JP2013100235A - Novel indole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an indole derivative useful as a therapeutic agent for diabetes, or a pharmaceutically acceptable salt thereof.SOLUTION: A compound represented by formula (1) or a pharmaceutically acceptable salt thereof is disclosed [in the formula, Ris not present, or one or a plurality of Rarepresent and each independently represents a halogen atom, an optionally substituted 1-8C alkyl, an optionally substituted 1-8C alkoxy, an optionally substituted amino, a hydroxy group, cyano, nitro, carboxy, an optionally substituted acyl, an optionally substituted nonaromatic heterocycle or an optionally substituted carbamoyl; Rrepresents a hydrogen atom, an optionally substituted 1-8C alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl].

Description

  The present invention relates to a novel heteroaryl compound having an antidiabetic action or a salt thereof. Specifically, it has an anti-diabetic action that improves insulin resistance and more safely controls blood glucose levels, and / or is useful for the prevention and treatment of metabolic diseases such as hyperlipidemia, arteriosclerosis, and metabolic syndrome The present invention relates to a novel heteroaryl compound. More specifically, the present invention relates to a novel heteroaryl compound having a peroxisome proliferator activated receptor (PPAR) α activation regulating action, a PPARγ activation regulating action, or a PPARα / γ activation regulating action.

  Compounds having various PPARα activation regulating action, PPARγ activation regulating action, or PPARα / γ activation regulating action have been reported. For example, Patent Document 1 reports that a compound having an indole ring is effective as a compound having a PPARα activation regulating action, a PPARγ activation regulating action, or a PPARα / γ activation regulating action. However, this reference does not specifically describe the compounds of the present invention.

International Publication No. 2006/075638 Pamphlet

  The problem to be solved by the present invention is to improve diabetes / insulin resistance by exerting PPARα activation regulating action, PPARγ activation regulating action, or PPARα / γ activation regulating action, and / or high fat. Not only is it useful for the prevention and treatment of metabolic diseases such as thrombosis, arteriosclerosis, and metabolic syndrome, but it is also safe to avoid side effects such as weight gain, edema, and heart weight increase found in existing PPARγ full agonists It is to supply a high preventive or therapeutic agent.

  As a result of intensive studies, the inventors have found that the compounds of the present invention clearly have stronger PPARγ affinity than the example compounds described in Patent Document 1, as will be apparent from test examples described later. Further, as will be apparent from the test examples described later, the present invention was also completed by finding that the compound of the present invention shows a clearly stronger antidiabetic action than the example compound described in Patent Document 1 even in diabetes model mice. .

That is, the present invention
[1] Formula (1):

(In the formula, R ¹ does not exist, or one or more thereof exist, and each independently represents a halogen atom, an optionally substituted C ₁ -C ₈ alkyl, or an optionally substituted C ₁ -C. _{8 represents} alkoxy, optionally substituted amino, hydroxyl, cyano, nitro, carboxyl, optionally substituted acyl, optionally substituted non-aromatic heterocyclic, or optionally substituted carbamoyl , R ² represents a hydrogen atom, an optionally substituted C ₁ -C ₈ alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, or a pharmaceutical thereof Top acceptable salt.
[2] Formula (2):

(Wherein, ^{R 3} and ^{R 4} are each independently a hydrogen atom, a halogen atom, an optionally substituted _C 1 -C ₈ alkyl, optionally substituted _C 1 -C ₈ alkoxy, substituted An optionally substituted amino, a hydroxyl group, cyano, nitro, carboxyl, an optionally substituted acyl, an optionally substituted non-aromatic heterocyclic ring, or an optionally substituted carbamoyl). A compound, or a pharmaceutically acceptable salt thereof.
[3] The following formula:

The compound of the above-mentioned [1], which is any one of the compounds represented by: or a pharmaceutically acceptable salt thereof.
[4] A pharmaceutical comprising the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] A PPARα, PPARγ, or PPARα / γ activation regulator containing the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[6] The present invention relates to a therapeutic agent for diabetes or hyperlipidemia containing the compound according to any one of [1] to [3] above or a pharmaceutically acceptable salt thereof as an active ingredient.

  According to the present invention, a novel heterozygous agent that improves insulin resistance and is useful as a highly safe prophylactic or therapeutic agent for diabetes that avoids the side effects such as weight gain, edema, and heart weight increase seen in existing PPARγ full agonists. An aryl derivative or a salt thereof can be provided.

