WO2019245194A1 - Novel compound for treating naprt negative cancer and composition comprising same - Google Patents

Abstract

The present invention relates to a use of N-(4-(5-(methylsulfonyl)benzo[d]oxazol-2-yl)benzyl)nicotinamide or hydrochloride salt compounds thereof for preventing, improving, or treating a nicotinate phosphoribosyltransferase (NAPRT) negative cancer cell.

Description

Novel compounds for treating NAPRT negative cancer and compositions comprising same

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.

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 (NamPT) is an enzyme that catalyzes phosphoribosylation of nicotinamide and is a rate-limiting enzyme in one of two pathways to restore NAD.

There is increasing evidence that 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]. For example, 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-λB 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. In the prior art, 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.

In addition, 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.

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. In addition, 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.

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.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

According to one embodiment of the present invention, 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:

[Formula 1]

In Chemical Formula 1,

R ₁ is a C ₁ -C ₆ alkyl group.

The term 'alkyl of C ₁ to C ₆ ' as used herein 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.

In the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below:

[Formula 2]

In Chemical Formula 2,

R ₁ is as defined in Chemical Formula 1.

In the present invention, 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)

[Formula 3]

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. At this time, 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.

However, preferably in the present invention, 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.

In the present invention, the salt may be prepared by conventional methods. For example, 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.

On the other hand, 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.

In addition, a hydrate or solvate form of the compound represented by any one of Formulas 1 to 3 may also be included in the scope of the present invention.

In 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.

In the present invention, "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.

In 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.

Wherein 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, procarbazine, alprostadil, holmium nitrate Chitosan, gemcitabine, doxyfluridin, pemetrexed, tegapur, capecitabine, gimerasin, oteracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enosi Tarbin, flutamide, Kefecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmoper, raltitrexed, docetaxel, paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine , Teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus , Temozolomide, busulfan, ifosfamide, cyclophosphamide, melfaran, altrethmin, dacarbazine, chiotepa, nimustine, chlorambucil, mitorlactol, leukovorin, tretonin, exmestan , Aminoglutesimid, anagrelide, olopalip, nabelbin, padrazole, tamoxifen, toremifene, testosterone, anastrozole, letrozole, borosol, bicalutamide, romustine, vorinoste , Entinostat, phenformin, metformin, One or more selected from the group consisting of thalazoparip and carmustine may be used, but is not limited thereto.

In the present invention, 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.

The pharmaceutical 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. For example, 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. have. And others, solutions, suspensions, tablets, capsules, sustained release preparations and the like.

Examples of 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. In addition, 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.

In the present invention, "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.

The pharmaceutical 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.

According to another embodiment of the present invention, 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.

By "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. Here, 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. In addition, 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.

In the present invention, a pharmaceutically acceptable carrier may be further administered together with the compound of the present invention. Here, 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. For topical administration, bases, excipients, lubricants, preservatives and the like can be used. Formulations of the compounds of the present invention can be prepared in a variety of mixtures with the pharmaceutically acceptable carriers described above. For example, 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. have. And others, solutions, suspensions, tablets, capsules, sustained release preparations and the like.

Examples of 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. In addition, 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.

In the present invention, "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.

In the present invention, "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. For example, 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. Thus, the expression “effective amount” generally refers to an amount in which the active substance has a therapeutic effect. In the case of the present invention, 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.

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.

In addition, 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, methylaminolevulinic acid , Amsacrine, Alemtuzumab, Procarbazine, Alprostadil, Holmium Nitrate Chitosan, Gemcitabine, Doxyfluidine, Pemetrexed, Tegapur, Capecitabine, Gimerasine, Oteracil, Azacity Dean, Methotrexei , Uracil, cytarabine, fluorouracil, fludagabine, enositabine, flutamide, kefecitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmofer, raltitrexed, docetaxel, Paclitaxel, irinotecan, velotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, dow Norubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melfaran, altretmin, dacarbazine, Chiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, exemstan, aminoglutesimid, anagrelide, olopalip, nabelbin, padrazole, tamoxifen, toremifene, Testosterone, anastrozole, letrozole, Rojol, it is not bikal rutile imide, Romuald sustaining, barley no stats, no entity stats, phenformin, metformin, Tallahassee Sowing granulated and can be used, but at least one selected from the group consisting of carboxylic estramustine, limited.

In the present invention, 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.

In addition, the hydrochloride of the compound can be formulated in high concentration solubility.

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.

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.

5 is a result of measuring the change in cell viability of each cell line according to the treatment concentration after treatment with various concentrations of the compound of Synthesis Example 1 according to an embodiment of the present invention to NAPRT positive or negative lung cancer cell line in Evaluation Example 3 Is shown in the graph.

