Method for treating or preventing diabetes with a combination drug

Abstract

One purpose of the present invention is to provide therapy or prophylaxis of diabetes, obesity, or diabetic complications. The present invention provides: a therapeutic or prophylactic medicine that is for diabetes, obesity, or diabetic complications, and that is characterized by combinational use of an SGLT1 inhibitor and at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors; and a therapeutic or prophylactic method that is for diabetes, obesity, or diabetic complications, and that is characterized by administering an SGLT1 inhibitor and at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors.

Description

Technical Field

[0001] The present invention relates to a medicament for the treatment or prevention of diabetes, obesity or diabetic complications, characterized by the combined use of an SGLT1 inhibitor and at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors, and to a method for the treatment or prevention of diabetes, obesity or diabetic complications, characterized by administering an SGLT1 inhibitor and at least one drug selected from SGLT2 inhibitors and DPP4 inhibitors.

Background Art

[0002] SGLT1 is known to be responsible for most of the absorption of glucose and galactose in the small intestine as one of the subtypes of SGLT (Na + -glucose cotransporter), and it has been reported that glucose and galactose absorption is impaired in patients lacking human SGLT1. Furthermore, it has been confirmed that the expression of intestinal SGLT1 is increased in diabetic patients, and the enhanced sugar absorption in diabetic patients is thought to be due to the high expression of this intestinal SGLT1.

[0003] From these findings, SGLT1 inhibitors are expected to normalize blood glucose levels by inhibiting sugar absorption from the small intestine and are thought to be effective against diabetic complications associated with diabetes and hyperglycemia. It is also thought to be effective against obesity by suppressing the influx of sugar into the body (Non-Patent Documents 1 and 2).

[0004] The generic name voglibose is a pharmaceutical product that has received approval for the manufacture and sale of pharmaceuticals, etc. based on the provisions of Article 14 of the Pharmaceutical Affairs Law of Japan (Approval Number: 21600AMZ00368, etc.). Voglibose inhibits disaccharide hydrolase (α-glucosidase), which is responsible for the decomposition of disaccharides to monosaccharides present in the intestinal mucosa, and improves postprandial hyperglycemia by inhibiting or delaying the digestion and absorption of carbohydrates in the intestine. It is known that this pharmacological effect is effective in suppressing the onset of type 2 diabetes in impaired glucose tolerance. From these findings, it is considered that inhibiting sugar absorption from the small intestine with an SGLT1 inhibitor and improving postprandial hyperglycemia are effective in suppressing the onset of type 2 diabetes in impaired glucose tolerance.

[0005] Diabetes is a disease in which blood glucose levels become high due to insufficient insulin action. Persistent hyperglycemia can cause diabetic complications (for example, retinopathy, nephropathy, and neuropathy known as microangiopathy, and cerebrovascular disorders, ischemic heart disease, and peripheral atherosclerotic obliterans known as macroangiopathy). Another disease associated with high blood glucose levels is obesity. There are type 1 and type 2 diabetes. Type 1 diabetes is thought to develop due to insufficient insulin action caused by the destruction of pancreatic β-cells that secrete insulin, and type 2 diabetes is thought to develop due to a combination of multiple genetic factors including decreased insulin secretion and insulin resistance, environmental factors such as overeating, lack of exercise, obesity, stress, etc., and aging. For the diagnosis of diabetes, three types (normal type, borderline type, diabetic type) classified based on blood glucose levels are used. (1) to (4) below: (1) Fasting blood glucose level of 126 mg / dL or more in the early morning (2) 2-hour value of 200 mg / dL or more in a 75 g OGTT (oral glucose tolerance test) (3) Random blood glucose level of 200 mg / dL or more (4) HbA1c of 6.5% or more If any of the above is confirmed, it is determined as the diabetic type, and there is diabetes or suspicion of diabetes (Non-Patent Document 3).

[0006] The OGTT used in (2) above is one of the methods for diagnosing diabetes. Generally, in humans, after fasting, a solution containing 75 g of glucose is administered, and if the blood glucose level a certain time after glucose administration is 200 mg / dL or more, it is diagnosed as diabetes (Non-Patent Document 3). Therefore, the OGTT is an index for diabetes diagnosis, and a compound that can lower the blood glucose level of a subject loaded with glucose in the OGTT is considered to be effective against diabetes.

[0007] One of the subtypes of SGLT is SGLT2, which is mainly localized in the proximal renal tubules of the kidney. SGLT2 has the function of reabsorbing glucose into cells in the proximal renal tubules, and SGLT2 inhibitors are thought to lower blood glucose levels by inhibiting the reabsorption of glucose from urine and increasing the urinary excretion of sugar. As a representative SGLT2 inhibitor, dapagliflozin is clinically used as an antidiabetic drug. Administration of dapagliflozin to diabetic model animals and diabetic patients has been reported to increase urinary glucose excretion and improve hyperglycemia.

[0008] Dipeptidyl peptidase-4 (DPP4) degrades and inactivates glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are insulin secretion-stimulating hormones dependent on sugar concentration. Therefore, DPP4 inhibitors are thought to promote sugar concentration-dependent insulin secretion and lower blood glucose levels by suppressing the degradation of GLP-1 and GIP. As a representative DPP4 inhibitor, sitagliptin is clinically used as an antidiabetic drug. Administration of sitagliptin to diabetic model animals and diabetic patients has been reported to increase blood GLP-1 and GIP concentrations and improve hyperglycemia.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

[0010] A pharmaceutical for the treatment or prevention of diabetes, obesity or diabetic complications, which comprises a combination of an SGLT1 inhibitor and at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor, and a method for treating or preventing diabetes, obesity or diabetic complications, which comprises administering an SGLT1 inhibitor and at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor are provided.

Brief Description of Drawings

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Mode for Carrying Out the Invention

[0012] Some specific embodiments are exemplified below. [Item 1] A pharmaceutical for the treatment or prevention of diabetes, obesity, or diabetic complications containing an SGLT1 inhibitor, characterized by the combined use of the SGLT1 inhibitor and at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0013] [Item 2] A pharmaceutical for the treatment or prevention of diabetes, obesity, or diabetic complications containing at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor, characterized by the combined use of the SGLT1 inhibitor and at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0014] [Item 3] Formula [I]:

Chemical formula

[0015] [Item 4] Formula [I]: [Chemical formula] [wherein, R 1 is hydrogen or halogen, R 2 is C 1-6 alkyl or haloC 1-6 alkyl, R 3 is (1) C 1-6 alkyl, (2) haloC 1-6 alkyl, (3) pyridyl substituted with R 3A or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R 3B , R 3A is cyano, halogen or haloC 1-3 alkyl, R3B is halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy or -N(R 4 )(R 5 ), and R 4 and R 5 are each independently hydrogen or C 1-3 alkyl) A pharmaceutical for the treatment or prevention of diabetes, obesity or diabetic complications, comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, characterized in that the at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor is used in combination with the compound or the salt thereof.

[0016] [Item 5] Administering to a subject undergoing treatment with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, a compound of formula [I]: [Chemical formula] [In the formula, R 1 is hydrogen or halogen, R 2 is C 1-6 alkyl or haloC 1-6 alkyl, R 3 is (1) C 1-6 alkyl, (2) haloC 1-6 alkyl, (3) pyridyl substituted with R 3A or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R 3B , R 3A is cyano, halogen or haloC 1-3 alkyl, R 3B is halogen, hydroxy, C 1-3 alkyl, haloC 1-3Alkyl, C 1-3 alkoxy or -N(R 4 )(R 5 ), where R 4 and R 5 are each independently hydrogen or C 1-3 alkyl) A medicament for the treatment or prevention of diabetes, obesity or diabetic complications, containing a compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0017] [Item 6] Formula [I]: [Chemical formula] [In the formula, R 1 is hydrogen or halogen, R 2 is C 1-6 alkyl or halo C 1-6 alkyl, R 3 is (1) C 1-6 alkyl, (2) halo C 1-6 alkyl, (3) pyridyl substituted by R 3A , or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted by R 3B , R 3A is cyano, halogen or halo C 1-3 alkyl, R 3B is halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy or -N(R 4 )(R 5 ), where R 4 and R 5 are each independently hydrogen or C 1-3 alkyl) A medicament for the treatment or prevention of diabetes, obesity or diabetic complications, which comprises at least one agent selected from SGLT2 inhibitors and DPP4 inhibitors, and is characterized by being administered to a subject being treated with a compound or a pharmaceutically acceptable salt thereof.

[0018] [Item 7] The medicament according to any one of Items 1 to 6, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of formulas [II] to [V]: [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0019] [Item 8] The medicament according to any one of Items 1 to 6, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is formula [II]: [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0020] [Item 9] The medicament according to any one of Items 1 to 6, wherein the SGLT2 inhibitor is dapagliflozin.

[0021] [Item 10] The medicament according to any one of Items 1 to 6, wherein the DPP4 inhibitor is sitagliptin.

[0022] [Item 11] The medicament according to any one of Items 1 to 6, wherein the diabetes is type 2 diabetes.

[0023] [Item 12] The medicament according to Item 5 or 6, wherein the subject is a human.

[0024] [Item 13] A method for treating or preventing diabetes, obesity, or diabetic complications, characterized by administering to a subject a therapeutically effective amount of an SGLT1 inhibitor and at least one agent selected from a therapeutically effective amount of an SGLT2 inhibitor and a DPP4 inhibitor.

[0025] [Item 14] An SGLT1 inhibitor for treating or preventing diabetes, obesity, or diabetic complications, characterized by being used in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0026] [Item 15] At least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor for treating or preventing diabetes, obesity, or diabetic complications, characterized by being used in combination with an SGLT1 inhibitor.

[0027] [Item 16] Use of an SGLT1 inhibitor in the manufacture of a medicament for treating or preventing diabetes, obesity, or diabetic complications for use in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0028] [Item 17] Use of at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor in the manufacture of a medicament for treating or preventing diabetes, obesity, or diabetic complications for use in combination with an SGLT1 inhibitor.

[0029] [Item 18] A pharmaceutical composition for treating or preventing diabetes, obesity, or diabetic complications, containing an SGLT1 inhibitor and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor.

[0030] [Item 19] Formula [I]:

Chemical formula

[0031] [Item 20] The composition according to item 18 or 19, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of formulas [II] to [V]:

Chemical formula

[0032] [Item 21] The composition according to item 18 or 19, wherein the SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is formula [II]:

Chemical formula

[0033] An SGLT1 inhibitor may be any substance that inhibits SGLT1, and may be a low-molecular compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. In one aspect, an SGLT1 inhibitor is a substance having a function of normalizing blood glucose levels by inhibiting the absorption of sugar from organs such as the small intestine and myocardium. In another aspect, an SGLT1 inhibitor is a substance that suppresses a rapid increase in plasma glucose concentration immediately after glucose loading, for example, 0 to 30 minutes after glucose loading, in an oral glucose tolerance test (OGTT), and maintains the plasma glucose concentration at the same or lower level as the suppressed concentration thereafter. In yet another aspect, an SGLT1 inhibitor is a substance that can increase the plasma active GLP-1 concentration after glucose loading in an OGTT. In yet another aspect, an SGLT1 inhibitor is a compound of formula [I]: [Chemical formula] [wherein each symbol has the same meaning as described above] or a pharmaceutically acceptable salt thereof. In yet another aspect, an SGLT1 inhibitor is a substance whose metabolite does not exhibit mutagenicity. Here, a substance that does not exhibit mutagenicity means, for example, a substance that does not exhibit the ability to induce reverse mutations based on the conditions of Test Example 4 described below. In yet another aspect, an SGLT1 inhibitor is a human SGLT1 inhibitor.

[0034] In the following partial structure: [Chemical formula] The double wavy line of indicates the binding site of the structure.

[0035] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine.

[0036] "C 1-3"Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. "C" 1-3 "Alkyl" includes methyl, ethyl, n-propyl, and isopropyl.

[0037] "C" 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. "C" 1-6 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.

[0038] "HaloC" 1-3 "Alkyl" means the above "C" substituted with 1 to 5 halogens independently selected from the group of the above "halogen". "C" 1-3 "Alkyl". "HaloC" 1-3 "Alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.

[0039] "FluoroC" 1-3 "Alkyl" means the above "C" substituted with 1 to 5 fluorines. "C" 1-3 "Alkyl". "FluoroC" 1-3 "Alkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, and 3,3,3-trifluoropropyl.

[0040] "HaloC" 1-6 "Alkyl" means the above "C" substituted with 1 to 5 halogens independently selected from the group of the above "halogen". "C" 1-6means "alkyl". "Halo C" 1-6 Examples of "alkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0041] "Fluoro C" 1-6 "alkyl" means the above-mentioned "C" substituted with 1 to 5 fluorines. 1-6 means "alkyl". "Fluoro C" 1-6 Examples of "fluoro C alkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0042] "C" 1-3 "alkoxy" means a group in which the above-mentioned "C" is bonded to an oxygen atom. "C" 1-3 "alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy. 1-3 Examples of "C alkoxy" include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0043] "Pyridyl" means any of the following formulas.

Chemical formula

[0044] "Pyrazinyl" means the following formula.

Chemical formula

[0045] "Pyrimidinyl" means any of the following formulas.

Chem.

[0046] "Pyridazinyl" means any of the following formulas.

Chem.

[0047] "Substituted" includes any chemically acceptable substitution. For example, "pyridyl substituted with R 3A " means any of the following formulas.

Chem.

[0048] Each substituent of the compound of formula [I] includes the specific embodiments exemplified below for each, and the embodiments combining the specific embodiments of these substituents are also included in the compound of formula [I].

[0049] In one embodiment, R 1 is halogen. In another embodiment, R 1 is fluorine.

[0050] In one embodiment, R 2 is C 1-6 alkyl or fluoro C 1-6 alkyl. In another embodiment, R 2 is C 1-6 alkyl. In yet another embodiment, R 2 is fluoro C 1-3 alkyl.