  Next, the definition in the formula of the heteroaryl derivative represented by the formula (1) according to the present invention will be specifically described below. In the present specification, the number of substituents in the group defined as “optionally substituted” or “substituted” is not particularly limited as long as substitution is possible, unless otherwise specified. One or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

  As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. are mentioned, for example, Preferably a fluorine atom and a chlorine atom are mentioned.

Examples of C ₁ -C ₈ alkyl include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl and the like. Examples of the alkyl containing a cyclic structure include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl and the like. Preferably, methyl, ethyl, 2-propyl, and cyclopropyl are mentioned.

Examples of the substituent in “optionally substituted C ₁ -C ₈ alkyl” include, for example, hydroxyl group, oxo, amino, C ₁ -C ₈ monoalkylamino (eg, methylamino, ethylamino, propylamino, etc.), C _2- C ₁₂ dialkylamino (eg dimethylamino, ethylmethylamino, diethylamino etc.), C ₁ -C ₈ alkoxy (eg methoxy, ethoxy, 1-propyloxy, 2-propyloxy etc.), halogen atom (eg fluorine atom, Chlorine, bromine, etc.), C ₁ -C ₈ haloalkoxy (eg, trifluoromethoxy, etc.), saturated heterocycle (eg, morpholino, piperidino, pyrrolidino, 4-methyl-1-piperazino, etc.), aryl (eg, phenyl, 1-naphthyl etc.) or heteroaryl (eg pyridyl, thienyl, furanyl) And preferably include methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, fluorine atom, chlorine atom, trifluoromethoxy, morpholino, piperidino, pyrrolidino, phenyl, pyridyl. .

Examples of C ₁ -C ₈ alkoxy include methoxy, ethoxy, 2-propoxy, cyclopentyloxy and the like, preferably methoxy, ethoxy and 2-propyloxy. Further, when there are adjacent alkyl or alkoxy, a ring having a substituent with the adjacent group may be formed. Specifically, methylenedioxy, ethylenedioxy, 2-methyl-methylenedioxy, 2 -Methyl-ethylenedioxy, 1-oxy-2-ethylene, 1-oxy-2-propylene and the like are preferable, and methylenedioxy and ethylenedioxy are preferable.

Examples of the substituent of “optionally substituted C ₁ -C ₈ alkoxy” include, for example, a halogen atom (preferably a fluorine atom, a chlorine atom), a C ₁ -C ₃ linear or branched alkoxy (preferably, methoxy, ethoxy, 2-propoxy), the linear or branched alkyl (preferably C ₁ -C ₃ methyl, ethyl, 2-propyl, etc.), trifluoromethyl, trifluoromethoxy, and the like.

Examples of the “optionally substituted amino” include amino, C ₁ -C ₈ alkyl (eg, methyl, ethyl, propyl etc.), C ₁ -C ₈ acyl (eg acetyl, propionyl etc.), aryl (eg , Phenyl and the like), or amino optionally mono- or di-substituted with heteroaryl. Preferably, methylamino, dimethylamino, ethylamino, diethylamino, cyclohexylamino, acetylamino, benzoylamino, phenylamino and the like can be mentioned.
Examples of the acyl of “optionally substituted acyl” include formyl and C ₁ -C ₈ alkyl (eg, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t -Butyl etc.), aryl (for example, phenyl etc.), or heteroaryl (for example, thienyl, pyridyl etc.) and a group in which a carbonyl group is bonded. Preferable examples of acyl include acetyl, propionyl, cyclobutanecarbonyl, cyclohexanecarbonyl, benzoyl and the like.

The acyl may have 1 to 3 substituents at substitutable positions. In this case, examples of the substituent include C ₁ -C ₃ linear or branched alkyl (preferably methyl, Ethyl, 2-propyl, etc.), C ₁ -C ₃ linear or branched alkoxy (preferably methoxy, ethoxy, 2-propoxy, etc.), halogen atom (preferably fluorine atom, chlorine atom), hydroxy, amino Etc.

  Examples of the “non-aromatic heterocycle” include those having 2 to 6 carbon atoms containing 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms, Examples include morpholino, thiomorpholino, piperidino, pyrrolidino, 4-methyl-1-piperazino, and preferably morpholino, piperidino, pyrrolidino.

