Methods of treating cancer using modified monosaccharide compounds

Abstract

The present invention relates to the field of medicine, in particular to oncology. The present invention relates to modified monosaccharide compounds for use in the treatment of cancer, more particularly tumor cancer.

Description

[Technical Field]

[0001] This invention relates to the medical field, particularly to oncology. The invention relates to modified monosaccharide compounds for use in the treatment of cancer, more specifically, tumor cancer. [Background technology]

[0002] Carbohydrates are important as signaling molecules and for cell recognition events. They undergo polyvalent interactions with carbohydrate-recognizing proteins (CRPs) and can be used as probes in living organisms. Therefore, carbohydrates offer many opportunities in the diagnosis and treatment of diseases. As a result, the development of carbohydrate-based bioactive compounds and sensors has become an active research area. Click chemistry is an effective and modular synthetic approach for preparing functional carbohydrate derivatives. In this regard, WO2016 / 177712 describes modified monosaccharide compounds such as 5-azido-5-deoxy-D-arabinofuranose (also referred to herein as "arabinose-N3" or "Ara-N3") in a method for specifically labeling living microorganisms.

[0003] However, modified carbohydrate / monosaccharide compounds used as biological probes have not been described as potent anticancer agents.

[0004] Cancer is one of the leading causes of death in developed countries, and because it affects all ages, genders, races, and ethnic groups, there is a constant need to find and develop new cancer treatments.

[0005] In this regard, the inventors have discovered a modified monosaccharide compound that can efficiently reduce tumor growth and / or volume, thereby treating cancer, more specifically tumor cancer. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] WO2016 / 177712 [Non-patent literature]

[0007] [Non-Patent Document 1] Mujaji BW, "the pentose phosphate pathway revised" in Biochemical education, 8(3) 1980, pp. 76-78 [Non-Patent Document 2] Jin and Zhou: Pentose Phosphate Pathway in Cancer-ONCOLOGY LETTERS 17: 4213-4221 (2019 DOI: 10.3892 / ol.2019.10112) [Overview of the project] [Means for solving the problem]

[0008] This invention relates to a compound of formula (I) for use in the treatment of cancer: [ka] (In the formula, R is a reactive group in click chemistry.) Alternatively, it is based on the metabolites of the compound of formula (I).

[0009] More specifically, the inventors have found that a compound of formula (I) or one of its metabolites can treat cancer by slowing tumor growth and / or reducing tumor mass (or volume).

[0010] Furthermore, it has been found that the assimilation of compounds according to the present invention, such as arabinose-N3, occurs in eukaryotic cells, and that such assimilation is more important in tumor eukaryotic cells compared to non-tumor cells (particularly in bladder, blood, skin, pancreas, brain, liver, kidney, lung, muscle, lymphocyte, prostate, stomach, and breast cancers compared to non-cancer cells). Therefore, the compounds of the present invention exhibit the advantage of more efficiently targeting cancer cells.

[0011] The present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a metabolite thereof in a pharmaceutically acceptable support.

[0012] In one embodiment, the present disclosure provides a method for treating cancer in a subject requiring it, comprising administering an effective amount of a compound of formula (I) or its metabolites, or an effective amount of a pharmaceutical containing the same, to the subject. [Brief explanation of the drawing]

[0013] [Figure 1a] This figure shows the tumor volume (mm3) after intravenous administration of 20 mg of Ara-N3 in Hela tumor-bearing mice, following Hela tumor transplantation (transplantation was performed on day 0, and Ara-N3 treatment was started on day 7). Mean CTL: No Ara-N3 treatment. [Figure 1b] This figure shows the tumor volume (mm3) after oral administration of 200 mg of Ara-N3 in Hela tumor-bearing mice, following transplantation of a Hela tumor (transplantation was performed on day 0, and Ara-N3 treatment was started on day 7). Mean CTL: No Ara-N3 treatment. [Figure 2a] This figure shows the tumor volume (mm3) after intravenous administration of 20 mg of Ara-N3 in Cal33 tumor-carrying mice, following Cal33 tumor transplantation (transplantation was performed on day 0, and Ara-N3 treatment was started on day 7). Mean CTL: No Ara-N3 treatment. [Figure 2b] This figure shows the tumor volume (mm3) after oral administration of 400 mg of Ara-N3 in Cal33 tumor-carrying mice, following Cal33 tumor transplantation (transplantation was performed on day 0, and Ara-N3 treatment was started on day 7). Mean CTL: No Ara-N3 treatment. [Figure 3a]This figure shows the tumor volume (mm3) after intravenous administration of 100 mg of Ara-N3 in Panc1 tumor-bearing mice, following transplantation of Panc1 tumors (transplantation was performed on day 0, and Ara-N3 treatment was started on day 10). Mean CTL: No Ara-N3 treatment. [Figure 3b] This figure shows the tumor volume (mm3) after oral administration of 200 mg of Ara-N3 in Panc1 tumor-bearing mice, following transplantation of Panc1 tumors (transplantation was performed on day 0, and Ara-N3 treatment was started on day 10). Mean CTL: No Ara-N3 treatment. [Modes for carrying out the invention]

[0014] definition According to the present invention, the following terms have the following meanings.

[0015] As used herein, the terms “patient” and “subject” may be used interchangeably and refer to both humans and animals, more specifically including humans.

[0016] Cancer cells are cells that continuously divide to form solid tumors or fill the blood with abnormal cells. Therefore, they can be solid tumors or hematopoietic cancers such as lymphoma or leukemia. According to certain embodiments, cancer is a tumorous cancer.

