CN117402199A - Gadolinium-tetronic acid derivative and preparation method and application thereof - Google Patents

Gadolinium-tetronic acid derivative and preparation method and application thereof Download PDF

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CN117402199A
CN117402199A CN202311349769.XA CN202311349769A CN117402199A CN 117402199 A CN117402199 A CN 117402199A CN 202311349769 A CN202311349769 A CN 202311349769A CN 117402199 A CN117402199 A CN 117402199A
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acid derivative
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戴利雄
徐维元
叶方富
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Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering
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Wenzhou Research Institute Of Guoke Wenzhou Institute Of Biomaterials And Engineering
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
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    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
    • A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract

The invention provides a gadolinium-tetronic acid derivative, a preparation method and application thereof, and belongs to the technical field of medicines. The invention provides a gadolinium-tetronic acid derivative with a structure shown in a formula I-1 or a formula I-2, which adopts sulfonamide compounds and glucosamine as targeting molecules, designs a contrast agent for targeting tumors on the basis of chiral gadolinium-tetronic acid (Gd-DOTA) compounds, and has excellent specific contrast effect on the tumors. The test example shows that the gadolinium-tetronic acid derivative provided by the invention has excellent targeting to breast cancer cells.

Description

Gadolinium-tetronic acid derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a gadoteric acid derivative, a preparation method and application thereof.
Background
Molecular imaging techniques can monitor, characterize, and use for accurate diagnosis, therapy monitoring, image-assisted therapy, and disease-suppressed progression assessment of cancer-related biomarkers. Among them, magnetic Resonance Imaging (MRI) is a common clinical examination means, has the advantages of non-invasiveness and no radiation, and can provide excellent spatial resolution and soft tissue contrast for locating lesions. The contrast between different tissues in magnetic resonance imaging depends on the differences of biochemical environments, however, the tumor and the surrounding normal tissues have no obvious proton magnetic field environment difference, so the magnetic resonance imaging detection effect of the tumor tissues is poor. The contrast between tissues can be obviously improved by using the contrast agent, but the contrast agent (shown in fig. 1) used in commercial use in the prior art has poor specific contrast effect on tumors.
Disclosure of Invention
The invention aims to provide a gadolinium-tetronic acid derivative, a preparation method and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a gadolinium-tetronic acid derivative, which has a structure shown in a formula I-1 or a formula I-2:
r in the formula I-1 and the formula I-2 is any one of the following groups:
the invention provides a preparation method of the gadoteric acid derivative, which comprises the following steps:
the compound Gd-L 1 Mixing a targeting compound, 2- (7-aza-benzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine with an organic solvent, and carrying out condensation reaction to obtain the gadolinium-specific acid derivative with the structure shown in the formula I-1 or the formula I-2;
the compound Gd-L 1 Has a structure shown in a formula II-1 or a formula II-2:
the targeting compound has a structure represented by formula III, formula IV, formula V or formula VI:
preferably, the compound Gd-L 1 The molar ratio of the compound to the targeting compound is 0.9-1.0: 1.1 to 1.2.
Preferably, the compound Gd-L 1 The molar ratio of the 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate to the N, N-diisopropylethylamine is 0.4-0.6: 0.5 to 0.7:1.5 to 2.2.
Preferably, the temperature of the condensation reaction is 15-35 ℃ and the time is 2-4 h; the condensation reaction is carried out in a protective atmosphere.
Preferably, the condensation reaction further comprises: and separating and purifying a product system obtained after the condensation reaction by adopting reverse-phase high performance liquid chromatography to obtain the gadoteric acid derivative with the structure shown in the formula I-1 or the formula I-2.
The invention provides application of the gadoteric acid derivative in preparation of a targeted tumor contrast agent.
Preferably, the targeted tumor contrast agent is a magnetic resonance imaging contrast agent.
Preferably, the targeted tumor contrast agent is T 1 A contrast agent.
Preferably, the tumor to which the targeted tumor contrast agent is applicable comprises one or more of breast cancer, liver cancer, brain glioma, ovarian cancer, colon cancer, pancreatic cancer and prostate cancer.
The invention provides a gadolinium-tetronic acid derivative with a structure shown in a formula I-1 or a formula I-2, which adopts sulfonamide compounds and glucosamine as targeting molecules, designs a contrast agent for targeting tumors on the basis of chiral gadolinium-tetronic acid (Gd-DOTA) compounds, and has excellent specific contrast effect on the tumors. The test example shows that the gadolinium-tetronic acid derivative provided by the invention has excellent targeting to breast cancer cells.
