Calix[4]arenes with potent anticancer properties.

Abstract

The present invention relates to a compound represented by formula (1a) and n is an integer between 1 and 4 (preferably equal to 1). These compounds exhibit high cytotoxicity against cancer cells.

Description

[Technical Field]

[0001] The present invention relates to the field of anti-cancer therapy, and in particular to calix[4]arenes that exhibit anti-cancer activity. [Background technology]

[0002] Cancer is one of the leading causes of death. Currently, one-third of new cancer cases exhibit multidrug resistance or chemotherapy resistance. More precisely, some substances used in cancer treatment may cause chemotherapy-resistant tumor cells and / or cause side effects. Therefore, there is still a demand for new and better substances for cancer treatment. Summary of the Invention

[0003] Copper (hereafter abbreviated as "Cu") is an element essential for human life. It plays an essential role in numerous cellular mechanisms and signal transduction pathways. For example, Cu ions are involved in metabolic processes such as cellular respiration, and numerous enzymes use Cu in their active sites, utilizing its redox and catalytic properties. Therefore, it is essential to uptake Cu and transport it across the cell membrane. Certain membrane proteins, such as Ctr1, transport Cu through the lipid bilayer to Cu. + Furthermore, mutations in genes encoding such proteins can result in Cu transport. + Dysregulation of Cu transport leads to disruption of Cu homeostasis, resulting in serious health problems. Because Cu is involved in redox reactions, Cu metabolism must be tightly controlled to avoid toxic effects. Indeed, disruption of Cu homeostasis has been shown to result in structural abnormalities and loss of important physiological functions.

[0004] In cancer, increased Cu levels can be observed in cancer cells. In particular, variability in Cu protein levels has been demonstrated in many types of cancer. These variabilities result in abnormal Cu concentrations and altered functional distribution of Cu in tumor cells. Such alterations in Cu homeostasis may promote tumor growth or invasion and even confer resistance to treatment (e.g., chemotherapy). More precisely, Cu acts on various molecular pathways to induce proangiogenic responses necessary for the carcinogenesis process. Cu also appears to affect the spread and formation of secondary tumors by activating enzymes responsible for cell proliferation.

[0005] The altered Cu metabolism in cancer cells and the differential response of tumor cells to Cu support the development of therapeutics that inhibit, reduce, or increase Cu levels in tumor cells. Indeed, the metallic nature of Cu is a key strategy for the development of anticancer drugs through the synthesis of Cu-based complexes.

[0006] In particular, therapeutic strategies based on Cu-containing chelators or ionophores have shown promising results in preclinical studies and even in clinical-stage cancer treatments. Indeed, the administration of Cu chelators and ionophores alters the concentration, distribution, and redox behavior of Cu within cancer cells.

[0007] Chelators either directly bind and sequester Cu cations, thereby removing them, or cause stress in cancer cells, ultimately leading to controlled cancer cell death (e.g., apoptosis or cuproptosis).

[0008] In contrast, ionophores reversibly bind Cu, cross the cell membrane, and release Cu on the other side. This generally results in an increase in the intracellular concentration of Cu cations. The bound Cu-ionophore complexes are sufficiently lipophilic to easily cross the membrane. Cu release can be triggered by low local Cu cation concentrations or by specific stimuli that promote Cu cation release. The ability of certain ionophores to kill cancer cells is well known and has attracted considerable attention in recent years.

[0009] For example, elesclomol, disulfiram, and clioquinol are known ionophores useful in cancer treatment. Clioquinol has been discontinued for clinical use due to its neurotoxicity. However, this compound and its analogs are currently being tested in combination with various administration routes to maintain anticancer efficacy while reducing toxicity. The anticancer effects of disulfiram have been demonstrated in in vitro and in vivo models of inflammatory breast cancer. Furthermore, the combination of disulfiram with docosahexaenoic acid has been shown to promote cancer cell death and inhibit cancer cell proliferation in vitro and in vivo.

[0010] Thus, the development of novel compounds capable of disrupting Cu homeostasis and proliferation in cancer cells is an interesting and promising approach for cancer therapy. Furthermore, combining these compounds with standard chemotherapy, targeted therapy, or immunotherapy may be an effective strategy for killing cancer cells.

[0011] Surprisingly, the present inventors have discovered novel calix[4]arenes that exhibit anticancer activity and represent a very promising solution for cancer therapy.

[0012] More precisely, these calix[4]arenes are capable of reacting with cations (e.g., Cu + , Cu 2+ , Ag + , Zn 2+ , preferably Cu +) and therefore have specific groups (especially imidazole groups) that coordinate with cations (preferably Cu + Furthermore, these calix[4]arenes can bind to cations (preferably Cu) through membranes. + ) and are not too lipophilic, so can be transported to the cancer cell membrane. + The present invention will be described in more detail with respect to the ability to allocate, but is not limited to, this aspect.

[0013] Furthermore, the cytotoxicity of the calix[4]arenes of the present invention against various cancer cells was demonstrated at micromolar concentrations, and this high cytotoxicity was observed to be related to the high concentration of Cu in cancer cells and the ability of these calix[4]arenes to transport Cu and disrupt Cu homeostasis in cancer cells, thereby suppressing their proliferation.

[0014] The subject of the present invention is therefore a compound of formula (1) calix[4]arene of formula (TIFF2026504140000002.tif71170), or a physiologically acceptable salt thereof; where: Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, NO2, amine, amide, azide, halogen, cyano, carboxylic acid ester, triazole and C1-C8 alkyl (preferably C1-C4 alkyl) groups, which C1-C8 alkyl (preferably C1-C4 alkyl) groups are optionally substituted with one or more substituents independently selected from the group consisting of alkynyl, alkene, azide, ether, halogen, carboxylic acid ester, amide, cyano and triazole, with the proviso that none of Y1, Y2, Y3 and Y4 is a tert-butyl group; X1, X2, X3, and X4 are each independently selected from the group consisting of CH2 and S; Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, purine, oxazole, pyrazole, and thiazole, which heterocyclic moiety is optionally substituted with 1-5 substituents selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, OH, ether, ester, amide, NO, amine, azide, and nitrile; R1, R2 and R3 each independently represent -(CH2) n Z, hydrogen, and a C1-C8 alkyl (preferably C1-C3 alkyl) group, which is optionally substituted with one or more substituents selected from the group consisting of a carboxylic acid ester, an alkenyl, an alkynyl, a phenyl, OH, an azido, an amide, a halogen, a SH, and a thioether group; n is an integer between 1 and 4 (preferably equal to 1), With the proviso that when R1 and R3 are each hydrogen and n is equal to 1, Z is not benzothiazole.

[0015] "Halogen" is understood to mean fluorine, chlorine, bromine and iodine.

[0016] "Alkyl" refers to a saturated aliphatic hydrocarbon group having the specified number of carbon atoms, and includes both branched and straight-chain groups. The term "C1-Cn alkyl" means that the alkyl group has from 1 to n carbon atoms.

[0017] "Alkenyl" refers to a branched or straight-chain unsaturated hydrocarbon having the specified number of carbon atoms and containing at least one carbon-carbon double bond and no carbon-carbon triple bonds. For example, the term "C2 alkenyl" refers to an ethenyl group.

[0018] "Alkynyl" refers to a branched or straight-chain unsaturated hydrocarbon having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, the term "C2 alkynyl" refers to an ethynyl group.

[0019] Y1, Y2, Y3 and Y4 may be the same or different. Preferably, they are the same. Preferably, they are hydrogen.

[0020] In some embodiments of the present invention, Y2 and Y4 are NO2 and Y1 and Y3 are hydrogen.

[0021] X1, X2, X3 and X4 may be the same or different. Preferably, they are the same. Preferably, they are each CH2.

[0022] In a preferred embodiment, R2 is -(CH2) n It's Z.

[0023] In a preferred embodiment, n is equal to one.

[0024] When Z is an imidazole group, it is preferably a 1-C1-C6-alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole) or 1-benzylimidazole group.

[0025] When Z is a purine group, it is preferably a 9-C1-C6-alkylpurine group (more preferably 9-methylpurine, 9-ethylpurine, 9-propylpurine, 9-isopropylpurine) or a 9-benzylpurine group.

[0026] When Z is an oxazole group, it is preferably unsubstituted. In some embodiments, Z is an oxazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0027] When Z is a thiazole group, it is preferably unsubstituted. In some embodiments, Z is a thiazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0028] When Z is a benzimidazole group, it is preferably a 1-C1-C6-alkylbenzimidazole group (more preferably 1-methylbenzimidazole, 1-ethylbenzimidazole, 1-propylbenzimidazole, 1-isopropylbenzimidazole) or 1-benzylbenzimidazole group.

[0029] When Z is a pyrazole group, it is preferably a 1-C1-C6-alkylpyrazole group (more preferably 1-methylpyrazole, 1-ethylpyrazole, 1-propylpyrazole, 1-isopropylpyrazole) or 1-benzylpyrazole group.

[0030] When Z is a benzoxazole group, it is preferably unsubstituted. In some embodiments, Z is a benzoxazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0031] When Z is a benzothiazole group, it is preferably unsubstituted. In some embodiments, Z is a benzothiazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0032] In some embodiments, R1 and R3 are each an ester group, preferably each an acetate group. In desirable embodiments of these embodiments, R2 is -(CH2) n In Z, n is an integer between 1 and 4 (preferably equal to 1), and Z is a substituted or unsubstituted imidazole group, preferably a 1-methylimidazole group.

[0033] In a preferred embodiment of the present invention, X1, X2, X3 and X4 are each CH2, Y1, Y2, Y3 and Y4 are each hydrogen, R1 and R3 are each selected from the group consisting of hydrogen, C1-C6 alkyl, propene and ethyl acetate groups, and R2 is -(CH2) nZ, where Z is selected from the group consisting of 1-methylimidazole, 1-methylbenzimidazole, 9-methylpurine, oxazole, and thiazole groups, and n is an integer between 1 and 4 (preferably equal to 1). In preferred embodiments of these embodiments, Z is 1-methylimidazole and n is an integer between 1 and 4 (preferably equal to 1).

[0034] In a preferred practice of the present invention, the calix[4]arene is represented by the formula (1a): TIFF2026504140000003.tif61170 or a physiologically acceptable salt thereof, where: Y1, Y2, Y3 and Y4 each independently represent Hydrogen, halogens, NO2, N3, CN, CHO, COOR' (R' is an alkyl (preferably C1-C3 alkyl) group), CONR″2 (wherein R″ is independently H or an alkyl (preferably C1-C4 alkyl) group); NR2 (wherein R is independently hydrogen, alkyl (preferably C1-C4 alkyl), or acetyl group); a triazole moiety (optionally substituted with an alkyl (preferably C1-C4 alkyl) group or a phenyl group), a C1-C3 alkyl group, the C1-C3 alkyl being optionally substituted with one substituent selected from the group consisting of N3, halogen, OR' (R' is an alkyl (preferably C1-C4 alkyl) group), COOR' (R' is an alkyl (preferably C1-C3 alkyl)), and CONR"2 (R" is independently H or an alkyl (preferably C1-C4 alkyl) group); Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, purine, tetrazine, oxazole, pyrazole, and thiazole, which heterocyclic moiety is optionally substituted with 1-5 substituents selected from the group consisting of hydrogen, halogen, alkyl (preferably C1-C4 alkyl), alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, NO2, nitrile, OR' (wherein R' is an alkyl (preferably C1-C4 alkyl) group), and COOR" (wherein R" is an alkyl (preferably C1-C3 alkyl) group); R1 and R2 are each independently selected from the group consisting of hydrogen and a C1-C8 alkyl (preferably C1-C3 alkyl) group, and the C1-C8 alkyl (preferably C1-C3 alkyl) group is optionally substituted by one or more substituents selected from the group consisting of alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, hydroxyl, N3, halogen, COOR' (R' is an alkyl (preferably C1-C4 alkyl) group), CONHR" (R" is an alkyl (preferably C1-C4 alkyl) group), or CONR"2 (R" are independently an alkyl (preferably C1-C4 alkyl) group); n is an integer between 1 and 4 (preferably equal to 1); provided that when R1 and R2 are each hydrogen, n is equal to 1 and Z is not a benzothiazole group; or Y1, Y2, Y3 and Y4 are each hydrogen, R1 and R3 are each a C3 alkyl group, n is equal to 1 and Z is a pyridine group.

[0035] In a preferred embodiment of the present invention, the calix[4]arene of formula (1a) is Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, halogen, N3, NO2, CHO, NH2, N(CH3)2, NH-CO-CH3, NCH3-CO-CH3, CH2-O-CH3, CO-O-CH3, CO-O-C2H5, CO-NHCH3, CO-N(CH3)2, triazole, C2 alkyl-substituted triazole and phenyl-substituted triazole; preferably, Y1, Y2, Y3 and Y4 are selected from the group consisting of halogen, N3, NO2, CHO and NH2.

[0036] Y1, Y2, Y3 and Y4 are all the same, or Y2 and Y4 are the same and Y1 and Y3 are the same and Y2 and Y1 are different.

[0037] Y1, Y2, Y3 and Y4 are all hydrogen.

[0038] Y2 and Y4 are hydrogen, and Y1 and Y3 are different from hydrogen.

[0039] Y1 and Y3 are hydrogen, and Y2 and Y4 are different from hydrogen.

[0040] Z may be an imidazole group, preferably a 1-C1-C6 alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole) or a 1-benzylimidazole group.

[0041] Z may be a purine group, preferably a 9-C1-C6-alkylpurine group (more preferably 9-methylpurine, 9-ethylpurine, 9-propylpurine, 9-isopropylpurine) or a 9-benzylpurine group.

[0042] Z may be an oxazole group, preferably unsubstituted. In some embodiments, Z is an oxazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0043] Z may be a thiazole group, preferably unsubstituted. In some embodiments, Z is a thiazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0044] Z may be a benzimidazole group, preferably a 1-C1-C6-alkylbenzimidazole group (more preferably 1-methylbenzimidazole, 1-ethylbenzimidazole, 1-propylbenzimidazole, 1-isopropylbenzimidazole) or 1-benzylbenzimidazole group.