[0017] As used herein, the terms “cancer” or “tumor” refer to the presence of cells that have characteristics typical of cancer-causing cells, such as uncontrolled growth, immortality, metastatic ability, rapid growth and proliferation rates, and certain characteristic morphological features. The terms refer to all types of malignant tumors (primary or metastatic). Typical cancers include solid cancers or hematopoietic cancers such as breast cancer, brain cancer, stomach cancer, liver cancer, skin cancer, prostate cancer, pancreatic cancer, esophageal cancer, sarcoma, ovarian cancer, endometrial cancer, bladder cancer, cervical cancer, rectal cancer, colon cancer, kidney cancer, lung cancer or ORL cancer, pediatric tumors (neuroblastoma, glioblastoma multiforme), lymphoma, carcinoma, glioblastoma, hepatoblastoma, leukemia, myeloma, seminoma, Hodgkin's cancer or malignant hematoma.

[0018] The reactive group R in the compound of formula (I) is a reactive group commonly used in click chemistry. Click chemistry is a method well known to those skilled in the art for ligating a target probe or substrate to a specific biomolecule, such as a modified monosaccharide compound. Click chemistry generally implements biorthogonal reactions. The reactive group R can be defined as a reactive group involved in a biorthogonal reaction. Several chemical ligation strategies have been developed that satisfy the biorthogonal requirement, including azide-cyclooctinate ligation (also known as copper-free click chemistry), 1,3-dipolar cycloaddition between nitrone and cyclooctinate, oxime / hydrazone formation from aldehydes, and ketone, tetrazine ligation, isocyanide-based click reactions, and more recently, quadricyclane ligation. As an example, azide-alkyne cycloaddition is a well-known so-called click chemistry reaction in which an azide group reacts with an alkyne group to produce a triazole, with or without a copper catalyst. The alkyne group (-C≡C-) may or may not be strained. More specifically, the alkyne group may be a terminal alkyne (i.e., -C≡CR', where R' is H or a (C1-C6) alkyl group, such as methyl, ethyl, propyl, or isopropyl), or the alkyne group may be a strained alkyne, more specifically a cyclic strained alkyne such as cyclooctyne.

[0019] According to the present invention, the terms “comprise(s)” or “comprising” (and other equivalent terms, e.g., “containing” and “including”) are “open-ended” and are generally interpreted to include the features specifically mentioned, as well as any optional, additional, and unspecified features. Depending on the particular embodiment, it may also be interpreted as “essentially consisting of” the specified features and any, additional, and unspecified features that do not substantially affect the basic and novel features of the invention as described in the claims, unless otherwise specified, or as “consisting of” the specified features only.

[0020] The present invention encompasses all stereoisomers and isomeric forms of the compounds disclosed herein, including all diastereomers, racemates, enantiomers, and mixtures thereof. It is also understood that compounds represented by formula I may exist as E and Z isomers, also known as cis and trans isomers. Therefore, this disclosure should be understood to include, for example, the E, Z, cis, trans, (R), (S), (L), (D), (+), and / or (-) forms of the compounds, as appropriate in each case. It should be understood that all possible isomers are included when a structure does not exhibit a specific stereoisomerism. The compounds of the present invention encompass all conformational isomers. The compounds of the present invention may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. Furthermore, the scope of the present invention includes all polymorphs and crystalline forms of the compounds disclosed herein.

[0021] Unless otherwise specified, percentages are expressed in this specification by weight.

[0022] compound In certain embodiments of the present invention, the compound of formula (I) includes any of its diastereoisomers. In further specific embodiments, the compound of formula (I) is selected from the group consisting of the following formulas. [ka] In the formula, R is a reactive group such as an azide (-N3) or an alkyne group.

[0023] According to certain embodiments, R is a reactive group suitable for click chemistry, as detailed above. More specifically, R is selected from groups consisting of or having an azide group (-N3) and groups consisting of or having an alkyne group (-C≡C-). Therefore, more specifically, R is a group that is typically involved in azide-alkyne cycloaddition.

[0024] In another embodiment, R is a strained alkyne such as azadibenzocyclooctin (ADIBO, DIBAC, or DBCO) or tetramethoxydibenzocyclooctin (TMDIBO). Other suitable strained alkynes frequently used in copper-free reactions include cyclooctin (OCT), aryl-free cyclooctin (ALO), monofluorocyclooctin (MOFO), difluorocyclooctin (DIFO), dibenzocyclooctin (DIBO), dimethoxyazacyclooctin (DIMAC), biarylazacyclooctin (BARAC), bicyclononine (BCN), tetramethylthiepinium (TMTI, TMTH), difluorobenzocyclooctin (DIFBO), oxadibenzocyclooctin (ODIBO), carboxymethylmonobenzocyclooctin (COMBO), or benzocyclononine.

[0025] Other reactants involved in other reactions include Staudinger ligation (first reactant = azide, and second reactant = phosphine), copper-free click chemistry (first reactant = azide, and second reactant = constrained alkyne (intraring alkyne)), carbonyl condensation (first reactant = aldehyde or ketone, and second reactant = hydrazide or oxyamine), thiol-enclick chemistry (first reactant = thiol, and second reactant = alkene), nitrile oxide-enclick chemistry (first reactant = nitrile oxide or aldehyde, oxime, or hydroxymoyl or chloroxime chloride, and second reactant = alkene or alkyne), and nitrile Examples include imine-enclyck chemistry (first reactant = nitrile imine or aldehyde, hydrazone, or hydrazonoyl chloride or chlorohydrazone, and second reactant = alkene or alkyne), reverse electron-required Diels-Alder ligation (first reactant = alkene, and second reactant = tetrazine), isonitrile-tetrazine clyck chemistry (first reactant = isonitrile, and second reactant = tetrazine), Suzuki-Miyaura coupling (first reactant = aryl halide, and second reactant = arylboronic acid), and His tag (first reactant = oligohistidine, and second reactant = nickel complex or nickel ligand). Therefore, R can be either the first or second reactant specified above.

[0026] According to certain embodiments, R is an alkyne group of formula -C≡CR', where R' is H or a (C1-C6) alkyl group, and the alkyl group is linear, cyclic, or branched, but is not limited to methyl, ethyl, propyl, or isopropyl. Preferably, R' is H.

