Gadoterate derivative, process for its preparation and use thereof

Abstract

The application provides a gadoterate derivative, a preparation method and application thereof, and belongs to the technical field of medicines.The application provides a gadoterate derivative with a structure shown in formula I-1 or formula I-2, and the application uses a sulfonamide compound and an amine glucose as a targeting molecule, designs a contrast agent for targeting tumors on the basis of a chiral gadoterate (Gd-DOTA) compound, and the specific contrast effect for tumors is excellent.The test results show that the gadoterate derivative has excellent targeting property for breast cancer cells.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a gadoteric acid derivative, its preparation method, and its application. Background Technology

[0002] Molecular imaging techniques can monitor and characterize cancer-related biomarkers and are used for accurate diagnosis, treatment monitoring, image-assisted therapy, and assessment of insidious disease progression. Magnetic resonance imaging (MRI) is a commonly used clinical examination method, offering advantages such as being non-invasive and radiation-free, and providing excellent spatial resolution and soft tissue contrast for lesion localization. The contrast between different tissues in MRI depends on their different biochemical environments; however, there is no significant difference in proton magnetic field environment between tumors and surrounding normal tissues, therefore, MRI detection of tumor tissues is often poor. The use of contrast agents can significantly improve the contrast between tissues, but currently available commercial contrast agents (such as...) Figure 1 (As shown) the specific imaging effect for tumors is poor. Summary of the Invention

[0003] The purpose of this invention is to provide a gadoteric acid derivative, its preparation method and application. The gadoteric acid derivative provided by this invention contains a tumor-targeting group and has excellent specific imaging effect against tumors.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides a gadoteric acid derivative having the structure shown in Formula I-1 or Formula I-2:

[0006]

[0007] In formulas I-1 and I-2, R can be any one of the following groups:

[0008]

[0009] This invention provides a method for preparing the gadoteric acid derivative described in the above technical solution, comprising the following steps:

[0010] The compound Gd-L1, the targeting compound, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine were mixed with an organic solvent and subjected to a condensation reaction to obtain the gadotonic acid derivative having the structure shown in Formula I-1 or Formula I-2.

[0011] The compound Gd-L1 has the structure shown in Formula II-1 or Formula II-2:

[0012]

[0013] The target compound has the structure shown in Formula III, Formula IV, Formula V or Formula VI:

[0014]

[0015] Preferably, the molar ratio of compound Gd-L1 to the target compound is 0.9–1.0:1.1–1.2.

[0016] Preferably, the molar ratio of the compound Gd-L1,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate to N,N-diisopropylethylamine is 0.4-0.6:0.5-0.7:1.5-2.2.

[0017] Preferably, the condensation reaction is carried out at a temperature of 15–35°C for 2–4 hours, and the condensation reaction is carried out in a protective atmosphere.

[0018] Preferably, the condensation reaction further includes: separating and purifying the product system obtained after the condensation reaction using reversed-phase high-performance liquid chromatography to obtain the gadotonic acid derivative having the structure shown in Formula I-1 or Formula I-2.

[0019] This invention provides the application of the gadoteric acid derivatives described in the above technical solution in the preparation of targeted tumor contrast agents.

[0020] Preferably, the targeted tumor contrast agent is a magnetic resonance imaging contrast agent.

[0021] Preferably, the targeted tumor contrast agent is a T1 contrast agent.

[0022] Preferably, the tumors to which the targeted tumor contrast agent is applicable include one or more of breast cancer, liver cancer, glioma, ovarian cancer, colon cancer, pancreatic cancer, and prostate cancer.