[0045] Z may be a pyrazole group, preferably a 1-C1-C6-alkylpyrazole group (more preferably 1-methylpyrazole, 1-ethylpyrazole, 1-propylpyrazole, 1-isopropylpyrazole) or a 1-benzylpyrazole group.

[0046] Z may be a benzoxazole group, preferably unsubstituted. In some embodiments, Z is a benzoxazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0047] Z may be a benzothiazole group, preferably unsubstituted. In some embodiments, Z is a benzothiazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0048] Z may be a tetrazine group, preferably a 1-C1-C6-alkyl-2,3,4,5-tetrazine (more preferably, 1-methyl-2,3,4,5-tetrazine) group or a 1-O-C1-C6-alkyl-2,3,4,5-tetrazine (more preferably, 1-methoxy-2,3,4,5-tetrazine) group.

[0049] Z is selected from the group consisting of imidazole (preferably a 1-C1-C6 alkylimidazole group, more preferably a 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole or 1-benzylimidazole group), purine (preferably 9-methylpurine), benzimidazole (preferably 1-methylbenzimidazole), oxazole, thiazole, benzoxazole, benzothiazole and triazine group (preferably a 1-C1-C6-alkyl-2,3,4,5-tetrazine group, more preferably a 1-methyl-2,3,4,5-tetrazine group or a 1-O-C1-C6-alkyl-2,3,4,5-tetrazine group, more preferably 1-methoxy-2,3,4,5-tetrazine).

[0050] R1 and R2 are the same.

[0051] R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e. 1 or 2 or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), preferably R1 and R2 are C1-C3 alkyl groups.

[0052] n is an integer between 1 and 4 (preferably n is equal to 1).

[0053] The present invention may include at least one of the above features alone or in combination with at least one other feature.

[0054] A preferred embodiment of the present invention is a calix[4]arene of formula (1a), wherein Y, Y, Y, and Y are each independently selected from the group consisting of hydrogen, halogen, N, NO, CHO, NH, N(CH), NH—CO—CH, NCH—CO—CH, CO—O—CH, CO—O—C H, CO—NHCH, CO—N(CH), triazole, C alkyl-substituted triazole, phenyl- and CH—O—CH substituted triazole.

[0055] A preferred embodiment of the present invention is a calix[4]arene of formula (1a) in which Y1, Y2, Y3 and Y4 are all the same, or Y2 and Y4 are the same and Y1 and Y3 are the same.

[0056] A preferred embodiment of the present invention is the calix[4]arene of formula (1a) wherein Y1, Y2, Y3 and Y4 are all hydrogen.

[0057] Another preferred embodiment of the present invention is the calix[4]arene of formula (1a), wherein Y2 and Y4 are hydrogen and Y1 and Y3 are different from hydrogen, or Y1 and Y3 are hydrogen and Y2 and Y4 are different from hydrogen.

[0058] Another preferred embodiment of the present invention is a calix[4]arene of formula (1a) wherein Z is selected from the group consisting of imidazole (preferably 1-methylimidazole, 1-benzylimidazole), purine (preferably 9-methylpurine), benzimidazole (preferably 1-methylbenzimidazole), oxazole, thiazole, benzoxazole, benzothiazole, and tetrazine groups (preferably 1-C1-C6-alkyl-2,3,4,5-tetrazine groups, more preferably 1-methyl-2,3,4,5-tetrazine or 1-O-C1-C6-alkyl-2,3,4,5-tetrazine, more preferably 1-methoxy-2,3,4,5-tetrazine).

[0059] Another preferred embodiment of the present invention is the calix[4]arene of formula (1a), wherein Z is an imidazole group, preferably a 1-C1-C6 alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole), or a 1-benzylimidazole group.

[0060] Another preferred embodiment of the present invention is a calix[4]arene of formula (1a), wherein R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl acetate group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e., 1, 2, or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), and preferably R1 and R2 are C1-C3 alkyl groups.

[0061] Another preferred embodiment of the present invention is the calix[4]arene of formula (1a), where n is equal to 1.

[0062] Another preferred embodiment of the present invention is a calix[4]arene of formula (1a): Y1, Y2, Y3 and Y4 are selected from the group consisting of hydrogen, halogen, N3, NO2, CHO, NH2, N(CH3)2, NH-CO-CH3, NCH3-CO-CH3, CO-O-CH3, CO-O-C2H5, CO-NHCH3, CO-N(CH3)2, triazole, triazole substituted with C2 alkyl, triazole substituted with phenyl group; R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e. 1 or 2 or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), preferably R1 and R2 are C1-C3 alkyl groups, Z is selected from the group consisting of imidazole (preferably 1-methylimidazole, 1-benzylimidazole), purine (preferably 9-methoxypurine), benzimidazole (preferably 1-methylbenzimidazole), oxazole, thiazole, benzoxazole, benzothiazole, and tetrazine group (preferably 1-C1-C6-alkyl-2,3,4,5-tetrazine group, more preferably 1-methyl-2,3,4,5-tetrazine or 1-O-C1-C6-alkyl-2,3,4,5-tetrazine, more preferably 1-methoxy-2,3,4,5-tetrazine), n is an integer between 1 and 4 (preferably n is equal to 1).

[0063] It is something.

[0064] Examples of calix[4]arenes of the present invention are calix[4]arenes shown in formulas (2) through (38). TIFF2026504140000004.tif224170TIFF2026504140000005.tif255170TIFF2026504140000006.tif245170TIFF2026504140000007.tif60170

[0065] "cLogP" is a calculated value using a chemical drawing tool such as ChemDraw.

[0066] Particularly preferred calix[4]arenes of the present invention are those of formulas (2), (3), and (4). The most preferred calix[4]arenes are those of formula (2).

[0067] The physiologically acceptable salts of the calix[4]arene of the present invention are physiologically acceptable non-toxic salts, particularly pharmaceutically acceptable salts.

[0068] Salts of the calix[4]arenes of the present invention can be obtained by conventional methods known to those skilled in the art, for example, by combining the calix[4]arenes of the present invention with inorganic or organic salts in a solvent or diluent, or by cation or anion exchange from other salts.

[0069] As described above, the present inventors have surprisingly discovered that the calix[4]arenes of the present invention inhibit Cu homeostasis and suppress proliferation, thereby exhibiting high cytotoxicity against cancer cells. Furthermore, the present inventors have discovered that 1:1 complexes of these calix[4]arenes and their physiologically acceptable salts also exhibit cytotoxicity against cancer cells.

[0070] Therefore, a further object of the present invention is to provide a method for the preparation of the above-mentioned calix[4]arene of the present invention and physiologically acceptable salts thereof, and a cation, preferably Cu. + It is a 1:1 complex consisting of

[0071] The above calix[4]arenes and their complexes are prepared by conventional methods known to those skilled in the art.

[0072] As a non-limiting example, the calix[4]arene of formula (2) + The complex was prepared by dissolving the calix[4]arene of formula (2) in a mixture of CHCl3 and MeCN with 1.5 equivalents of Cu. + (MeCN)4BF4, and evaporating the solvent to give the salt of formula (2a). The resulting file is TIFF2026504140000008.tif37170.

[0073] The calix[4]arenes of the present invention, their physiologically acceptable salts and complexes, are valuable pharmacologically active entities. As mentioned above, they exhibit cytotoxicity and are suitable, for example, for the treatment of cancer.

[0074] A further subject of the present invention is a compound of formula (1) Calix[4]arene of formula (1) or a physiologically acceptable salt thereof and a cation (preferably Cu) + and a 1:1 complex consisting of Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, NO2, amine, amide, azide, halogen, cyano, carboxylic acid ester, triazole and C1-C8 alkyl (preferably C1-C4 alkyl) groups, which C1-C8 alkyl (preferably C1-C4 alkyl) groups are optionally substituted with one or more substituents independently selected from the group consisting of alkynyl, alkene, azide, ether, halogen, carboxylic acid ester, amide, cyano and triazole, with the proviso that none of Y1, Y2, Y3 and Y4 is a tert-butyl group; X1, X2, X3, and X4 are each independently selected from the group consisting of CH2 and S; Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, pyridine, purine, oxazole, pyrazole, thiazole, triazole, pyrimidine, pyrazine, and pyridazine, which heterocyclic moiety is optionally substituted with 1-5 substituents selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, benzyl, imidazole, benzimidazole, benzothiazole, benzoxazole, pyridine, purine, oxazole, pyrazole, thiazole, triazole, pyrimidine, pyrazine, and pyridazine, OH, SH, thioether, ether, ester, amide, NO, amine, azide, and nitrile; R1, R2 and R3 each independently represent -(CH2) n Z, hydrogen, and a C1-C8 alkyl (preferably C1-C3 alkyl) group, which is optionally substituted with one or more substituents selected from the group consisting of a carboxylic acid ester, an alkenyl, an alkynyl, a phenyl, OH, an azido, an amide, a halogen, a SH, and a thioether group; n is an integer between 1 and 8 (preferably equal to 1); It is used in conjunction with at least one pharmaceutically acceptable carrier.

[0075] Y1, Y2, Y3 and Y4 may be the same or different. Preferably, they are the same. Preferably, they are hydrogen.

[0076] In some embodiments of the present invention, Y2 and Y4 are NO2 and Y1 and Y3 are hydrogen.

[0077] X1, X2, X3 and X4 may be the same or different. Preferably, they are the same. Preferably, they are each CH2.

[0078] In a preferred embodiment, R2 is -(CH2) nIt's Z.

[0079] In a preferred embodiment, n is equal to one.

[0080] When Z is an imidazole group, it is preferably a 1-C1-C6-alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole) or 1-benzylimidazole group.

[0081] When Z is a purine group, it is preferably a 9-C1-C6-alkylpurine group (more preferably 9-methylpurine, 9-ethylpurine, 9-propylpurine, 9-isopropylpurine) or a 9-benzylpurine group.

[0082] When Z is an oxazole group, it is preferably unsubstituted. In some embodiments, Z is an oxazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0083] When Z is a thiazole group, it is preferably unsubstituted. In some embodiments, Z is a thiazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0084] When Z is a benzoxazole group, it is preferably unsubstituted. In some embodiments, Z is a benzoxazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0085] When Z is a benzothiazole group, it is preferably unsubstituted. In some embodiments, Z is a benzothiazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0086] When Z is a benzimidazole group, it is preferably a 1-C1-C6-alkylbenzimidazole group (more preferably 1-methylbenzimidazole, 1-ethylbenzimidazole, 1-propylbenzimidazole, 1-isopropylbenzimidazole) or 1-benzylbenzimidazole group.

[0087] When Z is a triazole group, it is preferably a 1-C1-C6-alkyltriazole group (more preferably 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole) or 1-benzyltriazole group.

[0088] When Z is a pyrazole group, it is preferably a 1-C1-C6-alkylpyrazole group (more preferably 1-methylpyrazole, 1-ethylpyrazole, 1-propylpyrazole, 1-isopropylpyrazole) or 1-benzylpyrazole group.

[0089] When Z is a pyridine group, it is preferably unsubstituted. In some embodiments, Z is a pyridine group substituted at the 2-, 3-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl, alkynyl, phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0090] When Z is a pyrimidine group, it is preferably unsubstituted. In some embodiments, Z is a pyrimidine group substituted at the 2-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl, alkynyl, phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0091] When Z is a pyrazine group, it is preferably unsubstituted. In some embodiments, Z is a pyrazine group substituted at the 2-, 3-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl, alkynyl, phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0092] When Z is a pyridazine group, it is preferably unsubstituted. In some embodiments, Z is a pyridazine group substituted at the 3-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl, alkynyl, phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0093] In some embodiments, R1 and R3 are each an ester group, preferably each an acetate group. In desirable embodiments of these embodiments, R2 is -(CH2) n In Z, n is an integer between 1 and 4 (preferably equal to 1), and Z is a substituted or unsubstituted imidazole group, preferably a 1-methylimidazole group.

[0094] In a preferred embodiment of the present invention, X1, X2, X3 and X4 are each CH2, Y1, Y2, Y3 and Y4 are each hydrogen, R1 and R3 are each selected from the group consisting of hydrogen, C1-C6 alkyl, propene and ethyl acetate groups, and R2 is -(CH2) n Z, where Z is selected from the group consisting of 1-methylimidazole, 1-methylbenzimidazole, 9-methylpurine, oxazole, and thiazole groups, and n is an integer between 1 and 4 (preferably equal to 1). In preferred embodiments of these embodiments, Z is 1-methylimidazole and n is an integer between 1 and 4 (preferably equal to 1).

[0095] In a preferred embodiment of the present invention, the pharmaceutical composition comprises at least one compound of formula (1a) Calix[4]arene of formula (1) or a physiologically acceptable salt thereof and a cation (preferably Cu) + ) and a 1:1 complex consisting of where: Y1, Y2, Y3 and Y4 each independently represent Hydrogen, halogens, NO2, N3, CN, CHO, COOR' (R' is an alkyl (preferably C1-C3 alkyl) group), CONR″2 (wherein R″ is independently H or an alkyl (preferably C1-C4 alkyl) group); NR2 (wherein R is independently hydrogen, alkyl (preferably C1-C4 alkyl), or acetyl group); a triazole moiety (optionally substituted with an alkyl (preferably C1-C4 alkyl) group or a phenyl group), a C1-C3 alkyl group, the C1-C3 alkyl group being optionally substituted with one substituent selected from the group consisting of N3, halogen, OR' (R' is an alkyl (preferably C1-C4 alkyl) group), COOR' (R' is an alkyl (preferably C1-C3 alkyl)), and CONR"2 (R" is independently H or an alkyl (preferably C1-C4 alkyl) group); Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, pyridine, purine, oxazole, pyrazole, thiazole, triazole, tetrazine, tetrazole, pyrimidine, pyrazine, and pyridazine, which heterocyclic moiety is optionally substituted with 1-5 substituents selected from the group consisting of hydrogen, halogen, alkyl (preferably C1-C4 alkyl), alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, NO2, nitrile, OR' (R' is an alkyl (preferably C1-C4 alkyl) group), and COOR" (R" is an alkyl (preferably C1-C3 alkyl) group); R1 and R2 are each independently selected from the group consisting of hydrogen and a C1-C8 alkyl (preferably C1-C3 alkyl) group, and the C1-C8 alkyl (preferably C1-C3 alkyl) group is optionally substituted by one or more substituents selected from the group consisting of alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, hydroxyl, N3, halogen, COOR' (R' is an alkyl (preferably C1-C4 alkyl) group), CONHR" (R" is an alkyl (preferably C1-C4 alkyl) group), or CONR"2 (R" are independently an alkyl (preferably C1-C4 alkyl) group); n is an integer between 1 and 8, preferably between 1 and 4, and more preferably equal to 1; It is used in conjunction with at least one pharmaceutically acceptable carrier.