Examples of the substituent in the “optionally substituted non-aromatic heterocycle” include C ₁ -C ₈ alkyl (eg, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl). , T-butyl etc.), C ₁ -C ₈ alkoxy (eg methoxy, ethoxy, 1-propyloxy, 2-propyloxy etc.), halogen atom (eg fluorine, chlorine, bromine etc.), C ₁ -C ₈ haloalkoxy (e.g. trifluoromethoxy, etc.), C ₁ -C ₈ haloalkyl (trifluoromethyl etc.) are like, preferably methyl, ethyl, 2-propyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethoxy, trifluoromethyl And methyl.
Examples of the “optionally substituted carbamoyl group” include carbamoyl, linear or branched C ₁ -C ₆ monoalkylaminocarbonyl, or linear or branched C ₂ -C ₁₂ dialkylaminocarbonyl. It is done. Preferred examples of the linear or branched C ₁ -C ₆ alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and 2-propylaminocarbonyl. Examples of linear or branched C ₂ -C ₁₂ dialkylaminocarbonyl include carbamoyl substituted with the same or different alkyl, preferably dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl, methylpropyl Examples include aminocarbonyl and dicyclohexylaminocarbonyl.

  Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl and the like, and preferably phenyl.

  Examples of the heteroaryl include monocyclic or bicyclic heteroaryls containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Specifically, monocyclic 6-membered heteroaryl such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, monocyclic 6 such as pyridine, pyrimidine, pyrazine, pyridazine, and triazine. Membered heteroaryl, indole, isoindole, indolizine, indazole, purine, 4-H-quinolidine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, benzimidazole, benzthiazole, benzoxazole, benzofuran, benzothiophene, etc. Bicyclic heteroaryl and the like, and more preferably, thiophene, furan, pyrrole, pyridine, indole, benzthiazole, benzoxazole, benzofuran, benzothiophene. And the like.

The number of substituents of “optionally substituted aryl” and “optionally substituted heteroaryl” has 1 to 5, preferably 1 to 3 substituents at substitutable positions. May be. Examples of the substituent include a halogen atom (preferably a fluorine atom and a chlorine atom), a C ₁ -C ₃ linear or branched alkoxy (preferably methoxy, ethoxy, 2-propoxy), C ₁ -C _3. Straight chain or branched alkyl (preferably methyl, ethyl, 2-propyl and the like), trifluoromethyl, trifluoromethoxy, cyano and the like.

As the pharmaceutically acceptable salt, when the compound of the present invention has an acidic group, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, zinc salt and the like Examples include inorganic metal salts, triethylamine, triethanolamine, trihydroxymethylaminomethane, and organic base salts such as amino acids. When the compound of the present invention has a basic group, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, propionate, succinate, lactic acid Organic salts such as salts, malates, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc. .
The heteroaryl compound of the present invention can be produced, for example, by the production method described in detail below or a method analogous thereto. Each compound used as a raw material compound may be used as a salt. These reactions are merely examples, and can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

In each of the subsequent reactions, the functional group can be protected as necessary. Protecting groups and their protection and deprotection techniques are described in W. Greene and P.M. G. M.M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed. , John Wiley and Sons, inc. , New York (1999).
Manufacturing method (1)

The heteroaryl derivative of the formula (1) can be produced by forming a bond at each of the ad portions. Examples of the method for forming a bond at the a-d portion include production method (1-1) -production method (1-3). The order of bond formation at the a-d portion can be changed as appropriate. Moreover, the starting material in each manufacturing method can be manufactured by combining the bond formation method of an ad part from a well-known raw material.
Production method (1-1) Synthesis of a and b parts

(In the formula, R ₀ represents alkyl such as methyl, ethyl, or t-butyl, and X represents a leaving group such as chlorine, bromine, iodine, mesylate, tosylate, or triflate.)
Compounds (100), (101), (102), (103) are, for example, new experimental chemistry course 14 (Maruzen, published in 1977), experimental chemistry course 19-26 (Maruzen, published in 1992), precision Organic synthesis (Nanedo, published in 1983), peptide synthesis fundamentals and experiments (Maruzen, published in 1985), Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publishers) and the like, or a method analogous thereto.

  Compound (104) can be produced by reacting compound (100) and compound (101) or compound (102) and compound (103) in an inert solvent in the presence of a base. That is, Experimental Chemistry Course Volume 20 (Maruzen, published in 1992), J. Am. Org. Chem., 56, 1321 (1991), Heterocycles, 31, 1745 (1990) and the like, or a method analogous thereto.