[0051] In one embodiment, R 3 is (1) halo C 1-6 alkyl, (2) pyridyl substituted with R 3A or (3)R 3B which may be substituted with, and is pyrazinyl or pyrimidinyl. In another embodiment, R 3 is halo C 1-6 alkyl and is selected from the group consisting of formulas [H1] to [H14]. In yet another embodiment, R 3 is halo C 1-6 alkyl, formula [H2] or [H8].

Chemical formula

[0052] In one embodiment, R 3A is halogen or halo C 1-3 alkyl. In another embodiment, R 3A is fluorine or fluoro C 1-3 alkyl.

[0053] In one embodiment, R 3B is halogen or halo C 1-3 alkyl. In another embodiment, R 3B is fluoro C 1-3 alkyl.

[0054] In one embodiment, R 4 and R 5 are each independently C 1-3 alkyl.

[0055] In one embodiment, the compound of formula [I] is a compound of formula [II] or [III]:

Chemical formula

Chemical formula

[0056] As used herein, a pharmaceutically acceptable salt may be any salt known in the art that does not have excessive toxicity. Specifically, examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). The pharmaceutically acceptable salts can each be obtained by reacting the compound of formula [I] with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se.

[0057] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid. Preferably, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid are mentioned. Examples of salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydroxymethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, borneol acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanyl acid, hexylresorcinol acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylene bis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theobromic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid or glutamic acid. Preferably, salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid are mentioned.

[0058] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth or ammonium. Preferably, salts with sodium, potassium, calcium, magnesium or zinc are mentioned. Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine or lysine are mentioned.

[0059] The active ingredients of SGLT1 inhibitors (for example, compounds of formula [I] or pharmaceutically acceptable salts thereof), SGLT2 inhibitors and DPP4 inhibitors may exist as solvates. A solvate is, for example, a compound of formula [I] or a pharmaceutically acceptable salt thereof coordinated with solvent molecules. The solvate may be any pharmaceutically acceptable solvate, and examples include hydrates, ethanolates, and dimethyl sulfoxide solvates of the compound of formula [I] or a pharmaceutically acceptable salt thereof. Specifically, hemihydrates, monohydrates, dihydrates or 1-ethanolates of the compound of formula [I], or 1-hydrate of the sodium salt of the compound of formula [I] or 2 / 3-ethanolate of 2-hydrochloride, etc. are included. These solvates can be obtained according to known methods. For example, the compound of formula [III] can exist as a monohydrate as shown in the following formula [VI].

Chemical formula

[0060] The compound of formula [I] may be labeled with isotope elements ( 2 H, 3 H, 14 C, 35 S, etc.).

[0061] The compound of formula [I] or a pharmaceutically acceptable salt thereof that is substantially purified is preferred. More preferably, it is the compound of formula [I] or a pharmaceutically acceptable salt thereof purified to a purity of 80% or more.

[0062] Inhibiting SGLT1 means inhibiting the function of SGLT1 and disappearing or attenuating its activity, for example, meaning inhibiting the function of SGLT1 based on the conditions of Test Example 1 described later. Preferably, it is to inhibit human SGLT1. The inhibition of the function of SGLT1 or the disappearance or attenuation of its activity is preferably carried out in human clinical indications.

[0063] An SGLT2 inhibitor can be any substance that inhibits SGLT2, and can be a low-molecular compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. In certain embodiments, an SGLT2 inhibitor is a substance that has the function of lowering blood glucose levels by inhibiting the reuptake of glucose from urine and increasing the urinary excretion of sugar.

[0064] To inhibit SGLT2 means to inhibit the function of SGLT2 and cause its activity to disappear or weaken. Preferably, it is to inhibit human SGLT2. The inhibition of the function of SGLT2 or the disappearance or weakening of its activity is preferably carried out in human clinical applications.

[0065] In this specification, SGLT2 inhibitors include, for example, glycoside compounds or their salts or their solvates. Here, a glycoside compound is a compound in which a sugar or sugar derivative is glycosidically bonded (e.g., C-glycosidic bond or O-glycosidic bond) to an aglycone moiety, and the sugar or sugar derivative has the following structure. [Chemical formula] [In the formula, Y is O or S, and the glycosidic bond is formed with the carbon atom at the 1-position]

[0066] In this specification, SGLT2 inhibitors include, for example, the following. For convenience, common names are used throughout this specification. [Table 1] [Table 2-1] [Table 2-2]

[0067] A DPP4 inhibitor can be any substance that inhibits DPP4, and can be a low-molecular compound, nucleic acid, polypeptide, protein, antibody, vaccine, etc. In certain embodiments, a DPP4 inhibitor is a substance that has the function of promoting glucose concentration-dependent insulin secretion and reducing blood glucose levels by suppressing the degradation of GLP-1 and GIP.

[0068] To inhibit DPP4 means to inhibit the function of DPP4 and cause its activity to disappear or weaken. Preferably, it is to inhibit human DPP4. The inhibition of the function of DPP4 or the disappearance or weakening of its activity is preferably carried out in human clinical applications.

[0069] In this specification, DPP4 inhibitors include, for example, gliptins having at least one amide group or sulfonamide group, or salts thereof, or solvates thereof.

[0070] In this specification, DPP4 inhibitors include, for example, the following. For convenience, common names are used throughout this specification.

Table 3

Table 4-1

Table 4-2

[0071] SGLT1 inhibitors (for example, compounds of formula [I] or pharmaceutically acceptable salts thereof), SGLT2 inhibitors, and DPP4 inhibitors each have SGLT1 inhibitory activity, SGLT2 inhibitory activity, and DPP4 inhibitory activity. Therefore, various diseases or conditions expected to be improved by regulating these activities, or various diseases or conditions that may be caused by an increase in blood glucose level due to sugar absorption in the body, such as diabetes (for example, type 1 diabetes and type 2 diabetes), obesity, and / or diabetic complications (for example, retinopathy, nephropathy, and neuropathy known as microangiopathy, and cerebrovascular disorder, ischemic heart disease, and peripheral atherosclerotic occlusive disease known as macroangiopathy) may be useful for the treatment and / or prevention thereof. In one aspect, the various diseases or conditions are diabetes, obesity, or diabetic complications. In another aspect, the various diseases or conditions are diabetes. In yet another aspect, the various diseases or conditions are type 1 diabetes. In yet another aspect, the various diseases or conditions are type 2 diabetes.

[0072] As used herein, "combined use" means administering to a subject an SGLT1 inhibitor (e.g., a compound of formula [I] or a pharmaceutically acceptable salt thereof) and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor in any order. Since each agent has a different mechanism of action, the combined use of these agents may exhibit an additive or synergistic therapeutic or prophylactic effect on at least one of various diseases or conditions. In one embodiment, the combined use can significantly suppress a rapid increase in plasma glucose concentration immediately after glucose loading in an OGTT, for example, 0 to 30 minutes later, and maintain the subsequent plasma glucose concentration at or below the suppressed concentration compared to the administration of each agent alone. In another embodiment, the combined use can significantly increase the plasma active GLP-1 concentration immediately after glucose loading in an OGTT, for example, 0 to 30 minutes later, and maintain the subsequent plasma active GLP-1 concentration at a similar level to the increased concentration. In yet another embodiment, the combined use may reduce the dosage of each agent compared to the administration of a single agent alone by using multiple agents with different mechanisms of action, and can reduce the side effects inherent to each agent. In one embodiment, the SGLT1 inhibitor and the first agent and the second agent and / or the third agent, each selected from an SGLT2 inhibitor and a DPP4 inhibitor, may be administered to the subject simultaneously, continuously, or at intervals (e.g., within 30 minutes, within 1 hour, within 2 hours, within 4 hours) in any order, together or separately. The second agent and / or the third agent can be administered while the active ingredient contained in the first agent administered first is present in the subject's body in a therapeutically effective amount. In another embodiment, the SGLT1 inhibitor and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor may be administered to the subject as a single dosage form comprising a combination of these agents. The dosage ratio and formulation ratio of these agents may be appropriately selected depending on the administration subject, administration route, target disease, symptoms, severity of the disease, and combinations thereof. For example, when the administration subject is a human, 0.01 to 1000 parts by weight of at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor can be used per 1 part by weight of the SGLT1 inhibitor.

[0073] In one aspect, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combined use of a compound of formula [I] with a glycoside compound or a salt thereof or a solvate thereof.

[0074] In another aspect, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the combined use of a compound of formula [II] with a glycoside compound or a salt thereof or a solvate thereof.

[0075] In one aspect, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the compound of formula [I] and dapagliflozin, the compound of formula [I] and ipragliflozin, the compound of formula [I] and tofogliflozin, the compound of formula [I] and empagliflozin, the compound of formula [I] and canagliflozin, and the compound of formula [I] and luseogliflozin are included.

[0076] In another aspect, the combined use of an SGLT1 inhibitor and an SGLT2 inhibitor includes the compound of formula [II] and dapagliflozin, the compound of formula [II] and ipragliflozin, the compound of formula [II] and tofogliflozin, the compound of formula [II] and empagliflozin, the compound of formula [II] and canagliflozin, and the compound of formula [II] and luseogliflozin are included.

[0077] In one aspect, the combined use of an SGLT1 inhibitor and a DPP4 inhibitor includes the combined use of a compound of formula [I] with gliptins having at least one amide group or sulfonamide group or a salt thereof or a solvate thereof.

[0078] In another aspect, the combined use of an SGLT1 inhibitor and a DPP4 inhibitor includes the combined use of a compound of formula [II] and gliptins having at least one amide group or sulfonamide group, or salts or solvates thereof.

[0079] In one aspect, the combined use of an SGLT1 inhibitor and a DPP4 inhibitor includes a compound of formula [I] and sitagliptin, a compound of formula [I] and saxagliptin, a compound of formula [I] and vildagliptin, a compound of formula [I] and linagliptin, a compound of formula [I] and teneligliptin, a compound of formula [I] and alogliptin, a compound of formula [I] and anagliptin, a compound of formula [I] and treagliptin, and a compound of formula [I] and omarigliptin are included.

[0080] In another aspect, the combined use of an SGLT1 inhibitor and a DPP4 inhibitor includes a compound of formula [II] and sitagliptin, a compound of formula [II] and saxagliptin, a compound of formula [II] and vildagliptin, a compound of formula [II] and linagliptin, a compound of formula [II] and teneligliptin, a compound of formula [II] and alogliptin, a compound of formula [II] and anagliptin, a compound of formula [II] and treagliptin, and a compound of formula [II] and omarigliptin are included.

[0081] In one aspect, formula [II]:

Chemical Structure

[0082] In another aspect, formula [II]:

Chemical formula

[0083] In yet another aspect, formula [II]:

Chemical formula

[0084] In yet another aspect, formula [II]:

Chemical formula

[0085] In yet another aspect, formula [II]:

Chemical formula

[0086] In yet another aspect, formula [II]:

Chemical formula

[0087] In yet another aspect, formula [II]:

Chemical formula

[0088] In yet another aspect, formula [II]:

Chemical formula

[0089] In yet another aspect, formula [II]:

Chemical formula

[0090] In yet another aspect, formula [II]:

Chemical formula

[0091] In yet another aspect, formula [II]:

Chemical formula

[0092] In yet another aspect, formula [II]:

Chemical formula

[0093] In yet another aspect, formula [II]:

Chemical formula

[0094] In yet another aspect, formula [II]: [Chemical formula] There is provided a pharmaceutical composition for the treatment or prevention of type 2 diabetes, which contains a compound of or a pharmaceutically acceptable salt thereof and dapagliflozin.

[0095] In yet another aspect, formula [II]: [Chemical formula] There is provided a pharmaceutical composition for the treatment or prevention of type 2 diabetes, which contains a compound of or a pharmaceutically acceptable salt thereof and sitagliptin.

[0096] As used herein, the agent means any agent selected from SGLT1 inhibitors, SGLT2 inhibitors, and DPP4 inhibitors. Administering an agent to a subject being treated with another agent is one mode of combination therapy, for example, when administering an agent to a subject, it includes administering the agent while the active ingredient contained in another agent administered previously is present in the subject's body in a therapeutically effective amount.

[0097] As used herein, the therapeutically effective amount of an SGLT1 inhibitor may be appropriately changed depending on the administration subject, administration route, target disease, symptoms, severity of the disease, and combinations thereof. When orally administered to a human (body weight 60 kg), examples of the lower limit of the therapeutically effective amount include about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and examples of the upper limit of the therapeutically effective amount include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day.

[0098] In this specification, the therapeutically effective amount of an SGLT2 inhibitor (e.g., dapagliflozin) can be appropriately changed depending on the subject of administration, route of administration, target disease, symptoms, severity of the disease, and combinations thereof. When orally administered to a human (60 kg in weight), examples of the lower limit of the therapeutically effective amount include about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and examples of the upper limit of the therapeutically effective amount include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day. In certain embodiments, the therapeutically effective amount of an SGLT2 inhibitor (e.g., dapagliflozin) is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg, or about 15 mg per day. In another embodiment, the therapeutically effective amount of an SGLT2 inhibitor (e.g., dapagliflozin) is about 5 mg or about 10 mg per day.

[0099] In this specification, the therapeutically effective amount of a DPP4 inhibitor (e.g., sitagliptin) can be appropriately changed depending on the subject of administration, route of administration, target disease, symptoms, severity of the disease, and combinations thereof. When orally administered to a human (60 kg in weight), examples of the lower limit of the therapeutically effective amount include about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and examples of the upper limit of the therapeutically effective amount include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day. In certain embodiments, the therapeutically effective amount of a DPP4 inhibitor (e.g., sitagliptin) is about 2.5 mg, about 5 mg, about 10 mg, about 12.5 g, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg per day. In another embodiment, the therapeutically effective amount of a DPP4 inhibitor (e.g., sitagliptin) is about 12.5 mg, about 25 mg, about 50 mg, or about 100 mg per day.

[0100] In this specification, the number of administrations of each drug, medicine, and pharmaceutical composition may be once, twice, three times, or more per day.

