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WO2019245194A1 - Nouveau composé pour le traitement du cancer négatif à la naprt et composition comprenant celui-ci - Google Patents

Nouveau composé pour le traitement du cancer négatif à la naprt et composition comprenant celui-ci Download PDF

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Publication number
WO2019245194A1
WO2019245194A1 PCT/KR2019/006696 KR2019006696W WO2019245194A1 WO 2019245194 A1 WO2019245194 A1 WO 2019245194A1 KR 2019006696 W KR2019006696 W KR 2019006696W WO 2019245194 A1 WO2019245194 A1 WO 2019245194A1
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cancer
acid
compound
formula
naprt
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Korean (ko)
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김현석
한균희
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel compounds having excellent selective therapeutic effects on nicotinate phosphoribosyltransferase (NAPRT) negative cancer cells, compositions comprising the same, and various uses thereof.
  • NAPRT nicotinate phosphoribosyltransferase
  • NAD + (nicotinamide adenine dinucleotide) is a coenzyme that plays an important role in many physiologically essential processes. See Ziegkel, M. Eur. J. Biochem. 267,1550-1564, 2000]. NAD is essential for several signaling pathways, including mono-ADP-ribosylation in both the immune system and G-protein-coupled receptor signaling among other poly ADP-ribosylations in DNA repair, and NAD is also a sirtu Essential for deacetylase activity of phosphorus (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
  • Nicotinamide phosphoribosyltransferase is an enzyme that catalyzes phosphoribosylation of nicotinamide and is a rate-limiting enzyme in one of two pathways to restore NAD.
  • NamPT inhibitors have efficacy as anticancer agents. Cancer cells have a higher basal turnover of NAD and also require higher energy compared to normal cells. In addition, increased NamPT expression is associated with colorectal cancer [Van Beijnum, J.R. et al Int. J. Cancer 101, 118-127, 2002, and there have been reports that NamPT is involved in angiogenesis [Kim, S.R. et al. Biochem. Biophys. Res. Commun. 357, 150-156, 2007]. Small molecule inhibitors of NamPT cause depletion of intracellular NAD + levels and ultimately induce tumor cell death [Hansen, CM et al. Anticancer Res. 20, 42111-4220, 2000], as well as inhibiting tumor growth in xenograft models. Olese, U.H. et al. Mol Cancer Ther. 9, 1609-1617, 2010].
  • NamPT inhibitors also have potential as therapeutic agents in inflammatory and metabolic disorders. See Galli, M. et al Cancer Res. 70, 8-11, 2010].
  • NamPT is the dominant enzyme in T and B lymphocytes.
  • Selective inhibition of NamPT can reduce the development of autoimmune diseases by reducing NAD + in lymphocytes, but not in cell types with other NAD + synthesis pathways.
  • Small molecule NamPT inhibitors FK866 have been shown to inhibit the proliferation of activated T cells and induce apoptosis, and were effective in arthritis animal models (collagen-induced arthritis). Busso, N. et al. Plos One 3, e2267, 2008].
  • NamPT activity increases NF- ⁇ B transcriptional activity in human vascular endothelial cells and results in MMP-2 and MMP-9 activity, suggesting the role of NamPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes [Adya, R. et. Al. Diabetes Care, 31, 758-760, 2008].
  • One of the NamPT inhibitors can be selected from (E) -N- [4- (1-benzoylpiperidin-4-yl) butyl] -3- (pyridin-3-yl) -acrylamide (also APO866, FK866, WK175 or Known as WK22.175, 'FK866' (hereinafter referred to as the international non-trade name)) is in particular also known as an anticancer agent.
  • FK866 can be used to treat diseases associated with deregulated apoptosis, such as cancer.
  • FK866 has been demonstrated to interfere with nicotinamide adenyl dinucleotide (also known as NAD and referred to below) biosynthesis and induce apoptotic cell death without any DNA damaging effect.
  • NAD nicotinamide adenyl dinucleotide
  • FK866 induces apoptosis in HepG2 cells without imparting a major effect on cellular energy metabolism (Hasmann M, Schemainda I. FK866, a Highly Specific Noncompetitive Inhibitor of Nicotinamide Phosphoribosyltransferase, Represents a Novel Mechanism for Induction of Tumor Cell Apoptosis. Cancer Res 2003; 63: 7436-7442. PubMed: 14612543). Instead of causing immediate cytotoxicity, inhibiting NamPT and depleting the cell's NAD suggests that FK866 may be an effective agent for cancer cells that rely on nicotinamide to synthesize NAD.
  • the crystal structure of the NamPT-FK866 complex indicates that the compound binds to and inhibits the nicotinamide-binding site of NamPT.
  • FK866 has been tested in murine renal cell carcinoma models and has been shown to exhibit antitumor, antimetastatic and antiangiogenic activity (Drevs J, et al. Antiangiogenic potency of FK866 / K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma.Anticancer Res 2003; 23: 4853-4858. PubMed: 14981935.
  • NamPT Drugs that inhibit NamPT may have a number of uses in addition to inflammatory diseases or cancer as described above. Deficiency of NamPT expression can strongly affect the development of both T and B lymphocytes.
  • NamPT may affect endothelial cells with respect to high glucose levels, oxidative stress and aging, and furthermore, NamPT may be used to stimulate human endothelial cells in the process of proliferation from aging and high glucose oxidative stress. It is also known that excess glucose can be used productively to be able to withstand, to allow for replication longevity and angiogenic activity.
  • One object of the present invention is to provide a novel compound capable of selectively inhibiting the proliferation or growth of nicotinate phosphoribosyltransferase (NAPRT) negative cancer cells.
  • NAPRT nicotinate phosphoribosyltransferase
  • Another object of the present invention is to provide a composition capable of preventing, ameliorating or treating NAPRT negative cancer.
  • Another object of the present invention is to provide a method for preventing, ameliorating or treating NAPRT negative cancer using a novel compound capable of selectively inhibiting the proliferation or growth of NAPRT negative cancer cells.
