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WO2025039363A1 - Colorant de cyanine zwitterionique proche infrarouge, son procédé de préparation et son application - Google Patents

Colorant de cyanine zwitterionique proche infrarouge, son procédé de préparation et son application Download PDF

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Publication number
WO2025039363A1
WO2025039363A1 PCT/CN2023/127603 CN2023127603W WO2025039363A1 WO 2025039363 A1 WO2025039363 A1 WO 2025039363A1 CN 2023127603 W CN2023127603 W CN 2023127603W WO 2025039363 A1 WO2025039363 A1 WO 2025039363A1
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Prior art keywords
compound
infrared
zwitterionic
cyanine dye
condensation reaction
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Chinese (zh)
Inventor
黄佳国
伊淑娟
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Sun Yat Sen University
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Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/10—The polymethine chain containing an even number of >CH- groups
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence

Definitions

  • the present invention belongs to the field of biomedical technology, and more specifically, relates to near-infrared zwitterionic cyanine dyes and preparation methods and applications thereof.
  • the urinary system is composed of kidneys, ureters, bladder, and urethra, and is an important excretion pathway for human metabolic products. During the excretion process, abnormal metabolic waste, foreign microorganisms, drugs, etc. in the body can easily cause infection and damage to surrounding tissues and cells, leading to a series of diseases.
  • the current clinical diagnosis of urinary system diseases often relies on traditional imaging methods. However, these methods have defects such as high ionizing radiation, low sensitivity, and high cost, making it difficult to diagnose early and implement intervention.
  • optical imaging/detection technology has the advantages of high sensitivity, strong specificity, high safety, and convenience and popularity. Therefore, non-invasive, non-ionizing radiation, high specificity and sensitivity of fluorescence imaging technology for detecting urinary system diseases has excellent application prospects.
  • Fluorescence imaging has developed rapidly in the past decade. This technology allows real-time detection of specific targets such as malignant cells, nerves, blood vessels and lymph nodes during surgery.
  • fluorescent substances have specific properties such as hydrophilicity, they can selectively gather in water-rich organs such as the kidneys, ureters, and bladders. Based on this property, fluorescent imaging can be used to image organs and determine whether there are lesions in the organs. At the same time, such hydrophilic substances can also be metabolized and excreted from the body very quickly through the kidneys, and have high biocompatibility.
  • Indocyanine green is mainly metabolized by the liver and gallbladder, has poor hydrophilicity, and is almost not enriched in the urinary system.
  • methylene blue has a certain hydrophilicity and can be used for fluorescence imaging of the urinary system, it is still insufficient for the examination of kidney diseases due to its low renal clearance rate.
  • the fluorescent probes used for kidney disease detection mainly include inorganic nanoprobes and organic molecular probes.
  • the metabolism of inorganic nanoprobes is limited by the pore size of the glomerular basement membrane, and has strict selectivity for the size of nanoprobes. Only inorganic nanoparticles with a hydrated diameter of less than 6nm and a low protein binding rate can be effectively excreted through the kidneys.
  • inorganic nanomaterials have a slow metabolism rate and can be captured and accumulated by the endothelial reticular system of the liver when circulating in the body, resulting in long-term, potential biological toxicity.
  • organic molecular probes have the advantages of fast metabolism, high biocompatibility, and modifiable structure. They have a wide range of applications in the biomedical field, including cell imaging, tumor diagnosis and treatment, and clinical intraoperative navigation.
  • the technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing single-charge fluorescent probes, such as poor specificity and low signal-to-noise ratio in fluorescence imaging results, and to provide a near-infrared zwitterionic cyanine dye.
  • the near-infrared zwitterionic cyanine dye has a strong charge (sulfonate and quaternary ammonium salt) and a charge balance on the molecular surface. Therefore, after intravenous injection, the near-infrared zwitterionic cyanine dye exhibits extremely low nonspecific binding and tissue uptake in vivo, and the fluorescence imaging results have good specificity and a high signal-to-noise ratio.
  • another object of the present invention is to provide a use of a near-infrared zwitterionic cyanine dye as a fluorescent probe.
  • Another object of the present invention is to provide a method for preparing near-infrared zwitterionic cyanine dyes.
  • the present invention provides a near-infrared zwitterionic cyanine dye, characterized in that it has a structure shown in any one of formulas (I) to (IV):
  • X is N, O, or S; and n is an integer of 0 to 20.
  • n is an integer of 1-20.
  • the near-infrared zwitterionic cyanine dye provided by the present invention can be rapidly metabolized by the kidneys without being non-specifically taken up by other tissues or organs.
  • fluorescence imaging dynamic monitoring of lesions in the urinary system and visual identification of lesion areas can be achieved, which is of great significance for the diagnosis of kidney damage, ureteral obstruction, etc.
  • real-time fluorescence imaging equipment more accurate guidance can be provided for the precision treatment of ureteral surgery, so as to improve the surgical efficacy and patient prognosis, and it is expected to provide a new auxiliary method for the diagnosis and treatment of human diseases.