[0101] In this specification, treatment includes improvement of symptoms, prevention of exacerbation, maintenance of remission, prevention of relapse, and prevention of recurrence. In this specification, prevention includes suppressing the onset of symptoms. For example, prevention of diabetes includes suppressing the onset of type 2 diabetes in impaired glucose tolerance.

[0102] The pharmaceutical compositions in this specification may be manufactured by appropriately mixing, according to methods known in the technical field of pharmaceutical preparations, a therapeutically effective amount of each contained drug with at least one or more pharmaceutically acceptable carriers, etc. The content of each drug in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, from 0.1 to 100% by weight of the entire composition.

[0103] In this specification, the dosage forms of each drug, medicine, and pharmaceutical composition include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions, etc., and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, pulmonary preparations, etc.

[0104] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, and solvents, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, stabilizing agents, dispersants, plasticizers, pH adjusters, absorption promoters, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, coloring agents, sweetening agents, etc. may be added as necessary.

[0105] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic, etc. Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose, etc. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic, etc. Examples of fluidizing agents include light anhydrous silicic acid, magnesium stearate, etc. Examples of lubricants include magnesium stearate, calcium stearate, and talc, etc. Examples of solvents include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil, etc. Examples of solubilizing agents include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate, etc. Examples of suspending agents include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, and glycerol monostearate, etc. Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, and D-mannitol, etc. Examples of buffers include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate, etc. Examples of soothing agents include benzyl alcohol, etc. As the base, there are water, animal and vegetable oils (such as olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (such as ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (such as white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrolyzed lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (such as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (such as macrogol 200 - 600, etc.), and combinations of two or more of them. As preservatives, there are ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, etc. As antioxidants, there are sodium sulfite, ascorbic acid, etc. As colorants, there are food dyes (such as food red No. 2 or 3, food yellow No. 4 or 5, etc.), and β-carotene, etc. As sweeteners, there are sodium saccharin, dipotassium glycyrrhizinate, aspartame, etc.

[0106] In this specification, each drug, medicine, and pharmaceutical composition can be administered orally or parenterally (topical, rectal, intravenous administration, intramuscular, subcutaneous, etc.) to humans and non-human mammals (such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). The dosage varies depending on the administration subject, disease, symptoms, dosage form, administration route, etc. For example, when orally administered to an adult patient (weight 60 kg), the dosage for the active ingredient of each drug is usually in the range of about 0.01 mg to about 1 g per day. These amounts can be administered in one or several divided doses. In one aspect, each drug may be formulated into separate pharmaceutical compositions and administered to the subject in any order via different administration routes. In another aspect, the dosage of each drug may be reduced by combination compared to when each drug is administered alone, and when orally administered to an adult patient (weight 60 kg), the dosage may be in the range of about 0.01 mg to about 1000 mg per day.

[0107] In certain embodiments, a kit (such as an administration, treatment, and / or prevention kit), a package (such as a packaging), and a drug set (and / or container) are provided that include an SGLT1 inhibitor (e.g., a compound of formula [I] or a pharmaceutically acceptable salt thereof), at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, and a description stating that these agents can be used in combination or should be used in combination for treatment and / or prevention. Such kits, packages, and drug sets may comprise one or more containers filled with an SGLT1 inhibitor, at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, and optionally other drugs or pharmaceuticals (or ingredients). Examples of such kits, packages, and drug sets include commercial kits, commercial packages, and commercial drug sets appropriately directed for the treatment and / or prevention of a target disease. Descriptions included in such kits, packages, and drug sets include a caution or attachment in a form directed by a government agency that regulates the manufacture, use, or sale of a pharmaceutical or biological product, and that indicates approval by the government agency for the manufacture, use, or sale of the product related to administration to humans. The above kits, packages, and drug sets also include the packaged product, and may also include a structure configured for an appropriate administration process (step), or a structure configured to achieve a more preferred medical treatment and / or prevention, including the treatment and / or prevention of a target disease, etc.

[0108] [General Preparation Method] The general preparation method of the compound of formula [I] or a pharmaceutically acceptable salt thereof is exemplified below. However, the method for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof is not limited to the general preparation method. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., if necessary. However, in some cases, it is possible to proceed to the next step without isolation and / or purification. In this specification, room temperature refers to the temperature in a state where the temperature is not controlled, and in one embodiment, it ranges from 1°C to 40°C.

[0109] [General Preparation Method A] A compound of formula [I-1] or a pharmaceutically acceptable salt thereof R 3 is R 3A substituted pyridyl, or R 3B optionally substituted pyrazinyl, pyrimidinyl or pyridazinyl, a compound of formula [I] or a pharmaceutically acceptable salt thereof can be obtained, for example, by the preparation methods shown below.

Chemical Structure

[0110] (Step A1) The compound of formula [3] can be obtained by reacting the compound of formula [1] with the compound of formula [2] in a solvent in the presence of a base. Examples of the solvent include ether solvents such as 1,2-dimethoxyethane; and polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, and N,N'-dimethylpropyleneurea. The preferred solvent is 1,3-dimethyl-2-imidazolidinone. Examples of the base include cesium carbonate and sodium hydride. The preferred base is sodium hydride. The reaction temperature is, for example, from 60°C to 170°C, preferably from 100°C to 140°C. Both the compound of formula [1] and the compound of formula [2] may be commercially available products or may be produced by known methods. Alternatively, when R 2 is trifluoromethyl, the compound of formula [3] may be a commercially available product.

[0111] (Step A2) The compound of formula [5] can be obtained by subjecting the compound of formula [3] and the compound of formula [4] to a Mizoroki-Heck reaction. For example, the compound of formula [5] can be obtained by reacting the compound of formula [3] and the compound of formula [4] in a solvent in the presence of a palladium catalyst and a base. Examples of the solvent include alcohol solvents such as ethylene glycol; and polar solvents such as N,N-dimethylformamide. The preferred solvent is ethylene glycol. Examples of the palladium catalyst include a mixture of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene or 1,3-bis(diphenylphosphino)propane. The preferred palladium catalyst is a mixture of palladium(II) acetate and 1,1'-bis(diphenylphosphino)ferrocene. Examples of the base include organic bases such as triethylamine. The preferred base is triethylamine. The reaction temperature is, for example, from 80°C to 150°C, preferably from 100°C to 140°C. The compound of formula [4] may be a commercially available product or may be produced by known methods.

[0112] (Process A3) The compound of formula [6] is the -C(=CH2)OA compound of formula [5] 4 For example, the compound of formula [6] can be obtained by reacting the compound of formula [5] in a solvent in the presence of an acid. Examples of the solvent include ketone solvents such as acetone, alcohol solvents such as ethylene glycol, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, polar solvents such as N,N-dimethylformamide, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of tetrahydrofuran and water. Examples of acids include hydrochloric acid and trifluoroacetic acid. A preferred acid is hydrochloric acid. The reaction temperature is, for example, 20° C. to 50° C., and is preferably room temperature.

[0113] (Process A4) The compound of formula [8] can be obtained by reacting the compound of formula [6] with the compound of formula [7] in a solvent in the presence of a base. Examples of the solvent include ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; alcohol solvents such as methanol and ethanol; hydrocarbon solvents such as toluene; polar solvents such as N,N-dimethylformamide; and mixed solvents thereof. The preferred solvent is tetrahydrofuran. Examples of bases include lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazane, and sodium hydride. A preferred base is lithium tert-butoxide. The reaction temperature is, for example, from −78° C. to 110° C., preferably from 0° C. to room temperature. Compounds of formula [7] are either commercially available or may be prepared by known methods.

[0114] (Process A5) The compound of formula

[10] can be obtained by reacting the compound of formula [8] and the compound of formula [9] in a solvent in the presence of an acid. Examples of the solvent include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and hydrocarbon solvents such as toluene. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. The preferred acid is acetic acid. These acids may be used as the solvent. The reaction temperature is, for example, from 20°C to 130°C, preferably from 80°C to 110°C. The compound of formula [9] may be a commercially available product or may be produced by a known method, or may also be obtained by the general production method B described below.

[0115] (Process A6) The compound of formula

[11] can be obtained by removing the -A 7 group of the compound of formula

[10] . The removal reaction may be carried out under conditions suitable according to the type of A 7 . For example, when A 7 is ethyl, the compound of formula

[11] can be obtained by reacting the compound of formula

[10] in a solvent in the presence of a base. Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran; water; and mixed solvents thereof. The preferred solvent is a mixed solvent of two or more selected from the group consisting of methanol, tetrahydrofuran, and water. Examples of the base include lithium hydroxide, sodium hydroxide, and potassium hydroxide. The preferred base is sodium hydroxide. The reaction temperature is, for example, from 0°C to 100°C, preferably from room temperature to 40°C.

[0116] (Process A7) The compound of formula

[13] can be obtained by subjecting the compounds of formula

[11] and formula

[12] to a Curtius rearrangement reaction. For example, the compound of formula

[13] can be obtained by reacting the compound of formula

[11] with an azidating agent in the presence of a base in a solvent and then reacting with the compound of formula

[12] . Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; hydrocarbon solvents such as toluene. Alternatively, the compound of formula

[12] may be used as the solvent. A preferred solvent is toluene or a mixed solvent of toluene and the compound of formula

[12] . Examples of the azidating agent include diphenylphosphoric acid azide. Examples of the base include organic bases such as triethylamine and N,N-diisopropylethylamine. A preferred base is triethylamine. The reaction temperature is, for example, from 65 °C to 130 °C, preferably from 90 °C to 110 °C. The compound of formula

[12] may be a commercially available product or may be produced by a known method.

[0117] (Step A8) The compound of formula

[14] can be obtained by removing the -C(=O)OA 12 group of the compound of formula

[13] in a solvent. The removal reaction may be carried out under conditions suitable according to the type of A 12 . For example, when A 12 is tert-butyl, the compound of formula

[14] can be obtained by reacting the compound of formula

[13] with an acid in a solvent. Examples of the solvent include ester solvents such as ethyl acetate; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane; water; and mixed solvents thereof. A preferred solvent is 1,4-dioxane. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. A preferred acid is hydrochloric acid. These acids may be used as the solvent. The reaction temperature is, for example, from 0°C to 60°C, preferably from 0°C to room temperature.

[0118] (Step A9) The compound of formula [I-1] can be obtained by subjecting the compound of formula

[14] and the compound of formula

[15] to a condensation reaction in a solvent. Examples of the solvent include halogenated hydrocarbon solvents such as chloroform; ether solvents such as tetrahydrofuran; polar solvents such as pyridine, acetonitrile, and N,N-dimethylformamide; and mixed solvents thereof. A preferred solvent is pyridine. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride·n hydrate (DMT-MM), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, and propylphosphonic anhydride. A preferred condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl). The reaction temperature is, for example, from 0°C to 100°C, preferably room temperature. The compound of formula

[15] can be obtained, for example, by the method of General Preparation E described below.

[0119] [General Preparation B] Manufacturing method B1 The compound of formula [9] can be obtained, for example, by the production method shown below. [Chemical formula] [In the formula, R 31 has the same meaning as defined above, X 16 is a halogen] The compound of formula [9] can be obtained by reacting the compound of formula

[16] with hydrazine monohydrate in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; alcohol solvents such as ethanol and 2-propanol; halogenated hydrocarbon solvents such as dichloromethane; polar solvents such as N,N-dimethylformamide and pyridine; water; and mixed solvents thereof. Alternatively, hydrazine monohydrate may be used as the solvent. A preferred solvent is a mixed solvent of 2-propanol and hydrazine monohydrate. The reaction temperature is, for example, from room temperature to 140 °C, preferably from 60 °C to 100 °C. The compound of formula

[16] may be a commercially available product or may be produced by a known method.

[0120] Manufacturing method B2 The compound of formula [9] is also 31 when R 3A is pyridyl substituted with R

Chemical formula

[17] in a solvent in the presence of an acid. Examples of the solvent include water. Examples of the diazotizing agent include sodium nitrite. Examples of the acid include hydrochloric acid and sulfuric acid. A preferred acid is hydrochloric acid. Examples of the reducing agent include tin(II) chloride and sodium sulfite. A preferred reducing agent is tin(II) chloride. The reaction temperature for diazotization is, for example, from -20°C to 5°C, preferably from -5°C to 0°C. The reaction temperature for reduction is, for example, from -5°C to room temperature, preferably from 0°C to room temperature. The compound of formula

[17] may be a commercially available product or may be produced by a known method.

[0121] Manufacturing method B3 Alternatively, when the compound of formula [9] is also pyridyl substituted with (1) R 31 or (2) pyrimidinyl optionally substituted with R 3A , it can also be obtained, for example, by the production method shown below. 3B

Chemical formula

[0122] (Step B3-1) The compound of formula

[18] can be obtained by reacting the compound of formula

[16] with a base and a borate ester in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; and mixed solvents thereof. A preferred solvent is tetrahydrofuran. ​Examples of the base include n-butyllithium and isopropylmagnesium bromide. The preferred base is n-butyllithium. Examples of the borate ester include triisopropyl borate and trimethyl borate. The preferred borate ester is triisopropyl borate. The reaction temperature is, for example, from -78 °C to room temperature, preferably from -78 °C to 0 °C. The compound of formula

[16] may be a commercially available product or may be produced by a known method.

[0123] (Step B3-2) The compound of formula

[20] can be obtained by reacting the compound of formula

[18] and the compound of formula

[19] in a solvent in the presence of a copper catalyst. Examples of the solvent include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol. The preferred solvent is methanol. Examples of the copper catalyst include copper(II) acetate. The reaction temperature is, for example, from room temperature to 100 °C, preferably from 45 °C to 65 °C.

[0124] (Step B3-3) The compound of formula [9] can be obtained by removing the -A 19 group of the compound of formula

[20] in a solvent. The removal reaction may be carried out under conditions suitable for the type of A. For example, when A 19 is tert-butoxycarbonyl, the compound of formula [9] can be obtained by reacting the compound of formula

[20] in a solvent in the presence of an acid. 19 Examples of the solvent include ester solvents such as ethyl acetate; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbon solvents such as dichloromethane; water; and mixed solvents thereof. The preferred solvent is 1,4-dioxane. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. The preferred acid is hydrochloric acid. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. The preferred acid is hydrochloric acid. The reaction temperature is, for example, from 0°C to 60°C, preferably from 0°C to room temperature.