[0027] According to another specific embodiment, R is a strained alkyne, more specifically a cyclic strained alkyne such as cyclooctine. R can be selected from the group consisting of azadibenzocyclooctine (ADIBO, DIBAC, or DBCO) or tetramethoxydibenzocyclooctine (TMDIBO). Other suitable strained alkynes frequently used in copper-free reactions include cyclooctine (OCT), aryl-free cyclooctine (ALO), monofluorocyclooctine (MOFO), difluorocyclooctine (DIFO), dibenzocyclooctine (DIBO), dimethoxyazacyclooctine (DIMAC), biarylazacyclooctine (BARAC), bicyclononine (BCN), tetramethylthiepinium (TMTI, TMTH), difluorobenzocyclooctine (DIFBO), oxadibenzocyclooctine (ODIBO), carboxymethylmonobenzocyclooctine (COMBO), or benzocyclononine.

[0028] According to another embodiment, R is selected from groups consisting of or having an azide group (-N3). More specifically, R is an azide group.

[0029] According to a particular embodiment, the compound of formula (I) is selected from the group consisting of the following formulas. [ka]

[0030] In preferred embodiments, the compound of formula (I) is 5-azido-5-deoxy-D-arabinofuranose (also known as arabinose-N3 or Ara-N3), and in particular has the following formula (II). [ka]

[0031] In another specific embodiment, the compound of formula (I) is the following compound of formula (III) [ka] The formula has the following characteristics: [wherein CCR' is an alkyne group as defined above, and more specifically, R' is H or a (C1-C6) alkyl group, where the alkyl group is linear, cyclic, or branched, but is not limited to these, and includes methyl, ethyl, propyl, and isopropyl. Preferably, R' is H].

[0032] In further specific embodiments of the present invention, the compound for use according to the present invention is a metabolite of the compound of formula (I), more specifically a metabolite of the compound of formula (II) or (III). In preferred embodiments, the metabolite is a metabolite of arabinose, preferably a metabolite of L-arabinose.

[0033] As used herein, “metabolites of the compound of formula (I)” means compounds from the pentose phosphate pathway, the compounds further comprising the reactive group R as defined above, more specifically, R being selected from a group consisting of or having an azide group (-N3) and a group consisting of or having an alkyne group (-C≡C-). The pentose phosphate pathway is described in many reviews, such as Mujaji BW, “the pentose phosphate pathway revised” in Biochemical Education, 8(3) 1980, pp. 76-78, or Jin and Zhou: Pentose Phosphate Pathway in Cancer-ONCOLOGY LETTERS 17: 4213-4221 (2019 DOI: 10.3892 / ol.2019.10112). In certain embodiments, metabolites of the compound of formula (I) include ribose, ribose 5-P, ribulose, ribulose 5-P, L-ribulose, L-ribulose 5-P, arabinitol, L-arabinitol, lyxose (L or D-lyxose), xylulose, xylulose-5-P, D-xylulose, D-xylulose-5-P, L-xylulose, D-xylulose, or xylitol, wherein the compound further comprises the azide group (N3) or alkyne group as defined above. In preferred embodiments, the metabolite of the compound of formula (I) is a metabolite of arabinose, further comprising the azide group (N3) or alkyne group as defined above. In a preferred embodiment, the metabolites of arabinose include L-ribulose, L-ribulose-5-P, or D-xylulose-5-P, wherein the compound further comprises the azide (N3) group or alkyne group as defined above. In a further preferred embodiment, the "metabolites of the compound of formula (I)" include L-arabinitol, L-xylulose, xylitol, D-xylulose, or D-xylulose-5-P, wherein the compound further comprises the azide (N3) group or alkyne group as defined above.

[0034] According to a particular embodiment, the compound of formula (I) used as an active ingredient for treating cancer does not bind to the surface of eukaryotic cells, nor does it bind to any compound, such as a compound having a chemical group that can react with the azide (-N3) group or alkyne group of the compound of formula (I) via a click chemistry reaction.

[0035] Pharmaceutical composition The present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above or a metabolite thereof in a pharmaceutically acceptable support. According to the present invention, the compound of formula (I) is a therapeutic active ingredient, or preferably the sole active ingredient.

[0036] In certain embodiments, the compound of formula (I) as defined above, or its metabolites, used as an active ingredient, more specifically for the treatment of cancer, does not bind to the surface of eukaryotic cells, nor does it bind to any compound, such as a compound having a chemical group that can react with the azide (-N3) group of the compound of formula (I) via a click chemistry reaction.

[0037] The pharmaceutical compositions contemplated herein include an anticancer agent, which is at least one compound of formula (I), in addition to a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means any carrier (e.g., support, substance, solvent, etc.) that does not impede the efficacy of the biological activity of the active ingredient and is not toxic to the host to which it is administered. The pharmaceutical compositions may be administered intestinally or parenterally. The pharmaceutical compositions may be administered orally, intravenously, intraperitoneally, intratracheally, intratumorally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, or topically. Administration may include direct injection or perfusion. For example, in the case of parenteral administration, the active compound may be formulated into unit dosage forms for injection in a vehicle such as physiological saline, dextrose solution, serum albumin, and Ringer's solution. The pharmaceutical compositions may be formulated as a solution in a pharmaceutically suitable solvent, or as an emulsion, suspension, or dispersion in a suitable pharmaceutically acceptable solvent or vehicle, or as pills, tablets, or capsules containing a solid vehicle in a manner known in the art. Formulations suitable for parenteral administration conveniently include sterile oily or aqueous preparations of the active ingredient that are isotonic with the recipient's blood.

[0038] The carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is not harmful to its recipient. The pharmaceutical composition is advantageously administered by injection or intravenous infusion of a suitable sterile solution. Methods for safely and effectively administering most of these anticancer agents are known to those skilled in the art. Furthermore, their administration is described in standard literature.