  • a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate and a solvate comprising a compound selected from the active ingredient, cancer, preferably nicotine Nate phosphoribosyltransferase (NAPRT) relates to a pharmaceutical composition for the prevention or treatment of negative cancer:
  • R 1 is a C 1 -C 6 alkyl group.
  • 'alkyl of C 1 to C 6 ' refers to a straight or branched hydrocarbon moiety having 1 to 6 carbon atoms, unless otherwise noted. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below:
  • R 1 is as defined in Chemical Formula 1.
  • the compound represented by Chemical Formula 1 is preferably N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N) represented by the following Chemical Formula 3. -(4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide)
  • the present invention also provides a pharmaceutically acceptable salt of the compound represented by any one of the formulas (1) to (3).
  • Pharmaceutically acceptable salts are of low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of pharmaceutically acceptable free acids and base compounds represented by any one of formulas (1) to (3).
  • Preferred salt forms of the compounds according to the invention include salts with inorganic or organic acids.
  • the inorganic acid may be used hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the production of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like.
  • Amino acids that can be used to prepare amino acid addition salts are natural amino acids such as alanine, glycine and the like. It will be apparent to one of ordinary skill in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.
  • the pharmaceutically acceptable salt of the compound represented by any one of Formulas 1 to 3 is a hydrochloride salt of the compound, which has high solubility and may be formulated to a high concentration.
  • the salt may be prepared by conventional methods.
  • the compound represented by any one of the above Chemical Formulas 1 to 3 is dissolved in a solvent that can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized after adding a free acid or free base. It can manufacture.
  • the compounds according to the present invention may have asymmetric carbon centers and thus may exist as R or S isomers or racemic compounds and all these optical isomers and mixtures may be included in the scope of the present invention.
  • the compound represented by any one of Formulas 1 to 3, pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof not only effectively inhibit nicotinamide phosphoribosyltransferase (NamPT), , Nicotinate phosphoribosyltransferase (NAPRT) It has a high selectivity against negative cancer and effectively inhibits its proliferation or growth, and particularly, it is excellent in the prevention, improvement or treatment effect of the NAPRT negative cancer.
  • Cancers that are the subject of prevention, improvement or treatment in the present invention include liver cancer, biliary tract cancer, gallbladder cancer, esophageal cancer, stomach cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, skin cancer, pancreatic cancer, May be one or more selected from the group consisting of leukemia, lymphoma, Hodgkin's disease, lung cancer, bronchial cancer, multiple myeloma, leukemia, lymphoma, squamous cell cancer, kidney cancer, urethral cancer, bladder cancer, head and neck cancer, brain cancer and central nervous system cancer , Preferably gastric cancer, colon cancer, lung cancer or pancreatic cancer.
  • prophylaxis may include without limitation any action of blocking the symptoms of, or inhibiting or delaying the symptoms of, NAPRT-negative cancer using the pharmaceutical composition of the present invention.
  • treatment and “improvement” may be used without limitation as long as all actions to improve or benefit NAPRT negative cancer using the pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be further co-administered with other anticancer agents, thereby further enhancing the radiotherapy effect on cancer stem cells.
  • the anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zefitinib, vandetanib, nirotinib, semasanib, conservinib, axitinib, cediranib , Restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydroxycarba Amide, dasatinib, estramastine, gemtuzumab ozogamycin, ibritumab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab,
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, the pharmaceutical composition may be characterized in that it is intended for humans.
  • compositions of the present invention are not limited to these, but each may be formulated in the form of oral dosage forms, such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions according to conventional methods. Can be.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be used as oral administration binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, flavors, etc., and in the case of injections, buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used.
  • the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with the pharmaceutically acceptable carrier as described above.
  • oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms.
  • solutions, suspensions, tablets, capsules, sustained release preparations and the like may be used.
  • suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • Routes of administration of the pharmaceutical compositions according to the invention are not limited to these, but are oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , Sublingual or rectal. Oral or parenteral release is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • the pharmaceutical composition of the present invention is dependent on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, extent of disease, drug form, route of administration and duration, and may be appropriately selected by those skilled in the art and may be 0.0001 to 100 mg / day. It may be administered at kg or 0.001 to 100 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the pharmaceutical compositions according to the invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
  • composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
  • a compound represented by any one of the above Chemical Formulas 1 to 3 of the present invention, a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvent to a subject (eg, a human) in need of administration
  • a method for preventing or treating NAPRT negative cancer comprising administering a compound selected from the cargo in a pharmaceutically effective amount.
  • administration in the present invention is meant providing any compound of the present invention to a subject in any suitable manner.
  • Subject in need of such administration in the present invention may include both mammals and non-mammals.
  • examples of the mammal include humans, non-human primates such as chimpanzees, other apes or monkey species; Animal husbandry such as cattle, horses, sheep, goats, pigs; Farm animals such as rabbits, dogs or cats; Experimental animals such as, but not limited to, rodents such as rats, mice or guinea pigs, and the like.
  • examples of the non-mammalian in the present invention may include birds or fish, but are not limited thereto.
  • the formulation of the compound administered as above in the present invention is not particularly limited, and may be administered in a solid form, a liquid form, or aerosol preparation for aspiration, and a liquid form preparation for oral or parenteral administration immediately before use. It may be administered as a solid form preparation intended to be converted into, for example, oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injectable solutions. However, it is not limited thereto.
  • a pharmaceutically acceptable carrier may be further administered together with the compound of the present invention.
  • the pharmaceutically acceptable carrier may be a binder, a suspending agent, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a coloring agent, a flavoring agent, and the like, in the case of oral administration.
  • Preservatives, analgesic agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used.
  • bases, excipients, lubricants, preservatives and the like can be used for topical administration.
  • Formulations of the compounds of the present invention can be prepared in a variety of mixtures with the pharmaceutically acceptable carriers described above.
  • oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms.
  • solutions, suspensions, tablets, capsules, sustained release preparations and the like may be used.
  • suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • Routes of administration of the compounds according to the invention are not limited to these, but are oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual Or rectal. Oral or parenteral release is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • “pharmaceutically effective amount” refers to a sufficient amount of agent to provide the desired biological result.
  • the result may be a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system.
  • an “effective amount” for therapeutic use is the amount of a compound disclosed herein that is required to provide a clinically significant reduction in disease.
  • the appropriate “effective” amount in any individual case can be determined by one skilled in the art using routine experimentation.
  • the expression “effective amount” generally refers to an amount in which the active substance has a therapeutic effect.
  • the active substance is an inhibitor of the formation of nicotinamide phosphoribosyltransferase (NAMPT) and an agent for the prevention, amelioration or treatment of NAPRT negative cancers.
  • NAMPT nicotinamide phosphoribosyltransferase
  • the compounds of the present invention may vary depending on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed.
  • the dosage of the compound may vary depending on the patient's condition, body weight, extent of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art and may range from 0.0001 to 100 mg / kg or 0.001 to 1 per day. It may be administered at 100 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • the compounds according to the invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.
  • the compounds of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
  • the compounds of the present invention may be used in combination with other anticancer agents, wherein the anticancer agents include nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, zephytinib, vande Tanib, nirotinib, semasanib, conservinib, axitinib, cediranib, restautinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, Cisplatin, cetuximab, biscumalboom, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramastine, gemtuzumab ozogamycin, ibritumab tucetan, heptaplatin, methylaminolev
  • the compound represented by any one of Formulas 1 to 3 has a high selectivity against nicotinate phosphoribosyltransferase (NAPRT) negative cancer and effectively inhibits its proliferation or growth, so that the NAPRT Excellent prevention, improvement or treatment of negative cancer.
  • NAPRT nicotinate phosphoribosyltransferase
  • hydrochloride of the compound can be formulated in high concentration solubility.
  • FIG. 1 is a graph showing the results obtained by measuring the change in absorbance according to the treatment time when the compound of Synthesis Example 1 according to an embodiment of the present invention at various concentrations for the NamPT in Evaluation Example 1.
  • FIG. 1 is a graph showing the results obtained by measuring the change in absorbance according to the treatment time when the compound of Synthesis Example 1 according to an embodiment of the present invention at various concentrations for the NamPT in Evaluation Example 1.
  • Figure 2 shows the results of measuring the change in absorbance with treatment time when the compound of Synthesis Example 2 according to an embodiment of the present invention with respect to NamPT in Evaluation Example 1 at various concentrations.