[0125] [General Production Method C] A compound of formula [I-2] or a pharmaceutically acceptable salt thereof R 3 is C 1-6 alkyl or haloC 1-6 A compound of formula [I] wherein R is alkyl or a pharmaceutically acceptable salt thereof can be obtained, for example, by any of the production methods shown below. Manufacturing method C1 [Chemical formula] [wherein, R 1 and R 2 are as defined above, R 32 is C 1-6 alkyl or haloC 1-6 alkyl]

[0126] (Step C1-1) The compound of formula [I-2] can be produced by reacting a compound of formula

[21] or a salt thereof with a compound of formula

[15] or a salt thereof in a solvent in the presence of a condensing agent and an additive. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC·HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride·n hydrate (DMT-MM), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide, and propylphosphonic anhydride. Examples of the additive include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine, and 1-methylimidazole. Examples of the solvent include halogenated hydrocarbon solvents such as chloroform; ether solvents such as tetrahydrofuran; polar solvents such as pyridine, acetonitrile, and N,N-dimethylformamide; and mixed solvents thereof. The reaction temperature is, for example, from 0°C to 100°C. When using the salt of the compound of formula

[21] , this reaction may be carried out in the presence of a base. Examples of the base include organic bases such as triethylamine and alkali metal salts such as sodium carbonate.

[0127] The compound of formula [I-2] can also be produced by a method in which the compound of formula

[15] is converted to a carboxylic acid halide using a halogenating agent in a solvent and then reacted with the compound of formula

[21] in the presence of a base. Examples of the halogenating agent used in the reaction include oxalyl chloride and thionyl chloride. The preferred halogenating agent is oxalyl chloride. Examples of the base used in the reaction include organic bases such as pyridine, triethylamine, and N,N - diisopropylethylamine; and alkali metal salts such as sodium hydrogen carbonate and sodium carbonate. The preferred base is pyridine. Examples of the solvent include halogenated hydrocarbon solvents such as chloroform; ether solvents such as cyclopentyl methyl ether and tetrahydrofuran; hydrocarbon solvents such as toluene; and mixed solvents of these with water. The preferred solvent is chloroform. The reaction temperature is, for example, from 0°C to 80°C, preferably from 0°C to 60°C. In the production of the carboxylic acid halide, N,N - dimethylformamide may be added as an additive.

[0128] Manufacturing method C2 [Chemical formula] [In the formula, R 1 、R 2 and R 32 have the same meanings as defined above, and P N1 is a protecting group for the amino group. The preferred P N1 is a 2,4 - dimethoxybenzyl group.]

[0129] (Step C2 - 1) The compound of formula

[23] can be produced from the compound of formula

[21] or a salt thereof and the compound of formula

[22] or a salt thereof according to the method for producing in Step C1 of Production Method C1.

[0130] (Step C2 - 2) The compound of formula [I - 2] or a salt thereof can be produced by removing P N1 of the compound of formula

[23] by a deprotection reaction. The deprotection reaction may be carried out under conditions suitable according to the type of P N1 . For example, P N1When it is a 2,4-dimethoxybenzyl group, the compound of formula [I-2] or a salt thereof can be produced by reacting with an acid in the presence of an additive in a solvent. Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. The preferred acid is trifluoroacetic acid. Examples of the additive include anisole and triethylsilane. The preferred additive is anisole. Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, hydrocarbon solvents such as toluene, water, and mixed solvents thereof. Organic acids such as trifluoroacetic acid may be used as the solvent. The reaction temperature is, for example, from 0 °C to 130 °C, preferably from 25 °C to 80 °C. In this step, when an acid is used, formula

[24] :

Chemical formula

[24] or a salt thereof is obtained. The compound of formula [I-2] or a salt thereof can be produced by converting the hydroxyl group of the compound of formula

[24] or a salt thereof into a C 1-6 alkyl-O or halo C 1-6 alkyl-O group by a known method. For example, when R 1 is fluorine, R 2 is tert-butyl, and R 32 is trifluoromethyl, the compound of formula [I-2] (i.e., the compound of formula [II]) or a salt thereof can be produced by reacting the compound of formula

[24] or a salt thereof with di-tert-butyl dicarbonate in the presence of magnesium perchlorate. Examples of the solvent include halogenated hydrocarbon solvents such as chloroform, and ether solvents such as tetrahydrofuran. The preferred solvent is chloroform. The reaction temperature is, for example, from 0 °C to 100 °C, preferably from room temperature to 70 °C.

[0131] [General Production Method D] The compound of formula

[21] can be produced by the production method shown below. Manufacturing method D1 [Chemical Formula] [In the formula, R 1 , R 2 and R 32 are synonymous with the definitions in the above, L 1 is a leaving group. Preferred L 1 is chlorine, bromine, or iodine. P N2 are each independently an amine protecting group. Preferably, two P N2 together with the nitrogen to which they are attached form 2,5-dimethylpyrrole.]

[0132] (Step D1-1) The compound of formula

[26] can be produced by introducing P N2 into the amino group of the compound of formula

[25] or its salt by a known method. The introduction of the protecting group may be carried out under suitable conditions according to the type of P N2 . For example, when two P N2 together with the nitrogen to which they are attached form 2,5-dimethylpyrrole, the compound of formula

[26] can be produced by reacting the compound of formula

[25] with 2,5-hexanedione in a solvent under acidic conditions. Examples of the acid used in the reaction include concentrated hydrochloric acid, concentrated sulfuric acid, amidosulfuric acid, p-toluenesulfonic acid, and acetic acid. The preferred acid is acetic acid. Examples of the solvent include alcoholic solvents such as ethanol, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, polar solvents such as N,N-dimethylformamide, halogenated hydrocarbon solvents such as dichloroethane, and mixed solvents thereof. Organic acids such as acetic acid may also be used as the solvent. The reaction temperature is, for example, from room temperature to 150 °C, preferably from 80 °C to 140 °C.

[0133] (Step D1-2) The compound of formula

[27] can be produced by alkylating or haloalkylating the compound of formula

[26] by a known method. For example, when R 32 is trifluoromethyl, in a solvent, in the presence of a base and a catalyst, step (a) of reacting the compound of formula

[26] with dibromodifluoromethane, and step (b) of fluorinating in a solvent in the presence of tetramethylammonium fluoride or silver(I) tetrafluoroborate. Examples of the base used in step (a) include sodium hydride and potassium tert-butoxide. The preferred base is sodium hydride. Examples of the catalyst used in step (a) include tetrabutylammonium bromide and zinc. The preferred catalyst is tetrabutylammonium bromide. Examples of the solvent used in step (a) include ether solvents such as tetrahydrofuran and polar solvents such as N,N-dimethylformamide. The preferred solvent is N,N-dimethylformamide. The reaction temperature in step (a) is, for example, from 0 °C to 40 °C, preferably from 0 °C to room temperature. Examples of the solvent used in step (b) when using tetramethylammonium fluoride include ether solvents such as 1,4-dioxane and polar solvents such as sulfolane. The preferred solvent is sulfolane. When using silver(I) tetrafluoroborate, examples include halogenated hydrocarbon solvents such as dichloromethane. The preferred solvent is dichloromethane. The reaction temperature of step (b) is, when using tetramethylammonium fluoride, for example, from 80 °C to 180 °C, preferably from 100 °C to 140 °C. When using silver(I) tetrafluoroborate, it is, for example, from -78 °C to 50 °C, preferably from -78 °C to room temperature.

[0134] (Step D1-3) The compound of formula

[28] can be produced by introducing L into the compound of formula

[27] in a solvent in the presence of a base. For example, when L 1 is iodine, the compound of formula

[28] can be produced by iodinating the compound of formula

[27] in a solvent in the presence of a base. 1 Examples of the base used in the reaction include n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium tetramethylpiperidide. The preferred base is n-butyllithium. Examples of the iodinating agent include iodine, iodine monochloride, N-iodosuccinimide, and 1-chloro-2-iodoethane. The preferred iodinating agent is iodine. Examples of the solvent include ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, and mixed solvents thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -100°C to 40°C, preferably from -78°C to 20°C.

[0135] (Step D1-4) The compound of formula

[29] or a salt thereof can be produced by removing P of the compound of formula

[28] by a deprotection reaction. The deprotection reaction may be carried out under conditions suitable according to the type of P. For example, when two P N2 together with the nitrogen to which they are attached form 2,5-dimethylpyrrole, the compound of formula

[29] or a salt thereof can be produced by reacting the compound of formula

[28] with hydroxylamine in a solvent. N2 Examples of the solvent include alcohol solvents such as ethanol, water, and mixed solvents thereof. The preferred solvent is a mixed solvent of an alcohol solvent and water. N2 The reaction temperature is, for example, from 40°C to 150°C, preferably from 80°C to 130°C. ​​Hydroxylamine hydrochloride may be used instead of hydroxylamine, and in that case, this reaction may be carried out in the presence of a base. Examples of the base include organic bases such as triethylamine and alkali metal salts such as sodium carbonate. A preferred base is triethylamine.

[0136] (Step D1-5) The compound of formula

[21] or a salt thereof can be produced by subjecting the compound of formula

[29] or a salt thereof and the compound of formula

[30] to a Suzuki coupling reaction. For example, the compound of formula

[21] or a salt thereof can be produced by reacting the compound of formula

[29] or a salt thereof and the compound of formula

[30] in a solvent in the presence of a base and a palladium catalyst. Examples of the palladium catalyst used in the reaction include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), and a mixture of palladium(II) acetate and tricyclohexylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl or 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. A preferred palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct. Examples of the base used in the reaction include tripotassium phosphate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and triethylamine. Preferred bases are tripotassium phosphate, cesium carbonate or sodium carbonate. Examples of the solvent include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, 1-propanol, and 2-propanol; hydrocarbon solvents such as toluene, n-hexane, and xylene; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; and mixed solvents of these with water. Preferred solvents are 1,2-dimethoxyethane, toluene, dimethyl sulfoxide, or mixed solvents of these with water. The reaction temperature is, for example, from 20°C to 150°C, preferably from 80°C to 130°C.

[0137] The compound of formula

[30] can be produced according to a known method. Instead of the compound of formula

[30] , the reaction of step D1-5 may be carried out using the corresponding boronic acid ester. For example, the boronic acid ester

[33] can be produced by the production method shown below. Manufacturing method D2 [Chemical formula] [In the formula, R 1 and R 2 are synonymous with the definitions above, R 6 is fluorine or a hydroxyl group. L 2 is a leaving group. Preferred L 2 is chlorine, bromine, iodine, p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy. B(OR 7 )2 is a boronic acid ester. R 7 is, for example, each independently methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, or OR 7 may together with the boron to which they are attached form a cyclic boronic acid ester. Preferred B(OR 7 )2 is pinacol boronic acid ester.]

[0138] (Process D2-1) The compound of formula

[32] can be produced by converting R of the compound of formula

[31] 1 into a tert-butoxy group. This reaction may be carried out according to a known method. R 1 When R is fluorine, the compound of formula

[32] can be produced, for example, by reacting the compound of formula

[31] with sodium tert-butoxide or potassium tert-butoxide in a solvent. Examples of the solvent include ether solvents such as tetrahydrofuran; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, from 0 °C to 100 °C, preferably from room temperature to 85 °C. R 1 When R is a hydroxyl group, the compound of formula

[32] can be produced, for example, according to the method described in Step C2-2 of Production Method C2.

[0139] (Process D2-2) The compound of formula

[33] can be produced by reacting the compound of formula

[32] with a boron compound in a solvent in the presence of a palladium catalyst, an organic phosphorus compound and a base. Examples of the palladium catalyst include palladium(II) acetate, palladium(II) chloride, and tris(dibenzylideneacetone)dipalladium(0). Examples of the organic phosphorus compound include triphenylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl. Instead of the palladium catalyst and the organic phosphorus compound, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct, or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) may be used. Examples of the base include potassium acetate, sodium carbonate, cesium carbonate, and potassium carbonate. A preferred base is potassium acetate. Examples of the boron compound include bis(pinacolato)diboron. Examples of the solvent include ether solvents such as 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; hydrocarbon solvents such as toluene; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. A preferred solvent is dimethyl sulfoxide. The reaction temperature is, for example, from room temperature to 150 °C, preferably from 70 °C to 110 °C.

[0140] [General Production Method E] The compound of formula

[15] or a salt thereof and the compound of formula

[22] or a salt thereof can be produced by the production method shown below. Manufacturing method E1 [Chemical formula] [In the formula, P N1 is synonymous with the definition in the above, and P E1 and P E2 are each independently a protecting group for carboxy. Preferred P E1 and P E2 are each independently methyl, ethyl, tert-butyl, or benzyl. R 8 are each independently methoxy or ethoxy. L 3 is a leaving group. Preferred L 3 is bromine or chlorine.]

[0141] (Process E1-1) The compound of formula

[36] can be produced by reacting the compound of formula

[34] with the compound of formula

[35] in a solvent in the presence of a base. Examples of the base used in the reaction include potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate, and sodium hydride. The preferred base is potassium tert-butoxide. Examples of the solvent include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -78 °C to 100 °C, preferably from 0 °C to 70 °C.

[0142] (Process E1-2) The compound of formula

[37] can be produced by reacting the compound of formula

[36] with formaldehyde (preferably an aqueous formaldehyde solution) in a solvent in the presence of a base. Examples of the base used in the reaction include potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate and sodium hydride. The preferred base is potassium carbonate. Examples of the solvent include ether solvents such as tetrahydrofuran; alcohol solvents such as methanol and ethanol; and polar solvents such as N,N-dimethylformamide and dimethyl sulfoxide. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -78 °C to 100 °C, preferably from 0 °C to 70 °C.