6 is a result 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 lung cancer cell line in Evaluation Example 3 Is shown in the graph.

According to one embodiment of the present invention, 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:

[Formula 1]

In Chemical Formula 1,

R ₁ is a C ₁ -C ₆ alkyl group.

The term 'alkyl of C ₁ to C ₆ ' as used herein 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.

In the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below:

[Formula 2]

In Chemical Formula 2,

R ₁ is as defined in Chemical Formula 1.

In the present invention, 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)

[Formula 3]

According to another embodiment of the present invention, 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.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example

Preparation Example 1 (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) phenyl) methanamine ((4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl Preparation of) phenyl) methanamine)

4- (aminomethyl) benzoic acid (1 eq) and 2-amino-4- (methylsulfonyl) phenol (2-amino-4- (methylsulfonyl) phenol in 20 ml vials ) (1 eq) was added, and 4 g of polyphosphoric acid (PPA) was added thereto, followed by stirring at 120 ° C. for 12 hours. The reaction was adjusted to pH 7 using 10% K ₂ CO ₃ aqueous solution, transferred to a separatory funnel, and extracted three times with dichloromethane (MC). The extract was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The reaction residue was used for the next reaction without further purification.

Synthesis Example 1 N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N- (4- (5- (methylsulfonyl) benzo [d] oxazol Preparation of -2-yl) benzyl) nicotinamide) (A4510)

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. The 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%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (t, J = 5.8 Hz, 1H), 9.05 (s, 1H), 8.73-8.67 (m, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.26-8.16 (m, 3H), 8.03 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.6, 1.7 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.51 (dd, J = 7.9, 4.8 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 3.27 (s, 3H).

Synthesis Example 2 N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N- (4- (5- (methylsulfonyl) benzo [d] oxazol Preparation of Hydrochloride (A4510 HCl) of -2-yl) benzyl) nicotinamide)

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%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.23 (s, 1H), 8.88 (d, J = 4.1 Hz, 1H), 8.67-8.60 (m, 1H), 8.31 ( d, J = 1.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 8.6, 1.7 Hz, 1H), 7.87- 7.79 (m, 1 H), 7.60 (d, J = 8.2 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H), 3.27 (s, 3H).

[Comparative Examples 1 and 2]

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.

[Formula 4]

Evaluation Example 1 NamPT Enzyme Inhibitory Effect

The effect of the compounds prepared in Synthesis Examples 1 and 2 on the substrate degradation rate (Vmax / min) by the NAMPT enzyme was tested. First, in the step of synthesizing nicotine amide into NAD, NamPT recombinant protein, substrate PRPP, nicotine amide were added to the compound of Synthesis Example 1 or 2 at various concentrations and reacted at 30 ° C. for 30 minutes. OD values were measured at 450 nm for 60 minutes at 450 nm using WST-1 converted to WST-1 formazan by the generated NAD / NADH. At this time, a CycLex NAMPT colorimetric assay kit (CY-1251) was used as the measuring device. The results are shown in FIGS. 1 and 2.

As shown in Figures 1 and 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.

Evaluation Example 2 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

After treating the compound of Synthesis Example 1 or 2 at various concentrations with respect to NAPRT positive or negative gastric cancer cell lines, the change in cell viability of each cancer cell line was measured according to the treatment concentrations, and the results are shown graphically in FIGS. 3 and 4. It was.

As shown in Figures 3 and 4, 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.

Evaluation Example 3 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

After treating the compound of Synthesis Example 1 or 2 at various concentrations with respect to NAPRT positive or negative lung cancer cell lines, the change in cell viability of each cancer cell line was measured according to the treatment concentrations, and the results are shown graphically in FIGS. 5 and 6. It was.

As shown in Figures 5 and 6, 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.

Evaluation Example 4 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

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 . However, IC ₅₀ measured when the compounds of Comparative Examples 1 and 2 were treated for comparison is shown in Table 1 below.

cancer	Cell line	NAPRT expression	IC 50 (μM)
			Synthesis Example 1	Synthesis Example 2	Comparative Example 1	Comparative Example 2
Stomach cancer	MKN1	voice	0.137	0.208	0.316	0.2534
	SNU484	voice	0.039	0.051	0.103	0.087
	SNU668	voice	1.223	1.124	2.844	3.198
	SK4		positivity	100	100	8.975	3.416
	YCC11		positivity	100	100	7.437	6.444
Lung cancer	H322	voice	0.026	0.018	0.026	0.0273
	H661	voice	0.143	0.119	0.165	0.296
	H1155	voice	0.241	0.180	0.170	0.170
	H2122		positivity	100	100	12.082	100

As shown in Table 1, 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 μM. On the other hand, 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.