[0023] This invention provides a gadotate acid derivative having the structure shown in Formula I-1 or Formula I-2. This invention uses sulfonamide compounds and glucosamine as targeting molecules to design a tumor-targeting contrast agent based on chiral gadotate acid (Gd-DOTA) compounds, exhibiting excellent tumor-specific contrast effects. Test results show that the gadotate acid derivative provided by this invention has excellent targeting ability against breast cancer cells. Attached Figure Description

[0024] Figure 1 This is a molecular structure diagram of commercially available contrast agents in the prior art;

[0025] Figure 2 T1-weighted magnetic resonance imaging of compounds Gd-L1, Gd-L2, Gd-L3, Gd-L4, and Gd-L5 in a mouse 4T1 subcutaneous tumor model. Detailed Implementation

[0026] This invention provides a gadoteric acid derivative having the structure shown in Formula I-1 or Formula I-2:

[0027]

[0028] In formulas I-1 and I-2, R can be any one of the following groups:

[0029]

[0030] In this invention, the gadoteric acid derivative can specifically be compound Gd-L2, compound Gd-L3, compound Gd-L4 or compound Gd-L5;

[0031] The compound Gd-L2 is any one of the following compounds (denoted as compound R-Gd-L2 and compound S-Gd-L2, respectively):

[0032]

[0033] The compound Gd-L3 is any one of the following compounds (denoted as compound R-Gd-L3 and compound S-Gd-L3, respectively):

[0034]

[0035] The compound Gd-L4 is any one of the following compounds (denoted as compound R-Gd-L4 and compound S-Gd-L4, respectively):

[0036]

[0037] The compound Gd-L5 is any one of the following compounds (denoted as compound R-Gd-L5 and compound S-Gd-L5, respectively):

[0038]

[0039] This invention provides a method for preparing the gadoteric acid derivative described in the above technical solution, comprising the following steps:

[0040] The compound Gd-L1, the targeting compound, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine were mixed with an organic solvent and subjected to a condensation reaction to obtain the gadotonic acid derivative having the structure shown in Formula I-1 or Formula I-2.

[0041] The compound Gd-L1 has the structure shown in Formula II-1 or Formula II-2 (denoted as compound R-Gd-L1 and compound S-Gd-L1, respectively):

[0042]

[0043] The target compound has the structure shown in Formula III, Formula IV, Formula V or Formula VI:

[0044]

[0045] In this invention, unless otherwise specified, all raw materials used are commercially available products well known to those skilled in the art or prepared using methods well known to those skilled in the art.

[0046] This invention involves mixing compound Gd-L1, a targeting compound, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine with an organic solvent to undergo a condensation reaction. In this invention, the targeting compound has the structure shown in Formula III, IV, V, or VI, wherein the targeting compound with the structure shown in Formula III is an aminoglucose, and the preparation method of the targeting compound with the structure shown in Formula IV, V, or VI will be described in detail later. In this invention, the molar ratio of compound Gd-L1 to the targeting compound is preferably 0.9–1.0:1.1–1.2, more preferably 1.0:1.1. In this invention, the molar ratio of compound Gd-L1, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine is preferably 0.4–0.6:0.5–0.7:1.5–2.2, specifically 0.6:0.7:1.5 or 0.4:0.5:2.2. In this invention, the organic solvent is preferably N,N-dimethylformamide, and the preferred molar ratio of compound Gd-L1 to the organic solvent is 0.4–0.6 mmol:5–30 mL, specifically 0.6 mmol:30 mL or 0.4 mmol:5 mL.

[0047] In this invention, compound Gd-L1 is preferably dissolved in an organic solvent, and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine are added to the resulting solution for carboxyl activation treatment. Following this, a targeting compound is added to the activated solution for a condensation reaction. In this invention, the temperature for carboxyl activation treatment is preferably 15–35°C, more preferably room temperature; in an embodiment of this invention, room temperature is specifically 25°C; the time for carboxyl activation treatment is preferably 25–35 min, more preferably 30 min; and the carboxyl activation treatment is preferably carried out under stirring conditions. In this invention, the targeting compound can be added directly to the activation solution, or it can be dissolved in the organic solvent first, and then the resulting targeting compound solution is added to the activation solution; this invention does not have any particular limitation on this. In this invention, the temperature of the condensation reaction is preferably 15-35°C, more preferably room temperature; the time is preferably 2-4 hours, more preferably 2-3 hours; the condensation reaction is preferably carried out in a protective atmosphere, more preferably in a nitrogen atmosphere; the condensation reaction is preferably carried out under stirring conditions.