[0143] (Process E1-3) The compound of formula

[39] can be produced by reacting compound

[37] with compound

[38] in a solvent. Examples of the solvent include hydrocarbon solvents such as toluene; alcohol solvents such as methanol and ethanol; and mixed solvents thereof. A preferred solvent is toluene. The reaction temperature is, for example, from 20°C to 150°C, preferably from 80°C to 130°C.

[0144] (Step E1-4) Compound

[40] or a salt thereof can be produced by removing P of compound

[39] by a deprotection reaction. The deprotection reaction may be carried out under conditions suitable for each according to the type of P. For example, when P is ethyl, compound

[40] or a salt thereof can be produced by hydrolyzing compound

[39] in a solvent in the presence of a base. E1 E1 E1 Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, and sodium ethoxide. A preferred base is sodium ethoxide. Examples of the solvent include alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of ethanol and water. The reaction temperature is, for example, from 0°C to 100°C, preferably from 0°C to 40°C.

[0145] (Step E1-5) The compound of formula

[22] or a salt thereof can be obtained by separating it from the compound of formula

[40] or a salt thereof. The separation of the compound of formula

[22] or a salt thereof may be carried out under conditions suitable for the separation by a method well known in the art. For example, the compound of formula

[22] or a salt thereof can be obtained by separating it as a diastereomeric salt with a basic optical resolving agent and then decomposing this salt with an acid. Examples of the basic optical resolving agent include (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. Examples of solvents used for induction into diastereomeric salts include alcohol solvents such as 2-propanol, ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixed solvents of these and water. Preferred solvents are acetonitrile, 1,2-dimethoxyethane or a mixed solvent of these and water. The optical purity of this diastereomeric salt can be increased by recrystallization. Examples of solvents used for recrystallization include ether solvents such as 1,2-dimethoxyethane, polar solvents such as acetonitrile, and mixed solvents of these and water. Preferred solvents are mixed solvents of acetonitrile and water. Examples of acids used for decomposition of the diastereomeric salt include hydrochloric acid, sulfuric acid, and potassium hydrogen sulfate. Preferred acid is hydrochloric acid. Examples of solvents used for decomposition of the diastereomeric salt include ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, water, and mixed solvents of these. Preferred solvents are mixed solvents of ethyl acetate and water.

[0146] (Step E1-6) The compound of formula

[15] or a salt thereof can be produced by removing P of the compound of formula

[22] or a salt thereof by a deprotection reaction. The deprotection reaction may be carried out under conditions suitable according to the type of P. For example, when P is a 2,4-dimethoxybenzyl group, the compound of formula

[15] or a salt thereof can be produced according to Step C2-2 of Production Method C2. N1 by a deprotection reaction. The deprotection reaction may be carried out under conditions suitable according to the type of P. For example, when P N1 is a 2,4-dimethoxybenzyl group, the compound of formula

[15] or a salt thereof can be produced according to Step C2-2 of Production Method C2. N1 is a 2,4-dimethoxybenzyl group, the compound of formula

[15] or a salt thereof can be produced according to Step C2-2 of Production Method C2.

Examples

[0147] Here, the meanings of the abbreviations used in this specification are shown below. DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide THF: tetrahydrofuran CPME: cyclopentyl methyl ether WSC·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0148] Production examples, examples, reference examples, test examples, and formulation examples are illustrated and described below.

[0149] 1 The 1H-NMR spectrum was measured using tetramethylsilane as an internal standard in CDCl3 or DMSO-d6, and all δ values are shown in ppm. Unless otherwise specified, the measurement was performed using a 400 MHz NMR apparatus. 1 The symbols in the 1H-NMR spectrum have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet brs: broad singlet m: multiplet J: coupling constant

[0150] [Production Example 1] Production of 2-(3-(tert-Butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemical formula]

[0151] (Step 1) Production of 1-Bromo-3-(tert-butoxy)-5-fluorobenzene [Chemical formula] Under an argon stream, di-tert-butyl dicarbonate (1.14 g) and magnesium perchlorate (58 mg) were sequentially added to 3-bromo-5-fluorophenol (500 mg) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and 20 minutes. Di-tert-butyl dicarbonate was added to this reaction mixture at 50 °C. The reaction mixture was stirred at 50 °C for 1 hour, further stirred at 65 °C for 1 hour, and then cooled to room temperature. Di-tert-butyl dicarbonate was added to this reaction mixture at room temperature. The reaction mixture was stirred at 65 °C for 3 hours. The reaction mixture was cooled to room temperature, and an n-hexane / ethyl acetate (1 / 1) mixture was added. The reaction mixture was washed successively with 3N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 0 to 20 / 1) to obtain the title compound (437 mg) in a yield of 68%. 1 1H-NMR (CDCl3) δ: 1.35 (s, 9H), 6.62 - 6.66 (m, 1H), 6.92 - 6.98 (m, 2H).

[0152] (Step 2) Production of 2-(3-(tert-butoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemical formula] To a solution of 1-bromo-3-(tert-butoxy)-5-fluorobenzene (437 mg) obtained in Step 1 in DMSO (5 mL), potassium acetate (434 mg), bis(pinacolato)diboron (898 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct (144 mg) were sequentially added at room temperature under an argon atmosphere. The reaction mixture was stirred at 90 °C for 2.5 hours. The reaction mixture was cooled to room temperature. To the reaction mixture, an n-hexane / ethyl acetate (1 / 1) mixture and water were sequentially added. The reaction mixture was stirred at room temperature for 50 minutes and allowed to stand overnight. To the reaction mixture, an n-hexane / ethyl acetate (1 / 1) mixture, water, silica gel, and celite were sequentially added. After stirring the reaction mixture, the insoluble matter was filtered off, and the insoluble matter was washed with an n-hexane / ethyl acetate (1 / 1) mixture. The filtrate was extracted with an n-hexane / ethyl acetate (1 / 1) mixture. The organic layer was washed twice with water and then successively with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin-layer chromatography (developing solvent: n-hexane / ethyl acetate = 10 / 1) to obtain the title compound (443 mg) in a yield of 85%. 1 1H-NMR (CDCl3) δ: 1.33 (s, 12H), 1.36 (s, 9H), 6.77 - 6.82 (m, 1H), 7.18 - 7.23 (m, 2H).

[0153] [Production Example 2] Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid

Chemical formula

[0154] [Step 1] Production of diethyl 2-methyl-3-methylenebutanedioate

Chemical formula

[0155] (Step 2) Production of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester [Chemical formula] To a toluene solution (about 921 mL) of diethyl 2-methyl-3-methylenebutanedioate (equivalent to 2.66 mol) obtained in Step 1, 2,4-dimethoxybenzylamine (468 g) was added dropwise over 2 minutes at room temperature under a nitrogen stream. The reaction mixture was stirred at 120 °C for 5 hours and 45 minutes. The reaction mixture was allowed to stand at room temperature over the weekend. The reaction mixture was cooled with ice to an internal temperature of about 15 °C. 2N hydrochloric acid (1.33 L) was added dropwise to the reaction mixture and stirred. The reaction mixture was separated into layers. The aqueous layer was extracted with toluene (150 mL). The obtained organic layers were combined, washed with a mixture of saturated brine and water (600 mL, saturated brine / water = 1 / 1), dried over sodium sulfate (120 g), concentrated, and dried under reduced pressure at room temperature overnight to obtain a crude product of the title compound (790 g; cis / trans = about 1 / 1, containing 5.5 wt% of toluene). The formation of the title compound was confirmed by HPLC analysis. The measuring instrument and conditions of HPLC are shown below. Measuring instrument: HPLC system Shimadzu Corporation High Performance Liquid Chromatograph Prominence Measuring conditions: Column: Atlantis T3: 5μm, 150mm × 4.6mm (Waters) Column temperature: 40°C Flow rate: 1.15 mL / min. Analysis time: 18 min. Detection wavelength: UV (220 nm) Mobile phase: (Solution A) 10 mM phosphate (sodium) buffer (pH = 2.6), (Solution B) acetonitrile Liquid delivery of the mobile phase: The mixing ratio of Solution A and Solution B (Solution A / Solution B (volume %)) was maintained at 60 / 40 from 0 min to 0.5 min after injection, linearly changed from 60 / 40 to 10 / 90 from 0.5 min to 8 min, maintained at 10 / 90 from 8 min to 12.5 min, linearly changed from 10 / 90 to 60 / 40 from 12.5 min to 13.5 min, and maintained at 60 / 40 from 13.5 min to 18 min. Under the above HPLC measurement conditions, the retention time of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was about 6.6 min, and the retention time of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid ethyl ester was about 6.9 min.

[0156] (Step 3) Production of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemical formula] To the crude product of the mixture of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate obtained in Step 2 (790 g, containing 5.5 wt% toluene), ethanol (1.15 L) was added at room temperature under a nitrogen stream. Sodium ethoxide (20 wt% ethanol solution, 1.15 L) was added dropwise to this reaction mixture at room temperature over 31 minutes. The reaction mixture was stirred at room temperature for 2 hours and 57 minutes. The reaction mixture was ice-cooled, and water (1.84 L) was added dropwise over 33 minutes. CPME (1.8 L) and toluene (1.8 L) were added to this reaction mixture at room temperature, and it was separated into layers (organic layer 1). CPME (1.8 L) was added to this aqueous layer, and it was separated into layers (organic layer 2). 1.8 L of the solvent was distilled off from this aqueous layer. 6N hydrochloric acid (110 mL) was added dropwise to this aqueous layer under ice-cooling, and ethyl acetate (1.8 L) was added. 6N hydrochloric acid (300 mL) was added dropwise to this mixture under ice-cooling, and it was stirred for about 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% aqueous sodium hydrogen sulfate solution (300 mL), and ethanol (300 mL) were sequentially added to this mixture under ice-cooling. This mixture was stirred at room temperature overnight. Ethyl acetate (600 mL) was added to this mixture, and it was separated into layers. This aqueous layer was extracted twice with ethyl acetate (600 mL). The obtained organic layers were combined (excluding organic layer 1 and organic layer 2) and washed with a mixture of saturated brine and water (1 L, saturated brine / water = 1 / 1). Sodium sulfate (120 g) and activated carbon (30 g) were added to this organic layer, and it was stirred at room temperature for 1 hour. This mixture was filtered through celite to remove the insoluble matter. This insoluble matter was washed with ethyl acetate (3 L). The obtained filtrates were combined and concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain the crude product of the title compound (561 g). Separately, the above organic layer 1 and organic layer 2 were combined and concentrated. Toluene (450 mL) and water (450 mL) were added to this residue, and the layers were separated. This aqueous layer was washed twice with toluene (450 mL). Ethyl acetate (450 mL) was added to this aqueous layer. While ice-cooling, 6N hydrochloric acid (70 mL) was added dropwise to this mixture. Ethyl acetate (300 mL) was added to this mixture, and the layers were separated. This aqueous layer was extracted with ethyl acetate (150 mL). The obtained ethyl acetate organic layers were combined and washed with a mixed solution of saturated brine and water (225 mL, saturated brine / water = 1 / 1). Sodium sulfate (30 g) and activated carbon (7.5 g) were added to this organic layer, and the mixture was stirred at room temperature for 1 hour. This mixture was filtered to remove the insoluble matter. This insoluble matter was washed with ethyl acetate (750 mL). The obtained filtrates were combined and concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product (87.3 g) of the title compound. CPME (3 L) was added to a mixture obtained by combining this crude product with the crude product of the title compound obtained above under a nitrogen stream. This mixture was stirred at 120 °C. This mixture was stirred for 17 hours and 34 minutes and gradually cooled to room temperature. This mixture was ice-cooled and stirred at an internal temperature of about 1 °C for 3 hours. The precipitate was collected by filtration and washed with cold CPME (900 mL). The precipitate was dried under reduced pressure at 50 °C overnight to obtain the title compound (585 g) in a three-step yield of 75%. The formation of the title compound was confirmed by HPLC analysis and NMR. The measuring instrument and conditions for HPLC were the same as in Step 2. The retention time of the title compound under these HPLC measurement conditions was about 3.1 minutes. 1 1H-NMR (CDCl3) δ: 1.33 (d, 3H, J = 6.5 Hz), 2.68 - 2.85 (m, 2H), 3.33 - 3.48 (m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.42 - 6.46 (m, 2H), 7.11 - 7.15 (m, 1H).