Evaluation Example 5 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

After treating the compound of Synthesis Example 1 or 2 at various concentrations with respect to NAPRT positive or negative gastric cancer cell lines, 50% proliferation inhibitory concentration (ED ₅₀ ) was measured for cancer cell lines, and the results are shown in Tables 2 and 3, respectively. Indicated.

Synthesis Example 1 (A4510)
cell	NAPRT expression	AUC	ED 50 (μM)
SNU668	N	5.0684958	1.2408772
SNU484	N	2.4390213	0.0419418
MKN1	N	3.0942017	0.1442675
Hs746T	N	5.9613083	<3.16
YCC7	N	5.8977645	0.8184876
MKN28	N	4.5826786	0.5628918
MKN74	N	5.0797853	0.2939192
YCC11	P	7.5064696	100
SK4	P	7.6775659	100
NCC19	P	7.4980607	100
SNU1	P	6.0257615	100
SNU16	P	7.4548314	100
AGS	P	6.8690712	100
SNU638	P	6.7702284	100
SKGT2	P	7.5988113	100
SNU719	P	18.942192	100
MKN45	P	18.386929	100
SNU601	P	18.898424	100
SCH	P	7.6192378	100
NCC24	P	7.2435869	100
NCC59	P	7.5789815	100
YCC3	P	7.5876539	100
NCIN87	P	7.7609193	100

Synthesis Example 2 (A4510 H)
cell	NAPRT expression	AUC	ED 50 (μM)
SNU668	N	4.980924	1.1599384
SNU484	N	2.6731792	0.053549
MKN1	N	3.4135749	0.2195213
Hs746T	N	6.3923369	2.7448374
YCC7	N	5.2628384	0.7170349
MKN28	N	4.3973087	0.4405667
MKN74	N	4.612274	0.2093671
YCC11	P	7.4188639	100
SK4	P	7.5747412	100
NCC19	P	7.7821015	100
SNU1	P	6.4055956	100
SNU16	P	8.1242571	100
SNU638	P	7.3696752	100
AGS	P	6.9125192	100
SKGT2	P	7.442661	100
SNU719	P	7.9073395	100
MKN45	P	7.5691641	100
SNU601	P	7.5392029	100
NCC24	P	7.4773473	100
NCC59	P	7.5693247	100
YCC3	P	7.6009368	100
SCH	P	7.8047721	100
NCIN87	P	7.6121518	100

As can be seen in Tables 2 and 3, the compound of Synthesis Example 1 according to the present invention and the compound of Synthesis Example 2 in the form of the hydrochloride thereof can be seen that the selective proliferation inhibitory effect only for NAPRT negative cell line.

Evaluation Example 6 Inhibition of Proliferation on NAPRT Negative Cancer Cell Line

After treating the compound of Synthesis Example 1 or 2 at various concentrations with respect to NAPRT positive or negative lung cancer cell lines, 50% proliferation inhibitory concentration (ED ₅₀ ) was measured for cancer cell lines, and the results are shown in Tables 4 and 5, respectively. Indicated.

Synthesis Example 1 (A4510)
cell	NAPRT expression	AUC	ED 50 (μM)
H322	N	4.920072	0.0321165
H661	N	5.5772136	0.1441457
H1155	N	5.2817879	0.2914855
H1993	P	10.734276	100
H1975	P	9.9367429	100
H2030	P	9.8224795	100
H1299	P	10.40156	100
H2122	P	9.4581872	100
HBEC30	P	9.580241	100

Synthesis Example 2 (A4510 H)
cell	NAPRT expression	AUC	ED 50 (μM)
H322	N	4.3970552	0.0201182
H661	N	5.8002548	0.1189979
H1155	N	4.9280032	0.2074257
H1993	P	10.182116	100
H1975	P	10.114292	100
H2030	P	9.8761236	100
H1299	P	10.722583	100
H2122	P	9.8262575	100
HBEC30	P	9.592503	100

As can be seen in Tables 4 and 5, it can be seen that the compound of Synthesis Example 1 according to the present invention and the compound of Synthesis Example 2 in the form of a hydrochloride thereof have an excellent proliferation inhibitory effect only on NAPRT negative cell lines.