[0039] treatment The cancers treated according to the present invention are solid tumors or hematopoietic tumors, more specifically solid tumors. According to a particular embodiment, the cancers treated are selected from rectal cancer, colorectal cancer, gastric cancer, head and neck cancer, thyroid cancer, cervical cancer, uterine cancer, breast cancer, ovarian cancer, brain cancer, lung cancer, skin cancer, bladder cancer, blood cancer, kidney cancer, liver cancer, prostate cancer, multiple myeloma, and endometrial cancer. More specifically, the cancers are selected from the group consisting of cancers of the bladder, blood, skin, cervix, pancreas, brain, liver, kidney, lung, muscle, lymphocyte, prostate, stomach, and breast. According to a more specific embodiment, the cancers are selected from the group consisting of cancers of the bladder, blood, colon, cervix, stomach, breast, lung, skin, head and neck, and pancreas. In a particular embodiment, the cancers treated by the present invention are selected from the group consisting of head and neck cancers such as squamous cell carcinoma of the tongue, pancreatic cancer, and cervical cancer.

[0040] The compound of formula (I) or a metabolite of the compound of formula (I), or the pharmaceutical composition of the present invention, can be used in the treatment of cancer.

[0041] A preferred embodiment of the present invention is a compound of formula (I) as defined herein or its metabolite, or a pharmaceutical composition as defined herein, for use in the treatment of the cancer defined above.

[0042] More specifically, the compounds of formula (I) as defined herein, or their metabolites, are preferably intended for use in the treatment of cancer by slowing tumor growth and / or reducing tumor mass (or volume), or by reducing the doubling time of tumor cells.

[0043] A more preferred embodiment is a method for treating cancer in a subject requiring such treatment, comprising administering a therapeutically effective amount of a compound of formula (I) or its metabolite as defined herein, or a therapeutically effective amount of a pharmaceutical composition containing the same.

[0044] A more preferred embodiment is the use of a compound of formula (I) as defined herein or a metabolite thereof, or a pharmaceutical composition as defined herein, for the manufacture of a pharmaceutical for the treatment of cancer.

[0045] The terms “treating” or “treatment” as used herein refer to the implementation of a protocol that may involve administering one or more drugs to a patient to alleviate any signs or symptoms of cancer that may be present at any stage. Desired effects of treatment include a slowing of the rate of cancer progression, improvement or mitigation of the cancerous condition, and remission or improved prognosis. Alleviation may occur before the signs or symptoms of the disease or condition appear, and after they appear. Thus, “treating” or “treatment” may include “preventing” or “prevention” of the disease or undesirable condition. In addition, “treating” or “treatment” may include protocols that do not require complete elimination of signs or symptoms, do not require a cure, and specifically have only a minor effect on the patient.

[0046] "Prevention" or "prevention" includes (1) preventing the onset of a disease in subjects or patients who are at risk and / or predisposed to the disease but have not yet experienced or shown any or all of the pathologies or symptoms of the disease, and / or (2) delaying the onset of the pathologies or symptoms of the disease in subjects or patients who are at risk and / or predisposed to the disease but have not yet experienced or shown any or all of the pathologies or symptoms of the disease.

[0047] As used herein and / or in the claims, the term “effective” means sufficient to achieve the desired, expected, or intended result. “Effective dose,” “therapeutic effective dose,” or “pharmaceutical effective dose,” as used in the context of treating a patient or subject with a compound, means a quantity sufficient to produce such treatment or prevention of disease when administered to a subject or patient for the treatment or prevention of disease.

[0048] The amount administered is not explicitly limited, but is usually an effective dose or a molar equivalent of the pharmacologically active free form produced from the administered formulation upon metabolic release of the active drug to achieve the desired pharmacological and physiological effects. Oncologists in the field of cancer treatment can identify appropriate protocols for the effective administration of the compounds of the present invention by referring to previously published studies on compounds found to possess antitumor properties.

[0049] Further aspects and advantages of the present invention are described in the following examples, which should be considered illustrative and not limiting. [Examples]

[0050] (Example 1) Synthesis of the compound Materials and methods Thin-layer chromatography was performed on a Merck 60F254 by detection using UV light and / or carbonization with sulfuric acid, KMnO4, or phosphomolybdic acid solution. 40–63 mm silica gel 60 was used for flash column chromatography.

[0051] NMR spectra were acquired using a Bruker Avance 300 or 500 MHz spectrometer, with residual protonated solvent used as an internal standard. Chemical shifts δ are given in parts per million (ppm), and coupling constants are reported in Hertz (Hz). Splitting patterns are identified as singlets (s), doublets (d), triplets (t), doublets of doublets (dd), and doublets of doublets of doublets (ddd). Splitting patterns that cannot be interpreted or easily visualized are identified as multiplets (m).

[0052] Mass spectra were acquired on a Waters LCT Premier XE (ToF) using electrospray ionization in cation (ESI+) or anion (ESI-) detection mode.

[0053] The IR-FT spectrum was recorded using a PerkIn Elmer Spectrum 100 spectrometer. A characteristic absorption was observed at cm. -1 It will be reported.

[0054] Specific rotation was measured at 20°C and 589 nm in a 10 cm cell using an Anton Paar MCP 300 polarimeter.

[0055] All biological and chemical reagents were obtained from commercial sources in analytical or cell culture grade and were used without further purification.

[0056] Ara-N3 was synthesized following the procedure below. [ka] Here, R 1 , R 2 , and R 3 It is a methyl group.