  Examples of the inert solvent include ether solvents such as ether, tetrahydrofuran (THF) and dioxane, hydrocarbon solvents such as toluene, benzene and xylene, and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride. , Aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like. Two or more kinds of these solvents may be mixed and used at an appropriate ratio.

  Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, sodium methoxide, Examples thereof include metal alkoxides such as potassium t-butoxide.

The reaction temperature is selected from the range of about −20 ° C. to the vicinity of the boiling point of the solvent, preferably the range of about 0 ° C. to the vicinity of the boiling point of the solvent.
Production method (1-2) Synthesis of c moiety

(In the formula, all symbols have the same meaning as described above.)
Regarding the method for forming the c moiety bond and the method for producing the compound (105), for example, WO 02/085851, WO 02 / 10131-A1, WO 03 / 912121-A1, WO 04/048341, Organic Letters, 4, 973. (2002), Tetrahedron Letters, 40, 2657 (1997), Chemical Communication, 188 (2004), Tetrahedron Letters, 35, 4133 (1994), Bull. Korean Chem. Soc. 21, 618 (2000), Synlett, 10, 1591 (1999), Tetrahedron Letters, 46, 2405 (2005), J. Am. Am. Chem. Soc, 124, 11684 (2002), or a method analogous thereto.
Compound (104) can be produced by reacting compound (105) and compound (106) in an inert solvent in the presence of a base. That is, it can be produced by an N-alkylation reaction described in Experimental Chemistry Lecture Volume 20 (Maruzen, published in 1992), Tetrahedron, 54, 13915 (1998), or the like.

  Examples of the inert solvent include ether solvents such as ether, tetrahydrofuran (THF) and dioxane, hydrocarbon solvents such as toluene, benzene and xylene, and halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride. , Aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile and the like. Two or more kinds of these solvents may be mixed and used at an appropriate ratio.

  Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, sodium methoxide, Examples thereof include metal alkoxides such as potassium t-butoxide.

The reaction temperature is selected from the range of about −20 ° C. to the vicinity of the boiling point of the solvent, preferably the range of about 0 ° C. to the vicinity of the boiling point of the solvent.
Production Method (1-3) Synthesis of d Part

(In the formula, all symbols have the same meaning as described above.)
Regarding the bond formation method of the d moiety and the production methods of the compounds (107) and (108), for example, New Experimental Chemistry Course Vol. 14 (Maruzen, published in 1977), Experimental Chemistry Course Vol. 19-26 (Maruzen, 1992) Published), precision organic synthesis (Nanedo, published in 1983), fundamentals and experiments of peptide synthesis (Maruzen, published in 1985), Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons), Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press), Comprehensive Organic Transformations (1989, VCH Publishers) and the like, or a method analogous thereto.
Compound (106) can be produced by reacting compound (107) and compound (108) in an inert solvent in the presence of an acid. That is, it can be produced by the Friedel-Crafts acylation reaction described in Experimental Chemistry Lecture Volume 20 (Maruzen, published in 1992), Org. Lett, 10, 1487 (2000), or the like.
Examples of the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ether solvents such as dioxane, ether, tetrahydrofuran (THF), and dioxane, and hydrocarbons such as toluene, benzene, and xylene. Examples include system solvents, aprotic solvents such as ethyl acetate, acetone, dimethyl sulfoxide, N, N-dimethylformamide, and acetonitrile. Two or more kinds of these solvents may be mixed and used at an appropriate ratio.

  Examples of the acid include Lewis acids such as aluminum chloride, dimethylaluminum chloride, diethylaluminum chloride, and zinc chloride.

The reaction temperature is selected from the range of about −20 ° C. to the vicinity of the boiling point of the solvent, preferably the range of about 0 ° C. to the vicinity of the boiling point of the solvent.
Production method (1-4) Hydrolysis method

(In the formula, all symbols have the same meaning as described above.)
Compound (110) can be produced from compound (104) using a conventional deprotection technique. For example, it can be obtained by a hydrolysis reaction in the presence of an acid or a base.

  Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid and the like.

  Examples of the solvent include ether solvents such as ether, THF, dioxane, aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, and alcohol solvents such as methanol and ethanol. The above solvent and water may be mixed at an appropriate ratio, and may be used without a solvent.

  The reaction temperature is selected from a range of about −20 ° C. to the vicinity of the boiling point of the solvent, preferably a range of about −10 ° C. to the vicinity of the boiling point of the solvent.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and metal carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. Done.