Drawings
FIG. 1 is a molecular structure diagram of a commercial contrast agent of the prior art;
FIG. 2 shows a compound Gd-L 1 、Gd-L 2 、Gd-L 3 、Gd-L 4 And Gd-L 5 T for mouse 4T1 subcutaneous tumor model 1 A weighted magnetic resonance imaging map.
Detailed Description
The invention provides a gadolinium-tetronic acid derivative, which has a structure shown in a formula I-1 or a formula I-2:
r in the formula I-1 and the formula I-2 is any one of the following groups:
in the present invention, the gadoteric acid derivative may be specifically a compound Gd-L 2 Compound Gd-L 3 Compound Gd-L 4 Or the compound Gd-L 5 ；
The compound Gd-L 2 Is any one of the following compounds (respectively referred to as the compounds R-Gd-L) 2 With the compound S-Gd-L 2 )：
The compound Gd-L 3 Is any one of the following compounds (respectively referred to as the compounds R-Gd-L) 3 With the compound S-Gd-L 3 )：
The compound Gd-L 4 Is any one of the following compounds (respectively referred to as the compounds R-Gd-L) 4 With the compound S-Gd-L 4 )：
The compound Gd-L 5 Is any one of the following compounds (respectively referred to as the compounds R-Gd-L) 5 With the compound S-Gd-L 5 )：
The invention provides a preparation method of the gadoteric acid derivative, which comprises the following steps:
the compound Gd-L 1 Mixing a targeting compound, 2- (7-aza-benzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine with an organic solvent, and carrying out condensation reaction to obtain the gadolinium-specific acid derivative with the structure shown in the formula I-1 or the formula I-2;
the compound Gd-L 1 Has a structure shown in formula II-1 or formula II-2 (respectively referred to as a compound R-Gd-L 1 With the compound S-Gd-L 1 )：
The targeting compound has a structure represented by formula III, formula IV, formula V or formula VI:
in the present invention, unless otherwise specified, all materials are commercially available or prepared by methods well known to those skilled in the art.
The invention combines the compound Gd-L 1 The targeting compound, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine are mixed with an organic solvent to carry out condensation reaction. In the invention, the targeting compound has a structure shown in a formula III, a formula IV, a formula V or a formula VI, wherein the targeting compound with the structure shown in the formula III is glucosamine, and the preparation method of the targeting compound with the structure shown in the formula IV, the formula V or the formula VI is described in detail later. In the present invention, the compound Gd-L 1 The molar ratio to the targeting compound is preferably 0.9 to 1.0:1.1 to 1.2, more preferably 1.0:1.1. in the present invention, the compound Gd-L 1 The molar ratio of 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is preferably 0.4 to 0.6:0.5 to 0.7:1.5 to 2.2, and can be specifically 0.6:0.7:1.5 or 0.4:0.5:2.2. in the present invention, the organic solvent is preferably N, N-dimethylformamide, and the compound Gd-L 1 The ratio of the organic solvent to the organic solvent is preferably 0.4 to 0.6mmol:5 to 30mL, specifically 0.6mmol:30mL or 0.4mmol:5mL.
The present invention preferably uses the compound Gd-L 1 Dissolving in an organic solvent, adding 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine into the obtained solution for carboxyl activation, and then adding a targeting compound into the obtained activation solution for condensation reaction. In the present invention, the temperature of the carboxyl group activation treatment is preferably 15 to 35 ℃, more preferably room temperature; in an embodiment of the present invention, the room temperature is specifically 25 ℃; the time of the carboxyl activating treatment is preferably 25 to 35 minutes, more preferably 30 minutes; the carboxyl group activation treatment is preferably performed under stirring. In the present invention, the targeting compound may be directly added to the activation solution, or may be dissolved in the organic solvent and then the resulting targeting compound solution may be added to the activation solution, which is not particularly limited in the present invention. In the present invention, the temperature of the condensation reactionThe degree is preferably 15 to 35 ℃, more preferably room temperature; the time is preferably 2 to 4 hours, more preferably 2 to 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.
