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EP-4655305-B1 - RUTHENIUM COMPLEXES FOR INHIBITION OF GALECTINS, METHOD OF THEIR PREPARATION, AND USE THEREOF

EP4655305B1EP 4655305 B1EP4655305 B1EP 4655305B1EP-4655305-B1

Inventors

  • Hrstka, Roman
  • HOLCAKOVA, Jitka
  • KARBAN, Jindrich
  • HAMALA, Vojtech
  • KURFIRT, Martin

Dates

Publication Date
20260513
Application Date
20240328

Claims (11)

  1. A compound of general formula (I) wherein R 1 , R 2 , R 3 , R 4 , and R m are independently selected from the group consisting of H and (C 1 to C 6 ) alkyl; n is 1 or 2; X and Z are N; D and Y are CH; R is independently H or an acyl of general formula (G) wherein R' is selected from the group comprising C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 6 -C 12 aryl; A is selected from the group consisting of general formula (II) and (III) B is selected from the group comprising monovalent negatively charged ligands and neutral ligands, preferably B is selected from the group comprising F - , Cl - , Br - , I - , CN - , SNC - , OCN - , NO 2 - , NO 3 - , HSO 4 - , OH - , CH 3 COO - , CO, CO 2 , CH 3 CN, H 2 O, NH 3 , monovalent organic N-ligands, and organophopsphine ligands; and wherein the positive charge of the compound of general formula (I) is compensated by an anion, preferably selected from the group comprising F - , Cl - , Br, I - , CN - , SCN - , OCN - , PF 6 - , Zn 2 Cl 6 2- , BF 4 - , NO 2 - , NO 3 - , HSO 4 - , SO 4 2- , H 2 PO 4 - , HPO 4 2- , PO 4 3- , OH - and CH 3 COO - .
  2. The compound of general formula (I) according to claim 1, wherein R 1 , R 2 , R 3 , R 4 , and R m are independently selected from the group consisting of H, -CH 3 , and -CH(CH 3 ) 2 .
  3. The compound of general formula (I) according to any one of the preceding claims, wherein the structural unit (IV) is selected from the group comprising cyclopentadiene, pentamethylcyclopentadiene, benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene.
  4. The compound of general formula (I) according to any one of the preceding claims, wherein said compound is selected from the group consisting of: wherein the positive charge of the compound is compensated by an anion selected from the group comprising F - , Cl - , Br - , I - , CN - , SCN - , OCN - , PF 6 - , Zn 2 Cl 6 2- , BF 4 - , NO 2 - , NO 3 - , HSO 4 - , SO 4 2- , H 2 PO 4 - , HPO 4 2- , PO 4 3- , OH - and CH 3 COO - .
  5. A method of preparing a compound of the general formula (Ia): wherein B, D, R, R 1 , R 2 , R 3 , R 4 a R m are as defined in claim 1; and wherein E is characterized in that it comprises the following steps: (a) Huisgen cycloaddition of the azide precursor of the general formula (V) wherein R is as defined in claim 1, preferably R is H or CH 3 C(=O)-; and A' is with the ethynyl derivative of a six-membered nitrogenous heterocycle of general formula (VII), wherein D is defined in claim 1, resulting in the formation of an intermediate of general formula (VIa) wherein R and D are defined in claim 1, and A" is (b) if R is not H, optional step of hydrolysis of the OR groups to form an intermediate of general formula (VIb) wherein D is as defined in claim 1, and A‴ is (c) a reaction of the compound of general formula (VIb) with a ruthenium complex of general formula [RuLB 2 ] 2 , wherein L is the structural unit (IV) as defined in claim 3, and B is as defined in claim 1, to form the compound of general formula (Ia).
  6. The method according to claim 5, wherein between the step (a) or, if present step (b), and the step (c), the compound of general formula (VIb) reacts with an acyl chloride of formula R'-C(=O)Cl to form an intermediate of general formula (VIc) wherein R' and D are defined in claim 1, and A" is the step (c) is then performed with said compound of general formula (VIc) to give the compound of general formula (Ia).
  7. Use of the compound of general formula (I) according to any of the preceding claims 1 to 4 as an analytical probe for in vitro determining the affinity of ligands to galectins, especially to galectin-1.
  8. The compound of general formula (I) according to any of the preceding claims 1 to 4 for use as a medicament.
  9. The compound of general formula (I) according to any of the preceding claims 1 to 4 for use in the treatment of diseases associated with galectin overexpression, especially galectin 1 overexpression, preferably selected from the group comprising cancer, fibrotic diseases, and HIV-1 infection.
  10. The compound of general formula (I) according to any of the preceding claims 1 to 4 for use in the therapeutic inhibition of galectins in vivo.
  11. Use of the compound of general formula (I) according to any of the preceding claims 1 to 4 for the inhibition of galectins in vitro, especially for the inhibition of galectin-1.