  Examples of the hydrous solvent include one selected from ether solvents such as ether, THF and dioxane, aprotic solvents such as acetone, dimethyl sulfoxide, N, N-dimethylformamide and acetonitrile, and alcohol solvents such as methanol and ethanol. A mixed solvent of the above solvent and an appropriate ratio of water is used.

The reaction temperature is selected from a range of about −20 ° C. to the vicinity of the boiling point of the solvent, preferably a range of about −10 ° C. to the vicinity of the boiling point of the solvent.
Production Method (2) Construction Method of Indole Ring (107)

(In the formula, all symbols have the same meaning as described above.)
When an indole ring is constructed, and when substituents R ₁ and R ₂ are introduced into the indole ring, for example, The Chemistry of Heterocyclic Compounds (indole derivatives: vol. 25 part II, part III, part 4; -Weyl) (indole derivatives: Hetarene I, TEIL 2a, E6b1, p546-848, E6b2, p849-1336), Comprehensive Heterocyclic Chemistry (Indole Derivative: vol. 4), Comprehensive Hectolic C2 , Heterocycle Chemistry (Kodansha 1988), New Experimental Chemistry Course 14 [IV] (Maruzen, 1977), Tetrahedron Lett, 41, 1811 (2000), Chem Eur J, 14, 1351 (2008), Org Lett, 10, 3417 (2008). ), J Am Chem Soc, 128, 1058 (2006), Lett Chem Chem, 5, 507 (2008), Tetrahedron Lett, 49, 5309 (2008), J Am Chem Soc, 124, 15169 m (2002) Jr , 66, 638 (2001), etc., or a method analogous thereto. Although the example of the construction method of an indole ring is specifically mentioned below, it can manufacture also by another method without being restricted to these examples.
Production Method (2-1) Indole Ring Construction Example 1
Compound (107) can be produced by heating compound (108) and compound (109) or compound (110) in the presence of an acid such as acetic acid.

(In the formula, all symbols have the same meaning as described above.)
Production Method (2-2) Indole Ring Construction Example 2
Compound (107) is prepared by, for example, reacting compound (111) and compound (112) with a transition metal catalyst such as palladium from compound (113) using a reducing agent such as titanium chloride, or Pd / It can be produced by a hydrogenation reaction using a metal catalyst such as C or Raney nickel.

(In the formula, all symbols have the same meaning as described above.)
Production Method (2-3) Indole Ring Construction Example 3
Compound (107) is prepared by reacting compound (114) with compound (115) in the presence of a base such as potassium carbonate or cesium carbonate and reacting with acid such as hydrochloric acid from compound (116). And a hydrogenation reaction using a metal catalyst such as Pd / C or Raney nickel.

(In the formula, R ₃ represents an alkyl group such as a methyl group or an ethyl group, and other symbols have the same meaning as described above.)
Production Method (2-4) Indole Ring Construction Example 4
Compound (107) can be produced, for example, by reacting compound (114) with compound (118) in an inert solvent.

(In the formula, all symbols have the same meaning as described above.)
Production Method (2-5) Indole Ring Construction Example 5
Compound (107) can be produced, for example, by desulfurization with a metal catalyst such as Raney nickel from compound (121) that can be synthesized by reacting compound (119) and compound (120).