[0048] Following the condensation reaction, the present invention preferably employs reversed-phase high-performance liquid chromatography (RP-HPLC) to separate and purify the product system obtained after the condensation reaction, thereby obtaining the gadoteric acid derivative having the structure shown in Formula I-1 or Formula I-2. In the present invention, the mobile phase used in the R-HPLC preferably comprises mobile phase A and mobile phase B. Mobile phase A is preferably a 0.1% (v / v) aqueous solution of trifluoroacetic acid, and mobile phase B is preferably acetonitrile. The preferred flow rate is 7 mL / min, and the preferred elution program is: starting with 90% A and 10% B (v / v), increasing the mobile phase B linearly from 10% to 50% from 0 min to 20 min. The preferred chromatographic column used in the R-HPLC is a C18 column (preferably 5 μm, 19 × 250 mm).

[0049] The preparation method of the target compound with the structure shown in Formula IV, Formula V or Formula VI of the present invention will be described in detail below.

[0050] The preferred method for preparing the target compound with the structure shown in Formula IV of this invention includes the following steps:

[0051] Compound 1, N-Boc-3-chloropropane, NaHCO3 and acetonitrile were mixed and subjected to a first nucleophilic substitution reaction to obtain compound 2;

[0052] Compound 2, trifluoroacetic acid, and dichloromethane were mixed and subjected to a first deprotection reaction to obtain the target compound with the structure shown in Formula IV.

[0053] The structural formulas of compound 1 and compound 2 are shown below:

[0054]

[0055] In this invention, compound 1, N-Boc-3-chloropropane, NaHCO3, and acetonitrile are mixed and subjected to a first nucleophilic substitution reaction to obtain compound 2. In this invention, the preferred molar ratio of compound 1, N-Boc-3-chloropropane, NaHCO3, and acetonitrile is 6 mmol:8–10 mmol:11–13 mmol:25–35 mL, more preferably 6 mmol:9 mmol:12 mmol:30 mL. In this invention, the preferred temperature for the first nucleophilic substitution reaction is 45–55 °C, more preferably 50 °C; the preferred time is 10–15 h, more preferably 12 h. After the first nucleophilic substitution reaction, the resulting product system is preferably filtered, the solvent in the filtrate is evaporated to dryness, and anhydrous ethanol is added. Under stirring, a pale yellow compound precipitates, which is compound 2.

[0056] After obtaining compound 2, the present invention mixes compound 2, trifluoroacetic acid, and dichloromethane to carry out a first deprotection reaction to obtain the target compound (denoted as compound 3) with the structure shown in Formula IV. In the present invention, the preferred molar ratio of compound 2, trifluoroacetic acid, and dichloromethane is 0.6 mmol: 0.4–0.6 mL: 2.5–3.5 mL, more preferably 0.6 mmol: 0.5 mL: 3 mL. In the present invention, the preferred temperature for the first deprotection reaction is 15–35 °C, more preferably room temperature; the preferred time is 50–70 min, more preferably 60 min. After the first deprotection reaction, the present invention preferably evaporates the solvent in the obtained product system to dryness, and then directly uses the obtained product to prepare gadotonic acid derivatives having the structure shown in Formula I-1 or Formula I-2.

[0057] The method for preparing the target compound with the structure shown in formula V or formula VI of this invention preferably includes the following steps:

[0058] The starting compound, N-Boc-1,3-propanediamine, triethanolamine and acetonitrile were mixed and subjected to a second nucleophilic substitution reaction to obtain the intermediate compound;

[0059] The intermediate compound, trifluoroacetic acid and dichloromethane were mixed and subjected to a second deprotection reaction to obtain the target compound with the structure shown in Formula V or Formula VI.

[0060] Wherein, the raw material compound is

[0061] The intermediate compound is

[0062] This invention involves mixing a starting compound, N-Boc-1,3-propanediamine, triethanolamine, and acetonitrile to undergo a second nucleophilic substitution reaction to obtain an intermediate compound. In this invention, the preferred molar ratio of the starting compound, N-Boc-1,3-propanediamine, triethanolamine, and acetonitrile is 4.2–5.2 mmol: 6–7 mmol: 12–13 mmol: 25–35 mL, more preferably 4.2–5.2 mmol: 6.4 mmol: 12.6 mmol: 30 mL. In this invention, the preferred temperature for the second nucleophilic substitution reaction is 75–85 °C, more preferably 80 °C; the preferred time is 10–15 h, more preferably 12 h; the second nucleophilic substitution reaction is preferably carried out under a protective atmosphere, more preferably under a nitrogen atmosphere. After the second nucleophilic substitution reaction, this invention preferably cools the resulting product system to room temperature, evaporates the solvent, adds ethanol to the residue, and precipitates a yellow compound under continuous stirring. The precipitate is filtered, and the collected yellow compound is the intermediate compound.