Description

Field of Art The present invention relates to ruthenium complexes that exhibit significant affinity and selectivity towards human galectin 1 and thus have the potential to become active pharmaceutical ingredients inhibiting galectin 1 for use, for example, in the treatment of cancerous diseases, fibrotic diseases, and HIV infection. Background Art Galectins are proteins from the lectin group defined by sequence homology and the ability to non-covalently bind β-galactosides. 16 types of galectins are described in mammals, with 13 occurring in humans. All types of galectins have an evolutionarily conserved carbohydrate recognition domain (CRD) composed of approximately 130 amino acids arranged in a β-sandwich structure formed by five- and six-membered antiparallel β-sheet structures. Based on the type of quaternary structure, galectins are divided into 3 groups: 1. Prototypical galectins that contain one CRD which spontaneously forms a non-covalent homodimer under physiological conditions. Galectins 1, 2, 5, 7, 10, 11, 13, 14, 15, and 16 belong to this group.2. Tandem galectins that possess two CRDs linked by a short peptide linker. Galectins 4, 6, 8, 9, and 12 belong to this group.3. Chimeric galectin 3 that consists of CRD and an N-terminal polypeptide chain of approximately 120 amino acids, enabling the formation of non-covalently bound oligomeric structures. Typical endogenous galectin ligands are disaccharides N-acetyllactosamine (Galβ1-4GlcNAc) and lactose (Galβ1-4Glc). The binding between galectin and disaccharides occurs in a relatively shallow binding site on highly conserved binding subsites C and D. The interaction is mediated by 6 amino acids in the binding cavity by hydrogen bonds between these amino acids (typically histidine, arginine, and asparagine) and the disaccharide hydroxyl groups, as well as by CH-π interactions between the nonpolar α-face of β-galactoside and the tryptophan amino acid. Segments A, B, and E, neighboring segments C and D, exhibit lower conservation levels and display greater divergence, particularly influenced by the specific type of galectin. These segments participate in interactions with ligands larger than disaccharides. Galectins in the body perform various biological functions, including maintaining cellular homeostasis, regulating cellular apoptosis, or angiogenesis. Additionally, changes in galectin expression (often involving overproduction) are associated with many pathological conditions: cancer, HIV infection, pulmonary fibrosis, inflammation, or autoimmune diseases. In tumor cells and tissues, galectins are partly responsible for cellular malignant transformation and subsequent evasion of immune surveillance, leading to tumor progression, including enhanced invasiveness, angiogenesis, migration of tumor cells, and metastasis formation. Therefore, galectins are currently considered a promising therapeutic target. Natural and Synthetic Galectin Ligands In addition to the mentioned disaccharides, galectins bind to endogenous ligands comprising structures further modified (e.g., Lewis antigens) and oligomerized (e.g., poly-N-acetyllactosamines). Synthetic saccharide ligands with binding to galectins include, for example, α-thiogalactosides and thiodigalactosides (Cummings R. D.; Liu F. T.; Rabinovich G. A.; et al. Galectins. In: Varki A.; Cummings R. D.; Esko J. D.; et al., editors. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. Chapter 36. Available from: https://www.ncbi.nlm.nih.gov/books/NBK579987/ doi: 10.1101/glycobiology.4e.36). Hydroxyl groups that do not engage in interactions with galectin can undergo modification to enhance either the affinity or selectivity of the interaction. (Denavit, V.; Lainé, D.; Tremblay, T.; St-Gelais, J.; Giguère, D., Synthetic inhibitors of galectins: Structures and syntheses. Trends in Glycoscience and Glycotechnology 2018, 30, (172), SE21-SE40; Kurfiřt, M.; Dračínský, M.; Červenková Št'astná, L.; Cuřínová, P.; Hamala, V.; Hovorková, M.; Bojarová, P.; Karban, J., Selectively Deoxyfluorinated N-Acetyllactosamine Analogues as 19F NMR Probes to Study Carbohydrate-Galectin Interactions. Chemistry-A European Journal 2021, 27 (51), 13040-13051). Substituting certain non-binding hydroxyls with aromatic structures bearing halogen substituents leads to the creation of compounds with markedly higher affinity for galectins compared to their natural ligands. This enhanced affinity is attributed to both π-π interactions between aromatic structures and aromatic amino acids within galectins, as well as interactions between halogens and amino acid polar groups. Synthetic inhibitors with pharmacological promise generally exhibit significantly greater affinity for galectin-3 than for galectin-1. Conversely, inhibitors with high affinity and selectivity for galectin-1 have not yet been developed. Among the strongest and clinically most promising inhibitors of galecti