  • Figure 3 shows the results of measuring the change in cell viability of each cell line according to the treatment concentration after treatment of the compound of Synthesis Example 1 according to an embodiment of the present invention to NAPRT positive or negative gastric cancer cell line in Evaluation Example 2 Is shown in the graph.
  • Figure 4 shows the results of measuring the change in cell viability of each cell line according to the treatment concentration after treatment of the compound of Synthesis Example 2 according to an embodiment of the present invention to NAPRT positive or negative gastric cancer cell line in Evaluation Example 2 Is shown in the graph.
  • a compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate and a solvate comprising a compound selected from the active ingredient, cancer, preferably nicotine Nate phosphoribosyltransferase (NAPRT) relates to a pharmaceutical composition for the prevention or treatment of negative cancer:
  • R 1 is a C 1 -C 6 alkyl group.
  • 'alkyl of C 1 to C 6 ' refers to a straight or branched hydrocarbon moiety having 1 to 6 carbon atoms, unless otherwise noted. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 below:
  • R 1 is as defined in Chemical Formula 1.
  • the compound represented by Chemical Formula 1 is preferably N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N) represented by the following Chemical Formula 3. -(4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide)
  • a compound represented by any one of the above Chemical Formulas 1 to 3 of the present invention, a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvent to a subject (eg, a human) in need of administration
  • a method for preventing or treating NAPRT negative cancer comprising administering a compound selected from the cargo in a pharmaceutically effective amount.
  • Nicotinic acid (1 eq, 1.41 mmol), (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) phenyl) methanamine (1 eq, 1.41 mmol) prepared in Preparation Example 1, EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (1.1 eq, 1.55 mmol), HOBt (1-hydroxybenzotriazole monohydrate) (1.1 eq, 1.55 mmol) and DIPEA (N, N-diisopropylethylamine) (3 eq, 4.22 mmol) was dissolved in MC (0.1M, 14.1 ml) and then refluxed at room temperature overnight.
  • reaction mixture was then transferred to a separatory funnel and extracted three times with MC by addition of distilled water.
  • the extract was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the reaction residue was purified by flash column chromatography (5% MeOH in dichloromethane) and then dried in a vacuum pump to N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl ) Nicotinamide (N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide) (A4510) was obtained as a white solid (yield 66.9%).
  • A4510 (1 eq, 4.45 mmol) obtained in Synthesis Example 1 was added to a 20 ml vial, and 5 ml of a solution containing 4M hydrochloric acid (4M HCl in 1,4-dioxane) was added to 1,4-dioxane for 4 hours at room temperature. Was stirred. The reaction was diluted with ether and then stirred at room temperature for 30 minutes. The product was then filtered and dried in a vacuum pump to give A4510 hydrochloride (A4510H) as a white solid (yield 90%).
  • N- (4- (6-methylbenzo [d] oxazol-2-yl) benzyl) nicotinamide (N- (4- (6-methylbenzo [d] oxazol-2-yl) benzyl represented by Formula 4 below) ) nicotinamide) was prepared in Comparative Example 1, and the hydrochloride form of the compound was prepared in Comparative Example 2.
  • both the compound of Synthesis Example 1 and the compound of Synthesis Example 2 in the form of its hydrochloride according to the present invention was found to have a very good NamPT inhibitory activity, it can be seen that it can also function as a NamPT inhibitor could.
  • both the compound of Synthesis Example 1 and the compound of Synthesis Example 2 in the form of the hydrochloride thereof according to the present invention was found to selectively inhibit the proliferation only against NAPRT negative gastric cancer cell line, the proliferation inhibitory effect It was also outstanding.
  • the compound of Synthesis Example 1 and the compound of Synthesis Example 2 in the form of the hydrochloride thereof according to the present invention was confirmed that selectively inhibit the proliferation only for NAPRT negative lung cancer cell line, the proliferation inhibitory effect It was also outstanding.
  • the NAPRT positive or negative gastric cancer cell lines were treated with various concentrations of the compounds of Synthesis Example 1 or 2 and the cell viability was analyzed to determine IC 50 .
  • IC 50 measured when the compounds of Comparative Examples 1 and 2 were treated for comparison is shown in Table 1 below.
  • the compound of Comparative Example 1 or 2 can be seen that the IC 50 for the NAPRT negative cell line is inferior in selectivity for the NAPRT negative cell line with 5 to 20 ⁇ M.
  • the compound of Synthesis Example 1 according to the present invention and the compound of Synthesis Example 2 in the form of its hydrochloride can selectively inhibit proliferation only for NAPRT negative cell lines, and the degree of inhibition of the proliferation is also compared to Comparative Example 1 or 2. You can see a very good comparison.
  • NAPRT positive or negative colorectal cancer cell lines were treated with various concentrations of the compound of Synthesis Example 1 or 2, and then 50% proliferation inhibitory concentration (ED 50 ) was measured for cancer cell lines. Shown in
  • NAPRT positive or negative pancreatic cancer cell lines were treated with the compounds of Synthesis Example 1 or 2 at various concentrations, and then 50% proliferation inhibitory concentration (ED 50 ) was measured for cancer cell lines, and the results are shown in Tables 8 and 9, respectively. Indicated.
  • NAPRT-positive cells generally include normal cells
  • the compounds according to the present invention can be used as selective therapeutic agents for treating NAPRT-negative cancers.
  • the present invention relates to methods that can effectively prevent, ameliorate or treat nicotinate phosphoribosyltransferase (NAPRT) negative cancer cells using the novel compounds.
  • NAPRT nicotinate phosphoribosyltransferase