[0063] After obtaining the intermediate compound, the present invention mixes the intermediate compound, trifluoroacetic acid, and dichloromethane to carry out a second deprotection reaction to obtain a target compound with the structure shown in Formula V or Formula VI. In the present invention, the proportions of each material, reaction conditions, and post-processing methods during the second deprotection reaction are preferably the same as those during the first deprotection reaction, and will not be repeated here.

[0064] This invention provides the application of the gadoteric acid derivative described in the above-mentioned technical solution in the preparation of targeted tumor contrast agents. In this invention, the targeted tumor contrast agent is preferably a magnetic resonance imaging contrast agent. In this invention, the targeted tumor contrast agent is preferably a T1 contrast agent. In this invention, the tumor to which the targeted tumor contrast agent is applicable is preferably a solid tumor, and the tumor preferably includes one or more of breast cancer, liver cancer, glioma, ovarian cancer, colon cancer, pancreatic cancer, and prostate cancer, more preferably breast cancer.

[0065] This invention utilizes sulfonamide compounds and glucosamine as targeting molecules to design tumor-targeting contrast agents based on chiral gadoteric acid (Gd-DOTA) compounds, achieving excellent tumor-specific imaging effects. Specifically, due to the rapid growth rate of tumors, solid tumors often suffer from insufficient blood supply, leading to hypoxia. Tumor hypoxia often reduces the effectiveness of traditional chemotherapy and radiotherapy. Accurate imaging of hypoxic environments can locate hidden tumors within the patient and help in developing personalized treatment plans, thereby improving treatment outcomes. Sulfonamide compounds can bind to the overexpressed carbonic anhydrase IX / XII in hypoxic tumor cells, and tumor cells have an overexpression of glucose / glucosamine transporters compared to normal cells. Therefore, this invention uses sulfonamide compounds and glucosamine as targets to design tumor-targeting contrast agents. Chiral Gd-DOTA compounds are a class of T1 contrast agents with excellent stability constructed by introducing four chiral groups into the macrocyclic Gd-DOTA complex. This invention utilizes chiral Gd-DOTA compounds to link tumor-targeting sulfonamide compounds or glucosamine to construct tumor-targeting magnetic resonance imaging contrast agents, especially tumor-targeting T1 contrast agents, which can be used for MRI diagnosis of tumors and meet clinical diagnostic needs.

[0066] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0067] Example 1

[0068] The reaction formula for preparing compound Gd-L2 (specifically compound R-Gd-L2) is shown below:

[0069]

[0070] Compound Gd-L1 (specifically compound R-Gd-L1, 0.5 g, 0.6 mmol) was dissolved in 30 mL of N,N-dimethylformamide (DMF), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.3 g, 0.7 mmol) and N,N-diisopropylethylamine (DIEA, 0.2 g, 1.5 mmol). The mixture was subjected to carboxyl activation treatment for 30 min at room temperature (25 °C) with stirring. Then, aminoglucose (0.2 g, 1.1 mmol) was added to the resulting system, and a condensation reaction was carried out for 2 h under a nitrogen atmosphere with stirring. After the reaction, the obtained product was analyzed by reversed-phase high-performance liquid chromatography. The product system was separated and purified to obtain compound R-Gd-L2; wherein, the mobile phase used in the reversed-phase high-performance liquid chromatography included mobile phase A and mobile phase B, wherein mobile phase A was a 0.1% (v / v) aqueous solution of trifluoroacetic acid, and mobile phase B was acetonitrile, the mobile phase flow rate was 7 mL / min, and the elution program was as follows: the initial conditions were 90% A and 10% B by volume fraction, from 0 min to 20 min, and the mobile phase B was linearly increased from 10% to 50%; the chromatographic column used in the reversed-phase high-performance liquid chromatography was a C18 column (5 μm, 19 × 250 mm).