[0057] 2:3,4:5-Diisopropylidene-D-arabinose O-methyloxime (Compound II) A solution of D-(-)-arabinose (4.00 g, 26.6 mmol, 1.0 eq) in dry pyridine (90 mL) was added with methoxyamine hydrochloride (2.72 g, 32.0 mmol, 1.2 eq), and the mixture was stirred at room temperature for 15 h. The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene three times. The residue was resuspended in 2,2-dimethoxypropane (100 mL), added with 7-toluenesulfonic acid (1.01 g, 5.33 mmol, 0.2 eq), and the suspension was heated to reflux for 4 h and then stirred at room temperature for a further 15 h. The reaction mixture was filtered through Celite® and the solvent was evaporated. The residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous NaCl solution (2 × 150 mL). Purification by silica flash column chromatography (cyclohexane / ethyl acetate 9:1) afforded the isomers 2:3,4:5-diisopropylidene-D-arabinose O-methyloxime (IIE / IIZ) and an unknown impurity (NMR ratio 6:1:0.4, 5.83 g) as a colorless oil. This mixture was used in the next step without further purification. A pure (2E) aliquot was obtained by a second flash column chromatography (dichloromethane / MTBE 98:2) and characterized.

[0058] Isomer (IIE): Rf (CH2Cl2 / MTBE 98:2): 0.35 IR (cm -1 ): 2987, 2939, 2900, 2821, 1631, 1456, 1381, 1371, 1241, 1212, 1150, 1065, 1038, 887, 842. 1 1H-NMR (500 MHz, CDCl3) δ: 7.35 (d, 1H, J 1,2 6.3 Hz, H-l); 4.46 (dd, 1H, J 2,3 7.1, J 1,2 6.3 Hz, H-2); 4.13 (ddd, 1H, J 3,4 6.9, J 4,5a 6.1, J 4,5b 4.8 Hz, H-4); 4.08 (dd, 1H, J 5a,5b 8.5, J4,5a 6.1 Hz, H-5a); 3.97 (d, 1H, J 2,3 7.1, J 3,4 6.9 Hz, H-3); 3.94 (dd, 1H, J 5a,5b 8.5, J 4,5b 4.8 Hz, H-5b); 3.85 (s, 3H, CH3-O); 1.40 (s, 3H, CH3-C); 1.38 (s, 6H, 2 CH3-C); 1.32 (s, 3H, CH3-C). 13 C-NMR (125 MHz, CDCl3) δ: 147.8 (Cl); 110.8 (C-6); 110.0 (C-7); 79.4(C-3); 76.7 (C-2); 76.6 (C-4); 67.1 (C-5); 62.1 (CH3-O); 27.1, 27.0, 26.9, 25.4 (4 CH3-C). HRMS (ESI + ): [M+H] + (C 12 H 22 NO5 + Calculated value (m / z): 260.1492, Measured value: 260.1502.

[0059] 2:3-Isopropylidene-D-arabinose O-methyloxime (Compound III) A solution of 2:3,4:5-diisopropylidene-D-arabinose O-methyloxime (II) (IIE / IIZ) and impurities (1.50 g) in 80% (v / v) aqueous acetic acid solution (30 mL) was heated to 40°C at a pressure of 200 mbar on a rotary evaporator. After 2.5 hours, the solvent was removed under reduced pressure, and the residue was co-evaporated with toluene. After silica gel flash column chromatography (cyclohexane / ethyl acetate 1:1), a mixture of the isomers 2:3-isopropylidene-D-arabinose O-methyloxime (IIIE / IIIZ) (NMR ratio 4:1, 876 mg, 58% in 3 steps) was obtained as a colorless oil. Purity by NMR was 95% or higher.

[0060] Rf (Cyclohexane / Ethyl Acetate 1:1): 0.24 IR (cm -1 ): 3409, 2939, 1373, 1216, 1040, 885 HRMS (ESI + ): [M + H] + (C9H 18 NO5 + ) Calculated m / z: 220.1179, Measured: 220.1184 Isomer (IIIE) 1 1H-NMR (500 MHz, CDCl3) δ: 7.44 (d, 1H, J 1,2 5.5 Hz, H-l); 4.56 (dd, 1H, J 2,3 7.4, J 1,2 5.5 Hz, H-2); 4.07 (dd, 1H, J 2,3 7.4, J 3,4 5.6 Hz, H-3); 4.13 (ddd, 1H, J 3,4 5.6, J 4,5 5.1, J 4,5 4.7 Hz, H-4); 3.84 (s, 3H, CH3-O); 3.72 - 3.68 (m, 2H, 2 H-5); 1.42 (s, 3H, CH3-C); 1.38 (s, 3H, CH3-C). 13 13C-NMR (125 MHz, CDCl3) δ: 149.1 (C-1); 110.3 (C-6); 79.4 (C-3); 75.0 (C-2); 71.6 (C-4); 63.4 (C-5); 62.2 (CH3-O); 26.9, 26.7 (2 CH3-C). Isomer (IIIZ) 1 1H-NMR (500 MHz, CDCl3) δ: 6.86 (d, 1H, J 1,2 5.9 Hz, H-l); 4.95 (dd, 1H, J 2,3 7.7, J 1,2 5.9 Hz, H-2); 3.92 (s,​​3,4 6.9 Hz, H-3); 3.82-3.75 (m, 2H, H-4, H-5a); 3.72-3.68 (m, 1H, H-5b); 1.40 (2s, 6H, 2 CH3-C). 13 C-NMR (125 MHz, CDCl3) δ: 151.0 (C-1); 110.9 (C-6); 80.4(C-3); 72.9 (C- 2); 72.7 (C-4); 63.5 (C-5); 62.8 (CH3-O); 27.0, 26.5 (2 CH3-C).