[0096] In a preferred embodiment of the present invention, the pharmaceutical composition comprises at least one calix[4]arene of formula (1a), wherein the calix[4]arene is Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, halogen, N3, NO2, CHO, NH2, N(CH3)2, NH-CO-CH3, NCH3-CO-CH3, CO-O-CH3, CO-O-C2H5, CO-NHCH3, CO-N(CH3)2, CH2-O-CH3, triazole, C2 alkyl-substituted triazole and phenyl-substituted triazole, preferably Y1, Y2, Y3 and Y4 are selected from the group consisting of halogen, N3, NO2, CHO and NH2.

[0097] Y1, Y2, Y3 and Y4 are all the same, or Y2 and Y4 are the same and Y1 and Y3 are the same and Y2 and Y1 are different.

[0098] Y1, Y2, Y3 and Y4 are all hydrogen.

[0099] Y2 and Y4 are hydrogen, and Y1 and Y3 are different from hydrogen.

[0100] Y1 and Y3 are hydrogen, and Y2 and Y4 are different from hydrogen.

[0101] Z may be an imidazole group, preferably a 1-C1-C6 alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole) or a 1-benzylimidazole group.

[0102] Z may be a purine group, preferably a 9-C1-C6-alkylpurine group (more preferably 9-methylpurine, 9-ethylpurine, 9-propylpurine, 9-isopropylpurine) or a 9-benzylpurine group.

[0103] Z may be an oxazole group, preferably unsubstituted. In some embodiments, Z is an oxazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0104] Z may be a thiazole group, preferably unsubstituted. In some embodiments, Z is a thiazole group substituted at the 2-, 4-, or 5-position with halogen or C1-C6 alkyl.

[0105] Z may be a benzimidazole group, preferably a 1-C1-C6-alkylbenzimidazole group (more preferably 1-methylbenzimidazole, 1-ethylbenzimidazole, 1-propylbenzimidazole, 1-isopropylbenzimidazole) or 1-benzylbenzimidazole group.

[0106] Z may be a triazole group, preferably a 1-C1-C6-alkyltriazole group (more preferably 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole) or a 1-benzyltriazole group.

[0107] Z may be a pyrazole group, preferably a 1-C1-C6-alkylpyrazole group (more preferably 1-methylpyrazole, 1-ethylpyrazole, 1-propylpyrazole, 1-isopropylpyrazole) or a 1-benzylpyrazole group.

[0108] Z may be a benzoxazole group, preferably unsubstituted. In some embodiments, Z is a benzoxazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0109] Z may be a benzothiazole group, preferably unsubstituted. In some embodiments, Z is a benzothiazole group substituted at the 4-, 5-, 6-, or 7-position with halogen or C1-C6 alkyl.

[0110] Z may be a tetrazine group, preferably a 1-C1-C6-alkyl-2,3,4,5-tetrazine (more preferably, 1-methyl-2,3,4,5-tetrazine) group or a 1-O-C1-C6-alkyl-2,3,4,5-tetrazine (more preferably, 1-methoxy-2,3,4,5-tetrazine) group.

[0111] Z may be a pyridine group, preferably unsubstituted. In some embodiments, Z is a pyridine group substituted at the 2-, 3-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, CH2OH, CH2SH, CH2N3, CH2ClCH2F, CH2Br, CH2-O-alkyl (preferably C1-C4 alkyl), CHO, CO-O-alkyl (preferably C1-C4 alkyl), CO-NH2, CO-NH-alkyl (preferably C1-C4 alkyl), CO-NR2 (where R is independently H or alkyl (preferably C1-C4 alkyl), CH2amide, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0112] Z may be a pyrimidine group, preferably unsubstituted. In some embodiments, Z is a pyrimidine group substituted at the 2-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0113] Z may be a pyrazine group, preferably unsubstituted. In some embodiments, Z is a pyrazine group substituted at the 2-, 3-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0114] Z may be a pyridazine group, preferably unsubstituted. In some embodiments, Z is a pyridazine group substituted at the 3-, 4-, 5-, or 6-position with a halogen, C1-C6 alkyl, alkenyl (preferably C1-C4 alkenyl), alkynyl (preferably C1-C4 alkynyl), phenyl, benzyl, OH, SH, thioether, ether, ester, amide, NO2, amine, azide, or nitrile group.

[0115] Z is selected from the group consisting of imidazole (preferably a 1-C1-C6-alkylimidazole group, more preferably a 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole or 1-benzylimidazole group), purine (preferably 9-methylpurine), benzimidazole (preferably 1-methylbenzymidazole), oxazole, thiazole, benzoxazole, benzothiazole, tetrazine group (preferably a 1-C1-C6-alkyl-2,3,4,5-tetrazine group, more preferably a 1-methyl-2,3,4,5-tetrazine or 1-O-C1-C6-alkyl-2,3,4,5-tetrazine, more preferably 1-methoxy-2,3,4,5-tetrazine), pyridine and triazole (preferably 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole or 1-benzyltriazole).

[0116] R1 and R2 are the same.

[0117] R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e. 1 or 2 or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), preferably R1 and R2 are C1-C3 alkyl groups.

[0118] n is an integer between 1 and 4 (preferably equal to 1).

[0119] The present invention has at least one of the following features alone or in combination with at least one other feature:

[0120] In one embodiment of the present invention, a pharmaceutical composition comprises a calix[4]arene of formula (1a), wherein Y1, Y2, Y3, and Y4 are each hydrogen, R1 and R2 are each a C3 alkyl group, n is equal to 1, and Z is a pyridine group.

[0121] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Y1, Y2, Y3, and Y4 are each independently selected from the group consisting of hydrogen, halogen, N3, NO2, CHO, NH2, N(CH3)2, NH-CO-CH3, NCH3-CO-CH3, CO-O-CH3, CO-O-C2H5, CH2-O-CH3, CO-NHCH3, CO-N(CH3)2, triazole, C2 alkyl-substituted triazole, and phenyl-substituted triazole.

[0122] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Y1, Y2, Y3, and Y4 are all the same, or Y2 and Y4 are the same and Y1 and Y3 are the same, and Y2 and Y1 are different.

[0123] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Y 1 , Y 2 , Y 3 and Y 4 are all hydrogen.

[0124] Another preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Y2 and Y4 are hydrogen and Y1 and Y3 are different from hydrogen, or Y1 and Y3 are hydrogen and Y2 and Y4 are different from hydrogen.

[0125] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Z is selected from the group consisting of imidazole (preferably 1-methylimidazole or 1-benzylimidazole), purine (preferably 9-methylpurine), benzimidazole (preferably 1-methylbenzimidazole), oxazole, thiazole, benzoxazole, benzothiazole, tetrazine group (preferably 1-C1-C6-alkyl-2,3,4,5-tetrazine group (more preferably 1-methyl-2,3,4,5-tetrazine) or 1-O-C1-C6-alkyl-2,3,4,5-tetrazine (more preferably 1-methoxy-2,3,4,5-tetrazine)), pyridine, and triazole (preferably 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole, or 1-benzyltriazole).

[0126] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein Z is an imidazole group, preferably a 1-C1-C6 alkylimidazole group (more preferably 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1-isopropylimidazole), or a 1-benzylimidazole group.

[0127] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl acetate group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e., 1, 2, or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), and preferably R1 and R2 are C1-C3 alkyl groups.

[0128] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), wherein n is equal to 1.

[0129] A preferred embodiment of the present invention is a pharmaceutical composition comprising a calix[4]arene of formula (1a), Y1, Y2, Y3 and Y4 are each independently selected from the group consisting of hydrogen, halogen, N3, NO2, CHO, NH2, N(CH3)2, NH-CO-CH3, NCH3-CO-CH3, CO-O-CH3, CO-O-C2H5, CO-NHCH3, CO-N(CH3)2, CH2-O-CH3, triazole, C2 alkyl-substituted triazole and phenyl-substituted triazole; R1 and R2 are selected from the group consisting of hydrogen, a C1-C3 alkyl group, an ethyl group, a C1-C3 alkyl group substituted with N3, a C1-C3 alkyl group substituted with a hydroxyl group, a C1-C3 alkyl group substituted with at least one halogen (i.e. 1 or 2 or 3 halogens), a C1-C3 alkyl group substituted with an alkynyl group (preferably C2-alkynyl), and a C1-C3 alkyl group substituted with an alkenyl group (preferably C2-alkenyl), preferably R1 and R2 are C1-C3 alkyl groups, Z is selected from the group consisting of imidazole (preferably 1-methylimidazole, 1-benzylimidazole), purine (preferably 9-methylpurine), benzimidazole (preferably 1-methylbenzimidazole), oxazole, thiazole, benzoxazole, benzothiazole, tetrazine group (preferably 1-C1-C6-alkyl-2,3,4,5-tetrazine group, more preferably 1-methyl-2,3,4,5-tetrazine or 1-O-C1-C6-alkyl-2,3,4,5-tetrazine, more preferably 1-methoxy-2,3,4,5-tetrazine), pyridine, and triazole (preferably 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole, or 1-benzyltriazole), n is an integer between 1 and 4 (preferably equal to 1), It is something.

[0130] In a preferred embodiment, the pharmaceutical composition comprises at least one calix[4]arene of formulas (2) to (38) detailed above.

[0131] More preferably, the pharmaceutical composition comprises at least one calix[4]arene of formula (2) to (4).

[0132] Most preferably, the pharmaceutical composition comprises a calix[4]arene of formula (2).

[0133] "Carrier" refers to a solvent, dispersion medium, diluent, excipient, or vehicle used in administering at least one compound of the present invention. "Pharmaceutically acceptable carrier" refers to a substance, e.g., an excipient, diluent, or vehicle, that is useful for preparing pharmaceutical compositions and that is safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable carrier" includes one or more such carriers.

[0134] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to patients undergoing treatment. Carriers may be inert or may possess pharmacological effects of their own. The amount of carrier used with the compound is sufficient to provide a practical amount of material for administering the compound per unit dose.

[0135] Types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, flow enhancers, glidants, lubricants, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be classified into multiple categories. For example, vegetable oils may be used as lubricants in some formulations and as diluents in others. Pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. The pharmaceutical composition may contain any active and / or inactive agent as long as it does not substantially inhibit the activity of the compound of the present invention. The optional active agent is an additional active agent different from the substance, salt, or complex of the present invention.

[0136] In the pharmaceutical composition, the calix[4]arene or its physiologically acceptable salt, or the complex thereof, may be formulated in any suitable manner to improve or modify its solubility, target specificity, (bio)availability, stability, toxicity, efficacy, physiological / metabolic properties, pharmacokinetic properties, or distribution in the body.

[0137] In pharmaceutical compositions, the calix[4]arene or its physiologically acceptable salt, or the complex thereof, preferably satisfies the LADMET criteria, which is an acronym for "liberation, absorption, distribution, metabolism, excretion, and toxicity."

[0138] In a preferred embodiment of the pharmaceutical composition, the above-mentioned calix[4]arene or a physiologically acceptable salt thereof, or the above-mentioned complex thereof, due to its high lipophilicity, is formulated in the form of a lipid formulation (more preferably a nanoformulation), a lipoprotein such as low-density lipoprotein (LDL) or very-low-density lipoprotein (VLDL), or is incorporated into a natural or synthetic membrane, such as a red blood cell, artificial cell, or vesicle.

[0139] In a preferred embodiment of the present application, the pharmaceutical composition further comprises at least one compound selected from the group consisting of a chemotherapeutic compound (i.e., a cancer chemotherapeutic agent), an immunotherapeutic compound, an antiviral compound, an antiparasitic compound, an antifungal compound, and an antibiotic.

[0140] In the most preferred embodiment of the present invention, the pharmaceutical composition comprises: the calix[4]arene or a physiologically acceptable salt thereof, or a complex thereof, as described above; and At least one anti-cancer compound Includes:

[0141] In other words, in the most preferred embodiment of the present invention, calix[4]arene is used in combination with other anti-cancer compounds.

[0142] In a preferred embodiment of the present application, the pharmaceutical composition comprises: the calix[4]arene or a physiologically acceptable salt thereof, or a complex thereof, as described above; and at least one compound selected from the group consisting of Cu salts (encapsulated or not, e.g., encapsulated in liposomes), copper or copper oxide nanoparticles, and Cu chelates; Includes:

[0143] In other words, in the preferred embodiment described above, the calix[4]arenes of the present invention are used in combination with Cu salts (encapsulated or not), copper or copper oxide nanoparticles, or Cu chelates. Indeed, the inventors have discovered that these combinations enhance the cytotoxicity of the calix[4]arenes of the present invention.

[0144] In the most preferred embodiment of the present invention, the pharmaceutical composition comprises: the calix[4]arene or a physiologically acceptable salt thereof, or a complex thereof, as described above; and CuCl2, CuSO4 or other physiologically exchangeable Cu(II) molecules / salts Includes:

[0145] The Cu salt is preferably CuCl2.

[0146] In embodiments of the present invention, the calix[4]arene or a physiologically acceptable salt thereof, or the complexes thereof, may be administered, for example, by intravenous injection, and the Cu salt or copper or copper oxide particles may be administered by a patch.

[0147] The pharmaceutical compositions of the present invention may be administered orally, topically, parenterally (intravenously, intradermally, subcutaneously, intramuscularly), intratumorally, intraarticularly, by inhalation or spray, sublingually, transdermally, rectally, or as eye drops, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.