[0157] Production of Diastereomeric Salt of (3R,4R)-1-(2,4-Dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic Acid and (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol

Chemical Structure

[0158] (Step 5) Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid

Chemical formula

[0159] [Production Example 3] Production of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid

Chemical formula

[0160] (Step 1) Production of diethyl 2-methyl-3-methylenesuccinate

Chemical formula

[0161] (Step 2) Production of a mixture of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate

Chemical formula

[0162] (Step 3) Production of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid [Chemical formula] To a crude product (790 g, containing 5.5 wt% toluene) of a mixture of ethyl (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylate obtained in Step 2, ethanol (1.15 L) was added at room temperature under a nitrogen stream. To this reaction mixture, sodium ethoxide (20 wt% ethanol solution, 1.15 L) was added dropwise at room temperature over 31 minutes. The reaction mixture was stirred at room temperature for 2 hours and 57 minutes. The reaction mixture was ice-cooled, and water (1.84 L) was added dropwise over 33 minutes. CPME (1.8 L) and toluene (1.8 L) were added to this reaction mixture at room temperature, and it was separated into layers (organic layer 1). CPME (1.8 L) was added to this aqueous layer, and it was separated into layers (organic layer 2). 1.8 L of the solvent was distilled off from this aqueous layer. 6N hydrochloric acid (110 mL) was added dropwise to this aqueous layer under ice-cooling, and ethyl acetate (1.8 L) was added. 6N hydrochloric acid (300 mL) was added dropwise to this mixture under ice-cooling, and it was stirred for about 10 minutes. Water (2.2 L), 6N hydrochloric acid (50 mL), water (1.0 L), 10 wt% aqueous sodium hydrogen sulfate solution (300 mL), and ethanol (300 mL) were sequentially added to this mixture under ice-cooling. This mixture was stirred at room temperature overnight. Ethyl acetate (600 mL) was added to this mixture, and it was separated into layers. This aqueous layer was extracted twice with ethyl acetate (600 mL). The obtained organic layers were combined (excluding organic layer 1 and organic layer 2) and washed with a mixture of saturated brine and water (1 L, saturated brine / water = 1 / 1). Sodium sulfate (120 g) and activated carbon (30 g) were added to this organic layer, and it was stirred at room temperature for 1 hour. This mixture was filtered through celite to remove insoluble matters. This insoluble matter was washed with ethyl acetate (3 L). The obtained filtrates were combined and concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product (561 g) of the title compound. Separately, the above organic layer 1 and organic layer 2 were combined and concentrated. Toluene (450 mL) and water (450 mL) were added to this residue, and the layers were separated. This aqueous layer was washed twice with toluene (450 mL). Ethyl acetate (450 mL) was added to this aqueous layer. While ice-cooling, 6N hydrochloric acid (70 mL) was added dropwise to this mixture. Ethyl acetate (300 mL) was added to this mixture, and the layers were separated. This aqueous layer was extracted with ethyl acetate (150 mL). The obtained ethyl acetate organic layers were combined and washed with a mixed solution of saturated brine and water (225 mL, saturated brine / water = 1 / 1). Sodium sulfate (30 g) and activated carbon (7.5 g) were added to this organic layer, and the mixture was stirred at room temperature for 1 hour. This mixture was filtered to remove the insoluble matter. This insoluble matter was washed with ethyl acetate (750 mL). The obtained filtrates were combined and concentrated, and dried under reduced pressure at room temperature for 3 hours to obtain a crude product (87.3 g) of the title compound. CPME (3 L) was added to a mixture obtained by combining this crude product with the crude product of the title compound obtained above under a nitrogen stream. This mixture was stirred at 120 °C. This mixture was stirred for 17 hours and 34 minutes and gradually cooled to room temperature. This mixture was ice-cooled and stirred at an internal temperature of about 1 °C for 3 hours. The precipitate was collected by filtration and washed with cold CPME (900 mL). This precipitate was dried under reduced pressure at 50 °C overnight to obtain the title compound (585 g) in a three-step yield of 75%. The formation of the title compound was confirmed by HPLC analysis and NMR. The measuring instrument and conditions for HPLC were the same as in Step 2. The retention time of the title compound under these HPLC measurement conditions was about 3.1 minutes. 1 1H-NMR (CDCl3) δ: 1.33 (d, 3H, J = 6.5 Hz), 2.68 - 2.85 (m, 2H), 3.33 - 3.48 (m, 2H), 3.80 (s, 6H), 4.43 (s, 2H), 6.42 - 6.46 (m, 2H), 7.11 - 7.15 (m, 1H).

[0163] Preparation of Diastereomeric Salt of (3R,4R)-1-(2,4-Dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic Acid and (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol

Chemical Structure

[0164] (Step 5) Production of (3R,4R)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid

Chemical formula

[0165] (Step 6) Preparation of (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid

Chem.

[0166] [Production Example 4] Production of 3-Hydrazinyl-5-(trifluoromethyl)pyridine

Chemical Structure

[0167] (Step 1) Production of 3-Fluoro-5-hydrazinylpyridine

Chemical Structure

[0168] [Production Example 5] Production of 3 - Hydrazinyl - 5 - (trifluoromethyl)pyridine

Chemical Structure

[0169] (Step 1) Production of 3 - Hydrazinyl - 5 - (trifluoromethyl)pyridine

Chemical Structure

[0170] The seed crystal of the title compound used in Step 1 was obtained by purifying the residue obtained by performing the same reaction as in this step by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1).

[0171] [Production Example 6] Production of 5-Hydrazinyl-2-(trifluoromethyl)pyrimidine [Chemical Formula]

[0172] [Step 1] Production of 5-Hydrazinyl-2-(trifluoromethyl)pyrimidine [Chemical Formula] Under an argon atmosphere, hydrazine monohydrate (4.27 mL) and 2-propanol (1 mL) were added to 5-bromo-2-(trifluoromethyl)pyrimidine (2 g). Using an explosion-proof shield, the reaction mixture was stirred at 95 °C for 22 hours. The reaction mixture was cooled to room temperature. Water and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 5 times with ethyl acetate. The obtained organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. A mixed solution of n-hexane / ethyl acetate (3 / 1) was added to this residue at room temperature. This suspension was stirred at room temperature. The solid was collected by filtration from this suspension and washed with a mixed solution of n-hexane / ethyl acetate (3 / 1). By drying this solid under reduced pressure at room temperature, the title compound (647 mg) was obtained in a yield of 41%. 1 H-NMR (DMSO-D6) δ: 4.43 (br s, 2H), 7.94 (br s, 1H), 8.33 (s, 2H).

[0173] [Example 1] Synthesis of (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemical formula]

[0174] (Step 1) Preparation of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole [Chemical formula] To 1H-pyrazol-3-amine (100 g) at room temperature, acetic acid (1 L) was added and stirred for 5 minutes. To this mixture, 2,5-hexanedione (148 mL) was added at room temperature and stirred for 5 minutes. This reaction mixture was stirred at 120 °C for 2.5 hours and cooled to room temperature. Water (1 L) was added to this reaction mixture at room temperature. This reaction mixture was stirred at room temperature for 50 minutes. The precipitated solid was collected by filtration and washed with water (1 L). The obtained wet solid was dried overnight at room temperature and normal pressure, and then dried under reduced pressure at 65 °C for 3 days and 8.5 hours to obtain the title compound (172.47 g) in a yield of 89%. 1 H-NMR (CDCl3) δ: 2.11 (s, 6H), 5.90 (s, 2H), 6.25 (d, 1H, J = 2.4 Hz), 7.51 (d, 1H, J = 2.4 Hz).

[0175] (Step 2) Preparation of a mixture of 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole [Chemical formula] Under an argon stream, DMF (100 mL) was added to sodium hydride (14.9 g) under ice cooling. A suspension of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40 g) obtained in Step 1 in DMF (150 mL) was added dropwise to this mixed solution over 20 minutes under ice cooling. The dropping funnel used was washed with DMF (50 mL), and the washing solution was added to the reaction mixture. This reaction mixture was stirred for 1.5 hours under water cooling. Tetrabutylammonium bromide (0.80 g) was added to this reaction mixture under ice cooling. This reaction mixture was stirred for 15 minutes under ice cooling. A solution of dibromodifluoromethane (45 mL) in DMF (50 mL) was added dropwise to this reaction mixture over 15 minutes under ice cooling. This reaction mixture was stirred for 2 hours and 10 minutes under water cooling. Dibromodifluoromethane (20 mL) was added dropwise to this reaction mixture under water cooling under an argon atmosphere. This reaction mixture was stirred for 40 minutes under water cooling and then allowed to stand overnight. A saturated aqueous ammonium chloride solution (200 mL) was added to this reaction mixture under ice cooling. Ethyl acetate and water were added to this reaction mixture. This reaction mixture was filtered through celite and separated into layers. This aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, saturated brine was added thereto, and the mixture was filtered through celite and separated into layers. This aqueous layer was extracted with ethyl acetate. The obtained organic layers were combined, dried over sodium sulfate, and concentrated. Toluene (250 mL) was added to this residue and concentrated. This operation was performed again. Ethyl acetate (about 150 mL) was added to this residue, and the insoluble matter was filtered off. This insoluble matter was washed with ethyl acetate. The obtained filtrates were combined and concentrated. This residue was dried under reduced pressure at room temperature for 10 minutes while stirring. This residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 20 / 1) to obtain the title compound (40.6 g, containing 3.7 wt% of hexane, 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole: 1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole = about 3:1) in a yield of 54%. 11H-NMR (CDCl3) δ: 2.03 (s, 1.5H), 2.18 (s, 4.5H), 5.89 (s, 1.5H), 5.91 (s, 0.5H), 6.39 - 6.41 (m, 1H), 7.86 - 7.88 (m, 1H).

[0176] (Engineering 3) Preparation of a mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole and 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole [Chemical formula] To a solution of a mixture of 1-(bromodifluoromethyl)-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole and 1-(bromodifluoromethyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-pyrazole (40.6 g, containing 3.7 wt% hexane) in sulfolane (400 mL) was added tetramethylammonium fluoride (13.0 g) at room temperature under an argon stream. The reaction mixture was stirred at 100 °C for 1 hour. Tetramethylammonium fluoride (9.4 g) was added to the reaction mixture at 100 °C. The reaction mixture was stirred at 100 °C for 1 hour and 15 minutes. Tetramethylammonium fluoride (10 g) was added to the reaction mixture at 100 °C. The reaction mixture was stirred at 100 °C for 40 minutes. Further, tetramethylammonium fluoride (5 g) was added to the reaction mixture at 100 °C. The reaction mixture was stirred at 100 °C for 2 hours and 5 minutes and then cooled to room temperature. Water (400 mL) and a saturated aqueous sodium hydrogen carbonate solution (200 mL) were sequentially and slowly added to the reaction mixture under ice-cooling. An n-hexane / ethyl acetate (2 / 3) mixture (400 mL) was added to the reaction mixture. The reaction mixture was filtered through celite and separated into layers. The organic layer was washed with saturated brine. The obtained aqueous layers were combined and extracted with an n-hexane / ethyl acetate (2 / 3) mixture (300 mL). The organic layer was washed with saturated brine. The obtained organic layers were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 25 / 1) to obtain the title compound (21.85 g, containing 24.4 wt% n-hexane, 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole:5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole = about 6:1) in a yield of 51%. 11H-NMR (CDCl3) δ: 2.00 (s, 0.86H), 2.16 (s, 5.1H), 5.89 (s, 1.7H), 5.91 (s, 0.29H), 6.40 (d, 0.86H, J = 2.8 Hz), 6.42 (d, 0.14H, J = 1.6 Hz), 7.83 (d, 0.14H, J = 1.6 Hz), 7.87 (d, 0.86H, J = 2.8 Hz).

[0177] (Project 4) Preparation of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-iodo-1-(trifluoromethyl)-1H-pyrazole [Chemical formula] To a solution of a mixture of 3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole and 5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(trifluoromethyl)-1H-pyrazole (21.85 g, containing 24.4 wt% of n-hexane) in THF (180 mL) was added dropwise a solution of n-butyllithium in n-hexane (1.55 M, 51.1 mL) over 5 minutes at -70 °C under an argon atmosphere. The reaction mixture was stirred at -70 °C for 25 minutes. To the reaction mixture was added dropwise a solution of iodine (18.3 g) in THF (50 mL) over 5 minutes at -70 °C. The dropping funnel used was washed with THF (10 mL), and the washing solution was added to the reaction mixture. The reaction mixture was stirred at -70 °C for 30 minutes. Iodine (0.90 g) was added to the reaction mixture at -70 °C. The reaction mixture was stirred at -70 °C for 0.5 hour. Water (250 mL) and ethyl acetate (250 mL) were sequentially added to the reaction mixture at -70 °C. The reaction mixture was stirred at room temperature and separated. The organic layer was washed sequentially with a 10 wt% aqueous sodium bisulfite solution (250 mL) and saturated brine (150 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50 / 1 to 30 / 1). The fractions containing the title compound were collected and concentrated. n-Hexane was added to the residue. The residue was concentrated until its weight reached 27.5 g. n-Hexane (20 mL) was added to the residue. The suspension was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with n-hexane (30 mL), and dried under reduced pressure to obtain the title compound (17.14 g) in a yield of 67%. Further, the filtrate was concentrated. The residue was crystallized from n-hexane to obtain the title compound (1.63 g) in a yield of 6.4%. 1 H-NMR (CDCl3) δ: 2.15 (s, 6H), 5.88 (s, 2H), 6.60 (s, 1H).

[0178] (Step 5) Preparation of 5-iodo-1-(trifluoromethyl)-1H-pyrazol-3-amine

Chemical Structure

[0179] (Step 6) Production of 5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-amine

Chemical formula

[0180] (Step 7) Production of (3R,4R)-N-(5-(3-(tert-butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chemical Structure

[0181] (Step 8) Production of (3R,4R)-N-(5-(3-fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chemical Structure

[0182] (Step 9) Production of (3R,4R)-N-(5-(3-(tert-Butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemical Structure Diagram] (3R,4R)-N-(5-(3-Fluoro-5-hydroxyphenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide (30 mg) obtained in Step 8 was sequentially added with di-tert-butyl dicarbonate, chloroform (1 mL), and magnesium perchlorate at room temperature. The reaction mixture was stirred at 55 °C for 0.5 hour. Magnesium perchlorate was added to this reaction mixture at 55 °C. This reaction mixture was stirred at 55 °C for 1 hour and 10 minutes. Magnesium perchlorate was further added to this reaction mixture at 55 °C. This reaction mixture was stirred at 55 °C for 20 minutes. This reaction mixture was cooled to room temperature, and ethyl acetate was added. This reaction mixture was washed successively with 1N hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel thin layer chromatography (developing solvent: chloroform / methanol = 15 / 1) to obtain the title compound (19.2 mg) in a yield of 56%.

[0183] (Step 10) Preparation of Crystals of (3R,4R)-N-(5-(3-(tert-Butoxy)-5-fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide The title compound (100 mg) was dissolved by stirring in ethanol (0.4 mL) at 65 °C for 8 minutes. Water (0.4 mL) was added dropwise to this mixed solution at 65 °C over 2 minutes. This mixed solution was stirred at 65 °C for 10 minutes. This mixed solution was stirred for 2 hours until it reached 25 °C. Further, this mixed solution was stirred at room temperature for 2 hours. The solid precipitated from this mixed solution was collected by filtration. The obtained solid was washed with ethanol / water (= 1 / 1) and dried under reduced pressure at 60 °C to obtain crystals of the title compound (87.8 mg) in a yield of 88%.