[0061] 2:3-Isopropylidene-5-O-methanesulfonyl-D-arabinose O-methyloxime (Compound IV) To a solution of 2:3-isopropylidene-D-arabinose O-methyloxime (III) (IIIE / IIIZ) (100 mg, 0.46 mmol, 1.0 equivalent) in dried pyridine (2.0 mL), mesyl chloride (0.10 mL, 1.37 mmol, 3.0 equivalents) was added at -20°C, and the reaction mixture was stirred at -20°C for 1.5 hours. After quenching the reaction with CH3OH (0.3 mL), the solvent was removed under vacuum. The resulting residue was purified by silica flash column chromatography (cyclohexane / ethyl acetate 6:4) to obtain 2:3-isopropylidene-5-O-methanesulfonyl-D-arabinose O-methyloxime (IVE / IVZ) (NMR ratio 4:1, 110 mg, 81%) as a colorless oil. Aliquots of the pure (IVE) isomer were obtained by flash column chromatography (dichloromethane / diethyl ether 9:1) and characterized. Purity of over 95% as determined by NMR.

[0062] Rf(cyclohexane / ethyl acetate 6:4):0.24 IR(cm -1 ): 3500, 2989, 2941, 2824, 1631, 1458, 1350, 1215, 1170, 1067, 1033, 959, 887, 863, 833 HRMS (ESI + ):[M+H] + (C10 H 20 NO7S + ) Calculated m / z: 298.0955, Measured: 298.0947

[0063] Isomer (IVE) Rf (Cyclohexane / Ethyl acetate 6:4): 0.20 1 H-NMR (500 MHz, CDCl3) δ: 7.42 (d, 1H, J 1,2 5.6 Hz, H-l); 4.56 (dd, 1H, J 2,3 6.8, J 1,2 5.6 Hz, H-2); 4.41 (dd, 1H, J 5a,5b 11.0, J 4,5a 2.7 Hz, H-5a); 4.28 (dd, 1H, J 5a,5b 11.0, J 4,5b 5.7 Hz, H-5b); 4.03 (ddd, 1H, J 3,4 7.0, J 4,5b 5.7, J 4,5a 2.7 Hz, H-4); 4.01 (dd, 1H, J 2,3 6.8, J 3,4 7.0 Hz, H-3); 3.85 (s, 3H, CH3-O); 3.06 (s, 3H, CH3-S); 1.41 (s, 3H, CH3-C); 1.39 (s, 3H, CH3-C). 13 C-NMR (125 MHz, CDCl3) δ: 148.2 (C-1); 110.9 (C-6); 77.9 (C-3); 76.2 (C-2); 70.9 (C-5); 70.8 (C-4); 62.3 (CH3-O); 37.8 (CH3-S); 27.0, 26.9 (2 CH3-C). Isomer (IVZ) 1 H-NMR (300 MHz, CDCl3) δ: 6.87 (d, 1H, J 1,2 5.9 Hz, H-l); 4.96 (dd, 1H, J 2,3 7.3, J 1,25.9 Hz, H-2); 4.45 (dd, 1H, J 5a,5b 11.4, J 4,5a 2.4 Hz, H-5a); 4.29 (dd, 1H, J 5a,5b 11.4, J 4,5b 7.9 Hz, H-5b); 3.98 (ddd, 1H, J 4,5b 7.9, J 4,3 7.5, J 4,5a 2.4 Hz, H-4); 3.93 (s, 3H, CH3-O); 3.84 (dd, 1H, J 3,4 7.5, J 3,2 7.3 Hz, H-3); 3.06 (s, 3H, CH3-S); 1.40 (s, 3H, CH3-C); 1.39 (s, 3H, CH3-C). 13 C-NMR (75 MHz, CDCl3) δ: 150.7 (C-1); 111.2 (C-6); 79.1 (C-3); 72.9 (C-2); 71.3 (C-5); 70.9 (C-4); 62.9 (CH3-O); 37.9 (CH3-S); 27.0, 26.6 (2 CH3-C).

[0064] 5-Azido-5-deoxy-2:3-isopropylidene-D-arabinose O-methyloxime (compound V): To a solution of (IVE / IVZ) (810 mg, 2.72 mmol, 1.0 equivalent) in N,N-dimethylformamide (30.0 mL, 0.10 M), sodium azide (531 mg, 8.17 mmol, 3.0 equivalents) was added, and the reaction mixture was heated at 80°C for 15 hours. The solvent was then removed under reduced pressure, and the residue was purified by flash column chromatography (cyclohexane / ethyl acetate 9:1) to obtain a mixture of 5-azido-5-deoxy-2:3-isopropylidene-D-arabinose O-methyloxime (VE / VZ) (NMR ratio 7:3, 637 mg, 96%) as a yellowish oily substance. The (VE) fraction was isolated by flash column chromatography (dichloromethane / MTBE 97:3) for characterization. Purity by NMR was ≥95%.

[0065] Rf (cyclohexane / ethyl acetate 8:2): 0.30 IR (cm -1 ): 3458, 2989, 2939, 2823, 2100, 1630, 1443, 1373, 1213, 1164, 1066, 1036, 885, 865 HRMS (ESI + ): [M + H] + (C9H 17 N4O4 + ) Calculated m / z: 245.1245, Measured: 245.1250