Evaluation Example 7 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

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

Synthesis Example 1 (A4510)
cell	NAPRT expression	AUC	ED 50 (μM)
Colo320-DM	N	3.5048003	0.3027125
Colo320-HSR	N	2.9416409	0.0783045
SNU796B	N	2.3792017	0.0217638
SNU1746	N	2.6509915	0.0455343
SNU254	P	7.7036165	100
SW480	P	7.1597719	60.253397
Lovo	P	7.775065	55.719947
SNU81	P	7.207408	100
SNU1411	P	7.8501341	100
SNUC4	P	8.310652	100
H508	P	8.0523741	100
HT29	P	8.083465	100

Synthesis Example 2 (A4510 H)
cell	NAPRT expression	AUC	ED 50 (μM)
Colo320-DM	N	3.3494565	0.2648405
Colo320-HSR	N	2.8822141	0.073084
SNU796B	N	2.3792695	0.0360751
SNU1746	N	2.8351106	0.0821707
SNU254	P	7.5988113	100
SW480	P	7.9250933	100
Lovo	P	7.6302214	100
SNU81	P	7.7305682	100
SNU1411	P	8.1291442	100
SNUC4	P	8.3504212	100
H508	P	8.1555024	100
HT29	P	7.9943752	100

As can be seen in Tables 6 and 7, it can be seen that the compound of Synthesis Example 1 according to the present invention and the compound of Synthesis Example 2 in the form of its hydrochloride form have an excellent proliferation inhibitory effect only on NAPRT negative cell lines.

Evaluation Example 8 Effect of Proliferation Inhibition on NAPRT Negative Cancer Cell Line

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.

Synthesis Example 1 (A4510)
cell	NAPRT expression	AUC	ED 50 (μM)
SNU410	N	1.3392576	<0.031
Miapaca2	N	3.6458444	0.294727
Capan1	P	7.2474372	100
Capan2	P	8.049834	100
SNU213	P	7.490236	100

Synthesis Example 2 (A4510 H)
cell	NAPRT expression	AUC	ED 50 (μM)
SNU410	N	1.1986535	<0.031
Miapaca2	N	3.4158858	0.2077376
Capan1	P	7.1875173	100
Capan2	P	8.1340519	100
SNU213	P	7.8083609	100

As can be seen in Tables 8 and 9, it can be seen that the compound of Synthesis Example 1 according to the present invention and the compound of Synthesis Example 2 in the form of its hydrochloride form have an excellent proliferation inhibitory effect only on NAPRT negative cell lines.

Considering that NAPRT-positive cells generally include normal cells, it can be seen that the compounds according to the present invention can be used as selective therapeutic agents for treating NAPRT-negative cancers.

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

The present invention relates to methods that can effectively prevent, ameliorate or treat nicotinate phosphoribosyltransferase (NAPRT) negative cancer cells using the novel compounds.

Claims (11)

1. A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient a compound selected from Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof:

   [Formula 1]

   

   In Chemical Formula 1,

   R ₁ is a C ₁ -C ₆ alkyl group.
2. The method of claim 1,

   The compound is a compound represented by the formula (2),

   [Formula 2]

   

   In Chemical Formula 2,

   R ₁ is as defined in claim 1.
3. The method of claim 1,

   The compound is N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2 -yl) benzyl) nicotinamide).
4. The method of claim 1,

   Pharmaceutically acceptable salts of the compounds represented by Formula 1 are in the form of salts of inorganic or organic acids of the compounds represented by Formula 1.
5. The method of claim 4, wherein

   Wherein said inorganic acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid or bromic acid.
6. The method of claim 4, wherein

   The organic acid is 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 or glutamic acid.
7. The method of claim 1,

   The compound is a hydrochloride of the compound represented by the formula (1), pharmaceutical composition.
8. The method of claim 1,

   The compound is N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2-yl) benzyl) nicotinamide (N- (4- (5- (methylsulfonyl) benzo [d] oxazol-2 -yl) benzyl) nicotinamide).
9. The method of claim 1,

   The cancer is a nicotinate phosphoribosyltransferase (NAPRT) negative cancer, pharmaceutical composition.
10. The method of claim 1,

    The cancer is liver cancer, biliary 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, leukemia, lymphoma, Hodgkin's disease, lung cancer, bronchial cancer A pharmaceutical composition, which is at least one member selected from the group consisting of multiple myeloma, leukemia, lymphoma, squamous cell cancer, kidney cancer, urethral cancer, bladder cancer, head and neck cancer, brain cancer, and central nervous system cancer.
11. Preventing NAPRT negative cancer comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound selected from Formula 1, a pharmaceutically acceptable salt, an optical isomer, a hydrate, and a solvate thereof Or treatment method:

    [Formula 1]

    

    In Chemical Formula 1,

    R ₁ is a C ₁ -C ₆ alkyl group.

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