[0184] [Example 2] Synthesis of (3R,4R)-N-(5-(3-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide [Chemical]

[0185] (Process 1) Preparation of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene [Chemical] To a solution of 1-bromo-3,5-difluorobenzene (5.97 mL) in 1,3-dimethyl-2-imidazolidinone (10 mL) was added sodium hydride (4.14 g) at room temperature under a nitrogen stream. While cooling with water, 1,1,1-trifluoro-2-methylpropan-2-ol (8 mL) was added dropwise to this mixture. To this reaction mixture was added 1,3-dimethyl-2-imidazolidinone (2 mL) at room temperature. To this reaction mixture was added 1,1,1-trifluoro-2-methylpropan-2-ol (3.16 mL) dropwise at room temperature. The addition of all these alcohols took 45 minutes. This reaction mixture was stirred at room temperature for 20 minutes, at 80 °C for 20 minutes, at 100 °C for 20 minutes, and at 130 °C for 20 hours and 40 minutes. Water was added to this reaction mixture while cooling with ice. This mixture was extracted three times with n-hexane. The combined organic layers were washed three times with water, washed with saturated brine, dried over sodium sulfate, and concentrated at 35 °C under a reduced pressure of 140 mmHg. This residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (8.31 g; containing 12 wt% of n-hexane) in a yield of 47%. 1 H-NMR (DMSO-D6) δ: 1.46 (s, 6H), 7.08 (dt, 1H, J = 10.2, 2.1 Hz), 7.18 (s, 1H), 7.39 - 7.45 (m, 1H).

[0186] (Process 2) Preparation of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene [Chemistry] To a solution of ethylene glycol (69 mL) of a mixture of 1-bromo-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene (2.86 g; containing 12 wt% of n-hexane) obtained in Step 1 and the same compound (10.2 g; containing 12 wt% of n-hexane) obtained in the same manner as in Step 1 were added butyl vinyl ether (19.77 mL), triethylamine (10.65 mL), 1,1'-bis(diphenylphosphino)ferrocene (1.271 g), and palladium(II) acetate (0.257 g) at room temperature. The reaction mixture was stirred at 110 °C for 19 hours under an argon atmosphere. The reaction mixture was cooled to room temperature. Water and n-hexane were added to the reaction mixture. The mixture was filtered through celite. The filtrate was extracted twice with n-hexane. The combined organic layers were washed twice with water and then with saturated brine, dried over magnesium sulfate, and concentrated at 35 °C under a reduced pressure of 140 mmHg. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5) to obtain the title compound (6.39 g; containing 15 wt% of n-hexane) in a yield of 44%. 1 H-NMR (DMSO-D6) δ: 0.95 (t, 3H, J = 7.3 Hz), 1.40 - 1.51 (m, 2H), 1.44 (s, 6H), 1.69 - 1.76 (m, 2H), 3.84 (t, 2H, J = 6.3 Hz), 4.39 (d, 1H, J = 3.0 Hz), 4.90 (d, 1H, J = 3.0 Hz), 6.96 - 7.01 (m, 1H), 7.12 (s, 1H), 7.24 - 7.29 (m, 1H).

[0187] (Step 3) Preparation of 1-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)ethan-1-one [Chemistry] To a solution of 1-(1-butoxyvinyl)-3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)benzene (6.39 g; containing 15 wt% of n-hexane) in THF (25 mL) was added 2N hydrochloric acid (12.71 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour and 10 minutes. To this reaction mixture was added 2N aqueous sodium hydroxide solution under ice-cooling to adjust the pH to 12. The mixture was extracted twice with n-hexane. The combined organic layers were washed twice with saturated brine, dried over sodium sulfate, and concentrated at 35 °C under a reduced pressure of 120 mmHg. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (4.09 g; containing 6 wt% of n-hexane) in a yield of 86%. 1 H-NMR (DMSO-D6) δ: 1.47 (s, 6H), 2.60 (s, 3H), 7.32 (dt, 1H, J = 9.7, 2.3 Hz), 7.42 - 7.43 (m, 1H), 7.58 - 7.62 (m, 1H).

[0188] (Step 4) Preparation of Ethyl 4-(3-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-2,4-dioxobutanoate

Chemical Structure

[0189] (Step 5) Preparation of ethyl 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylate

Chemical Structure

[0190] (Step 6) Production of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazole-3-carboxylic acid

Chemical Structure

[0191] (Step 7) Preparation of tert-butyl (5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)carbamate

Chemical Structure

[0192] (Step 8) Preparation of 5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-amine

Chemical Structure

[0193] (Step 9) Preparation of (3R,4R)-N-(5-(3-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)phenyl)-1-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chemical Structure

[0194] [Example 3] Synthesis of (3R,4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chemical formula

[0195] Production of Benzyl 4-(3-Fluoro-5-(trifluoromethoxy)phenyl)-2,4-dioxobutanoate

Chemical formula

[0196] Production of Benzyl 5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate

Chemical formula

[0197] (Step 3) Preparation of 5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylic acid [Chemical Structure] To a solution of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (589.5 mg) in ethyl acetate (5.90 mL) was added 5 wt% palladium on carbon (88 mg) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere at 1 atm. After changing to a nitrogen atmosphere, the palladium on carbon in the reaction solution was filtered off through celite. The used celite was washed with a mixture of ethyl acetate / methanol (9 / 1). The obtained filtrates were combined and concentrated. Toluene was added to the residue and concentrated. The residue was dried under reduced pressure at room temperature to obtain the title compound (425.9 mg) in 89% yield. 1 H-NMR (DMSO-D6) δ: 7.06 - 7.09 (m, 1H), 7.33 (s, 1H), 7.45 (ddd, 1H, J = 9.2, 2.4, 1.5 Hz), 7.47 - 7.52 (m, 1H), 7.96 (ddd, 1H, J = 9.2, 2.5, 2.1 Hz), 8.44 - 8.47 (m, 1H), 8.73 (d, 1H, J = 2.5 Hz), 13.23 (br s, 1H).

[0198] (Step 4) Preparation of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)carbamate

Chem.

[0199] (Step 5) Preparation of 5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-amine

Chem.

[0200] (Process 6) Preparation of ((3R,4R)-N-(5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide)

Chem.

[0201] [Example 4] Preparation of the monohydrate of ((3R,4R)-N-(5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide)

Chem.

[0202] [Example 5] Synthesis of ((3R,4R)-N-(5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chemical formula

[0203] (Step 1) Preparation of benzyl 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate

Chemical formula

[0204] (Step 2) Production of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid

Chemical Structure

[0205] (Step 3) Preparation of tert-butyl (5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)carbamate [Chemical formula] To a solution of the crude product of 5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (525 mg) obtained in Step 2 and triethylamine (0.403 mL) in tert-butanol (5 mL) / toluene (10 mL) was added diphenylphosphoric azide (0.311 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 97 / 3 to 70 / 30) to obtain the title compound (420 mg) in a 68% yield over two steps. The formation of the title compound was confirmed by thin layer chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1, Rf value: 0.46).

[0206] (Step 4) Preparation of 5-(3-Fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-amine

Chem.

[0207] (Step 5) Preparation of ((3R,4R)-N-(5-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)-4-methyl-5-oxopyrrolidine-3-carboxamide

Chem.

[0208] Compounds of other Examples were obtained by the same method as the above general production method, production examples, and examples, and by using other known methods as necessary. The structural formulas and physical property data of the compounds of Examples 1 to 40 are shown in the following table.

[0209] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

Table 5-8

[0210]

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

[0211] [Reference Example] Compounds A to H represented by the following table were obtained based on the description in International Publication No. 2013 / 031922.

Table 7-1

Table 7-2

[0212] Metabolites 1, 3, and 5 (metabolites of the compounds of Examples 1, 3, and 5) and metabolites C to H (metabolites of compounds C to H) represented by the following table were obtained based on the descriptions of the above Examples and WO 2013 / 031922, respectively. [Table 8-1] [Table 8-2]

[0213] [Test Example 1] Evaluation of SGLT1 inhibitory activity The SGLT1 inhibitory activity (IC 50 value) of the test compound was calculated based on the intracellular uptake amount of the labeled form of α-methyl-D-glucopyranoside ( 14 C-AMG) transported by SGLT1. 1) Construction of human SGLT1 expression plasmid Using pCMV6-hSGLT1 (OriGene) as a template, an NheI recognition cleavage sequence was added in front of the Kozac consensus sequence derived from the vector, and a stop codon TAG and a SalI recognition cleavage sequence were added immediately after the protein translation region of human SGLT1. A DNA fragment containing human SGLT1 was amplified by PCR (Polymerase Chain Reaction). After digesting the purified DNA fragment with restriction enzymes NheI and SalI, it was ligated with pcDNA3.1(+) digested with NheI and XhoI to construct a human SGLT1 expression plasmid pcDNA-hSGLT1. The nucleotide sequence of human SGLT1 inserted into the vector was completely identical to the protein translation region of the human SGLT1 sequence (Accession number NM_000343) registered in GenBank, and the sequence of the connection part with the vector was also as expected.

[0214] 2) Establishment of human SGLT1 stable expression cell line The human SGLT expression plasmid pcDNA-hSGLT1 was transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen), and drug-resistant cell lines were selected in the presence of G418 (Nacalai Tesque). From the obtained drug-resistant cell lines, the 14 C-AMG uptake per cell and the 14 ratio of C-AMG uptake (S / B ratio) when phlorizin, an SGLT inhibitor, was added were measured. The cell line with the highest ratio was selected as the human SGLT1 stable expression cell line.

[0215] 3) Evaluation of SGLT1 inhibitory activity The human SGLT1 stable expression cell line was seeded at 5×10 TM cells / well in a BioCoat 4 Poly-D-Lysine 96 well plate with Lid (Becton, Dickinson and Company) and cultured overnight at 37°C in 5% CO2. The medium was replaced with 100 μL / well of Na(-) buffer (140 mM choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4), and the plate was left standing at 37°C in 5% CO2 for 20 minutes. After removing the Na(-) buffer, a test compound solution prepared using Na(+) buffer (140 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) containing BSA was added at 40 μL / well. Furthermore, 40 μL / well of Na(+) buffer containing 8 kBq of 14 C-AMG and 2 mM AMG was added and mixed. For the blank, 40 μL / well of Na(-) buffer containing BSA was added, and furthermore 8 kBq of 1440 μL / well of Na(-) buffer containing C-AMG and 2 mM AMG was added and mixed. After standing at 37 °C and 5% CO2 for 1 hour, the cells were washed twice with 100 μL / well of ice-cold wash buffer (100 mM AMG, 140 mM choline chloride, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, 5 mM Tris, pH 7.4) to stop the reaction. 50 μL / well of 0.2 N aqueous NaOH solution was added to prepare cell lysates. 14 For the evaluation of the uptake ability of C-AMG, the entire amount of cell lysate was transferred to an OptiPlate 96 (Perkin-Elmer) with 100 μL / well of MicroScint-40 (Perkin-Elmer) dispensed, and measured with a TOPCOUNT NXT (Perkin-Elmer) 14 for the CPM of C. The value obtained by subtracting the average CPM of the blank well from the average CPM of each treated well was used as the data. The inhibition rate of each concentration of the test compound was calculated from the following formula: [(A - B) / A] × 100 (where A represents the data of the solvent control and B represents the data of the test compound treatment) The IC 50 value (50% inhibitory concentration) was calculated from the two concentrations sandwiching 50% inhibition rate and their inhibition rates. By this test, it was confirmed that Compound 1 has SGLT1 inhibitory activity. This test was also conducted for other example compounds. The results are shown in the following table.

[0216]

Table 9

[0217] [Test Example 2] OGTT (Oral Glucose Tolerance Test) Male, SD rats (8 weeks old, Charles River Japan, Inc.) that had been fasted for approximately 4 hours (6 rats per group) were orally administered a vehicle (0.5% methylcellulose solution) or Compound 1 (1, 3, or 10 mg / kg) suspended in 0.5% methylcellulose solution at 5 mL / kg. Sixteen hours later, glucose loading was performed by orally administering a 0.4 g / mL glucose solution at 5 mL / kg. Blood was collected from the tail vein immediately before glucose loading, 30 minutes after loading, 60 minutes after loading, and 120 minutes after loading, and blood glucose levels were measured using an automated biochemical analyzer (HITACHI, model 7180). The results are shown in Figure 1. The data represent the mean ± standard deviation of the ratio (% of Vehicle) of the area under the curve (ΔAUC) of blood glucose levels up to 120 minutes after glucose loading in the compound-administered groups to the vehicle group. Statistical analysis was performed using Steel's multiple test. The significance level was set at 5% two-sided. As a result, Compound 1 significantly decreased blood glucose levels after glucose loading compared to the vehicle.

[0218] [Test Example 3] OGTT (Oral Glucose Tolerance Test) Male, SD rats (8 weeks old, Charles River Japan, Inc.) that had been fasted for approximately 4 hours (5 rats per group) were orally administered a vehicle (0.5% methylcellulose solution) or Compound 1, Compound A, or Compound B (each 3 mg / kg) suspended in 0.5% methylcellulose solution at 5 mL / kg. Sixteen hours later, glucose loading was performed by orally administering a 0.4 g / mL glucose solution at 5 mL / kg. Blood was collected from the tail vein immediately before glucose loading, 30 minutes after loading, 60 minutes after loading, and 120 minutes after loading, and blood glucose levels were measured using an automated biochemical analyzer (HITACHI, model 7180). The results are shown in Figure 2. The data represent the mean ± standard deviation of the ratio (% of Vehicle) of the area under the curve (ΔAUC) of blood glucose levels up to 120 minutes after glucose loading in the compound-administered groups to the vehicle group. Statistical analysis was performed using Dunnett's multiple group test. The significance level was set at 5% two-sided. As a result, Compound 1 significantly decreased blood glucose levels after glucose loading compared to the vehicle.