After the condensation reaction, the gadolinium-tetronic acid derivative with the structure shown in the formula I-1 or the formula I-2 is obtained by separating and purifying a product system obtained after the condensation reaction by adopting reverse-phase high performance liquid chromatography. In the present invention, the mobile phase used in the reverse phase high performance liquid chromatography preferably includes a mobile phase a and a mobile phase B, wherein the mobile phase a is preferably a trifluoroacetic acid aqueous solution with a volume fraction of 0.1%, the mobile phase B is preferably acetonitrile, the flow rate of the mobile phase is preferably 7mL/min, and the elution procedure is preferably: starting conditions were 90% a and 10% B by volume, from 0min to 20min, the mobile phase B increasing linearly from 10% to 50%; the column used for the reverse phase high performance liquid chromatography is preferably a C18 column (specification is preferably 5 μm, 19X 250 mm).
The following is a detailed description of the preparation method of the targeting compound of formula IV, formula V or formula VI.
The preparation method of the targeting compound with the structure shown in the formula IV preferably comprises the following steps:
compound 1, N-Boc-3-chloropropylamine and NaHCO 3 Mixing with acetonitrile, and carrying out a first nucleophilic substitution reaction to obtain a compound 2;
mixing the compound 2, trifluoroacetic acid and dichloromethane, and performing a first deprotection reaction to obtain a targeting compound with a structure shown in a formula IV;
wherein, the structural formulas of the compound 1 and the compound 2 are shown in the following sequence:
the invention prepares the compound 1, N-Boc-3-chloropropylamine and NaHCO 3 And mixing with acetonitrile, and carrying out a first nucleophilic substitution reaction to obtain a compound 2. In the present invention, the compound 1, N-Boc-3-Chloropropylamine, naHCO 3 The ratio of the amount of the catalyst to acetonitrile is preferably 6mmol: 8-10 mmol: 11-13 mmol:25 to 35mL, more preferably 6mmol:9mmol:12mmol:30mL. In the present invention, the temperature of the first nucleophilic substitution reaction is preferably 45 to 55 ℃, more preferably 50 ℃; the time is preferably 10 to 15 hours, more preferably 12 hours. After the first nucleophilic substitution reaction, the obtained product system is preferably filtered, the solvent in the filtrate is evaporated to dryness, absolute ethyl alcohol is added, and a pale yellow compound is separated out under the stirring condition, namely the compound 2.
After the compound 2 is obtained, the compound 2, trifluoroacetic acid and dichloromethane are mixed, and a first deprotection reaction is carried out, so that a target compound (marked as a compound 3) with a structure shown in a formula IV is obtained. In the present invention, the ratio of the amount of the compound 2, trifluoroacetic acid to dichloromethane is preferably 0.6mmol: 0.4-0.6 mL:2.5 to 3.5mL, more preferably 0.6mmol:0.5mL:3mL. In the present invention, the temperature of the first deprotection reaction is preferably 15 to 35 ℃, more preferably room temperature; the time is preferably 50 to 70 minutes, more preferably 60 minutes. After the first deprotection reaction, the solvent in the obtained product system is preferably evaporated to dryness, and the obtained product is directly used for preparing the gadolinium tetronic acid derivative with the structure shown in the formula I-1 or the formula I-2.
The preparation method of the targeting compound with the structure shown in the formula V or the formula VI preferably comprises the following steps:
mixing a raw material compound, N-Boc-1, 3-propylene diamine, triethanolamine and acetonitrile, and performing a second nucleophilic substitution reaction to obtain an intermediate compound;
mixing the intermediate compound, trifluoroacetic acid and dichloromethane, and performing a second deprotection reaction to obtain a targeting compound with a structure shown in a formula V or a formula VI;
wherein the raw material compound is
The intermediate compound is
The invention mixes the raw material compound, N-Boc-1, 3-propylene diamine, triethanolamine and acetonitrile to carry out a second nucleophilic substitution reaction, thus obtaining an intermediate compound. In the invention, the dosage ratio of the raw material compound, N-Boc-1, 3-propylene diamine, triethanolamine and acetonitrile is preferably 4.2-5.2 mmol: 6-7 mmol: 12-13 mmol:25 to 35mL, more preferably 4.2 to 5.2mmol:6.4mmol:12.6mmol:30mL. In the present invention, the temperature of the second nucleophilic substitution reaction is preferably 75 to 85 ℃, more preferably 80 ℃; the time is preferably 10 to 15 hours, more preferably 12 hours; the second nucleophilic substitution reaction is preferably performed in a protective atmosphere, more preferably in a nitrogen atmosphere. After the second nucleophilic substitution reaction, the present invention preferably cools the obtained product system to room temperature, evaporates the solvent, adds ethanol into the residue and precipitates yellow compound under the condition of continuous stirring, and filters, and collects the yellow compound, namely the intermediate compound.