[0071] The characterization data of the compound R-Gd-L2 are as follows: ESI-MS m / z: [M] - calcd.forC 37 H 55 GdN5O 14 951.3; found 951.3.

[0072] Example 2

[0073] The reaction formula for preparing compound Gd-L2 (specifically compound S-Gd-L2) is shown below:

[0074]

[0075] Compound Gd-L1 (specifically, compound S-Gd-L1, 0.5 g, 0.6 mmol) was dissolved in 30 mL of DMF, followed by the addition of HATU (0.3 g, 0.7 mmol) and DIEA (0.2 g, 1.5 mmol). The carboxyl group was activated for 30 min under stirring at room temperature. Then, glucosamine (0.2 g, 1.1 mmol) was added to the resulting system, and a condensation reaction was carried out for 2 h under a nitrogen atmosphere with stirring. After the reaction, the product system was separated and purified by reversed-phase high-performance liquid chromatography (specific conditions were the same as in Example 1), yielding compound S-Gd-L2. Characterization data are as follows: ESI-MS m / z: [M] -calcd.forC 37 H 55 GdN5O 14 951.3; found 951.3.

[0076] Example 3

[0077] The reaction formula for preparing compound Gd-L3 (specifically compound R-Gd-L3) is shown below:

[0078]

[0079] Compound 1 (1.1 g, 6 mmol), N-Boc-3-chloropropane (1.7 g, 9 mmol), and NaHCO3 (1.0 g, 12 mmol) were mixed with 30 mL of acetonitrile and heated to 50 °C for a nucleophilic substitution reaction for 12 h. After the reaction was completed, the resulting product system was filtered, the solvent in the filtrate was evaporated to dryness, and anhydrous ethanol was added. A pale yellow compound, compound 2, precipitated under stirring. Characterization data are as follows: 1 HNMR (400MHz, DMSO-d6, δppm) 1.38 (s, 9H), 1.75 (t, J = 6.72Hz, 2H), 3.04 (q, J = 6.18Hz, 2H), 3.44 (q, J = 6.46Hz, 2H), 6.22 (t, J = 6.32Hz, 1H), 7.53 (s, 2H). 13 C NMR (100MHz, DMSO-d6, δppm)28.81,38.23,76.17,110.34,125.78,158.52,164.54,169.90.ESI-MS m / z:[M+H] + calcd.for C 10 H 20 N5O4S2337.5 was found to be 337.5.

[0080] Compound 2 (0.2 g, 0.6 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 0.5 mL of trifluoroacetic acid. The deprotection reaction was carried out at room temperature for 1 h. After the reaction was completed, the solvent in the resulting product system was evaporated to dryness to obtain compound 3, which was then used directly in the next reaction.

[0081] Gd-L1 (specifically compound R-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 3 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under a nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound R-Gd-L3. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 36 H 53 GdN9O 11 S21009.2; found 1009.2.

[0082] Example 4

[0083] The reaction formula for preparing compound Gd-L3 (specifically compound S-Gd-L3) is shown below:

[0084]

[0085] Gd-L1 (specifically compound S-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 3 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under a nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound S-Gd-L3. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 36 H 53 GdN9O 11 S21009.2; found 1009.2.

[0086] Example 5

[0087] The reaction formula for preparing compound Gd-L4 (specifically compound R-Gd-L4) is shown below:

[0088]

[0089] Compound 4 (1.0 g, 5.2 mmol) was dissolved in 30 mL of acetonitrile, followed by the addition of N-Boc-1,3-propanediamine (1.1 g, 6.4 mmol) and triethanolamine (TEA, 1.3 g, 12.6 mmol). A nucleophilic substitution reaction was carried out at 80 °C for 12 h under a nitrogen atmosphere. After the reaction, the resulting product system was cooled to room temperature, and the solvent was evaporated. 20 mL of ethanol was added to the residue, and a yellow compound precipitated under continuous stirring. The precipitate was filtered, and the yellow compound was collected as compound 5. Characterization data are as follows: 1 H NMR(400MHz, DMSO-d6, δppm)1.39(s,9H),1.75(t,J=6.36Hz,2H),3.04(q,J=6.36Hz,2H ), 3.44 (q, J = 6.52Hz, 2H), 7.69 (d, J = 8.78Hz, 2H), 7.83 (d, J = 8.80Hz, 2H), 8.31 (s, 2H). 13 C NMR (100MHz, DMSO-d6, δppm)25.47,36.36,79.14,112.68,125.29,137.40,139.57,143.95,152.85.ESI-MS m / z:[M+H] + calcd.for C 14 H 24 N3O4S 330.4 found 330.4.