[0148] The pharmaceutical composition can be formulated into any pharmaceutically useful form, for example, an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an eye drop, etc. Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient, for example, an amount effective to achieve a desired purpose.

[0149] The pharmaceutical composition is preferably formulated for intravenous administration.

[0150] The pharmaceutical composition may contain 0.001% to 99% by weight of the above-described calix[4]arene or a physiologically acceptable salt thereof, or the above-described complex thereof.

[0151] A further subject of the present invention is a calix[4]arene as defined above or a physiologically acceptable salt thereof, or a complex thereof as defined above, for use as a medicament.

[0152] A further subject of the present invention is a calix[4]arene as defined above or a physiologically acceptable salt thereof, or a complex thereof as defined above, for use in the treatment of a disease selected from the group consisting of cancer or its metastasis, or viral, bacterial, parasitic or fungal infections.

[0153] The cancer may be any type of solid cancer or hematological malignancy, particularly selected from the group consisting of oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, genitourinary cancer, gastrointestinal cancer, cancer of central or peripheral nervous system tissue, endocrine, neuroendocrine, or hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, kidney cancer, biliary tract cancer, pheochromocytoma, pancreatic islet cell carcinoma, Li-Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal tumor, osteosarcoma, multiple neuroendocrine tumors type I and II, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, gastric cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer, and skin cancer. In some embodiments, the patient has an epithelial cancer. In yet another embodiment, the patient has endometrial cancer, ovarian cancer, or melanoma. In some embodiments, the patient has a hematopoietic malignancy, such as B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, non-Hodgkin's lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasms, and myeloid neoplasms, including acute myeloid leukemia. In further embodiments, the patient has previously undergone one or more anti-cancer treatments or has previously responded inadequately to one or more anti-cancer therapies. Thus, in some embodiments, the cancer is resistant to at least one anti-cancer therapy.

[0154] The bacterial infection may be any bacterial infection caused by a gram-positive or gram-negative bacterium, and may, for example, be selected from the group consisting of pneumonia, bacterial meningitis, cholera, diphtheria, tuberculosis, anthrax, botulism, brucellosis, campylobacteriosis, typhoid, gonorrhea, listeriosis, Lyme disease, rheumatic fever, whooping cough, plague, salmonellosis, scarlet fever, shigellosis, syphilis, tetanus, trachoma, tularemia, typhoid fever, and urinary tract infections.

[0155] The parasitic infection may be selected from the group consisting of malaria, leishmaniasis, trypanosomiasis, Chagas' disease, cryptosporidiosis, fascioliasis, filariasis, amebiasis, giardiasis, pinworm infection, schistosomiasis, taeniasis, toxoplasmosis, trichinosis, and trypanosomiasis.

[0156] The fungal infection may be selected from the group consisting of candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and tinea pedis.

[0157] A further subject of the present invention is the use of the calix[4]arene described above or a physiologically acceptable salt thereof, or a complex thereof described above, against yeasts, fungi, bacteria, viruses, or other microorganisms in or on the surface of a living human or living animal. [Brief explanation of the drawings]

[0158] [Figure 1] FIG. 1 shows the proliferation index Nt / N0 profiles of A549 cells after exposure or without exposure to calix[4]arene of formula (2). [Figure 2] FIG. 2 shows the proliferation index Nt / N0 profile of PC9 cells after exposure or without exposure to calix[4]arene of formula (2). [Figure 3] FIG. 3 shows the proliferation index Nt / N0 profiles of H322 cells after exposure or without exposure to calix[4]arene of formula (2). DETAILED DESCRIPTION OF THE INVENTION

[0159] The present invention will now be illustrated by the following examples.

[0160] (Example) <i 本発明及び2つの比較例のカリックス〔4〕アレーンの説明及び調製> Example 1: Synthesis and characterization of calix[4]arenes of formula (2) TIFF2026504140000011.tif47170

[0161] In a 50 mL round-bottom flask, calix[4]arene of formula (B) (309 mg, 0.61 mmol, 1.0 equiv.) was stirred with NaH (60% dispersion in mineral oil, 520 mg, 13.0 mmol, 36 equiv.) in anhydrous THF (12 mL) for 30 min under an inert atmosphere. 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (407 mg, 3.11 mmol, 5.1 equiv.) dissolved in anhydrous DMF (3 mL) was then added. The mixture was refluxed under an inert atmosphere and stirred for 24 h. After the reaction, the mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (10 mL × 3). The organic phase was evaporated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH 95:5 v / v). The resulting product was washed with H2O to give calix[4]arene of formula (2) (269 mg, 0.38 mol) as a white solid in a 64% yield.

[0162] 1 H NMR (400 MHz, CDCl3): H (ppm) = 7.04 (s, 2H, 1mH), 6.88-6.94 (m, 6H, ArH and 1mH), 6.80 (bt, 2H, ArH), 6.33 (bt, 2H, ArH), 6.24 (s, 4H, ArH), 4.92 (s, 4H, OCH2Im), 4.34 (d, J = 13 Hz, 4H, ArCH ax ), 3.81 (t, J = 8 Hz, 4H, OCH2Et), 3.50 (s, 6H, NCH3), 3.04 (d, J = 13 Hz, 4H, ArCH eq ), 1.71-1.77 (m, 4H, CH2), 0.75 (t, J = 8 Hz, 6H, CH3). HRMS (ESI): C 44 H 49 N4O4 + M+H + The calculated value is 696.3676 and the measured value is 696.3674.

[0163] Example 1a: Synthesis and characterization of calix[4]arene·CuBF4 complexes of formula (2a) TIFF2026504140000012.tif37170

[0164] Cu in calix〔4〕arenes of formula (2a) + The complex was prepared by dissolving (2) in a mixture of CHCl3 and MeCN with 1.5 equivalents of Cu. + The salt of formula (2a) was obtained by stirring with (MeCN)4BF4 and evaporating the solvent.

[0165] 1 H NMR (400 MHz, CDCl3 / CD3CN 1 / 4, 298 K): δ(ppm) = 7.41 (s, ImH, 2H), 7.22 (bd, ArH, 4H), 7.11 (s, ImH, 2H), 7.09 (bt, ArH, 2H), 6.20 (bt, ArH, 2H), 6.03 (bd, ArH, 4H), 5.33 (s, OCH2Im, 4H), 3.78 (bd, ArCH2, 4H), 3.70 (t, 3 J = 7.6 Hz,, OCH2Et, 4H), 3.10 (bd, J = 11.6 Hz, ArCH2, 4H), 2.85 (s, NCH3, 6H), 1.75-1.86 (m, CH2, 4H), 0.96 (t, J = 7.6 Hz, CH3, 6H).

[0166] Example 2: Synthesis and characterization of calix[4]arenes of formula (5) TIFF2026504140000013.tif39170

[0167] A 100 mL round-bottom flask was charged with calix[4]arene of formula (A) (1.0 g, 2.21 mmol, 1 equiv.), dried under high vacuum for 1 hour, purged under argon, and dissolved in 25 mL of freshly distilled THF. The mixture was cooled to 0°C, and NaH (washed three times with petroleum ether and then dried under high vacuum; 1.11 g, 77.3 mmol, 35 equiv.) was added. The reaction mixture was stirred at this temperature for 15 minutes, after which 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (dried under high vacuum; 1.84 g, 11.05 mmol, 5 equiv.) was added in one portion. The reaction mixture was refluxed overnight. 1 The reaction mixture was monitored by H NMR. The reaction mixture was then cooled to room temperature, and the volatiles were removed under reduced pressure. 50 mL of dichloromethane was added, followed by 50 mL of distilled water, and the product was extracted twice with 50 mL of dichloromethane. The organic layers were combined, and the volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica (DCM / MeOH:98 / 2) to give calix[4]arene of formula (5) as a white solid in 35% yield (500 mg, 0.77 mmol).

[0168] HRMS (ESI):C 40 H 41 N4O4 + [M+H + ] calculated value is 641.3122, measured value is 641.3129 [M+H] + and 663.2951 [M+Na] + Calix[4]arene of formula (5) in CDCl3 1 The H NMR spectrum was broad. Therefore, 1 equiv. of Cu + (MeCN)4BF4 was added to the calix[4]arene of formula (5) + The properties of the complexes were measured. 1 H NMR (CDCl3 / CD3CN 4 / 1, 400 MHz) δ H (ppm) = 7.44 (s, 2H, ImH), (bd, J= 7.2 Hz, 4H, ArH), 7.13 (s, 2H, ImH), 7.09 (bt, J = 7.2 Hz, 2H, ArH), 6.26 (bt, J = 6.8 Hz, 2H, ArH), 6.16 (bd, 2 J = 7.2 Hz, 4H, ArH), 5.41 (s, OCH2, 4H), 3.8-3.57 (m, 10H, ArCH2 and NCH3), 3.12 (bd, J = 12.8 Hz, 4H, ArCH2), 2.88 (s, 6H, CH3).

[0169] Example 3: Synthesis and characterization of calix[4]arene·CuBF4 complexes of formula (3) TIFF2026504140000014.tif47170

[0170] A 100 mL round-bottom flask was charged with calix[4]arene of formula (C) (0.200 g, 0.40 mmol, 1 equiv.), dried under high vacuum for 1 hour, purged under argon, and dissolved in 25 mL of freshly distilled THF. NaH (washed three times with petroleum ether and then dried under high vacuum; 0.1427 g, 9.9 mmol, 25 equiv.) was added. The reaction mixture was stirred at this temperature for 15 minutes, after which 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (dried under high vacuum; 0.3310 g, 1.98 mmol, 5 equiv.) was added in one portion. The reaction mixture was refluxed overnight. 1 The reaction mixture was monitored by H NMR. The reaction mixture was then cooled to room temperature, and the volatile components were removed under reduced pressure. 50 mL of dichloromethane was added, followed by 50 mL of distilled water. The product was extracted twice with 50 mL of dichloromethane. The organic layer was collected, and the volatile components were removed under reduced pressure. The resulting brownish oil was purified by column chromatography on silica (DCM / MeOH:98 / 2) to give calix[4]arene of formula (3) as a white solid in 70% yield (0.1922 g, 0.30 mmol).

[0171] 1 H NMR (CDCl3, 300 MHz) δ H (ppm) = 7.06-7.04 (m, ArH and ImH, 6H), 6.94-6.84 (m, ArH and ImH, 4H), 6.32 to 6.14 (m, ArH and CH2-CH=, 8H), 5.02-4.90 (m, =CH2, 4H), 4.88 (s, OCH2, 4H), 4.49 (d, J = 6.7 Hz, CH2-CH=, 4H), 4.33 (d, J = 13.4 Hz, ArCH ax , 4H), 3.49 (s, NCH3, 6H), 3.02 (d, J = 13.5 Hz, ArCH eq , 4H). HRMS (ESI):C 44 H 45 N4O4 + [M+H + ] calculated value is 693.3435, measured value is 693.3448 [M+H] + and 715.3276 [M+Na] + .

[0172] Example 4: Synthesis and characterization of calix[4]arenes of formula (6) TIFF2026504140000015.tif47170

[0173] To a round-bottom flask were added calix[4]arene of formula (3) (0.400 g, 0.58 mmol), Pd(OAc) (0.0194 g, 0.09 mmol, 0.15 equiv.), and PPh (0.0454 g, 0.173 mmol, 0.3 equiv.) along with 25 mL of freshly distilled THF and 5 mL of distilled water. NEtH (3.5 mL, 1.478 g, 20.2 mmol, 35 equiv.) was added, and the reaction was refluxed overnight under argon. The conversion was 1 The reaction was monitored by H NMR and terminated upon completion. The reaction was cooled to room temperature, filtered through Celite, and washed three times with 30 mL of dichloromethane. The combined organic fractions were washed three times with 25 mL of distilled water, and the volatile components were removed under reduced pressure. The resulting oil was then purified by column chromatography on silica (DCM to DCM / MeOH 95 / 5) to give calix[4]arene of formula (6) as a pale pink solid in 60% yield (0.213 g, 0.35 mmol).

[0174] 1 H NMR (CDCl3, 300 MHz) δ H (ppm) = 7.49 (s, OH, 2H), 7.11-7.01 (m, ArH and ImH, 6H), 6.98 (s, ImH, 2H), 6.87 (d, J = 7.4 Hz, ArH, 4H), 6.79 to 6.62 (m, ArH, 4H), 5.05 (s, OCH2, 4H), 4.22 (d, J = 13.1 Hz, ArCH ax , 4H), 3.77 (s, NCH3, 4H), 3.37 (d, J = 13.1 Hz, ArCH eq , 4H). HRMS (ESI):C 38 H 37 N4O4 + [M+H + ] calculated value is 613.2809, measured value is 613.2833 〔M+H〕 + and 635.2654 [M+Na] + .

[0175] Example 5: Synthesis and characterization of calix[4]arene·CuBF4 complex of formula (7) TIFF2026504140000016.tif47170

[0176] Calix[4]arene of formula (2) (0.050 g, 0.072 mmol, 1 equiv.) was dissolved in CHCl (2.5 mL). Glacial acetic acid (CHCOOH) / fuming nitric acid (HNO) (1:1, 0.54 mL) was added at 0 °C, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in CHCl and washed with H0 until pH 6. The solvent was evaporated under reduced pressure to give calix[4]arene of formula (7) as a solid (0.042 g, 74%).

[0177] 1 H NMR (400 MHz, CDCl3 / CD3CN 1 / 4, 298 K): δ (ppm) = 7.53 (s, ImH, 2H), 7.3-7.38 (m, ArH, 4H), 7.16-7.25 (m, ArH and ImH, 4H), 6.88 (s, ArH, 4H), 5.31 (s, OCH2Im, 4H), 3.91 (bd, J = 14 Hz, ArCH2, 4H), 3.67 (t, 3 J = 7.2 Hz, OCH2Et, 4H), 3.28 (d, J = 14 Hz, ArCH2, 4H), 3.16 (s, NCH3, 6H), 1.61-1.72 (m, CH2, 4H), 0.90 (t, 3 J = 7.2 Hz, CH3, 6H).