After obtaining an intermediate compound, the intermediate compound, trifluoroacetic acid and dichloromethane are mixed, and a second deprotection reaction is carried out, so that the targeting compound with the structure shown in the formula V or the formula VI is obtained. In the present invention, the ratio of each material, the reaction condition and the post-treatment method in the second deprotection reaction are preferably identical to those in the first deprotection reaction, and are not described in detail herein.
The invention provides application of the gadoteric acid derivative in preparation of a targeted tumor contrast agent. In the present invention, the tumor-targeted contrast agent is preferably a magnetic resonance imaging contrast agent. In the present invention, the tumor-targeting contrast agent is preferably T 1 A contrast agent. In the present invention, the tumor to which the targeted tumor contrast agent is applied is preferably a solid tumor, and the tumor preferably includes one or more of breast cancer, liver cancer, brain glioma, ovarian cancer, colon cancer, pancreatic cancer and prostate cancer, more preferably breast cancer.
The invention adopts sulfonamide compound and glucosamine as targeting molecules, and uses chiral gadolinium as a target moleculeThe (Gd-DOTA) compound is based on a tumor-targeted contrast agent, and the specific contrast effect on tumors is excellent. Specifically, because the growth speed of the tumor is high, the blood supply in the solid tumor is insufficient, and then the hypoxia phenomenon of the tumor is generated, and the treatment effect of the traditional chemotherapy and radiotherapy is reduced. Accurate imaging for the hypoxic environment can locate hidden tumors in a patient on one hand, and can help to formulate a personalized treatment scheme on the other hand, so that the treatment effect is improved. The sulfonamide compound can be combined with carbonic anhydrase IX/XII which is overexpressed in hypoxic tumor cells, and the tumor cells have glucose/glucosamine transport proteins which are overexpressed relative to normal cells, so the invention adopts the sulfonamide compound and the glucosamine as target points to design a contrast agent aiming at tumors. The chiral Gd-DOTA compound is a T with excellent stability constructed by introducing four chiral groups into Gd-DOTA macrocyclic symmetry 1 A contrast agent. The invention uses chiral Gd-DOTA compound to connect tumor targeted sulfonamide compound or aminoglucose to construct a magnetic resonance imaging contrast agent with tumor targeting, in particular to a T with tumor targeting 1 The contrast agent can be used for MRI diagnosis of tumors and meets the clinical diagnosis requirement.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Preparation of the Compound Gd-L 2 (in particular to a compound R-Gd-L 2 ) The reaction formula is as follows:
the compound Gd-L 1 (in particular, compound R-Gd-L 1 0.5g,0.6 mmol) was dissolved in 30mL of N, N-Dimethylformamide (DMF), followed by addition of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 0.3g,0.7 mmol) and N, N-diisopropylethylamine (DIEA, 0.2g,1.5 mmol), carboxyl activation treatment was performed with stirring at room temperature (25 ℃ C.) for 30min, and then glucosamine (0.2 g,1.1 mmol) was added to the resultant system, and condensation reaction was performed under nitrogen atmosphere with stirring for 2h; after the reaction is finished, separating and purifying the obtained product system by utilizing reverse-phase high performance liquid chromatography to obtain a compound R-Gd-L 2 The method comprises the steps of carrying out a first treatment on the surface of the The mobile phase used by the reversed-phase high-performance liquid chromatography comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is trifluoroacetic acid aqueous solution with the volume fraction of 0.1%, the mobile phase B is acetonitrile, the flow rate of the mobile phase is 7mL/min, and the elution procedure is as follows: starting conditions were 90% a and 10% B by volume, from 0min to 20min, the mobile phase B increasing linearly from 10% to 50%; the chromatographic column used for the reversed-phase high-performance liquid chromatography is a C18 chromatographic column (5 μm,19×250 mm).