  • the near-infrared zwitterionic cyanine dye has any of the following structures:
  • the preparation method of the above-mentioned near-infrared zwitterionic cyanine dye comprises the following steps:
  • n is an integer from 1 to 20.
  • the reaction temperature of the condensation reaction is 45 to 100° C.
  • the reaction time is 12 to 24 hours.
  • the solvent selected for the condensation reaction is one or more of anhydrous ethanol, anhydrous methanol, N,N-dimethylformamide or acetic anhydride
  • the activating agent selected is one or more of potassium carbonate, cesium carbonate, sodium acetate, potassium acetate or triethylamine.
  • the compound 5 is prepared by the following steps:
  • Compound 1 undergoes a condensation reaction with compound 20 (preferably in the presence of acetic acid at 80 to 110° C.) to obtain compound 2, which is then used;
  • Compound 2 undergoes a substitution reaction with compound 30 (preferably the solvent is toluene or o-dichlorobenzene, the reaction temperature is preferably 110° C. to 130° C., and the reaction time is preferably 48 h to 72 h) to obtain compound 4, which is then used;
  • compound 30 preferably the solvent is toluene or o-dichlorobenzene, the reaction temperature is preferably 110° C. to 130° C., and the reaction time is preferably 48 h to 72 h
  • Compound 4 undergoes a substitution reaction with compound 3 (preferably in the presence of sodium acetate at 80° C., preferably the solvent is one or more of anhydrous ethanol, anhydrous methanol, N,N-dimethylformamide or acetic anhydride) to obtain compound 5;
  • the solvent is one or more of anhydrous ethanol, anhydrous methanol, N,N-dimethylformamide or acetic anhydride
  • compound 7 or compound 9 is prepared by the following steps:
  • step S12 Compound 6 undergoes a substitution reaction with compound 21 to obtain compound 7 or compound 9; preferably, the reaction time of the substitution reaction in step S12 is 6 to 24 hours; more preferably, the reaction time is 6 to 8 hours to obtain compound 7, and the reaction time is 12 to 24 hours to obtain compound 9;
  • compound 14 or compound 17 is prepared by the following steps:
  • step S13 Compound 11 undergoes a substitution reaction with compound 21 to obtain compound 14 or compound 17; preferably, the reaction time of the substitution reaction in step S13 is 6 to 24 hours; more preferably, the reaction time is 6 to 8 hours to obtain compound 14, and the reaction time is 12 to 24 hours to obtain compound 17;
  • compound 15 or compound 18 is prepared by the following steps:
  • step S14 Compound 12 undergoes a substitution reaction with compound 21 to obtain compound 15 or compound 18; preferably, the reaction time of the substitution reaction in step S14 is 6 to 24 hours; more preferably, the reaction time is 6 to 8 hours to obtain compound 15, and the reaction time is 12 to 24 hours to obtain compound 18;
  • compound 16 or compound 19 is prepared by the following steps:
  • step S15 Compound 13 undergoes a substitution reaction with compound 21 to obtain compound 16 or compound 19; preferably, the reaction time of the substitution reaction in step S15 is 6 to 24 hours; more preferably, the reaction time is 6 to 8 hours to obtain compound 16, and the reaction time is 12 to 24 hours to obtain compound 19;
  • the substitution reaction is carried out in the presence of a base, the reaction temperature is 0 to 25° C., and the solvent is acetonitrile; more preferably, the base is quinoline or pyridine.
  • compound 7 undergoes a reduction reaction to obtain compound 8; compound 9 undergoes a reduction reaction to obtain compound 10; preferably, the reduction reaction is carried out in the presence of stannous chloride, the solvent is one or more of anhydrous methanol, anhydrous ethanol or anhydrous acetonitrile, and the reaction temperature is 25°C to 40°C;
  • the present invention also claims the application of the near-infrared zwitterionic cyanine dye and its pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, and tautomers in the preparation of fluorescent probes. use.
  • the fluorescent probe is a renal-cleared fluorescent probe.
  • the pharmaceutically acceptable salt is hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, aminosulfate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, enanthate, phthalate, oxalate, succinate, benzoate, o-acetyl At least one of oxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, bishydroxynaphthoate, malonate, laurate, glutarate
  • This study provides a class of chemically balanced, electrically neutral, multi-ion near-infrared cyanine dyes (abbreviated as zwitterionic cyanine dyes), which use derivatives of the cyanine dye structure as fluorophores and modify hydrophilic groups on the benzene ring. They not only have high specificity and sensitivity, but also have good biocompatibility and optical stability. As fluorescent probes, they can be rapidly metabolized by the kidneys without being nonspecifically taken up by other tissues or organs. They have a high renal clearance rate and can be used for more accurate early diagnosis of diseases, intraoperative navigation treatment, tissue and organ function evaluation, etc. They can play an important role in future medical optical examinations and have excellent application prospects.
  • FIG. 1 shows the ultraviolet absorption spectra and fluorescence emission spectra of the near-infrared zwitterionic cyanine dye compounds 22 and 26 of Examples 3 and 4.
  • FIG. 1 shows the ultraviolet absorption spectra and fluorescence emission spectra of the near-infrared zwitterionic cyanine dye compounds 22 and 26 of Examples 3 and 4.
  • FIG. 1 shows the ultraviolet absorption spectra and fluorescence emission spectra of the near-infrared zwitterionic cyanine dye compounds 22 and 26 of Examples 3 and 4.