[0178] Example 6: Synthesis and characterization of calix[4]arenes of formula (8) TIFF2026504140000017.tif47170

[0179] Calix[4]arene (B) (0.200 g, 0.39 mmol) was added to a 50 mL round-bottom flask, dried under high vacuum for 1 hour, purged under argon, and dissolved in 25 mL of freshly distilled THF. The solution was cooled to 0 °C, and then NaH (0.236 g, 9.8 mmol, 25 equiv., freshly washed twice with 15 mL of petroleum ether, then dried under high vacuum and purged with argon) was added. The reaction mixture was stirred at 0 °C for 30 minutes, after which 2-(chloromethyl)-1-methyl-1H-benzimidazole (0.123 g, 1.18 mmol, 3 equiv.), which had been dried and purged under argon, was added. The reaction mixture was allowed to warm to room temperature and then refluxed overnight under argon. The reaction mixture was then cooled to room temperature, quenched by slowly adding 30 mL of distilled water, and the product was extracted twice with 50 mL of dichloromethane. The organic layers were combined and the volatiles were removed under reduced pressure. The product was purified by column chromatography on silica (DCM to DCM / MeOH:98 / 2) and the volatiles were removed under reduced pressure. The product was dissolved in a minimum amount of chloroform and precipitated by slowly adding 100 mL of pentane to give calix[4]arene of formula (8) as a purple solid in 59% yield (0.184 g, 0.23 mmol).

[0180] 1 H NMR (CDCl3, 300 MHz) δ H (ppm) = 7.78 (d, J = 6.7 Hz, BzImH, 2H), 7.35-7.21 (m, BzImH, 6H), 6.93 (d, J = 7.3 Hz, ArH, 4H), 6.80 (t, J = 7.4 Hz, ArH, 2H), 6.35 (t, J = 7.3 Hz, ArH, 2H), 6.25 (d, J = 7.4 Hz, ArH, 4H), 5.14 (s, OCH2, 4H), 4.41 (d, J = 13.4 Hz, ArCH ax , 4H), 3.76 to 3.70 (m, NCH3+ OCH2, 10H), 3.09 (d, J = 13.4 Hz, ArCH eq , 4H), 1.59 (sext, J = 8.3 Hz, CH2CH3, 4H), 0.44 (t, J = 7.4 Hz, CH3, 6H). HRMS (ESI):C 52 H 53 N6O6 + [M+H + ] calculated value is 797.4061, measured value is 797.4070 〔M+H〕 + and 819.3891 [M+Na] + .

[0181] Example 7: Synthesis and characterization of calix[4]arenes of formula (4) TIFF2026504140000018.tif47170

[0182] A 100 mL round-bottom flask was charged with calix[4]arene of formula (D) (0.500 g, 0.84 mmol, 1 equiv.) and 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (dried under high vacuum, 0.700 g, 4.19 mmol). The mixture was dried under high vacuum for 1 h, purged with argon, and dissolved in 25 mL of freshly distilled THF. The mixture was cooled to 0 °C, and NaH (washed three times with petroleum ether and then dried under high vacuum, 0.503 g, 20.9 mmol, 25 equiv.) was added. The reaction was refluxed overnight. 1 The reaction mixture was monitored by H NMR. The reaction mixture was then cooled to room temperature, and the volatiles were removed under reduced pressure. 50 mL of dichloromethane was added, followed by 50 mL of distilled water. The product was extracted twice with 50 mL of dichloromethane. The organic layers were combined, and the volatiles were removed under reduced pressure. The resulting brownish oil was purified by column chromatography on silica (DCM to DCM / MeOH:90 / 10) to give calix[4]arene of formula (4) as a white solid in 15% yield (0.104 g, 0.13 mmol).

[0183] 1 H NMR (CDCl3, 300 MHz) δ H (ppm) = 7.03 (bs, ImH, 2H), 6.93 to 6.74 (m, ImH and ArH, 6H), 6.36 (t, J = 7.2 Hz, ArH, 2H), 6.26 (bd, J = 7.6 Hz, ArH, 4H), 5.01 (s, OCH2, 4H), 4.65 (s, OCH2, 4H), 4.59 (d, J = 13.9 Hz, ArCH ax , 4H), 4.10 (q, J = 7.1 Hz, CH2CH3, 4H), 3.44 (s, NCH3, 6H), 3.05 (d, J = 13.9 Hz, ArCH eq , 4H), 1.23 (t, J = 7.2 Hz, CH2CH3, 6H). HRMS (ESI):C 46 H 49 N4O8 + [M+H + ] calculated value is 785.3545, measured value is 785.3542 〔M+H〕 + and 807.3366 [M+H+Na] + .

[0184] Example 8: Synthesis and characterization of calix[4]arenes of formula (9) TIFF2026504140000019.tif47170

[0185] In a 10 mL round-bottom flask, calix[4]arene of formula (B) (85.6 mg, 0.17 mmol, 1.0 equiv.) was stirred with NaH (60% dispersion in mineral oil, 135 mg, 3.37 mmol, 22 equiv.) in anhydrous DMF (3 mL) for 30 min under inert atmosphere. 2-(Chloromethyl)oxazole (89.5 mg, 0.67 mmol, 5.0 equiv.) was then added. The mixture was stirred at reflux under inert atmosphere for 24 h. After the reaction, the mixture was allowed to warm to room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic layer was evaporated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH 95:5 v / v) to give calix[4]arene of formula (9) (57 mg, 0.08 mmol) as an oil in 50% yield.

[0186] 1 H NMR (400 MHz, CDCl):δ H (ppm) = 7.65 (s, 2H, OxH), 7.11 (s, 2H, OxH), 6.91 (d, 8 Hz, 4H, ArH), 6.79-6.83 (m, 2H, ArH), 6.31-6.39 (m, 6H, ArH), 5.6 (s, 4H, OCH2Ox), 4.29 (d, J = 14 Hz, 4H, ArCH2), 3.67 (t, J = 8 Hz, 4H, OCH2Et), 3.14 (d, J = 14 Hz, 4H, ArCH2), 1.76-1.85 (m, 4H, CH2), 0.95 (t, J = 8 Hz, 6H, CH3).

[0187] Example 9: Synthesis and characterization of calix[4]arenes of formula (10) TIFF2026504140000020.tif39170

[0188] In a 10 mL round-bottom flask, calix[4]arene of formula (B) (105 mg, 0.21 mmol, 1.0 equiv.) was stirred with NaH (60% dispersion in mineral oil, 165 mg, 4.11 mmol, 23 equiv.) in anhydrous DMF (3 mL) for 30 min under inert atmosphere. 2-(Chloromethyl)thiazole (123 mg, 0.82 mmol, 5.6 equiv.) was then added. The mixture was stirred at reflux under inert atmosphere for 24 h. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic layer was evaporated under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH 95:5 v / v) to give calix[4]arene of formula (10) (84.0 mg, 0.12 mmol) as an oil in 58% yield.

[0189] 1 H NMR (400 MHz, CDCl):δ H (ppm) = 7.82 (d, J = 3.2 Hz, 2H, Thiazole H), 7.39 (d, J = 3.2 Hz, 2H, Thiazole H), 6.84 (d, J = 8 Hz, 4H, ArH), 6.71-6.76 (m, 2H, ArH), 6.47-6.51 (m, 2H, ArH), 6.41 (d, J = 8 Hz, 4H, ArH), 5.27 (s, 4H, OCH2 thiazole), 4.43 (d, J = 14 Hz, 4H, ArCH2), 3.89 (t, J = 8 Hz, 4H, OCH2Et), 3.18 (d, J = 14 Hz, 4H, ArCH2), 1.77-1.87 (m, 4H, CH2), 0.82 (t, J = 8 Hz, 6H, CH3).

[0190] Example 10: Synthesis and characterization of calix[4]arene of formula (38) TIFF2026504140000021.tif47170

[0191] In a 10 mL round-bottom flask, calix[4]arene of formula (B) (101 mg, 0.199 mmol, 1.0 equiv.) was dissolved in anhydrous THF (5 mL) under an inert atmosphere. NaH (60% dispersion in mineral oil, 151 mg, 6.29 mmol, 32 equiv.) and chloromethylpyridine hydrochloride (328 mg, 2.00 mmol, 10 equiv.) were then added with stirring. The mixture was stirred at reflux under an inert atmosphere. After 16 h, the mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. Distilled water (5 mL) was added to the residue, and the mixture was sonicated for 1 min and finally filtered. The resulting solid was purified by flash chromatography (DCM / acetone 90:10 v / v) to give calix[4]arene of formula (38) (72.8 mg, 0.105 mmol) as a white solid. The yield was 53%.

[0192] 1 H NMR (300 MHz, CDCl):δ H (ppm) = 8.60 (dt, J = 4.7 Hz, 1.2 Hz, 2H, PyrH), 7.73-7.70 (m, 4H, PyrH), 7.25-7.21 (m, 2H, PyrH), 6.98 (d, J = 7.4 Hz, 4H, ArH), 6.83 (dd, J = 7.9, 6.9 Hz, 2H, ArH), 6.36 (dd, J = 8.5, 6.5 Hz, 2H, ArH), 6.26 (d, J = 7.4 Hz, 4H, ArH), 4.94 (s, 4H, OCH2Pyr), 4.48 (d, J = 13.4 Hz, 4H, ArCH ax ), 3.90-3.85 (m, 4H, OCH2Et), 3.16 (d, J = 13.5 Hz, 4H, ArCH eq ), 1.82-1.65 (m, 4H, CH2), 0.67 (t, J = 7.6 Hz, 6H, CH3).

[0193] First comparative example: the following formula (X) Calix[4]arene of TIFF2026504140000022.tif45170 is a comparative example for the present invention.

[0194] For the calix[4]arenes of the present invention, in the compound of formula (X), Y1, Y2, Y3 and Y4 are tert-butyl groups.

[0195] Ag of the compound of formula (X) + The complex was formed by stirring 600 μL of a 0.5 mM solution of X in CDCl 3 with 600 μL of a 0.5 mM solution of AgNO 3 in H 2 O for 60 min to give complex (Xa).

[0196] 1 1H NMR (400 MHz, CDCl3, 298 K): δ (ppm) = 7.57 (s, ImH, 2H), 7.10 (s, ArH, 4H), 6.92 (s, ImH, 2H), 6.28 (s, ArH, 4H), 4.94 (s, OCH2Im, 4H), 3.78 (bd, ArCH2, 4H), 3.68 (bt, OCH2Et, 4H), 2.99 (bd, ArCH2, 4H), 2.85 (s, NCH3, 6H), 1.69 - 1.75 (m, CH2, 4H), 1.33 (s, t Bu, 18H), 0.90 (bt, CH3, 6H), 0.76 (s, t Bu, 18H).

[0197] Second Comparative Example: The following formula (XI) TIFF2026504140000023.tif37170's calix [4] arene is a comparative example in the present invention.

[0198] <II Experiments on cLogP, Cu + binding, transport and delivery properties, and cytotoxicity of calix [4] arenes in the present invention and comparative examples> (II - A Determination of cLogP of calix [4] arenes in the present invention and comparative examples) An important requirement for the usefulness of synthetic transporters (such as the above ionophores, etc.) is the ability to deliver to target cells. A highly lipophilic molecule that can strongly bind to ions is usually considered an excellent candidate for synthetic transporters. However, a high lipophilicity may sometimes prevent the delivery of the compound to the membrane. Therefore, it is necessary to balance the ability of the molecule to stay within the membrane and transport ions through it and the ability to reach the membrane in the first place. For pharmaceuticals, LogP is a value selected to evaluate lipophilicity. LogP is the logarithm of the partition coefficient P between water and octanol. The LogP value can be measured or calculated in a water / octanol system. In the latter case, it is called cLogP. Chemical drawing tools such as ChemDraw can provide cLogP values.

[0199] To assess the lipophilicity of the calix[4]arenes of the present invention, their cLogP values ​​were determined using the chemical properties function in ChemDraw 20.0.

[0200] Table 1 below details the cLogP values ​​for examples and comparative examples of calix[4]arenes of the present invention (ie, the "cLogP" column).

[0201] (II-B:Cu + (Determination of Bonding) at 298K using copper(I) tetrakis(acetonitrile) tetrafluoroborate 1 1H NMR titration revealed that the calix[4]arenes of the examples and comparative examples of the present invention + The binding ability and complexation constant were evaluated.

[0202] For example, for each calix[4]arene, a stock solution of the calix[4]arene being tested was prepared in a 4 / 1 mixture of CDCN / CDCl3. This stock solution was used to prepare a Cu(MeCN)4BF4 solution, and copper(I) was added in 0.25 equivalent increments up to 1 equivalent, followed by 0.5 equivalent increments until a total of at least 2 equivalents was reached. After each addition of the calix[4]arene stock solution and Cu(MeCN)4BF4, a 400 MHz spectrometer was used at 298 K. 1 1 H NMR spectra were recorded. 1 Addition was continued until no significant changes in the 1 H NMR signals were observed.

[0203] After the addition of 1 equivalent of Cu(MeCN)4BF4, a new set of signals was observed that completely replaced the first set of signals. 5 M -1 It is believed to have an affinity constant (Ka) of at least 100 kJ / kg.

[0204] When 4-5 equivalents of Cu(MeCN)4BF4 were added, 1 Calix[4]arenes with gradual changes in the chemical shifts of their 1 H NMR signals (at least one signal greater than 0.1 ppm) are considered to indicate weak bonding.

[0205] Table 1 below shows the Cu content of the calix[4]arene of the present invention for examples and comparative examples. + The details of the binding capacity for Cu are shown (i.e., + Join column).

[0206] More precisely, in Table 1: "Strong binding" is defined as an affinity constant (Ka) of 10 5 M -1 This means that it is more than or equal to this.

[0207] "Weak bond" occurs when 4-5 equivalents of Cu(MeCN)4BF4 are added. 1 This means that a change in the chemical shift of the 1 H NMR signals (more than 0.1 ppm in at least one signal) is observed.

