Search

CN-121991028-A - Compounds targeting c-Met, radionuclide-labeled complexes based thereon, and uses thereof

CN121991028ACN 121991028 ACN121991028 ACN 121991028ACN-121991028-A

Abstract

The invention provides a compound targeting c-Met, a radionuclide-labeled complex based on the compound, and application of the compound and the radionuclide-labeled complex. The c-Met targeting compound has a structure shown in a formula (I) or (II). The c-Met targeting compound provided by the invention shows higher tumor uptake after being marked by radionuclide such as 68 Ga, can be used for specifically detecting tumors with high expression of c-Met receptors, such as glioma, colon cancer, liver cancer, gastric cancer and the like, and has wide clinical application scenes.

Inventors

  • CHENG ZHEN
  • JI AIYAN
  • LOU HONGYUE

Assignees

  • 中国科学院上海药物研究所

Dates

Publication Date
20260508
Application Date
20241104

Claims (10)

  1. 1. A compound of formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotopically labeled compound thereof, Wherein each R 1 、R 2 、R 4 、R 5 is independently selected from H, methoxy, halogen; r 3 is selected from the group consisting of-Br, -NH 2 , -OH, Wherein each R a 、R b 、R c is independently selected from H, nitro, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -OH, -NH 2 , and aliphatic carboxyl; (i) When R 3 is selected from-Br, -NH 2 or-OH, R 6 is absent or -(W 1 )n 1 -(W 1 )n 2 -(W 1 )n 3 -(W 1 )n 4 -(W 1 )n 5 -(W 1 )n 6 -; wherein n 1 to n 6 are each independently 0 or 1 and not all 0, each W 1 is each independently selected from the following structures: - (CO) (CR a R b )n 7 NH-, wherein N 7 is an integer of 1 to 4, each R a 、R b is independently selected from H, C 1 -C 4 alkyl groups, each W 1 is connected by a carbonyl group and N to form an amide bond, and3 or more adjacent W 1 are not identical; (ii) When R 3 is selected from When R 6 is -(W 1 )n 1 -(W 1 )n 2 -(W 1 )n 3 -(W 1 )n 4 -(W 1 )n 5 -(W 1 )n 6 -;, wherein n 1 to n 6 are each independently 0 or 1 and not all 0, each W 1 is each independently selected from the following structures: - (CO) (CR a R b )n 7 NH-wherein N 7 is an integer between 1 and 4, each R a 、R b is independently selected from H, C 1 -C 4 alkyl groups, each W 1 is connected by a carbonyl group to N to form an amide bond, and 3 or more adjacent W 1 are not exactly the same, and at least 1W 1 is selected from the following structures: r 7 is Wherein X is- (CH 2 )n 8 ) -wherein n 8 is an integer of 1-10, preferably an integer of 1 to 8; wherein each CH 2 is independently and optionally replaced with-O-, -NH-, - (CO) -, -NH (CO) -, - (CO) -NH-, or Replacement, provided that no two adjacent CH 2 groups are replaced simultaneously; Y is connected with the X group by substituting one H in the X group, wherein Y is-NH-, - (CO) -, -NH (CO) -or- (CO) -NH-; l is absent or L is- (CH 2 )n 9 -, where n 9 is an integer from 1 to 40, wherein each CH 2 is independently optionally replaced with-O-, -NH-, - (CO) -, -NH (CO) -or- (CO) NH-, provided that no two adjacent CH 2 groups are replaced simultaneously; Wherein the substituent positions of L and R 6 can be interchanged; c is a group derived from a bifunctional chelator or therapeutic drug.
  2. 2. A compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotopically labeled compound thereof, wherein the group derived from a bifunctional chelating agent is selected from: Preferably is More preferably Or (b) The therapeutic drugs comprise small molecule inhibitors, monoclonal antibodies, biological alkylating agents, cytotoxic drugs, hormone drugs and biological response modifiers.
  3. 3. The compound of formula (I) or (II) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotopically labeled compound thereof, R 1 、R 2 、R 4 and R 5 are together H, and/or When R 3 is selected from-Br, -NH 2 or-OH, R 6 is absent or is selected from the following structures: Preferably, R 6 is absent or is a structure selected from the group consisting of: When R 3 is selected from When R 6 is selected from the following structures: Preferably is And/or R 7 is selected from the following structures: Preferably is And/or L is absent, or L is- (CH 2 )n 9 ) -wherein n 9 is an integer from 1 to 30, more preferably an integer from 1 to 18; wherein each-CH 2 -is independently optionally replaced by-O-, -NH-or- (CO) -, provided that no two adjacent-CH 2 -groups are replaced; preferably, L is absent, or L is-NH- (CH 2 )n10(OCH 2 CH 2 )n 11 (CO)-,n10、n 11 ) each independently an integer from 1 to 4, more preferably L is absent, or L is-NH (CH 2 ) 2 OCH 2 CH 2 (CO) -.
  4. 4. A compound of formula (I) or (II) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotopically labelled compound thereof, wherein the compound of formula (I) or (II) is selected from the following structures: Wherein R 6 、R 7 , L are as defined in any one of claims 1 to 3.