(In the formula, all symbols have the same meaning as described above.)
As a substituent on the indole ring, chlorine R ₁ or R _2, bromine, iodine, tosylate, when there is a leaving group triflate, etc., aryl boronic acid, Suzuki and heteroaryl boronic acid or alkyl boronic acids (Suzuki ) Coupling reaction (described in J. Organomet. Chem, 576, 147 (1999), J. Am. Chem. Soc, 122, 4020 (2000), J. Am. Chem. Soc, 124, 6343 (2002), etc. Or a tin-coupling reaction with an aryltin compound, heteroaryltin compound or alkyltin compound (Angew. Chem. Int. Ed. Engl, 25, 508 (1986)). Way, or it Aryl, heteroaryl, and alkyl can be introduced into R ₁ or R ₂ by Heck reaction, Negishi reaction, Kumada reaction, Tamao reaction, or the like. On the contrary, after introducing boronic acid, boronic acid ester, organotin, organozinc, organomagnesium, organosilicon into R ₁ or R ₂ , the above coupling with aryl halide, heteroaryl halide, alkyl halide, etc. Aryl, heteroaryl, and alkyl can be introduced into R ₁ or R ₂ also by reaction.
The compound of the present invention may have an asymmetry or may have a substituent having an asymmetric carbon, and such compounds have optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones. Examples of a method for obtaining such an optical isomer purely include optical resolution.
As an optical resolution method, the compound of the present invention or an intermediate thereof in an inert solvent (for example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, toluene, etc. Aromatic hydrocarbon solvents such as acetonitrile, and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylidene tartaric acid, Salts can also be formed with dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid.
When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxy group, an optically active amine (for example, α-phenethylamine, 1,2-diphenyl-ethanolamine, (1R, 2S)-(−)-2- Amino-1,2-diphenylethanol, (1S, 2R)-(+)-2-amino-1,2-diphenylethanol, quinine, quinidine, cinchonidine, cinchonine, strychnine and other organic amines) to form a salt You can also.
Examples of the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. The precipitated salt can be cooled as necessary before filtration to improve the yield. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, and aromatic hydrocarbons such as toluene) Recrystallization with a system solvent, acetonitrile, etc. and a mixed solvent thereof) to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a conventional method to obtain a free form.
The compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like. Examples of the oral or rectal administration agent include capsules, tablets, pills, powders, cachets, suppositories, and liquids. Examples of injections include sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
The above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.

Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter Etc. Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
Examples of the liquid for injection include solutions, suspensions, emulsions and the like. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water. A solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. A solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
Examples of the topical administration agent include the above liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned topical preparation can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier that are usually used. Ointments and creams are obtained, for example, by adding a thickener and / or gelling agent to an aqueous or oily base. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like. Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax and the like.

Lotions can add one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifying agents, diffusing agents, thickening agents, coloring agents, flavorings, etc. to an aqueous or oily base. .
Powders are formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.
The topical administration agent may contain antiseptics such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and bacterial growth inhibitors as necessary.
The compounds of the present invention can be administered to diabetic patients, particularly type 2 diabetics or non-insulin dependent diabetics. Further, the compound of the present invention can control the blood glucose level of diabetic patients. In this case, the dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 500 mg per day for adults, preferably about 5 A range of ˜about 100 mg can be administered in one or several divided doses. In the case of administration as an injection, the range of about 0.1 to about 300 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.
The compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, etc. Can be used in combination. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
As therapeutic agents for diabetes, insulin preparations (for example, animal insulin preparations extracted from bovine and porcine pancreas, human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast, etc.), insulin resistance improvers (for example, Pioglitazone or its hydrochloride, rosiglitazone or its maleate, riboglitazone (CS-011), roseglitazone, MBX-2044, INT-131, alleglitazar (R-1439), GSK-376501, netoglitazone (MCC) -555), AVE-0897, AVE-5376, DRL-11605, DSP-8658, etc.), α-glycosidase inhibitors (for example, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (for example, metformin, buformin, phenformin, etc.) ), Insulin secretagogues (e.g. tolptamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetic acid) Sulfonyl ureas such as hexamide, glyclopyramide, glimepiride, repaglinide, senaglinide, nateglinide, mitiglinide, etc.), dipeptidyl peptidase IV inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin (BMS-477118), alogliptin (SYR-322), P93 01, BI-1356-BS, GRC-8200, T-6666, ALS-2-0426, etc.), GLP-1, GLP-1 analogues (e.g. exenatide, liraglutide, taspoglutide (BIM-51077), AVE-0010, etc.) , Amylin agonist (eg, pramlintide), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-1, 6-bisphosphatase inhibitor, glucagon antagonist, etc.), GPR40 agonist, β3 agonist (E.g. solabegron (GW-427353B) etc.), protein tyrosine phosphater Inhibitors (e.g., sodium vanadate etc.), SGLUT inhibitor, 11 [beta] - hydroxysteroid dehydrogenase inhibitors, leptin resistance-improving agents, somatostatin receptor agonists, and the like.
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (for example, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat (SK-860), ranirestat (AS-3201)), neurotrophic factors (for example, NGF) , NT-3, BDNF, etc.), AGE inhibitors (eg, Alagebrium (ALT-766), etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, thiaprid, mexiletine, etc.)
Antihyperlipidemic agents include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their sodium salts), squalene synthase inhibitors, fibrates For example, fenofibrate etc.), ACAT inhibitor, cholesterol absorption inhibitor (eg ezetimibe etc.) and the like.
Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (e.g. captolyl, enalapril, alacepril, delapril, lizinopril, benazepril, imidapril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (e.g. olmesartan, medoxomil, candesartan, candesartan, Losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlidipine, efonidipine, etc.), etc. Etc.), β-blockers (eg, atenolol, bisoprolol, betaxolol, metoprolol, etc.), α-blockers (eg Rapidyl, terazosin, doxazosin, bunazosin, etc.), αβ blockers (eg, amosulalol, alotinolol, labetalol, carvedilol, etc.), renin inhibitors (eg, aliskiren, etc.), aldosterone receptor antagonists (eg, spironolactone, eplerenone, etc.) .
Anti-obesity agents include central anti-obesity drugs (e.g., phentermine, sibutramine, ampepramon, mazindol), pancreatic lipase inhibitors (e.g., orlistat), peptide anorectic agents (e.g. leptin, CNTF (ciliary neurotrophic) Factors) and the like, and cholecystokinin agonists.
Examples of diuretics include xanthine derivatives (e.g. sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (e.g. etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, pentylhydrochloroazide, pentfurizide, polythiazide, methicolo Thiazide, etc.), anti-aldosterone pharmaceuticals (e.g., spironolactone, triamterene, etc.), carbonic acid dehydrogenase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamides (e.g., chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide and the like can be mentioned.
The concomitant drug is preferably GLP-1, a GLP-1 analog, an α-glucosidase inhibitor, a biguanide, an insulin secretagogue, an insulin resistance improver, or the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
When the compound of the present invention is used in combination with a concomitant drug, the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. In particular, biguanides can be reduced from normal dosages. Therefore, side effects that may be caused by these drugs can be safely prevented. In addition, the dosage of diabetic complications, antihyperlipidemic agents, antihypertensives, etc. can be reduced, and as a result, side effects that may be caused by these agents can be effectively prevented.

Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but the present invention is not limited to these examples. In addition, the nomenclature of the compounds shown in the following Reference Examples and Examples was ACDLABS 11.0 Name.
In the present specification, the following abbreviations may be used.

The following abbreviations are used in NMR data and reference examples and examples. s: singlet d: doublet t: triplet m: multiplet
br: broad J: coupling constant Hz: Hertz CDCl ₃ : deuterated chloroform DMSO-d ₆ : deuterated dimethyl sulfoxide
LC-MS analysis conditions body: ZQ2000 (waters), ionization method: ESI
Column: XTerra MS C ₁₈ 2.5μm (2.1x20mm) (waters)
Liquid A: H ₂ O, liquid B: acetonitrile, flow rate: 1 ml / min
Analysis conditions;
0.0min → 0.5min: A solution 95% constant (B solution 5%)
0.5min → 2.5min: A liquid 95% → 1% (B liquid 5% → 99%)
2.5min → 3.5min A liquid 1% constant (B liquid 99%)
0min → 3.5min, analysis in the presence of 0.06% formic acid for liquid A + liquid B (= total amount)
rt = Retention Time
In this specification, the following abbreviations may be used for the sake of simplicity.
THF: Tetrahydrofuran DMF: N, N-dimethylformamide

Reference example 1
6-Methoxy-2-methyl-1H-indole Reference Example 1-1
1- (4-Methoxy-2-nitrophenyl) propan-2-one

1-Bromo-2-nitro-4-methoxybenzene (2.80 g, 12.07 mmol) was dissolved in toluene (24 ml), and acetone (5.3 ml, 72.40 mmol), 4-methoxyphenol (300 mg, 2.41) were dissolved in this solution. mmol), potassium phosphate (5.64 g, 26.55 mmol), 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl (190 mg, 0.48 mmol), tris (dibenzylideneacetone) dipalladium (0 ) (111 mg, 0.12 mmol) was sequentially added and stirred at 50 ° C. for 10 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction solution for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (2.34 mg, 93%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.65 (d, 1H, J = 2.5 Hz), 7.18-7.12 (m, 2H), 4.04 (s, 2H), 3.87 (s, 3H), 2.31 (s , 3H).