[0208] "Not significant" means that no significant change in chemical shift is observed (less than 0.1 ppm) upon addition of 4-5 equivalents of Cu(MeCN)4BF4.

[0209] (II-C-1: Example of calix[4]arene Cu + Transport Measurements) The calix[4]arenes of the present invention, in examples and comparative examples, were tested for their ability to be delivered from solution into the lipid bilayer of liposomes and then to be transported into Cu. + We evaluated the ability of bathocuproine disulfonate (BCS) to function as a transporter of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and cholesterol in a 7:3 ratio using large unilamellar vesicles (LUVs, also known as liposomes).

[0210] BCS is a fluorescent, water-soluble phenanthroline derivative that forms a non-fluorescent 2:1 complex with Cu. + It can be used as a fluorescent dye to detect

[0211] Lipid stock solutions were prepared using deacidified CHCl3 and stored in a freezer. CHCl3 was deacidified by passing it through activated basic alumina. The lipids used to prepare liposomes were 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) (purity ≥99%) and cholesterol (purity 95%). 50 mM sodium phosphate buffer was prepared in Millipore water at pH 7 (±0.1) by mixing monoprotonated and diprotonated phosphate solutions. A dye (BCS) solution was prepared at a concentration of 0.5 mM in phosphate buffer.

[0212] Lipid solutions were mixed in various ratios in a 5 mL round-bottom flask. The POPC / cholesterol molar ratio was 7:3 in all experiments. The total amount of lipid per batch varied depending on the amount of liposome solution required for the experiment. After mixing the lipid solutions in the round-bottom flask, the chloroform was evaporated under a gentle airflow, and the resulting lipid film was dried under high vacuum for at least 1 hour. 500 μL of BCS solution in phosphate buffer and a magnetic stir bar were added to the flask. The flask was sonicated for 30 seconds and stirred on the magnetic stirrer for at least 1 hour. The solution was frozen in liquid nitrogen and heated to room temperature in hot water 10 times to form large unilamellar vesicles (LUVs). The liposome solution was extruded 29 times using an extrusion kit equipped with a membrane with 200 nm pores. The external BCS was then removed by elution through a size-exclusion column (Sephadex G-25) using the buffer used in the experiment. The solution was then diluted with phosphate buffer to a lipid concentration of 0.4 mM.

[0213] A solution of calix[4]arene was prepared in DMSO at a concentration of 0.24 mM, and 5 μL was added 2 min before each transport measurement, resulting in a calix[4]arene to lipid ratio of 1:1000, corresponding to the calix[4]arene concentration tested, 0.4 μM.

[0214] Alternatively, lipid films were prepared by pre-incorporating calix[4]arene (dissolved in chloroform) with lipids before evaporating the chloroform. The concentration and volume were chosen to give a calix[4]arene to lipid ratio of 1:1000.

[0215] Fluorescence measurements were performed on a Horiba FluoroMax 4 spectrometer using a four-sided quartz cuvette (10 mm × 10 mm). + For transport assays, excitation was set at 278 nm and emission was recorded at 393 nm, which correspond to the excitation and emission maxima of BCS encapsulated within the LUVs.

[0216] Cu added to liposomes + The solution was prepared by dissolving Cu(MeCN)BF in MeCN at a concentration of 15.25 mM. During the first 30 seconds of the experiment, this copper solution was diluted 5-fold with phosphate buffer to a copper concentration of 3.05 mM. 50 μL of the diluted copper solution was added to 3 mL of liposomes, resulting in a 50 μM copper gradient. Fluorescence levels were monitored for 600 seconds after the addition of the copper solution.

[0217] In each experiment, the initial plateau and initial vertical drop (1–4 s after application of the external dye and Cu) were measured. + The fluorescence (F) was then normalized by dividing the fluorescence value (F) by the value at t = 0 s (F). The mean value of the normalized triplicate experiments (F / F) was calculated and plotted over time to determine the final F / F level (after 600 s).

[0218] The following Table 1 shows the Cu content in the examples and comparative examples of calix[4]arene of the present invention. + Shows details of transport capacity (i.e., "Cu + Transportation column).

[0219] More precisely, in Table 1, when calix[4]arene was introduced into liposomes from a DMSO solution or when it was pre-incorporated into liposomes, "Yes" indicates that the liposome contains Cu. + This means that when HCl was added, a significant decrease in the fluorescence of the encapsulated BCS was observed (after 600 seconds, F / F<0.65).

[0220] "None" means that the liposome contains Cu. + This means that when HCl was added, no significant decrease in the fluorescence of the encapsulated BCS was observed (after 600 seconds, F / F>0.65).

[0221] (II-C-2: Ag synthesis by calix(4)arene of formula (2) + (Measurement of transport) Liposomes encapsulating BCS were investigated in "II-C-1: Cu synthesis using calix[4]arene as an example." + Transport measurements were performed as described in this section.

[0222] Ag + The solution was prepared by dissolving 3.05 mM AgNO3 in phosphate buffer. After the first 30 seconds of the experiment, Ag + 50 μL of the solution was added to 3 mL of liposomes to obtain a 50 μM silver gradient. After adding the silver solution, the fluorescence level was monitored for 600 seconds.

[0223] When a DMSO solution containing calix[4]arene of formula (2) was added to liposomes (5 μL, resulting in a lipid transfer ratio of 1:1000), the decrease in BCS fluorescence intensity was significantly faster (F / F = 0.55 after 100 s) than when DMSO (5 μL) without calix[4]arene of formula (2) was added (F / F = 0.85 after 100 s).

[0224] (II-D: Measurement of deliverability) Examples of calix[4]arenes of the present invention and comparative examples were tested for their ability to be inserted into the membrane of liposomes after formation.

[0225] For this purpose, "II-C-1: Example of calix[4]arene Cu + Calix[4]arene was added to the liposomes from a DMSO solution as detailed in "Transport Measurements," and transport curves were recorded.

[0226] Calix[4]arenes that showed little or no activity by this procedure were tested through pre-incorporation.

[0227] More precisely, calix[4]arene (dissolved in chloroform) was mixed with lipids, and the chloroform was evaporated to obtain a lipid film. The concentration and volume were chosen to give a calix[4]arene to lipid ratio of 1:1000.

[0228] Table 1 below details the delivery of the tested calix[4]arenes and comparative examples from DMSO solution into liposomes (ie, the "Delivery" column).

[0229] More precisely, in this Table 1: "Yes" indicates that when calix[4]arene was added to liposomes from a DMSO solution, Cu was not added to the liposomes. + This means that the addition of HCl resulted in a significant decrease in the fluorescence of the encapsulated BCS (after 600 seconds, F / F<0.65).

[0230] "Moderate" means that the final levels achieved when calix[4]arene was pre-incorporated were significantly lower (after 600 s, F / F<0.4) than when it was added to liposomes from DMSO solution (after 600 s, F / F= 0.4-0.65).

[0231] "None" means that when calix[4]arene was added to liposomes from a DMSO solution, no significant decrease in the fluorescence of the encapsulated BCS was observed (after 600 s, F / F>0.65), but when pre-loaded, good transport was observed (after 600 s, F / F<0.4).

[0232] "-" indicates that no transport was observed when calix[4]arene was pre-loaded or added to liposomes from a DMSO solution. This is because calix[4]arene was not transported by the described method. + It is not transport-active, which means that this method cannot be used to verify the delivery properties of calix[4]arenes.

[0233] [Table 1] Table 1: Details of the cLogP values ​​and binding capacities of some calix[4]arenes of the present invention and comparative examples.

[0234] Additionally, delivery of calix[4]arenes of formula (2) and formula (X) and the first comparative example from liposomes was tested instead of being added from DMSO solutions.

[0235] For the study of delivery using liposomes, two batches of liposomes were prepared. Liposomes encapsulating BCS were prepared as described above, and liposomes that did not contain BCS but in which calix[4]arene of formula (2) or the first comparative example of formula (X) was pre-incorporated so that the ratio of transporter to lipid was 1:500 were prepared as described above. 1.5 mL of each batch of liposomes was added to a cuvette and stirred in a spectrometer for 5 minutes before starting the experiment using the above settings.

[0236] When liposomes containing BCS were mixed with liposomes containing calix[4]arene of formula (2), good transport activity was observed. This suggests that calix[4]arene of formula (2) can be delivered from other liposomes to the liposome membrane. On the other hand, when liposomes containing BCS were mixed with liposomes containing the first comparative example of formula (X), no transport activity was observed. This suggests that the lipophilic comparative example of formula (X) cannot be delivered from liposomes.

[0237] Considering Table 1, the calix[4]arenes of formulas (2), (3) and (4) bind and transport Cu + and have excellent ability to be delivered from DMSO solution. Furthermore, their lipophilicity is not so high (i.e., between 7.4 and 9.2). These calix[4]arenes are preferred calix[4]arenes in the present invention.

[0238] In contrast, the comparative example of formula (X) binds strongly to Cu + and can transport it, but because of its high lipophilicity (cLogP = 16.5) and lack of delivery ability, it is not an interesting calix[4]arene for anticancer treatment. In fact, the comparative example of formula (X) cannot be delivered from DMSO solution or from liposomes.

[0239] <III Cell Proliferation Experiment> (III-A: Inhibition of Proliferation of A549 Cells) The growth inhibition of the A549 human lung cancer cell line by calix[4]arene of formula (2) was measured by exposing the A549 human lung cancer cell line to calix[4]arene of formula (2) (concentration: 2 μM) for 72 hours. The treated and untreated conditions were analyzed before treatment (N0) and after 72 hours (N t ) The absolute number of cells was counted.

[0240] Figure 1 shows that The proliferation index (N) of A549 cells after exposure to calix(4)arene of formula (2) t / N0) time course profile (i.e., the curve labeled "Calix[4]arene(2)"). The proliferation index (N) of A549 cells not exposed to calix(4)arene (Eq. (2)) t / N0) time course profile (i.e., the curve marked "untreated") is.

[0241] "N t " is the number of cells at time "t" and "N0" is the number of cells before treatment.

[0242] From the curves in the graph of FIG. 1, it can be seen that the calix[4]arene of formula (2) clearly inhibits the proliferation of A549 human lung cancer cells.

[0243] (III-B: Inhibition of PC9 cell proliferation) The growth inhibition of PC9 human lung cancer cell line by calix[4]arene of formula (2) was measured. This was done by exposing PC9 human lung cancer cell line to calix[4]arene of formula (2) (concentration 3 μM) for 72 hours. The treated and untreated conditions were analyzed before treatment (N0) and after 72 hours (N t ) The absolute number of cells was counted.

[0244] Figure 2 shows that The proliferation index (N) of PC9 cells after exposure to calix(4)arene (Eq. (2)) t (N0) Time-course profile (i.e., the curve labeled "calix[4]arene (2)") · Proliferation index (N) of PC9 cells not exposed at all to the calix[4]arene of formula (2) t (N0) Time-course profile (i.e., the curve labeled "untreated") It is.

[0245] From the curve of the graph in Fig. 2, it is considered that the calix[4]arene of formula (2) clearly inhibits the proliferation of PC9 human lung cancer cells.

[0246] (III-C: Inhibition of H322 cell proliferation) The inhibition of the proliferation of H322 lung cancer cell line by the calix[4]arene of formula (2) was measured. This was carried out by exposing the H322 lung cancer cell line to the calix[4]arene of formula (2) (concentration 3 μM) for 72 hours. For the treated and untreated conditions, the absolute cell numbers before treatment (N0) and after 72 hours (N t ) were measured.

[0247] Fig. 3 shows · Proliferation index (N) of H322 cells after exposure to the calix[4]arene of formula (2) t (N0) Time-course profile (i.e., the curve labeled "calix[4]arene (2)") · Proliferation index (N) of H_{322} cells not exposed at all to the calix[4]arene of formula (2) t (N0) Time-course profile (i.e., the curve labeled "untreated") It is.

[0248] From the curve of the graph in Fig. 3, it is considered that the calix[4]arene of formula (2) clearly inhibits the proliferation of H322 lung cancer cells.

[0249] <IV Experiment on the cytotoxicity of the calix[4]arene of formula (2), measurement of IC 50 > (IV-A: Experiments on malignant H322, A549, and PC9 cells) H322 lung cancer cells were seeded in a 96-well plate with the calix[4]arene of formula (2). TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the calix[4]arene of formula (2). After 72 hours of treatment, the cells were analyzed by Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0250] A549 human lung cancer cells were seeded in 96-well plates with the calix[4]arene of formula (2). The cells were incubated with GlutaMAX TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the calix[4]arene of formula (2). After 72 hours of treatment, the cells were analyzed by Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0251] PC9 human lung cancer cells were seeded in a 96-well plate with the calix[4]arene of formula (2). The cells were incubated with GlutaMAX TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the calix[4]arene of formula (2). After 72 hours of treatment, the cells were analyzed by Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0252] Table 2 below shows the average IC of calix[4]arenes against H322, A549, and PC9 cells obtained using the MTS cytotoxicity assay. 50 and IC obtained by GraphPad Prism software. 50 Confidence intervals (95% statistical significance) are shown.

[0253] [Table 2] Table 2: IC values ​​of calix[4]arenes of formula (2) against H322, A549, and PC9 cells by MTS assay 50 Shows.

[0254] Considering Table 2, calix[4]arenes of formula (2) exhibit high antitumor activity in the micromolar range against H322, A549, and PC9 cells, which is in a range comparable to that of other anticancer chemotherapeutic drugs.