  5. 5. The compound of formula (I) or (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate or isotopically labeled compound thereof, wherein the compound of formula (I), (II) is selected from the following structures:
  6. 6. A radionuclide-labeled complex obtained by labeling a radionuclide M with a compound of formula (I), (II) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotopically labeled compound thereof according to any one of claims 1 to 5; In particular, the radionuclides M include radiodiagnostic and radiotherapeutic radionuclides; In particular, the radiodiagnostic nuclides are selected from any one of ： 86 Y、 18 F、 51 Mn、 52m Mn、 52g Mn、Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc、 111 In、 123 I、 124 I、 125 I、 44 Sc、 47 Sc, preferably any one of 86 Y、Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99m Tc、 124 I; In particular, the radionuclide is selected from any one of ： 67 Cu、 90 Y、 125 I、 131 I、 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb、 203 Pb、 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Th, preferably any one of 67 Cu、 90 Y、 125 I、 131 I、 177 Lu、 223 Ra、 225 Ac、 211 At, more preferably 68 Ga、 177 Lu or 90 Y; Preferably, the radionuclide-labeled complex has a structure represented by the following formulas (III), (IV): Wherein, the L, R 1 -R 7 are as defined in any one of claims 1 to 4; M is as defined above, preferably M is any one selected from 68 Ga、 177 Lu and 90 Y.
  7. 7. A process for the preparation of a radionuclide-labeled complex according to claim 6, wherein a radionuclide M is labeled with a compound of formula (I), (II) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotopically labeled compound thereof according to any one of claims 1 to 5; in particular, the labeling method is a wet labeling method or a freeze-drying labeling method; In particular, the wet labeling method comprises the steps of dissolving a proper amount of the compound of the formula (I) and the compound of the formula (II) or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates, atropisomers, polymorphs, solvates or isotopically labeled compounds thereof in buffer solution or deionized water to obtain a solution, adding a radionuclide M solution into the obtained solution, and performing airtight reaction for 5-40min to obtain a radionuclide-labeled complex; The freeze-drying labeling method comprises the following steps of dissolving a proper amount of the compound of the formula (I) and the compound of the formula (II) or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates, atropisomers, polymorphs, solvates or isotopically labeled compounds of the formula (I) and the compound of the formula (II) in buffer solution or deionized water to obtain a solution, sterile filtering the obtained solution, split charging the solution into a container, freeze-drying, adding a plug, sealing to obtain a freeze-drying medicine box, adding a proper amount of acetic acid solution or buffer solution into the freeze-drying medicine box for dissolving, adding corresponding radionuclide M solution, and performing airtight reaction for 5-40min to obtain radionuclide labeled complex; the radionuclide M is defined as in claim 6.
  8. 8. A pharmaceutical composition comprising one or more selected from the group consisting of compounds of formula (I), (II) according to any one of claims 1 to 5, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, atropisomers, polymorphs, solvates, isotopically labeled compounds, and radionuclide-labeled complexes according to claim 6, and optionally pharmaceutically acceptable excipients.
  9. 9. Use of a compound of formula (I), (II) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotopically-labeled compound thereof according to any one of claims 1 to 5, or a radionuclide-labeled complex according to claim 6, or a pharmaceutical composition according to claim 8, for the preparation of an agent for inhibiting c-Met activity.
  10. 10. Use of a compound of formula (I), (II) or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, atropisomer, polymorph, solvate, or isotopically-labeled compound thereof according to any one of claims 1 to 5, or a radionuclide-labeled complex according to claim 6, or a pharmaceutical composition according to claim 8, for the preparation of a medicament or agent for diagnosing, preventing and/or treating a disease characterized by high c-Met expression; preferably in the preparation of a medicament or agent for nuclide treatment or imaging of tumors with high c-Met expression; Preferably, the c-Met high-expression tumor comprises brain glioma, colorectal cancer, gastric cancer, liver cancer, lung cancer, prostate cancer, breast cancer, esophageal cancer, pancreatic cancer, ovarian cancer and cervical cancer.