The compound R-Gd-L 2 The characterization data of (2) are as follows: ESI-MS M/z: [ M ]] - calcd.for C 37 H 55 GdN 5 O 14 951.3；found 951.3。
Example 2
Preparation of the Compound Gd-L 2 (in particular to a compound S-Gd-L 2 ) The reaction formula is as follows:
the compound Gd-L 1 (in particular to a compound S-Gd-L 1 0.5g,0.6 mmol) was dissolved in 30mL of DMF, followed by HATU (0.3 g,0.7 mmol) and DIEA (0.2 g,1.5 mmol) and carboxyl-activating treatment with stirring at room temperature for 30min, after which glucosamine (0.2 g,1.1 mmol) was added to the resulting system and condensation reaction was carried out under nitrogen atmosphere with stirring for 2h; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions were the same as in example 1 to obtain a compound S-Gd-L 2 . Watch (watch)The characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 37 H 55 GdN 5 O 14 951.3；found 951.3。
Example 3
Preparation of the Compound Gd-L 3 (in particular to a compound R-Gd-L 3 ) The reaction formula is as follows:
compound 1 (1.1 g,6 mmol), N-Boc-3-chloropropylamine (1.7 g,9 mmol), naHCO 3 (1.0 g,12 mmol) was mixed with 30mL of acetonitrile and heated to 50deg.C for nucleophilic substitution reaction for 12h; and after the reaction is finished, filtering the obtained product system, evaporating the solvent in the filtrate, adding absolute ethyl alcohol, and separating out a light yellow compound under the stirring condition to obtain the compound 2. Characterization data are as follows: 1 HNMR(400MHz,DMSO-d 6 ,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-d 6 ,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 N 5 O 4 S 2 337.5 found 337.5。
compound 2 (0.2 g,0.6 mmol) was dissolved in 3mL of dichloromethane, followed by the addition of 0.5mL of trifluoroacetic acid and deprotection reaction at room temperature for 1h; after the reaction, the solvent in the obtained product system was evaporated to dryness to obtain compound 3, which was directly used for the next reaction.
Gd-L 1 (in particular to a compound R-Gd-L 1 0.3g,0.4 mmol), HATU (0.2 g,0.5 mmol), DIEA (0.2 g,2.2 mmol) were mixed with 5mL DMF and subjected to carboxyl activation treatment for 30min under stirring at room temperature, then compound 3 was dissolved in 5mL DMF and added to the system obtained after carboxyl activation treatment, and condensation reaction was carried out under nitrogen atmosphere and stirring at room temperature for 4h; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions were the same as in example 1) to obtain a purified productCompound R-Gd-L 3 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 36 H 53 GdN 9 O 11 S 2 1009.2；found 1009.2。
Example 4
Preparation of the Compound Gd-L 3 (in particular to a compound S-Gd-L 3 ) The reaction formula is as follows:
Gd-L 1 (in particular to a compound S-Gd-L 1 0.3g,0.4 mmol), HATU (0.2 g,0.5 mmol), DIEA (0.2 g,2.2 mmol) were mixed with 5mL DMF and subjected to carboxyl activation treatment for 30min under stirring at room temperature, then compound 3 was dissolved in 5mL DMF and added to the system obtained after carboxyl activation treatment, and condensation reaction was carried out under nitrogen atmosphere and stirring at room temperature for 4h; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions were the same as in example 1) to obtain a compound S-Gd-L 3 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 36 H 53 GdN 9 O 11 S 2 1009.2；found 1009.2。
Example 5
Preparation of the Compound Gd-L 4 (in particular to a compound R-Gd-L 4 ) The reaction formula is as follows:
compound 4 (1.0 g,5.2 mmol) was dissolved in 30mL of acetonitrile, followed by addition of N-Boc-1, 3-propanediamine (1.1 g,6.4 mmol) and triethanolamine (TEA, 1.3g,12.6 mmol) and nucleophilic substitution reaction at 80deg.C under nitrogen for 12h; after the reaction is finished, the obtained product system is cooled to room temperature, the solvent is evaporated, 20mL of ethanol is added into the residue, a yellow compound is precipitated under the condition of continuous stirring, and the yellow compound is filtered and collected to obtain the compound 5. Characterization ofThe data are as follows: 1 H NMR(400MHz,DMSO-d 6 ,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-d 6 ,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 N 3 O 4 S 330.4found 330.4。
compound 5 (0.2 g,0.6 mmol) was dissolved in 3mL of dichloromethane, followed by the addition of 0.5mL of trifluoroacetic acid and deprotection reaction was carried out under stirring at room temperature for 1h; after the reaction, the solvent in the obtained product system was evaporated to dryness to obtain compound 6, which was directly used for the next reaction.