[0066] Isomer (VE) Rf (dichloromethane / MTBE 97:3): 0.23.<00千0464> 1 1H-NMR (500 MHz, CDCl3) δ: 7.4^ (d, 1H, J 1,2 5.8 Hz, H-1); 4.54 (dd, 1H, J 2,3 7.2, J 1,2 5.8 Hz, H-2); 3.98 (dd, 1H, J 2,3 7.2, J 3,4 6.4 Hz, H-3); 3.92 (dddd, 1H, J 3,4 6.4, J 4,5b 6.2, J 4,OH 3.9, J 4,5a 3.8 Hz, H-4); 3.85 (s, 3H, CH3-O); 3.46 (dd, 1H, J 5a,5b 12.5, J 4,5a 3.8 Hz, H-5a); 3.42 (dd, 1H, J 5a,5b 12.5, J 4,5b 6.2 Hz, H-5b); 2.61 (d, 1H, J 4,OH 3.9 Hz, OH); 1.41 (s, 3H, CH3-C); 1.39 (s, 3H, CH3-C). 13C-NMR (125 MHz, CDCl3) δ: 148.4 (Cl); 110.6 (C-6); 78.8 (C-3); 75.8 (C-2); 71.5 (C-4); 62.3 (CH3-O); 53.7 (C-5); 27.0, 26.8 (2 CH3-C). VZ (Virginia Zygomorpha) 1 H-NMR (500 MHz, CDCl3) δ: 6.86 (d, 1H, J 1,2 6.1 Hz, HCl); 4.94 (dd, 1H, J) 2,3 7.2, J 1,2 6.1 Hz, H-2); 3.93 (s, 3H, CH3-O); 3.87 (ddd, 1H, J 3,4 7.5, J 4,5b 6.4, J 4,5a 2.8 Hz, H-4); 3.82 (dd, 1H, J 3,4 7.5, J 2,3 7.2 Hz, H-3); 3.47 (dd, 1H, J 5a,5b 12.8, J 4,5a 2.8 Hz, H-5a); 3.39 (dd, 1H, J 5a,5b 12.8, J 4,5b 6.4 Hz, H-5b); 1.40 (s, 3H, CH3-C); 1.38 (s, 3H, CH3-C). 13 C-NMR (75 MHz, CDCl3) δ: 150.8 (Cl); 111.0 (C-6); 80.0 (C-3); 72.9 (C-2); 72.5 (C-4); 62.8 (CH3-0); 53.5 (C-5); 26.9, 26.5 (2 CH3-C).

[0067] 5-アジド-5-デオキシ-2:3-イソプロピリデン-D-アラビノース(Compound VI) To 120 mL of an 80% (v / v) aqueous solution of (VE / VZ) (820 mg, 3.36 mmol, 1.0 equivalent) of acetic acid, formaldehyde (0.8 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and co-evaporation with toluene was carried out to ensure complete removal of acetic acid. Crude compound 5-azido-5-deoxy-2:3-isopropylidene-D-arabinose (VI) (682 mg) was obtained.

[0068] colorless oil Rf(cyclohexane / ethyl acetate 7:3):0.56. IR(cm -1 ): 3408, 2988, 2936, 2100, 1733, 1440, 1373, 1238, 1213, 1164, 1063, 863 1 H-NMR (500 MHz, CDCl3) δ: 9.79 (d, 1H, J 1,2 1.2 Hz, Hl); 4.41 (dd, 1H, J 2,3 6.4, J 1,2 1.2 Hz, H-2); 4.04 (dd, 1H, J 2,3 6.4, J 3,4 6.1 Hz, H-3); 3.90 (ddd, 1H, J 4,5b 6.4, J 3,4 6.1, J 4,5a 3.4 Hz, H-4); 3.51 (dd, 1H, J 5a,5b 12.8, J 4,5a 3.4 Hz, H-5a); 3.43 (dd, 1H, J 5a,5b 12.8, J 4,5b 6.4 Hz, H-5b); 1.47 (s, 3H, CH3-C); 1.37 (s, 3H, CH3-C). HRMS (ESI + ): [2M+Na] + (C 16 H 26 N6NaO8 + Calculated value m / z: 453.1704, measured value: 453.1726.

[0069] 5-Azido-5-deoxy-D-arabinofuranose (Compound VII, Ara-N3) A solution of 5-azido-5-deoxy-2:3-isopropylidene-D-arabinose (VI) (100 mg) in a CH2Cl2 / H2O (20:1, 21 mL) mixture was mixed with trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was then evaporated, and the crude residue was resuspended in water and freeze-dried. After silica flash column chromatography (dichloromethane / methanol 92:8), compound 5-azido-5-deoxy-D-arabinofuranose or Ara-N3(VII) was obtained as a colorless oily mixture of β-anomers (NMR ratio 55:45) (50 mg, 58% from compound (V) in two steps). Purity by NMR was 95% or higher.

[0070] Rf(dichloromethane / methanol 92:8):0.28 IR(cm -1 ):3367, 2106, 1281, 1040 HRMS (ESI + ):[M+H-N2] + (C5H 10 NO4 + Calculated value m / z: 148.0604, measured value: 148.0610. Anomer Alpha (VIIα) 1 H-NMR (500 MHz, D2O) δ: 5.24 (d, 1H, J 1,2 2.9 Hz, Hl); 4.17 (ddd, 1H, J 3,4 6.4, J4 ,5b 5.8, J 4,5a 3.5 Hz, H-4); 4.01 (dd, 1H, J 2,3 4.6, J 1,2 2.9 Hz, H-2); 3.97 (dd, 1H, J 3,4 6.4, J 3,2 4.6 Hz, H-3); 3.64 (dd, 1H, J 5a,5b 13.6, J 4,5a 3.5 Hz, H-5a); 3.44 (dd, 1H, J 5a,5b 13.6, J4,5b 5.8 Hz, H-5b). 13 C-NMR (125 MHz, D2O) δ: 101.0 (Cl); 81.3 (C-4); 81.2 (C-2); 76.3 (C- 3); 51.5 (C-5). Anomerbeta (VIIβ) 1 H-NMR (500 MHz, D2O) δ: 5.28 (br d, 1H, J 1,2 3.1 Hz, Hl); 4.10-4.05 (m, 2H, H-2, H-3); 3.89 (ddd, 1H, J 3,4 7.1, J 4,5b 6.5, J 4,5a 3.5 Hz, H-4); 3.59 (dd, 1H, J 5a,5b 13.3, J 4,5a 3.5 Hz, H-5a); 3.42 (dd, 1H, J 5a,5b 13.3, J 4,5b 6.5 Hz, H-5b). 13 C-NMR (125 MHz, D2O) δ: 95.2 (Cl); 79.6 (C-4); 75.8 (C-2); 74.7 (C-3); 52.6 (C-5).