[0255] (IV-B: Experiments on non-malignant MRC5-SVII cells, MSC cells, and HaCaT cells) Non-malignant MRC5-SVII cells were seeded in 96-well plates with the calix[4]arene of formula (2). The cells were grown in Gibco PBS containing sodium pyruvate (1 μM) and fetal calf serum (FCS, 10%). TM The cells were cultured in a minimum essential medium-non-essential amino acid medium (MEM NEAA) and treated with various concentrations of the calix[4]arene of formula (2). After 72 hours of treatment, the cells were cultured in a Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0256] Non-malignant MCS cells were seeded in 96-well plates with the calix[4]arene of formula (2). The cells were grown in mesenchymal stem cell growth medium (Promega TM The cells were cultured on a Promega Pharma (C-28009) and treated with various concentrations of calix[4]arene of formula (2). After 72 hours of treatment, the cells were cultured on a Promega Pharma (C-28009) and treated with various concentrations of calix[4]arene of formula (2). TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0257] Non-malignant HaCaT cells were seeded in 96-well plates with the calix[4]arene of formula (2). The cells were incubated with GlutaMAX TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 20% fetal calf serum (FCS) and treated with various concentrations of the calix[4]arene of formula (2). After 72 hours of treatment, the cells were analyzed by Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0258] Table 3 below shows the mean IC of calix[4]arenes against MRC5-SVII, MCS, and HaCaT cells obtained using the MTS cytotoxicity assay. 50 and confidence intervals (95% statistical significance) of IC50 obtained by GraphPad Prism software are shown.

[0259] [Table 3] Table 3: IC of calix[4]arenes of formula (2) on MRC5-SVII, MSC, and HaCaT cells by MTS assay 50 Shows.

[0260] Considering Table 3, calix[4]arenes of formula (2) exhibit a range of cytotoxicity against non-malignant MRC5-SVII, MSC and HaCaT cells that is comparable to that against cancer cells.

[0261] (IV-C: Experiments on 60 malignant cell lines) In these experiments, the IC of the calix[4]arene of formula (2) was measured with the control compound bortezomib (an anticancer drug that inhibits the proteasome). 50 The values ​​were measured.

[0262] Cytotoxicity was assessed using the PROLiFiler Cell Panel Screening (Reaction Biology TM ) and IC 50 The values ​​were measured.

[0263] Cells were cultured in various media, and Table 4 below details the media corresponding to each malignant cell type tested.

[0264] For the assay, cells were seeded into white, flat, clear-bottom, 384-well multiwall plates treated for cell culture and incubated overnight at 37°C. Calix[4]arene of formula (2) or a control compound was then added. After 72 hours of incubation at 37°C under 5% or 10% CO2, depending on the medium, the cell plates were allowed to equilibrate to room temperature (i.e., 20°C) for 1 hour. Promega's CellTiterGlo® reagent was added, and luminescence was measured using a luminometer approximately 1 hour later.

[0265] Raw data were converted to percentage of cell viability, with upper and lower control values ​​set at 100% and 0%, respectively. IC 50 Calculations were performed using GraphPad Prism software with 0% viability as the lower constraint and 100% viability as the upper constraint, using a variable slope sigmoidal response fitting model.

[0266] Table 4 below details the culture media used for each malignant cell line.

[0267] [Table 4] TIFF2026504140000028.tif144170 Table 4 details the culture media for the calix[4]arene of formula (2) and control compounds for each malignant cell line.

[0268] In this Table 4, "DMEM" is an abbreviation for Dulbecco's Modified Eagle's Medium. "FCS" is an abbreviation for fetal calf serum. "RPMI-1640" is an abbreviation for Roswell Park Memorial Institute.

[0269] Table 5 below shows the IC values ​​of the malignant cell lines tested for the calix[4]arene of formula (2) and the control compound bortezomib. 50 The details of the values ​​are shown below.

[0270] [Table 5] TIFF2026504140000030.tif Table 5 shows the details of the IC values for each of the malignant cell lines tested for the calix[4]arene of formula (2) and the control compound. 50 Value details are shown.

[0271] Considering Table 5, the calix[4]arene of formula (2) shows antitumor activity equivalent to that against the lung cancer cell line against all the malignant cells tested (see Table 2).

[0272] <Experiment on the cytotoxicity of the second comparative example of formula (XI), measurement of IC 50 Measurement> (V-A: Experiment on malignant H322, A549, PC9 cells) H322 lung cancer cells were seeded in a 96-well plate together with the compound of the second comparative example of formula (XI). The cells were cultured in RPMI-1640 medium supplemented with GlutaMAX TM (Gibco TM ) and fetal bovine serum (FCS, 10%) and treated with various concentrations of the second comparative example of formula (XI). After 72 hours of treatment, the cytotoxicity was measured by the IC value using the kit "CellTiter 96R AQ TM One Solution Cell Proliferation Assay (MTS)" from Promega. After incubation with the MTS reagent for 30 minutes, endpoint measurements were taken three times at 485 nm using a fluorescence plate reader. uous One Solution Cell Proliferation Assay (MTS)」を用いて、IC 50 値により細胞毒性を測定した。MTS試薬により30分間インキュベートした後、蛍光プレートリーダーを用いて485 nmで終点測定を3回行った。

[0273] A549 human lung cancer cells were seeded in a �6-well plate together with the compound of the second comparative example of formula (XI). The cells were cultured in RPMI-1640 medium supplemented with GlutaMAX TM (Gibco TM ) and fetal bovine serum (FCS, 10%) and treated with various concentrations of the second comparative example of formula (XI). After 72 hours of treatment, the cytotoxicity was measured by the IC value using the kit "CellTiter 96R AQ TM のキット「CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0274] PC9 human lung cancer cells were seeded in 96-well plates with the second comparative compound of formula (XI). TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the second comparative example of formula (XI). After 72 hours of treatment, the cells were cultured in Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0275] Table 6 below shows the IC20 of the second comparative example of formula (XI) against H322, A549 and PC9 cells obtained using the MTS cytotoxicity assay. 50 Details are shown below.

[0276] [Table 6] Table 6: IC of the second comparative example of formula (XI) against H322, A549 and PC9 cells by MTS assay 50 .

[0277] The second comparative example of formula (XI) shows no significant cellular properties against lung cancer cell lines.

[0278] (VB: Experiments on non-malignant MRC5-SVII cells) Non-malignant MRC5-SVII cells were seeded in a 96-well plate along with the second comparative example of formula (XI). The cells were grown in Gibco PBS supplemented with sodium pyruvate (1 μM) and fetal calf serum (FCS, 10%). TM The cells were cultured in a minimum essential medium-non-essential amino acid medium (MEM NEAA) of 1000 kJ / ml and treated with various concentrations of the second comparative example of formula (XI). After 72 hours of treatment, the cells were cultured in Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0279] Table 7 below shows the IC20 of the second comparative example of formula (XI) against MRC5-SVII cells obtained using the MTS cytotoxicity assay. 50 Shows.

[0280] [Table 7] Table 7 shows the IC value of the second comparative example of formula (XI) against MRC5-SVII cells by MTS assay. 50 Shows.

[0281] The second comparative example of formula (XI) does not exhibit significant cytotoxicity to MRC5-SVII cells.

[0282] <VI IC 50 Experiment on cytotoxicity of the first comparative example of formula (X) based on (Experiments on malignant H322, A549, and PC9 cells) H322 lung cancer cells were seeded in a 96-well plate with the first comparative example of formula (X). TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). After 72 hours of treatment, the cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0283] A549 human lung cancer cells were seeded in a 96-well plate with the first comparative example of formula (X). TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). After 72 hours of treatment, the cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0284] PC9 human lung cancer cells were seeded in a 96-well plate along with the first comparative example of formula (X). TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). After 72 hours of treatment, the cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the first comparative example of formula (X). TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0285] Table 8 below shows the IC of the first comparative example of formula (X) against H322, A549 and PC9 cells obtained using the MTS cytotoxicity assay. 50 Details are shown below.

[0286] [Table 8] Table 8: IC of the first comparative example of formula (X) against H322, A549 and PC9 cells by MTS assay 50 Shows.

[0287] The first comparative example of formula (X) does not show significant cellular properties against lung cancer cell lines.

[0288] <VII IC 50 Experiments on the cytotoxicity of other calix[4]arenes of the present invention based on (Experiments on malignant H322 cells) H322 lung cancer cells were seeded in 96-well plates with the calix[4]arenes tested. TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of the tested calix[4]arenes. After 72 hours of treatment, the cells were analyzed by Promega TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0289] Table 9 below shows the IC of calix[4]arenes of the present invention against H322 cells obtained using the MTS cytotoxicity assay. 50 Details are shown below.

[0290] [Table 9] Table 9: IC of calix[4]arenes of the present invention against H322 by MTS assay 50 Shows.

[0291] I C 50 Compounds at >10 μM (Table 9) appear to be inactive against the H322 cancer cell line.

[0292] <VIII DL 50 Experiments on the cytotoxicity of the calix[4]arene of the present invention based on Cytotoxicity was assessed using the MTT assay. 1 × 10 cells were cultured per well in a flat-bottom 96-well plate. 4 Cells were seeded and incubated at 37°C and 5% CO2 for 48 hours. Various calix[4]arenes were then added at concentrations up to 200 μM. Each condition was performed in triplicate within the plate. Each experiment was performed independently in triplicate. After 24 hours of incubation in the presence of compounds, the medium was discarded, the cells were washed with PBS, and 100 μL of medium containing 0.5 mg / mL MTT was added to each well. After 30 minutes of incubation at 37°C, the MTT solution was discarded, and the formed formazan crystals were dissolved in isopropanol (containing 4 mM HCl and 0.1% NP40). The absorbance in the wells was measured at 570 nm using a Tecan Microplate Reader-550 microplate reader.

[0293] Table 10 below shows: The nine calix[4]arenes of the present invention Comparative Examples of Formulas (X) and (XI) Disulfiram Disulfiram / Cu 2+ (1:1) complex Clioquinol Clioquinol / Cu 2+ (1:1) Complex DL against hepatocellular carcinoma (HepG2 / C3A) cells of 50 is shown in detail.

[0294] As described above, disulfiram and chloroquine are well-known ionophores in cancer treatment.

[0295]

Table 10

[0296] Considering Table 10, · DL of chloroquine complex / Cu (1:1) and disulfiram complex / Cu (1:1) 50 is lower than that of chloroquine and disulfiram 50 . These two substances become more toxic when forming a complex with Cu 2+ .

[0297] · In contrast, the calix [4] arene of the present invention has equivalent toxicity either alone or in a complex with Cu + . The DL value for Example 1 is 3.1 vs. 4.0. 50

[0298] · The calix [4] arenes of formulas (2), (3) and (4) have the lowest DL 50 values. These are the most toxic calix [4] arenes.

[0299] <Experiment on the cytotoxicity of the calix [4] arene of formula (2) combined with IX CuCl2> (IX-A: Experiment on malignant H322 cells) H322 lung cancer cells were seeded in a 96-well plate together with the calix [4] arene of formula (2) and CuCl2. The cells were in GlutaMAX TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of calix[4]arene of formula (2) and / or CuCl2 from Merck. After 72 hours of treatment, the cells were incubated at 4°C for 1 hour at 2°C. TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0300] Table 11 below shows the concentration of calix[4]arene of formula (2) and Cu 2+ The concentration-dependent cell viability is shown in detail.

[0301] [Table 11] Table 11: Details on percentage of cell viability.

[0302] Table 11 details the effect of combining calix[4]arene of formula (2) with CuCl on H322 cells using the MTS cytotoxicity assay. More precisely, the detailed cell viability data in Table 11 demonstrates that the combination of calix[4]arene of formula (2) with Cu (in the form of CuCl) enhances the efficacy of calix[4]arene of formula (2) in the H322 cell line.

[0303] (IX-B: Experiments on malignant A549 cells) A549 human lung cancer cells were seeded in a 96-well plate with the calix[4]arene of formula (2) and CuCl. The cells were incubated with GlutaMAX TM (Gibco TM The cells were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum (FCS) and treated with various concentrations of calix[4]arene of formula (2) and / or CuCl2 from Merck. After 72 hours of treatment, the cells were incubated at 4°C for 1 hour at 2°C. TM Kit "CellTiter 96R AQ uous Using the One Solution Cell Proliferation Assay (MTS), IC 50 Cytotoxicity was measured by the values ​​shown in Table 1. After 30 minutes of incubation with the MTS reagent, endpoint measurements were performed in triplicate at 485 nm using a fluorescent plate reader.

[0304] Table 12 below shows the concentration of calix[4]arene of formula (2) and Cu 2+ The concentration-dependent cell viability is shown in detail.

[0305] [Table 12] Table 12: Details on the percentage of cell viability.

[0306] Table 12 details the effect of combining calix[4]arene of formula (2) with CuCl on A549 cells using the MTS cytotoxicity assay. More precisely, the detailed cell viability data in Table 12 demonstrates that the combination of calix[4]arene of formula (2) with Cu (in the form of CuCl) enhances the efficacy of calix[4]arene of formula (2) in A549 cells.

[0307] (IX-C: Experiments on malignant PC9 cells) PC9 human lung cancer cells were seeded in a 96-well plate with the calix[4]arene of formula (2) and CuCl. The cells were incubated with GlutaMAX TM (Gibco TM ) and cultured in RPMI-1640 medium supplemented with fetal calf serum (FCS, 10%) and treated with calix[4]arene of formula (2) and / or CuCl2 from Merck at various concentrations. After 72 hours of treatment, Promega TM 's kit "CellTiter 96R AQ uous One Solution Cell Proliferation Assay (MTS)" was used to measure cytotoxicity by IC 50 value. After incubation with the MTS reagent for 30 minutes, endpoint measurements were performed three times at 485 nm using a fluorescence plate reader.

[0308] Table 13 below shows details regarding the cell viability depending on the concentration of calix[4]arene of formula (2) and the concentration of Cu 2+ .

[0309]

Table 13

[0310] Table 13 shows details regarding the effect of combining calix[4]arene of formula (2) with CuCl2 on PC9 cells obtained using the MTS cytotoxicity assay. More precisely, considering the detailed cell viability in this Table 13, it is shown that the potency of calix[4]arene of formula (2) in PC9 cells is enhanced by the combination of calix[4]arene of formula (2) and Cu (in the form of CuCl2).

[0311] In conclusion, considering Tables 11 to 13, the potency of calix[4]arene of formula (2) is enhanced in various lung adenocarcinoma cell lines by the combination of calix[4]arene of formula (2) and Cu (in the form of CuCl2). Thus, a synergistic effect between calix[4]arene of formula (2) and copper in salt form is observed.

[0312] <Experiment on X bacteria and yeast> The efficacy of a target compound against a bacterial strain is evaluated by measuring the minimum inhibitory concentration (MIC) of the compound, which is determined by tracking the growth of bacteria exposed to various concentrations of the compound in 96-well plates.

