39.70, 38.63, 36.76, 36.15, 31.91, 31.66, 30.97, 30.93, 29.65, 29.28, 28.87, 28.47, 25.77, 25.64, 24.96, 22.59 and 22.51 (CH ₂ ), 14.13 (CH ₃ ).

In summary, the present invention discloses in detail a liver cancer therapeutic agent precursor and a method for producing the same, which utilizes a flag precursor HOC-NODA containing a long-chain alkyl group and a N ₂ S ₂ ligand, and contains The Libido architecture and the N ₂ S ₂ ligand's signature precursor TDI-NODA are used in the field of nuclear medicine for the treatment of liver cancer using radioisotopes such as 铼-188 or 鎝99m. Whether it is in the ability to preserve, the ability to combine with radioisotopes or the ability to stay in the liver cancer tissue of patients, it is concluded that the present invention does provide a liver cancer treatment that fully demonstrates economic and practical value. The agent label precursor and the method for producing the same can be expected to be applied as a novel liver cancer therapeutic agent.

The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the variations, modifications, and modifications of the shapes, structures, features, and spirits described in the claims of the present invention. All should be included in the scope of the patent application of the present invention.

Claims (14)

A liver cancer therapeutic agent precursor precursor, the chemical structure of which is: Wherein the functional group R is 8-heptadecenyl or 5,6-diiodotetradecyl. The liver cancer therapeutic agent precursor precursor according to claim 1, which is used for combining a radioisotope to form a liver cancer therapeutic agent marker, and the radioisotope is 铼-188 or 鎝-99m. A method for producing a liver cancer therapeutic agent precursor according to claim 1, which comprises the steps of: using a L-Nε-t-butoxycarbonyl lysine methyl ester and a trityl ethane thiol acid to decylamine a reaction to form L-Nε-tert-butoxycarbonyl-Nα-[2-(trityl)thioethylidene]-methyl methacrylate (hereinafter referred to as compound 1); hydrolysis of the compound 1 to form L-Nε-t-butoxycarbonyl-Nα-[2-(trityl)thioethylidene]-amino acid (hereinafter referred to as compound 2); using the compound 2 with [2-(triphenyl) Amidoxime reaction with thiol]ethylamine to form L-Nε-tert-butoxycarbonyl-Nα-[2-(trityl)thioethylidene]-6-aza-5-oxo Base-9-(trityl)thio-1,5-nonanediamine (hereinafter referred to as compound 3); acidolysis of compound 3 to form L-Nε-[2-(trityl)thio Indenyl]-6-aza-5-oxy-9-(trityl)thio-1,5-nonanediamine (hereinafter referred to as compound 4); using the compound 4 with oleic acid or 6, 7-Diiodotetradecanoic acid undergoes guanidation to form L-Nε-[2-(trityl)thioethenyl]-Nα-8-heptadecenylcarbonyl-6-aza-5 -oxy -9-(trityl)thio-1,5-nonanediamine (hereinafter referred to as HOC-NODA) or L-Nε-[2-(trityl)thioethyl]-Nα-5 6-Diiodotetradecylcarbonyl-6-aza-5-oxy-9-(trityl)thio-1,5-nonanediamine (hereinafter referred to as TDI-NODA). The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein the HOC-NODA and the TDI-NODA are used to combine a radioisotope to form a liver cancer therapeutic agent marker, the radioisotope. It is 铼-188 or 鎝-99m. The method for producing a liver cancer therapeutic agent precursor precursor according to claim 4, wherein the HOC-NODA is first dissolved in Lipiodol, and then combined with the radioisotope to form a liver cancer therapeutic agent marker. . The method for producing a liver cancer therapeutic agent precursor according to the fourth aspect of the invention, wherein the TDI-NODA system directly binds the radioisotope to form a liver cancer therapeutic agent marker. The method for producing a liver cancer therapeutic agent precursor according to the fourth aspect of the invention, wherein the liver cancer therapeutic agent formed by combining the radioisotope is applied to a nuclear medicine therapeutic agent for liver cancer. The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein the step of acidifying the compound 3 is carried out in a hydrogen chloride-containing tetrahydrofuran solution. The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein the amidoxime reaction is bis(cycloheximide)methane and N-hydroxybutylimine. The reaction was carried out in a chloroform solution at a reaction temperature of 50 ° C and a reaction time of 24 hours. The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein in the step of hydrolyzing the compound 1, the potassium hydroxide or sodium methoxide is used as a catalyst, and the reaction is carried out in a methanol solution. The reaction temperature was room temperature and the reaction time was 30 minutes. The method for producing a liver cancer therapeutic agent precursor according to claim 3, wherein in the step of acidifying the compound 3, hydrogen chloride gas is used as a reactant, and the reaction is carried out in an anhydrous tetrahydrofuran solution. The temperature was room temperature and the reaction time was 1 hour. The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein in the step of acidifying the compound 3, the reaction temperature is room temperature, and the reaction time is 1 hour. The method for producing a liver cancer therapeutic agent precursor according to the third aspect of the invention, wherein the 6,7-diiodotetradecanoic acid is formed by a hydrolysis reaction of the ribido. The method for producing a liver cancer therapeutic agent precursor according to the invention of claim 13, wherein the hydrolysis reaction is carried out by using potassium hydroxide or sodium methoxide as a catalyst in a methanol solution, and the reaction temperature is room temperature. The reaction time was 3 hours.