  • FIG. 2 is a statistical graph showing the recovery rate of the dye in urine within 24 hours after injection of the near-infrared zwitterionic cyanine dye compound 22 of Example 3.
  • FIG3 is a statistical graph of the in vitro plasma protein binding rate data of the near-infrared zwitterionic cyanine dye compound 22 of Example 3.
  • FIG4 is a graph showing the plasma half-life of the near-infrared zwitterionic cyanine dye compound 22 of Example 3 measured at different time points after injection in an acute kidney injury rat model.
  • FIG5 is a graph showing the plasma half-life of the near-infrared zwitterionic cyanine dye compound 22 of Example 3 measured at different time points after administration of an anion blocker and a cation blocker in an acute kidney injury rat model.
  • Figure 6 is an organ imaging diagram of the near-infrared zwitterionic cyanine dye compound 22 of Example 3 in normal rats; wherein He represents heart, Li represents liver, Sp represents spleen, Lu represents lung, Ki represents kidney, Bl represents bladder, Sk represents skin, Mu represents muscle, and In represents small intestine.
  • Figure 7 is an organ imaging diagram of the near-infrared zwitterionic cyanine dye compound 22 of Example 3 in an acute kidney injury rat model; wherein He represents the heart, Li represents the liver, Sp represents the spleen, Lu represents the lungs, Ki represents the kidneys, Bl represents the bladder, Sk represents the skin, Mu represents the muscles, and In represents the small intestine.
  • the present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.
  • Example 1 A precursor compound 8 of a near-infrared zwitterionic cyanine dye compound
  • This embodiment provides a precursor of a near-infrared zwitterionic cyanine dye compound, and the synthesis route is as follows:
  • the specific steps include:
  • Example 2 A precursor compound 10 of a near-infrared zwitterionic cyanine dye compound
  • This embodiment provides a precursor of a near-infrared zwitterionic cyanine dye compound, and the synthesis route is as follows:
  • the specific steps include:
  • Example 3 A near-infrared zwitterionic cyanine dye compound 22
  • This embodiment provides a near-infrared zwitterionic cyanine dye compound, and the synthesis route is as follows:
  • the specific steps include:
  • Example 4 A near-infrared zwitterionic cyanine dye compound 26
  • This embodiment provides a near-infrared zwitterionic cyanine dye compound, and the synthesis route is as follows:
  • the specific steps include:
  • the test results are shown in Figure 2.
  • the urine recovery rates of the probes were high, at 96%, 99%, and 98%, proving that the zwitterionic fluorescent probe provided by the present invention has good renal clearance efficiency and can be used to detect urinary system diseases.
  • Control group intraperitoneal injection of 1 mL of normal saline
  • AKI model group intraperitoneal injection of 10 mg/kg cisplatin solution
  • NAC group tail vein injection of 400 mg/kg NAC solution, and 30 minutes later, intraperitoneal injection of 10 mg/kg cisplatin solution.
  • Plasma half-life test Prepare a PBS solution of 0.05 mg/mL of the ever-bright fluorescent probe compound 22. Take 18 SD rats with the above-mentioned acute kidney injury model and randomly divide them into 6 groups: Control, 24h, 36h, 48h, 72h, and NAC groups, with 3 rats in each group, and inject 150 ⁇ L of the probe solution into the tail vein. Blood was collected from the tail vein every 10 minutes after the injection, and the concentration of the fluorescent probe was measured by HPLC according to the peak area of the plasma, and a plasma half-life curve was drawn. As shown in Figure 4, the fluorescent probe developed by the present invention can detect significant changes in kidney metabolism about 36 hours after kidney injury, indicating kidney injury. The experimental results show that the near-infrared zwitterionic cyanine dye has a diagnostic effect on renal injury.
  • Control group intraperitoneal injection of 1 mL of normal saline
  • Cation transporter inhibitor (cemitidine) group intraperitoneal injection of 50 mg/kg of cemitidine solution
  • Anion transporter inhibitor (probenecid) group tail vein injection of 50 mg/kg of probenecid solution.
  • Eighteen SD rats were randomly divided into six groups, namely, blank control group (control group), NAC control group, model group (24h group, 36h group, 48h group, 72h group), three rats in each group.
  • Control group intraperitoneal injection of 1 mL of normal saline
  • AKI model group intraperitoneal injection of 10 mg/kg of cisplatin solution, and imaging examination was performed at 24h, 36h, 48h, and 72h after injection
  • NAC group tail vein injection of 400 mg/kg of NAC solution, 30 minutes later, intraperitoneal injection of 10 mg/kg of cisplatin solution, and imaging examination was performed at 48h after cisplatin injection.
  • mice were euthanized and imaging of each organ (heart He, liver Li, spleen Sp, lung Lu, kidney Ki, bladder Bl, small intestine In, skin Sk, muscle Mu) was performed.
  • the test results are shown in Figure 7.
  • the probe fluorescence signal intensity was also low because the kidneys in the control group were normal and without lesions.
  • cisplatin gradually damages kidney tissue, induces acute kidney injury, and leads to a decrease in kidney glomerular filtration rate.
  • the probe cannot be metabolized out of the body in time, and is enriched in the kidney.
  • the intensity of the kidney fluorescence signal increases with time.
  • NAC N-acetylcysteine
  • NAC N-acetylcysteine
  • the intensity of the kidney fluorescence signal of rats in the NAC group is similar to that of rats in the normal group, and no obvious lesions are found in the kidney.
  • the experimental results show that near-infrared zwitterionic cyanine dye compound 22 can be used for the diagnosis of kidney injury and the evaluation of the therapeutic effect of anti-kidney injury drugs, and has good application prospects.