[0313] All following procedures were performed near an open flame to ensure sterility. All contact surfaces were cleaned with ethanol.

[0314] The MIC of the calix[4]arene of formula (2) is Staphylococcus aureus (hereinafter abbreviated as "SA"), -Methicillin-resistant Staphylococcus aureus (hereinafter abbreviated as "MRSA"), Escherichia coli (hereinafter referred to as "E. coli"), Vancomycin-resistant enterococcus (VRE) and Candida albicans yeast cells, was evaluated against.

[0315] A small amount of frozen bacteria (stored in glycerol at -80°C) was mixed with 25 mL of lysogeny broth (i.e., a rich medium used for bacterial growth, containing 10 g tryptophan, 5 g yeast extract, 10 g NaCl, and 1 L distilled water, adjusted to pH 7.0 with 1 N NaOH, and autoclaved at 120°C for 25 min) in a Falcon tube, which was then placed in an incubation chamber at 180 rpm and 37°C.

[0316] After 16 to 24 hours, 25 mL of lysogeny broth was added to the growth medium, and the mixture was returned to the incubation chamber and cultured for 2 hours. The absorbance of the resulting solution was measured at 600 nm using lysogeny broth as a blank (hereinafter referred to as "OD"). 600 "), and then the solution was diluted to 0.1 ± 0.01.

[0317] A 96-well plate was filled with 20 μL of 1 mM CuSO solution, followed by the addition of 160 μL of growth medium, and finally, 20 μL of a DMSO solution containing various concentrations of the calix[4]arene of formula (2) being tested was added.

[0318] The concentrations of calix[4]arene of formula (2) were 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.2 μM, 3.1 μM, 1.6 μM, 0.8 μM, 0.4 μM, and 0.2 μM. Three wells were used for each condition. The top and bottom rows served as controls; the top row contained lysogeny broth alone, while the bottom row contained growth medium, DMSO, and CuSO4. The plates were placed in an incubator for 16 to 24 hours. The absorbance of each well was measured at 600 nm using a multiplate reader (Optima Fluostar).

[0319] Additionally, the same protocol was repeated using Candida albicans yeast cells, but instead of lysogeny broth, yeast extract-peptone-dextrose (20 g / L cytological peptone, 20 g / L glucose, 10 g / L yeast extract) was used as the growth medium.

[0320] The growth value was calculated by subtracting the average optical density (OD) of the 12 negative controls (OD(negative)) from the average optical density (OD) of the three wells under the same conditions, and the ratio of this to the average optical density (OD(positive)) of the 12 positive controls (OD(positive)) was subtracted from the negative control. The inhibition rate was calculated by subtracting this value from 1 and multiplying the result by 100 (Equation 1).

[0321] Inhibition value % = 100 × (1 - [OD - OD (negative)] / [OD (positive) - OD (negative)]) (Equation 1) The MIC50 or MIC90 was defined as the lowest concentration at which the inhibition value was ≥ 50% or ≥ 90%. Three rows of the plate were used for each experimental condition. This entire process was repeated three times, and triplicate experiments were performed. The MIC value was determined by the average value obtained.

[0322] Table 14 details the MIC50 and MIC90 values ​​for different test strains of SA, MRSA, E. coli, and VRE for calix[4]arene of formula (2) and 100 μM CuSO4.

[0323] [Table 14] Table 14: Details of MIC50 and MIC90 values ​​for calix[4]arene of formula (2).

[0324] Furthermore, the minimum inhibitory concentration of calix[4]arene of formula (2) against Candida albicans yeast in the presence of 100 μM CuSO4 was determined to be 0.8 μM.

[0325] The lowest measured value of 0.8 μM corresponds to 0.5 μL / mL, which is considered a low value for antibiotics. The fact that the MIC values ​​against each bacterial strain were similar indicates that calix[4]arene of formula (2) is an effective antibacterial agent regardless of the resistance of various strains and the class of bacteria.

Claims

1. Formula (1a) or a physiologically acceptable salt thereof, where: Y 1 , Y 2 , Y 3 and Y 4 are each independently ・Hydrogen, halogens, NO 2 , N 3 ,CN,CHO, COOR' (R' is alkyl (preferably C 1 -C 3 alkyl) groups), ・CONR” 2 (R" is independently H or alkyl (preferably C 1 -C 4 alkyl) groups), ・NR 2 (R independently represents hydrogen, alkyl (preferably C 1 -C 4 alkyl), or acetyl group), Triazole moiety (alkyl (preferably C 1 -C 4 alkyl) or phenyl), ・C 1 -C 3 Alkyl group, the C 1 -C 3 The alkyl group may optionally be N 3 , halogen, OR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), COOR' (R' is alkyl (preferably C 1 -C 3 alkyl)), CONR” 2 (R" is independently H or alkyl (preferably C 1 -C 4 and optionally substituted with one substituent selected from the group consisting of (alkyl) groups; Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, purine, tetrazine, oxazole, pyrazole, and thiazole, and the heterocyclic moiety optionally contains hydrogen, halogen, alkyl (preferably C 1 -C 4 alkyl), alkenyl (preferably C 1 -C 4 alkenyl), alkynyl (preferably C 1 -C 4 alkynyl), phenyl, benzyl, NO 2 , nitrile, OR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), COOR" (R" is alkyl (preferably C 1 -C 3 and optionally substituted with 1-5 substituents selected from the group consisting of (alkyl) groups; R 1 and R 2 are each independently hydrogen and C 1 -C 8 Alkyl (preferably C 1 -C 3 alkyl) groups, 1 -C 8 Alkyl (preferably C 1 -C 3 Alkyl) groups are preferably alkenyl (preferably C 1 -C 4 alkenyl), alkynyl (preferably C 1 -C 4 alkynyl), phenyl, hydroxyl, N 3 , halogen, COOR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), CONHR″ (R″ is alkyl (preferably C 1 -C 4 alkyl) group), or CONR 2 (R" is independently alkyl (preferably C 1 -C 4 and optionally substituted by one or more substituents selected from the group consisting of (alkyl) groups; n is an integer between 1 and 4 (preferably equal to 1); However, R 1 and R 2 are each hydrogen, n is equal to 1, and Z is not a benzothiazole group; or Y 1 , Y 2 , Y 3 and Y 4 are hydrogen, and R 1 and R 3 are C 3 is an alkyl group, n is equal to 1, and Z is a pyridine group; The compound or a physiologically acceptable salt thereof.

2. 2. The compound according to claim 1 or a salt thereof, Y 1 , Y 2 , Y 3 and Y 4 are each independently hydrogen, halogen, or N 3 , NO 2 , CHO, NH 2 , N(CH 3 ) 2 , NH-CO-CH 3 , NCH 3 -CO-CH 3 , C.H. 2 -O-CH 3 , CO-O-CH 3 , CO-O-C 2 H 5 , CO-NHCH 3 , CO-N(CH 3 ) 2 , triazole, C 2 selected from the group consisting of alkyl-substituted triazoles and phenyl-substituted triazoles; A compound or a salt thereof.

3. Y 1 , Y 2 , Y 3 and Y 4 The compound or salt thereof according to claim 2, wherein all of are hydrogen.

4. The compound or salt thereof according to any one of claims 1 to 3, R 1 and R 2 is hydrogen, C 1 -C 3 Alkyl group, ethyl acetate group, N 3 C replaced by 1 -C 3 C substituted with alkyl or hydroxyl groups 1 -C 3 alkyl group, C substituted with at least one halogen 1 -C 3 Alkyl groups, alkynyl groups (preferably C 2 -alkynyl) 1 -C 3 Alkyl groups and alkenyl groups (preferably C 2 -alkenyl) 1 -C 3 alkyl groups, A compound or a salt thereof.

5. R 1 and R 2 is C 1 -C 3 The compound or salt thereof according to claim 4, which is an alkyl group.

6. The compound or salt thereof according to any one of claims 1 to 5, Z is an imidazole, a purine (preferably 9-methylpurine), a benzimidazole (preferably 1-methylbenzimidazole), an oxazole, a thiazole, a benzoxazole, a benzothiazole, and a tetrazine group (preferably 1-C 1 -C 6 -alkyl-2,3,4,5-tetrazine group, more preferably 1-methyl-2,3,4,5-tetrazine or 1-OC 1 -C 6 -alkyl-2,3,4,5-tetrazine groups, more preferably 1-methoxy-2,3,4,5-tetrazine groups), A compound or a salt thereof.

7. Z is 1-C 1 -C 6 7. The compound or salt thereof according to claim 6, wherein the aryl group is a 1-alkylbenzimidazole group or a 1-benzylimidazole group.

8. 8. The compound or salt thereof according to any one of claims 1 to 7, wherein n is equal to 1.

9. Formula (2) or equation (3) or equation (4) 2. The compound according to claim 1, or a salt thereof,

10. A method for treating a calix[4]arene or a physiologically acceptable salt thereof according to any one of claims 1 to 9 with a cation, preferably Cu + A 1:1 complex composed of

11. Formula (1a) a calix[4]arene of formula (1a) or a physiologically acceptable salt thereof, or a calix[4]arene of formula (1a) or a physiologically acceptable salt thereof and a cation (preferably Cu + and a 1:1 complex consisting of where: Y 1 , Y 2 , Y 3 and Y 4 are each independently ・Hydrogen, halogens, NO 2 , N 3 ,CN,CHO, COOR' (R' is alkyl (preferably C 1 -C 3 alkyl) groups), ・CONR” 2 (R" is independently H or alkyl (preferably C 1 -C 4 alkyl) groups), ・NR 2 (R independently represents hydrogen, alkyl (preferably C 1 -C 4 alkyl), or acetyl group), Triazole moiety (alkyl (preferably C 1 -C 4 alkyl) or phenyl), ・C 1 -C 3 Alkyl group, the C 1 -C 3 The alkyl group may optionally be N 3 , halogen, OR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), COOR' (R' is alkyl (preferably C 1 -C 3 alkyl)), CONR” 2 (R" is independently H or alkyl (preferably C 1 -C 4 and optionally substituted with one substituent selected from the group consisting of (alkyl) groups; Z is a heterocyclic moiety selected from the group consisting of imidazole, benzimidazole, benzothiazole, benzoxazole, pyridine, purine, oxazole, pyrazole, thiazole, triazole, tetrazine, tetrazole, pyrimidine, pyrazine, and pyridazine, and the heterocyclic moiety optionally contains hydrogen, halogen, alkyl (preferably C 1 -C 4 alkyl), alkenyl (preferably C 1 -C 4 alkenyl), alkynyl (preferably C 1 -C 4 alkynyl), phenyl, benzyl, NO 2 , nitrile, OR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), COOR" (R" is alkyl (preferably C 1 -C 3 and optionally substituted with 1-5 substituents selected from the group consisting of (alkyl) groups; R 1 and R 2 are each independently hydrogen and C 1 -C 8 Alkyl (preferably C 1 -C 3 alkyl) groups, 1 -C 8 Alkyl (preferably C 1 -C 3 Alkyl) groups are preferably alkenyl (preferably C 1 -C 4 alkenyl), alkynyl (preferably C 1 -C 4 alkynyl), phenyl, hydroxyl, N 3 , halogen, COOR' (R' is alkyl (preferably C 1 -C 4 alkyl) group), CONHR″ (R″ is alkyl (preferably C 1 -C 4 alkyl) group), or CONR 2 (R" is independently alkyl (preferably C 1 -C 4 and optionally substituted by one or more substituents selected from the group consisting of (alkyl) groups; n is an integer between 1 and 8, preferably between 1 and 4, and more preferably equal to 1; used together with at least one pharmaceutically acceptable carrier, Pharmaceutical compositions.

12. 12. The pharmaceutical composition of claim 11, ・Y 1 , Y 2 , Y 3 and Y 4 are each independently hydrogen, halogen, or N 3 , NO 2 , CHO, NH 2 , N(CH 3 ) 2 , NH-CO-CH 3 , NCH 3 -CO-CH 3 , CO-O-CH 3 , CO-O-C 2 H 5 , CO-NHCH 3 , CO-N(CH 3 ) 2 , C.H. 2 -O-CH 3 , triazole, C 2 selected from the group consisting of alkyl-substituted triazoles and phenyl-substituted triazoles; ・R 1 and R 2 is hydrogen, C 1 -C 3 Alkyl group, ethyl acetate group, N 3 C replaced by 1 -C 3 C substituted with alkyl or hydroxyl groups 1 -C 3 alkyl group, C substituted with at least one halogen 1 -C 3 Alkyl groups, alkynyl groups (preferably C 2 -alkynyl) 1 -C 3 Alkyl groups and alkenyl groups (preferably C 2 -alkenyl) 1 -C 3 alkyl groups; Z is an imidazole (preferably 1-methylimidazole, 1-benzylimidazole), a purine (preferably 9-methylpurine), a benzimidazole (preferably 1-methylbenzimidazole), an oxazole, a thiazole, a benzoxazole, a benzothiazole, a tetrazine group (preferably 1-C 1 -C 6 -alkyl-2,3,4,5-tetrazine group, more preferably 1-methyl-2,3,4,5-tetrazine or 1-OC 1 -C 6 1-methyltriazole, 1-ethyltriazole, 1-propyltriazole, 1-isopropyltriazole, or 1-benzyltriazole; n is an integer between 1 and 4 (preferably equal to 1), Pharmaceutical compositions.

13. 13. The pharmaceutical composition according to claim 11 or 12, The pharmaceutical composition further comprises at least one compound selected from the group consisting of chemotherapeutic compounds, immunotherapeutic compounds, antiviral compounds, antiparasitic compounds, antifungal compounds, and antibiotics.

14. A calix[4]arene of formula (1a) or a physiologically acceptable salt thereof according to any one of claims 1 to 12, or a calix[4]arene of formula (1a) or a physiologically acceptable salt thereof and a cation (preferably Cu), for use in the treatment of a disease selected from the group consisting of cancer or its metastasis, viral, bacterial, parasitic and fungal infections. + ) and a 1:1 complex.

Images