[0090] Compound 5 (0.2 g, 0.6 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 0.5 mL of trifluoroacetic acid. The deprotection reaction was carried out at room temperature with stirring for 1 h. After the reaction was completed, the solvent in the resulting product system was evaporated to dryness to obtain compound 6, which was then used directly in the next reaction.

[0091] Gd-L1 (specifically compound R-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 6 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound R-Gd-L4. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 40 H 57 GdN7O 11S1001.2; found 1001.2.

[0092] Example 6

[0093] The reaction formula for preparing compound Gd-L4 (specifically compound S-Gd-L4) is shown below:

[0094]

[0095] Gd-L1 (specifically compound S-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 6 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under a nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound S-Gd-L4. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 40 H 57 GdN7O 11 S1001.2; found 1001.2.

[0096] Example 7

[0097] The reaction formula for preparing compound Gd-L5 (specifically compound R-Gd-L5) is shown below:

[0098]

[0099] Compound 7 (1.0 g, 4.2 mmol) was dissolved in 30 mL of acetonitrile, followed by the addition of N-Boc-1,3-propanediamine (1.1 g, 6.4 mmol) and TEA (1.3 g, 12.6 mmol). A nucleophilic substitution reaction was carried out at 80 °C for 12 h under a nitrogen atmosphere. After the reaction, the resulting product system was cooled to room temperature, the solvent was evaporated, and 20 mL of ethanol was added to the residue. A yellow compound precipitated under continuous stirring. The precipitate was filtered and collected as compound 8. Characterization data are as follows: 1HNMR(400MHz, DMSO-d6, δppm)1.37(s,9H),1.71(t,J=6.72Hz,2H),3.01(q,J=6.28Hz,2H),3.44(q,J=6.48H z,2H),6.94(s,1H),7.22(d,J=9.32Hz,1H),7.32(s,2H),7.82(d,J=9.20Hz,1H),8.47(s,1H),8.59(s,1H). 13 C NMR (100MHz, DMSO-d6, δppm)28.74,37.74,78.12,115.86,125.29,129.99,130.47,133.25,146.96,156.25.ESI-MS m / z:[M+Na] + calcd.for C 14 H 22 N4O6SNa 397.1 found397.1.

[0100] Compound 8 (0.2 g, 0.6 mmol) was dissolved in 3 mL of dichloromethane, followed by the addition of 0.5 mL of trifluoroacetic acid. The deprotection reaction was carried out at room temperature with stirring for 1 h. After the reaction was completed, the solvent in the resulting product system was evaporated to dryness to obtain compound 9, which was then used directly in the next reaction.

[0101] Gd-L1 (specifically compound R-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 9 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under a nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound R-Gd-L5. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 40 H 56 GdN8O 13 S1046.3; found 1046.3.

[0102] Example 8

[0103] The reaction formula for preparing compound Gd-L5 (specifically compound S-Gd-L5) is shown below:

[0104]

[0105] Gd-L1 (specifically compound S-Gd-L1, 0.3 g, 0.4 mmol), HATU (0.2 g, 0.5 mmol), and DIEA (0.2 g, 2.2 mmol) were mixed with 5 mL of DMF and subjected to carboxyl activation treatment for 30 min under stirring at room temperature. Then, compound 9 was dissolved in 5 mL of DMF and added to the carboxyl-activated system. A condensation reaction was carried out under nitrogen atmosphere and stirring at room temperature for 4 h. After the reaction, the resulting product system was separated and purified by reversed-phase high-performance liquid chromatography (under the same conditions as in Example 1) to obtain compound S-Gd-L5. Characterization data are as follows: ESI-MS m / z: [M] - calcd.forC 40 H 56 GdN8O 13 S1046.3; found 1046.3.