[0071] (Example 2) In vivo treatment with Ara-N3 in mice Materials and methods Animal models 45 female NMRI nude mice, 6 weeks old Day 0: - 8 million Panc-1 cells in 200 μL of PBS were subcutaneously transplanted into the right flank (n=15 mice). - 10 million HeLa cells in 200 μL of PBS were subcutaneously transplanted into the right flank (n=15 mice). - 5 million Cal33 cells in 200 μL of PBS were subcutaneously transplanted into the right flank (n=15 mice). Clinical follow-up: Animal body weight and tumor volume: 2-3 times per week. The assay was conducted in accordance with the animal experiment authorization application submitted to the Ministry of Research and the Ethics Committee.

[0072] Ara-N3 treatment For each cell line, three control mice (CTLs) were not treated with Ara-N3. >Intravenous injection (IV) Three doses of Ara-N3 were evaluated. Hela and Cal33 cell lines - Cumulative dose 20 mg (5 mg / mouse / injection, repeated every other day for 8 days (total of 4 injections)) Panc-1 cell line - Cumulative dose 100 mg (9 mg / mouse / injection, repeated every other day for 21 days (total of 11 injections))

[0073] >Drinking water Hela cell line - Cumulative dose per mouse: 200mg / day (8mL / day @ 3.13mg / mL) for 8 days. Cal33 cell line - Cumulative dose per mouse: 400 mg: 50 mg / day (8 mL / day @ 6.25 mg / mL) for 8 days Panc-1 cell line - Cumulative dose per mouse: 200 mg (9.5 mg / day, 8 mL / day @ 1.19 mg / mL) for 21 days

[0074] result: Clinical follow-up • The introduction of Ara-N3 into drinking water (up to 6.25 mg / mL) did not alter the water consumption of mice. Treatment with Ara-N3, whether administered in drinking water or intravenously, did not induce weight loss. Figures 1(a) and 1(b) show the tumor volume results in mice with Hela tumors after intravenous administration of 20 mg of Ara-N3 or oral administration of 200 mg of Ara-N3. Figures 2(a) and 2(b) show the tumor volume results in mice with Cal33 tumors after intravenous administration of 20 mg of Ara-N3 or oral administration of 400 mg of Ara-N3. Figures 3(a) and 3(b) show the tumor volume results after intravenous administration of 100 mg of Ara-N3 or oral administration of 200 mg of Ara-N3 in mice with Panc1 tumors.

[0075] conclusion Treatment with Ara-N3 via intravenous injection (iv) slowed tumor growth in Hela, PANC-1, and al33 strains. • Oral (drinking water) treatment with Ara-N3 also reduced tumor volume compared to the untreated control group. • Intravenous treatment with Ara-N3 increased the doubling time of Hela, PANC-1, and Cal33 strains compared to the untreated control group.

Claims

1. Compound of formula (I) for use in the treatment of cancer 【Chemistry 1】 (In the formula, R is a click chemistry reaction group selected from a group consisting of or having an azide group (-N3) and a group consisting of or having an alkyne group (-C≡C-)). or, A composition comprising a metabolite of a compound of formula (I) selected from the group consisting of ribose, ribose 5-P, ribose, ribose 5-P, L-ribose, L-ribose 5-P, arabinitol, L-arabinitol, xylulose, xylulose-5-P, D-xylulose, D-xylulose-5-P, L-xylulose, D-xylulose, and xylitol, and containing an azide (N3) or alkyne group.

2. R is an azide group (-N 3 The composition according to claim 1, which is the same as the composition according to claim 1.

3. The composition according to claim 1 or 2, wherein the compound of formula (I) is selected from the group consisting of one of the following formulas. 【Chemistry 2】 (wherein R is as defined in claim 1 or 2).

4. The composition according to claim 1 or 2, wherein the compound of formula (I) is 5-azido-5-deoxy-D-arabinofuranose having the following formula. 【Transformation 3】

5. The composition according to any one of claims 1 to 4, wherein the cancer is selected from the group consisting of rectal cancer, colorectal cancer, gastric cancer, head and neck cancer, thyroid cancer, cervical cancer, uterine cancer, breast cancer, ovarian cancer, brain cancer, lung cancer, skin cancer, bladder cancer, hematological cancer, kidney cancer, liver cancer, prostate cancer, multiple myeloma, and endometrial cancer.

6. A pharmaceutical composition for use in the treatment of cancer, comprising a pharmaceutically acceptable support containing at least one modified monosaccharide compound of formula (I), or a metabolite of a compound of formula (I), wherein formula (I) is as follows: 【Chemistry 4】 (In the formula, R is a click chemistry reactant selected from a group consisting of or having an azide group (-N3) and a group consisting of or having an alkyne group (-C≡C-).) And, A pharmaceutical composition comprising a metabolite of the compound of formula (I), selected from the group consisting of ribose, ribose 5-P, ribulose, ribulose 5-P, L-ribulose, L-ribulose 5-P, arabinitol, L-arabinitol, xylulose, xylulose-5-P, D-xylulose, D-xylulose-5-P, L-xylulose, D-xylulose, and xylitol, and containing an azide (N3) or alkyne group.

7. A compound of formula (I) is selected from the group consisting of one of the following formulas. 【Transformation 5】 (In the formula, R is azide (N 3 ) or alkyne group), The pharmaceutical composition according to claim 6.

8. The compound of formula (I) is the following formula 【Transformation 6】 The pharmaceutical composition according to claim 6 or 7, wherein 5-azido-5-deoxy-D-arabinofuranose has .

9. The pharmaceutical composition according to any one of claims 6 to 8, wherein the cancer is selected from the group consisting of rectal cancer, colorectal cancer, gastric cancer, head and neck cancer, thyroid cancer, cervical cancer, uterine cancer, breast cancer, ovarian cancer, brain cancer, lung cancer, skin cancer, bladder cancer, hematological cancer, kidney cancer, liver cancer, prostate cancer, multiple myeloma, and endometrial cancer.

10. The pharmaceutical composition according to claim 7, wherein R is azide.

Images