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Abstract

L'invention concerne un colorant de cyanine zwitterionique proche infrarouge, son procédé de préparation et son application. Le zwitterion proche infrarouge prend un dérivé à structure de colorant de cyanine en tant que fluorophore, et un groupe amphotère est modifié sur un cycle benzène, de telle sorte que le composé présente une solubilité dans l'eau extrêmement élevée, et devient ainsi une nouvelle sonde fluorescente à petites molécules pouvant être éliminée par le rein. De plus, le composé présente également une bonne biocompatibilité et une bonne stabilité optique, et en tant que sonde fluorescente, peut être utilisé pour effectuer plus précisément un diagnostic précoce, un traitement de navigation peropératoire, une évaluation de fonction tissulaire et d'organe, etc. lors de maladies rénales.
PCT/CN2023/127603 2023-08-23 2023-10-30 Colorant de cyanine zwitterionique proche infrarouge, son procédé de préparation et son application Pending WO2025039363A1 (fr)

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CN202311069021.4A CN117186151B (zh) 2023-08-23 2023-08-23 一种近红外两性离子花菁染料及其制备方法和应用
CN202311069021.4 2023-08-23

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117186151B (zh) * 2023-08-23 2024-05-17 中山大学 一种近红外两性离子花菁染料及其制备方法和应用
CN119684272B (zh) * 2024-12-16 2025-10-03 遵义医科大学 一种肾清除型长循环近红外荧光探针及其制备方法和应用

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CN114377152A (zh) * 2021-12-06 2022-04-22 中山大学 一种生物标志物响应型荧光示踪剂及其制备方法和应用
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CN104704358A (zh) * 2012-02-06 2015-06-10 Hq医药荷兰有限公司 细胞死亡测定
CN104937413A (zh) * 2012-02-06 2015-09-23 Hq医药荷兰有限公司 靶蛋白复合物
EP4147724A1 (fr) * 2013-10-31 2023-03-15 Beth Israel Deaconess Medical Center Agents de contraste pour la bioimagerie dans le proche infrarouge et leurs méthodes d'utilisation
US20150328342A1 (en) * 2014-05-16 2015-11-19 Cyanagen S.R.L. Novel tricarbocyanine-cyclodextrin(s) conjugates and use thereof
CN109121429A (zh) * 2016-03-29 2019-01-01 国立癌症研究中心 一种抗原反应型抗体-荧光染料缀合物以及使用其检测靶细胞荧光图像的方法
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CN117186151A (zh) * 2023-08-23 2023-12-08 中山大学 一种近红外两性离子花菁染料及其制备方法和应用

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