[0106] Test Example 1

[0107] 4T1 breast cancer is a rapidly growing malignant tumor, and mouse 4T1 subcutaneous tumor is a hypoxic tumor model. In this example, normal BALB / c mice were subcutaneously injected with 0.1 mL of a solution containing 1×10⁻⁶ ppm of 4T1 carcinoma. 7 The subcutaneous tumor, with a diameter of 0.5 cm, was observed to have grown to 4 T1 cells per mL in PRMI1640 medium and was ready for magnetic resonance imaging. Subcutaneous tumor mice were anesthetized with isoflurane and then administered compounds Gd-L1 (including compounds R-Gd-L1 and S-Gd-L1), Gd-L2 (including compounds R-Gd-L2 and S-Gd-L2), Gd-L3 (including compounds R-Gd-L3 and S-Gd-L3), Gd-L4 (including compounds R-Gd-L4 and S-Gd-L4), and Gd-L5 (including compounds R-Gd-L5 and S-Gd-L5) via the tail vein at a dose of 0.1 mmol / kg body weight. Following administration, T1-weighted scans were performed using a 3.0T magnetic resonance scanner (Ingenia Elition, Philips) with the following parameters: TE = 9.7 ms, TR = 191.1 ms, FA = 50°, FOV = 50 × 50 mm, and matrix... Size = 200×135, 12 layers, layer thickness 1.5mm, with a 0.15mm spacing.

[0108] Figure 2 T1-weighted magnetic resonance imaging (MRI) images of compounds R-Gd-L1, S-Gd-L1, R-Gd-L2, S-Gd-L2, R-Gd-L3, S-Gd-L3, R-Gd-L4, S-Gd-L4, R-Gd-L5, and S-Gd-L5 in a mouse 4T1 subcutaneous tumor model. Figure 2It is known that compounds R-Gd-L2, S-Gd-L2, R-Gd-L3, S-Gd-L3, R-Gd-L4, S-Gd-L4, R-Gd-L5 and S-Gd-L5 have more obvious targeting of tumors. Among them, compounds R-Gd-L4, S-Gd-L4, R-Gd-L5 and S-Gd-L5 have a more significant effect on prolonging the penetration and retention time of solid tumors.

[0109] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A gadoteric acid derivative, characterized in that, It has the structure shown in Equation I-1 or Equation I-2: Equation I-1; Equation I-2; In formulas I-1 and I-2, R can be any one of the following groups: ， 。 2. The method for preparing the gadolinium derivative according to claim 1, characterized in that, Includes the following steps: Compound Gd-L1, the targeting compound, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine were mixed with an organic solvent and subjected to a condensation reaction to obtain the gadotonic acid derivative having the structure shown in I-1 or I-2. The compound Gd-L1 has the structure shown in Formula II-1 or Formula II-2: Formula II-1; Formula II-2; The targeted compound has the structure shown in Formula V or Formula VI: Formula V; Formula VI.

3. The preparation method according to claim 2, characterized in that, The molar ratio of compound Gd-L1 to the target compound is 0.9~1.0:1.1~1.

2.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the compound Gd-L1,2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate to N,N-diisopropylethylamine is 0.4~0.6:0.5~0.7:1.5~2.

2.

5. The preparation method according to claim 2, characterized in that, The condensation reaction is carried out at a temperature of 15~35 ℃ for 2~4 h; the condensation reaction is carried out in a protective atmosphere.

6. The preparation method according to claim 2 or 5, characterized in that, The condensation reaction further includes: separating and purifying the product system obtained after the condensation reaction using reversed-phase high-performance liquid chromatography to obtain the gadotonic acid derivative having the structure shown in Formula I-1 or Formula I-2.

7. The use of the gadotonic acid derivative of claim 1 in the preparation of a targeted tumor contrast agent, wherein the targeted tumor contrast agent is a magnetic resonance imaging contrast agent, and the tumor in the targeted tumor contrast agent is breast cancer.

8. The application according to claim 7, characterized in that, The targeted tumor contrast agent is a T1 contrast agent.

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