Description

Compounds targeting c-Met, radionuclide-labeled complexes based thereon, and uses thereof Technical Field The invention belongs to the field of medical diagnosis and treatment, and particularly relates to a compound targeting c-Met, a radionuclide-labeled complex based on the compound, and application of the compound and the radionuclide-labeled complex in preparation of medicines for diagnosing, preventing and/or treating diseases characterized by high expression of c-Met. Background Mesenchymal transition factor (c-Met) is a multifunctional transmembrane tyrosine kinase with autophosphorylation activity encoded by the Met proto-oncogene, expressed mainly in epithelial and endothelial cells. c-Met is a heterodimer consisting of an extracellular alpha chain (50 kDa) and a transmembrane beta chain (145 kDa). Normally, the c-Met signaling pathway is fully activated in adults only during wound healing and tissue regeneration. Human Hepatocyte Growth Factor (HGF) is the only currently known natural ligand with high affinity for c-Met. When HGF binds to c-Met, it induces dimerization of c-Met and activates intracellular signaling pathways, thereby regulating a series of biological effects such as growth, survival, motility, proliferation of cells (Nature Reviews Molecular Cell Biology,2003,4 (12): 915-925). More and more studies have demonstrated that c-Met signaling is frequently abnormally activated in a variety of solid tumors, including glioma, lung cancer, prostate cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, and cervical cancer (Nat Med.2011;18：74-82.Metab Brain Dis.2013;28：355-66.Cancer Res.2000;60：4277-4283.Eur J Nucl Med Mol Imaging 2024;51,656-668)., while high expression of c-Met in tumors tends to promote proliferation, metastasis, invasion, growth of tumors and lead to poor patient prognosis (Journal of Clinical Oncology,2012,30 (26): 3287.Int J Cancer.1996;66:678-685). Based on the role of c-Met in tumors, the development of diagnostic and therapeutic drugs targeting c-Met has become a focus of attention for researchers. At present, each big medicine enterprise also targets the c-Met small molecule therapeutic medicine market in a dispute way. Up to now, 8 small molecule drugs have been approved for the market, including cabotinib, carbamatinib, crizotinib, ensartinib, tepontinib, gu Meiti, sivortinib, and beritinib. Despite such heat in the field of drug development, it is undeniable that the overall reactivity of such drugs in clinical applications is very poor. The response was detected by immunohistochemical staining (IHC) with no progression and no significant improvement in overall survival after administration in tumor patients with high c-Met expression, whereas the prognosis was not significantly improved in tumor patients with low c-Met expression (cancer.2009; 115:140-148.Clin Transl Oncol.2014;16:173-177.Cancer Res.2005;65:9355-9362.). In addition, the development of resistance of tumors to c-Met inhibitors (CANCER TREAT Rev.2013; 39:793-801) forces researchers to develop diagnostic tools to screen patients with c-Met high-expressing tumors as early as possible and to dynamically monitor resistance in real time. The nuclear medicine imaging technology is widely used in preclinical research and clinical practice due to the advantages of infinite penetrating power, high sensitivity, high space-time resolution, accurate quantification and the like. Nuclear medicine imaging probes developed for c-Met are mainly focused on three of antibodies, polypeptides and small molecule radioactive probes. Through literature investigation, the number of c-Met targeted radiation probes based on small molecules is extremely limited at present. 11 C-SU11274 was used to evaluate C-Met expression levels in a non-small cell lung cancer (NSCLC) mouse subcutaneous tumor model (j.med. Chem.2010,53,1,139-146). Imaging results showed that 11 C-SU11274 uptake SUV in C-Met positive tumors was only around 0.5. Meanwhile, the half-life of 11 C is only 20.38min, which limits the wide application of the probe. 18 The results of the F-FPC imaging in the c-Met positive NSCLC mouse model showed extremely high nonspecific uptake in the liver and abdomen with slight defluorination (Bioorganic & MEDICINAL CHEMISTRY,2020,28 (15): 115577). 18 F-AZC, although showing better tumor uptake in both U87MG brain glioma in situ and in the subcutaneous mouse model, has a higher uptake in liver, intestine, stomach etc. resulting in poor imaging contrast (Eur J Nucl Med Mol Imaging 2024;51, 656-668). CN106008339a discloses a radioactive c-Met targeted affinity small molecule compound, but 18 F-AZC reported in this patent and related papers, despite better radioactive uptake at the tumor site, also has high radioactive uptake in other normal tissues and organs, such as liver and abdomen, limiting imaging contrast. Disclosure of Invention In consideration of th