Gd-L 1 (in particular to a compound R-Gd-L 1 0.3g,0.4 mmol), HATU (0.2 g,0.5 mmol), DIEA (0.2 g,2.2 mmol) were mixed with 5mL DMF, carboxyl-activated for 30min with stirring at room temperature, then compound 6 was dissolved in 5mL DMF and added to the system obtained after carboxyl-activation, and condensation reaction was carried out under nitrogen atmosphere with stirring at room temperature for 4h; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions are the same as in example 1) to obtain the compound R-Gd-L 4 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 40 H 57 GdN 7 O 11 S1001.2；found 1001.2。
Example 6
Preparation of the Compound Gd-L 4 (in particular to a compound S-Gd-L 4 ) The reaction formula is as follows:
Gd-L 1 (in particular to a compound S-Gd-L 1 0.3g,0.4 mmol), HATU (0.2 g,0.5 mmol), DIEA (0.2 g,2.2 mmol) and 5mL DMF were mixed and subjected to carboxyl activation with stirring at room temperature for 30min, then Compound 6 was dissolved in 5mL DMF and added to the system obtained after carboxyl activation, inCarrying out condensation reaction for 4h in nitrogen atmosphere under the condition of stirring at room temperature; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions were the same as in example 1) to obtain a compound S-Gd-L 4 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 40 H 57 GdN 7 O 11 S1001.2；found 1001.2。
Example 7
Preparation of the Compound Gd-L 5 (in particular to a compound R-Gd-L 5 ) The reaction formula is as follows:
compound 7 (1.0 g,4.2 mmol) was dissolved in 30mL of acetonitrile, followed by addition of N-Boc-1, 3-propanediamine (1.1 g,6.4 mmol) and TEA (1.3 g,12.6 mmol) and nucleophilic substitution reaction at 80℃for 12h under nitrogen atmosphere; after the reaction is finished, the obtained product system is cooled to room temperature, the solvent is evaporated, 20mL of ethanol is added into the residue, a yellow compound is precipitated under the condition of continuous stirring, and the yellow compound is filtered and collected to obtain the compound 8. Characterization data are as follows: 1 HNMR(400MHz,DMSO-d 6 ,δppm)1.37(s,9H),1.71(t,J＝6.72Hz,2H),3.01(q,J＝6.28Hz,2H),3.44(q,J＝6.48Hz,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-d 6 ,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 N 4 O 6 SNa 397.1found397.1。
compound 8 (0.2 g,0.6 mmol) was dissolved in 3mL of dichloromethane, followed by the addition of 0.5mL of trifluoroacetic acid and deprotection reaction was carried out under stirring at room temperature for 1h; after the reaction, the solvent in the obtained product system was evaporated to dryness to obtain compound 9, which was directly used for the next reaction.
Gd-L 1 (in particular to a compound R-Gd-L 1 ,0.3g,0.4mmol)、HATU(0.2g,0.5mmol)、DIEA(02g,2.2 mmol) and 5mL of DMF are mixed, carboxyl activation treatment is carried out for 30min under the condition of stirring at room temperature, then compound 9 is dissolved in 5mL of DMF and added into the system obtained after carboxyl activation treatment, and condensation reaction is carried out for 4h under the condition of stirring at room temperature under the nitrogen atmosphere; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions are the same as in example 1) to obtain the compound R-Gd-L 5 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 40 H 56 GdN 8 O 13 S1046.3；found 1046.3。
Example 8
Preparation of the Compound Gd-L 5 (in particular to a compound S-Gd-L 5 ) The reaction formula is as follows:
Gd-L 1 (in particular to a compound S-Gd-L 1 0.3g,0.4 mmol), HATU (0.2 g,0.5 mmol), DIEA (0.2 g,2.2 mmol) were mixed with 5mL DMF and subjected to carboxyl activation treatment at room temperature under stirring for 30min, then compound 9 was dissolved in 5mL DMF and added to the resultant system after carboxyl activation treatment, and condensation reaction was carried out under nitrogen atmosphere under stirring at room temperature for 4h; after the reaction, the obtained product system was separated and purified by reverse-phase high performance liquid chromatography (the specific conditions were the same as in example 1) to obtain a compound S-Gd-L 5 . Characterization data are as follows: ESI-MS M/z: [ M ]] - calcd.for C 40 H 56 GdN 8 O 13 S1046.3；found 1046.3。