[0219] [Test Example 4] Ames test (Reverse Mutation Test) Metabolites 1, 3, and 5 and Metabolites C through H were tested as follows. The purpose of this test was to evaluate the presence or absence of the ability to induce reverse mutations in the standard strains of Salmonella typhimurium (TA98, TA1537, TA100, and TA1535) and Escherichia coli (WP2uvrA) in the presence or absence of a rat liver metabolic activation system (S9 mix) for each metabolite. In this test, dimethyl sulfoxide (DMSO, 100 μL / plate) was used as the solvent. The test was conducted using the pre-incubation method in the presence or absence of S9 mix. In the test without S9 mix, sodium phosphate buffer (pH 7.4) was added. 0.5 mL of S9 mix or 0.5 mL of 0.1 mol / L sodium phosphate buffer (pH 7.4) and 0.1 mL of the bacterial culture solution were added to test tubes containing 0.1 mL of the negative control substance (DMSO only), the metabolite, or the positive control substance. This mixture was pre-incubated with shaking at 37 °C for 20 minutes. After pre-incubation, 2 mL of top agar was added, the mixture was mixed with a vortex mixer, and seeded onto plates. Two plates were used for each treatment. Each plate was incubated at 37 ± 1 °C for 48 hours or more, and the reverse mutation colonies were counted. Next, the average number of reverse mutation colonies per treated plate was calculated. The presence or absence of growth inhibition due to the antibacterial action of the test compound and precipitation of the test compound was observed visually or with a stereomicroscope. When the average number of reverse mutation colonies showed a dose-dependent increase exceeding twice that of the negative control at a dose where the average number of reverse mutation colonies was 1 or more, the result was judged positive. Evaluation was based on the average value without using statistical comparison.

[0220] The results of this test are shown in the following table. As a result, Metabolites 1, 3, and 5 did not show the ability to induce reverse mutations in any of the test strains, whereas Metabolites C through H showed the ability to induce reverse mutations in at least one test strain in the presence and / or absence of S9 mix. Specifically, it is described below. Metabolite C showed the ability to induce reverse mutations in the test strains of TA98 in the presence of S9 mix and TA100 in the presence of S9 mix. Metabolite D showed the ability to induce reverse mutations in the test strains of TA98 and TA1537 in the presence of S9 mix. Metabolite E showed the ability to induce reverse mutations in the test strains of TA98, TA1537, TA100 and TA1535 in the presence of S9 mix, and in the test strain of TA1537 in the absence of S9 mix. Metabolite F showed the ability to induce reverse mutations in the test strains of TA98, TA1537 and TA100 in the presence of S9 mix, and in the test strain of WP2uvrA in the absence of S9 mix. Metabolite G showed the ability to induce reverse mutations in the test strain of TA100 in the presence of S9 mix, and in the test strain of TA1535 in the absence of S9 mix. Metabolite H showed the ability to induce reverse mutations in the test strains of TA98, TA1537 and TA100 in the presence of S9 mix.

[0221]

Table 10

[0222]

Table 11

[0223]

Table 12

[0224]

Table 13

[0225]

Table 14

[0226]

Table 15

[0227]

Table 16

[0228]

Table 17

[0229]

Table 18

[0230]

Table 19

[0231]

Table 20

[0232]

Table 21

[0233]

Table 22

[0234]

Table 23

[0235]

Table 24

[0236]

Table 25

[0237] [Table 26]

[0238] [Table 27]

[0239] [Table 28]

[0240] [Table 29]

[0241] [Table 30]

[0242] [Test Example 5] Combined effect with SGLT2 inhibitor in OGTT (Oral Glucose Tolerance Test) Male Zucker Fatty rats (7 weeks old, Charles River Laboratories Japan, Inc.) that had been fasted overnight were grouped based on blood glucose levels and body weight (8 rats per group). After grouping, the vehicle (0.5% methylcellulose solution), compound 1 alone (1 mg / kg), dapagliflozin alone (3 mg / kg), or a combination of compound 1 and dapagliflozin was orally administered at 5 mL / kg. Four hours later, a glucose load was performed by orally administering a 0.4 g / mL glucose solution at 5 mL / kg. Blood was collected from the tail vein immediately before the glucose load, 30 minutes, 60 minutes, 120 minutes, and 240 minutes after the load. Blood glucose levels were measured using an automated biochemical analyzer (HITACHI, model 7180). The results were represented by the changes in blood glucose levels, the values at 30 minutes after glucose loading, and the values at 60 minutes after glucose loading. For statistical analysis, Tukey-kramer's multiple group test was performed. The significance level was set at 5% on both sides. As a result, the combined use of Compound 1 and dapagliflozin significantly reduced blood glucose levels compared to each single agent. The results are shown in Figures 3 to 5.

[0243] [Test Example 6] Combined effect with DPP4 inhibitor in OGTT (Oral Glucose Tolerance Test) Male Zucker Fatty rats (8 weeks old, Charles River Laboratories Japan, Inc.) that had fasted overnight were used, and they were grouped based on blood glucose levels and body weight (8 rats per group). After grouping, the vehicle (0.5% methylcellulose solution), Compound 1 alone (1 mg / kg, 4 hours before glucose loading), sitagliptin alone (3 mg / kg, 30 minutes before glucose loading), or a combination of Compound 1 and sitagliptin was orally administered at 5 mL / kg. Thereafter, glucose loading was performed by orally administering a 0.4 g / mL glucose solution at 5 mL / kg. Blood was collected from the tail vein immediately before glucose loading, 30 minutes after loading, 60 minutes after loading, and 120 minutes after loading. Blood glucose levels were measured using an automated biochemical analyzer (HITACHI, model 7180). Active GLP-1 was measured using a GLP-1 assay kit (IBL, #27700). The results were represented for blood glucose levels by the changes and the values at 30 minutes after glucose loading. For active GLP-1, they were represented by the changes and the concentration AUC. For statistical analysis, Steel Dwass' multiple group test was performed for the values at 30 minutes after glucose loading of blood glucose levels and the concentration AUC of active GLP-1. The significance level was set at 5% on both sides. As a result, the combined use of Compound 1 and sitagliptin significantly reduced blood glucose levels compared to each single agent (Figures 6 and 7). Also, the combined use of Compound 1 and sitagliptin significantly increased the plasma active GLP-1 concentration (Figures 8 and 9).

[0244] [Formulation Example] Examples of the formulation of the compound of formula [I] include, but are not limited to, the following formulation prescriptions. Formulation example 1 (Manufacture of capsules) (1) Compound 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19 mg (4) Magnesium stearate 1 mg Mix components (1), (2), (3) and (4) and fill into gelatin capsules.

[0245] Formulation example 2 (Manufacture of tablets) (1) Compound 1 10 g (2) Lactose 50 g (3) Corn starch 15 g (4) Calcium carboxymethylcellulose 44 g (5) Magnesium stearate 1 g Mix the total amounts of components (1), (2), (3) and 30 g of component (4) with water, perform vacuum drying, and then perform sizing. Mix 14 g of component (4) and 1 g of component (5) into this sized powder and tablet it with a tableting machine. In this way, 1000 tablets each containing 10 mg of Compound 1 per tablet are obtained.

Industrial Applicability

[0246] The combined use of an SGLT1 inhibitor and at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor is expected to be useful for the treatment and / or prevention of various diseases or conditions that are expected to be improved by regulating these activities, or various diseases or conditions that may be caused by an increase in blood glucose level due to sugar absorption in the body.

Claims

1. Formula [I]: 【Chemical 1】 [In the formula, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ), R ４ and R ５ are each independently hydrogen or C １－３ alkyl]. A pharmaceutical comprising a compound of formula [I] or a pharmaceutically acceptable salt thereof, in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, wherein the SGLT2 inhibitor is a compound selected from the following compounds: 【Chemical 2】 【Chemical】 and the DPP4 inhibitor is a compound selected from the following compounds: 【Chemical 3】 【Chemical】 A medicine selected from

2. Formula [I]: [Chemical Formula 4] [In the formula, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ) and R ４ and R ５ are each independently hydrogen or C １－３ alkyl] A medicine containing at least one medicine selected from SGLT2 inhibitors and DPP4 inhibitors, characterized by combining a compound of the formula or a pharmaceutically acceptable salt thereof with at least one medicine selected from SGLT2 inhibitors and DPP4 inhibitors, wherein the SGLT2 inhibitor is the following compound: [Chemical Formula 5] [Chemical Formula] selected from The DPP4 inhibitor is the following compound: 【Chemical Formula 6】 【Chemical Formula】 A medicament selected from the following.

3. A medicament for administration to a subject undergoing treatment with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, of formula [I]: 【Chemical Formula 7】 [In the formula, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ , or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ , R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ), R ４ and R ５ are each independently hydrogen or C １－３ alkyl] A medicament containing the compound of formula [I] or a pharmaceutically acceptable salt thereof, wherein the SGLT2 inhibitor is the following compound: 【Chemical Formula 8】 【Chemical Formula】 selected from wherein the DPP4 inhibitor is the following compound: 【Chemical Formula 9】 【Chemical Formula】 selected from, a medicament.

4. Formula [I]: 【Chemical Formula 10】 [wherein, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ wherein, R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ) and R ４ and R ５ are each independently hydrogen or C １－３ alkyl] administering to a subject undergoing treatment with a compound of formula [I] or a pharmaceutically acceptable salt thereof, a medicament comprising at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, wherein the SGLT2 inhibitor is the following compound: 【Chemical Formula 11】 [Chemical formula] selected from and the DPP4 inhibitor is the following compound: [Chemical formula 12] [Chemical formula] selected from, a pharmaceutical.

5. The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of formulas [II] to [VI]: [Chemical formula 13] [Chemical formula] a compound or a pharmaceutically acceptable salt thereof, and the pharmaceutical according to any one of claims 1 to 4.

6. The SGLT1 inhibitor or the compound of formula [I] or a pharmaceutically acceptable salt thereof is formula [II]: [Chemical formula 14] a compound or a pharmaceutically acceptable salt thereof, and the pharmaceutical according to any one of claims 1 to 5.

7. A pharmaceutical containing an SGLT1 inhibitor, characterized in that the SGLT1 inhibitor is used in combination with at least one drug selected from an SGLT2 inhibitor and a DPP4 inhibitor, and the SGLT1 inhibitor is formula [II]: [Chemical formula 15] a compound or a pharmaceutically acceptable salt thereof, the SGLT2 inhibitor is the following compound: [Chemical formula 16] [Chemical formula] selected from the DPP4 inhibitor is the following compound: [Chemical formula 17] [Chemical formula] selected from, a pharmaceutical.

8. The pharmaceutical according to any one of claims 1 to 7, wherein the SGLT2 inhibitor is dapagliflozin.

9. The pharmaceutical according to any one of claims 1 to 7, wherein the DPP4 inhibitor is sitagliptin.

10. The pharmaceutical according to claim 3 or 4, wherein the subject is a human.

11. A combined pharmaceutical comprising an SGLT1 inhibitor and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, wherein the SGLT1 inhibitor and the at least one agent are used so as to be administered together or separately in any order simultaneously, continuously, or at intervals. The SGLT1 inhibitor is of formula [I]: 【Chemical Formula 18】 [In the formula, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ), R ４ and R ５Each is independently hydrogen or C １－３ alkyl], which is a compound or a pharmaceutically acceptable salt thereof, wherein the SGLT2 inhibitor is the following compound: [Chemical Formula 19] [Chemical Formula] selected from wherein the DPP4 inhibitor is the following compound: [Chemical Formula 20] [Chemical Formula] selected from, a combination medicament.

12. Use of an SGLT1 inhibitor in the manufacture of a medicament for use in combination with at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, wherein the SGLT1 inhibitor is of formula [I]: [Chemical Formula 21] [wherein, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl which may be substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ), and R ４ and R ５ are each independently hydrogen or C １－３ alkyl. ] is a compound or a pharmaceutically acceptable salt thereof, wherein the SGLT2 inhibitor is the following compound: [Chemical Formula 22] [Chemical Formula] selected from wherein the DPP4 inhibitor is the following compound: [Chemical Formula 23] [Chemical Formula] selected from. Use

13. Use of at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor in the manufacture of a medicament for use in combination with an SGLT1 inhibitor, wherein the SGLT1 inhibitor is of formula [I]: [Chemical Formula 24] [wherein, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl optionally substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３ alkoxy or -N(R ４ )(R ５ ) and is R ４ and R ５ are each independently hydrogen or C １－３ alkyl] is a compound or a pharmaceutically acceptable salt thereof, the SGLT2 inhibitor is the following compound: [Chemical formula 25] [Chemical formula] selected from the DPP4 inhibitor is the following compound: [Chemical formula 26] [Chemical formula] selected from.

14. Formula [I]: [Chemical formula 27] [wherein, R １ is hydrogen or halogen, R ２ is C １－６ alkyl or halo C １－６ alkyl, R ３ is (1) C １－６ alkyl, (2) halo C １－６ alkyl, (3) pyridyl substituted with R ３Ａ or (4) pyrazinyl, pyrimidinyl or pyridazinyl optionally substituted with R ３Ｂ and R ３Ａ is cyano, halogen or halo C １－３ alkyl, R ３Ｂ is halogen, hydroxy, C １－３ alkyl, halo C １－３ alkyl, C １－３alkoxy or -N(R ４ )(R ５ ) and R ４ and R ５ are each independently hydrogen or C １－３ alkyl], a pharmaceutical composition comprising a compound of ] or a pharmaceutically acceptable salt thereof and at least one agent selected from an SGLT2 inhibitor and a DPP4 inhibitor, wherein the SGLT2 inhibitor is a compound selected from the following compounds: [Chemical Formula 28] [Chemical Formula] selected from and the DPP4 inhibitor is a compound selected from the following compounds: [Chemical Formula 29] [Chemical Formula] selected from, a pharmaceutical composition.

15. An SGLT1 inhibitor or a compound of formula [I] or a pharmaceutically acceptable salt thereof is any one of [II] to [VI]: [Chemical Formula 30] [Chemical Formula] a compound of or a pharmaceutically acceptable salt thereof, the composition according to claim 14.

16. An SGLT1 inhibitor or a compound of formula [I] or a pharmaceutically acceptable salt thereof is formula [II]: [Chemical Formula 31] a compound of or a pharmaceutically acceptable salt thereof, the composition according to claim 14.

Images