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une utilisation de N-(4-(5-(méthylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide ou des composés sels de chlorhydrate de celui-ci pour prévenir, améliorer ou traiter une cellule cancéreuse négative à la nicotinate phosphoribosyltransférase (NAPRT).
PCT/KR2019/006696 2018-06-20 2019-06-04 Nouveau composé pour le traitement du cancer négatif à la naprt et composition comprenant celui-ci Ceased WO2019245194A1 (fr)

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KR10-2018-0070895 2018-06-20
KR1020180070895A KR102104949B1 (ko) 2018-06-20 2018-06-20 Naprt 음성 암 치료용 신규 화합물 및 이를 포함하는 조성물

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KR20230164932A (ko) * 2022-05-26 2023-12-05 주식회사 체크메이트테라퓨틱스 NamPT 억제용 신규 화합물 및 이를 포함하는 조성물
WO2025143782A1 (fr) * 2023-12-28 2025-07-03 대상 주식회사 Micro-organisme mutant pouvant produire davantage de nicotinamide mononucléotide et procédé de production de nicotinamide mononucléotide par son utilisation

Citations (3)

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WO2008006561A1 (fr) * 2006-07-12 2008-01-17 Bayer Schering Pharma Aktiengesellschaft Isoxazolines substituées, compositions pharmaceutiques les contenant, procédés de préparation de celles-ci et utilisations de celles-ci
KR20130114119A (ko) * 2010-09-03 2013-10-16 포르마 티엠, 엘엘씨. Ｎａｍｐｔ의 억제를 위한 신규 화합물 및 조성물
WO2017160116A2 (fr) * 2016-03-17 2017-09-21 연세대학교 산학협력단 Nouveau composé pour inhiber la nicotinamide phosphoribosyltransférase et composition contenant le nouveau composé

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WO2008006561A1 (fr) * 2006-07-12 2008-01-17 Bayer Schering Pharma Aktiengesellschaft Isoxazolines substituées, compositions pharmaceutiques les contenant, procédés de préparation de celles-ci et utilisations de celles-ci
KR20130114119A (ko) * 2010-09-03 2013-10-16 포르마 티엠, 엘엘씨. Ｎａｍｐｔ의 억제를 위한 신규 화합물 및 조성물
WO2017160116A2 (fr) * 2016-03-17 2017-09-21 연세대학교 산학협력단 Nouveau composé pour inhiber la nicotinamide phosphoribosyltransférase et composition contenant le nouveau composé

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Title
CHRISTENSEN, M. K. ET AL: "Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure-activity relationship", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, no. 22, 27 November 2013 (2013-11-27), pages 9071 - 9088, XP055664417 *
HASMANN, M. ET AL: "FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis", CANCER RESEARCH, vol. 63, no. 21, 1 November 2003 (2003-11-01), pages 7436 - 7442, XP055664424 *

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KR20190143219A (ko) 2019-12-30

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