Test example 1
4T1 breast cancer is a rapidly growing malignancy, and mouse 4T1 subcutaneous tumor is a hypoxic tumor model. In this example, 0.1mL of the right hind limb of a normal BALB/C mouse was subcutaneously injected with 1X 10 7 PRMI1640 medium of/mL 4T1 cells was used for magnetic resonance imaging by visual observation of subcutaneous tumor growth to a diameter of 0.5 cm. Subcutaneous tumor mice were anesthetized with isoflurane and then administered compound Gd-L via tail vein 1 (comprising the compound R-Gd-L 1 、S-Gd-L 1 )、Gd-L 2 (including the compound R-Gd-L 2 、S-Gd-L 2 )、Gd-L 3 (including the compound R-Gd-L 3 、S-Gd-L 3 )、Gd-L 4 (including the compound R-Gd-L 4 、S-Gd-L 4 ) And Gd-L 5 (including the compound R-Gd-L 5 、S-Gd-L 5 ) The dose was 0.1mmol/kg body weight, and T was performed after the administration by using a 3.0T magnetic resonance scanner (Ingenia resolution, philips) 1 Weighted scan, scan parameters te=9.7ms, tr=191.1 ms, fa=50 °, fov=50×50mm, matrix size=200×135, 12 layers, 1.5mm thick, with 0.15mm pitch reserved.
FIG. 2 is a compound R-Gd-L 1 、S-Gd-L 1 、R-Gd-L 2 、S-Gd-L 2 、R-Gd-L 3 、S-Gd-L 3 、R-Gd-L 4 、S-Gd-L 4 、R-Gd-L 5 And S-Gd-L 5 T for mouse 4T1 subcutaneous tumor model 1 As can be seen from FIG. 2, the compound R-Gd-L 2 、S-Gd-L 2 、R-Gd-L 3 、S-Gd-L 3 、R-Gd-L 4 、S-Gd-L 4 、R-Gd-L 5 And S-Gd-L 5 Has more obvious targeting to tumor, wherein, the compound R-Gd-L 4 、S-Gd-L 4 、R-Gd-L 5 And S-Gd-L 5 The penetration and retention time extension for solid tumors is more pronounced.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A gadoteric acid derivative, which has a structure represented by formula I-1 or formula I-2:
r in the formula I-1 and the formula I-2 is any one of the following groups:
2. a process for the preparation of a gadoteric acid derivative according to claim 1, comprising the steps of:
the compound Gd-L 1 Mixing a targeting compound, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine with an organic solvent, and carrying out condensation reaction to obtain the gadotec acid derivative with the structure shown in I-1 or formula I-2;
the compound Gd-L 1 Has a structure shown in a formula II-1 or a formula II-2:
the targeting compound has a structure represented by formula III, formula IV, formula V or formula VI:
3. the preparation method according to claim 2, wherein the compound Gd-L 1 The molar ratio of the compound to the targeting compound is 0.9-1.0: 1.1 to 1.2.
4. The method of claim 3, wherein the compound Gd-L 1 The molar ratio of the 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate to the N, N-diisopropylethylamine is 0.4-0.6: 0.5 to 0.7:1.5 to 2.2.
5. The preparation method according to claim 2, wherein the temperature of the condensation reaction is 15-35 ℃ for 2-4 hours; the condensation reaction is carried out in a protective atmosphere.
6. The method according to claim 2 or 5, wherein the condensation reaction further comprises: and separating and purifying a product system obtained after the condensation reaction by adopting reverse-phase high performance liquid chromatography to obtain the gadoteric acid derivative with the structure shown in the formula I-1 or the formula I-2.
7. Use of a gadoteric acid derivative according to claim 1 for the preparation of a targeted tumour contrast agent.
8. The use of claim 7, wherein the targeted tumor contrast agent is a magnetic resonance imaging contrast agent.
9. The use of claim 8, wherein the targeted tumor contrast agent is T 1 A contrast agent.
10. The use according to any one of claims 7 to 9, wherein the tumor for which the targeted tumor contrast agent is suitable comprises one or more of breast cancer, liver cancer, glioma, ovarian cancer, colon cancer, pancreatic cancer and prostate cancer.
CN202311349769.XA 2023-10-18 2023-10-18 Gadolinium-tetronic acid derivative and preparation method and application thereof Pending CN117402199A (en)

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