Reference Example 1-2
6-Methoxy-2-methyl-1H-indole

To titanium chloride (20% aqueous solution, 69 g, 89.48 mmol), 6.6 M aqueous ammonium acetate solution (81.3 ml, 536.88 mmol) and ethanol (22 ml) were added. To this solution, a solution of the compound of Reference Example 1-1 (2.34 g, 11.12 mmol) in ethanol (70 ml) was added dropwise and stirred at room temperature for 3 and a half hours. The reaction solution was extracted three times with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.35 g, 75%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.71 (brs, 1H), 7.37 (d, 1H, J = 8.6 Hz), 6.80 (d, 1H, J = 2.2 Hz), 6.73 (dd, 1H, J = 8.6, 2.2 Hz), 6.13 (brs, 1H), 3.83 (s, 3H), 2.40 (s, 3H).

Reference example 2
2-Methyl-6- (trifluoromethyl) -1H-indole

The title compound was synthesized in the same manner as in Reference Example 1 using 1-chloro-2-nitro-4-trifluoromethylbenzene (2.99 g, 64%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.08 (brs, 1H), 7.57 (d, 1H, J = 8.0 Hz), 7.55 (d, 1H, J = 1.3 Hz), 7.30 (dd, 1H, J = 8.0, 1.3 Hz), 6.28 (brs, 1H), 2.48 (s, 3H).

Reference example 3
2-Methyl-1H-indole-6-carbonitrile

The title compound was synthesized in the same manner as in Reference Example 1 using 1-chloro-2-nitro-4-cyanobenzene (0.819 g, 32%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.23 (brs, 1H), 7.61 (s, 1H), 7.54 (d, 1H, J = 8.2 Hz), 7.30 (dd, 1H, J = 8.2, 1.4 Hz ), 6.31 (brs, 1H), 2.50 (s, 3H).

Reference example 4
6-Fluoro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 1 using 1-chloro-2-nitro-4-fluorobenzene (1.69 g, 50%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.83 (brs, 1H), 7.39 (dd, 1H, J = 8.6, 5.4 Hz), 6.97 (dd, 1H, J = 9.6, 1.2 Hz), 6.85-6.80 (m, 1H), 6.18 (brs, 1H), 2.43 (s, 3H).

Reference Example 5
6-Chloro-2-methyl-1H-indole

Reference Example 5-1
1- (4-Chloro-2-nitrophenyl) propan-2-one

To a solution of ethyl acetoacetate (195 mg, 1.50 mmol) in DMF (10 ml), cesium carbonate (651 mg, 2.00 mmol) was added and stirred. To this solution was added 1,4-dichloro-2-nitrobenzene (192 mg, 1.00 mmol), and the mixture was stirred at 70 ° C. for 6 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and separated. The organic layer was washed with water, dried over magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. Acetic acid (10 ml) and concentrated sulfuric acid (10 ml) were added to the resulting residue, and the mixture was stirred at 100 ° C. for 4 hours. After cooling to 0 ° C., the reaction solution was neutralized with 4N sodium hydroxide solution, extracted with chloroform, and separated. The organic layer was dried over magnesium sulfate and filtered through silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (135 mg, 63%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.15 (d, 1H, J = 2.2 Hz), 7.59 (dd, 1H, J = 8.2, 2.2 Hz), 7.24 (d, 1H, J = 8.2 Hz), 4.13 (s, 2H), 2.35 (s, 3H).

Reference Example 5-2
6-Chloro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 2-2 using the compound of Reference Example 5-1 (1.79 g, 94%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.87 (brs, 1H), 7.42 (d, 1H, J = 8.4 Hz), 7.29 (d, 1H, J = 1.8 Hz), 7.30 (dd, 1H, J = 8.4, 1.8 Hz), 6.21 (brs, 1H), 2.46 (s, 3H).

Reference Example 6
6-Bromo-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 5 using 1-fluoro-2-nitro-4-bromobenzene (8.19 g, 82%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.84 (brs, 1H), 7.42 (brs, 1H), 7.36 (d, 1H, J = 8.4 Hz), 7.16 (dd, 1H, J = 8.4, 1.7 Hz ), 6.19 (brs, 1H), 2.43 (s, 3H).

Reference Example 7
7-Fluoro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 5 using 2,6-difluoronitrobenzene (1.82 g, 70%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.04 (brs, 1H), 7.27 (d, 1H, J = 8.0 Hz), 7.00-6.95 (m, 1H), 6.83 (ddd, 1H, J = 11.2, 8.0, 0.8 Hz), 6.26 (brs, 1H), 2.47 (s, 3H).

Reference Example 8
2-Methyl-6- (trifluoromethoxy) -1H-indole

Reference Example 8-1
2-Nitro-4- (trifluoromethoxy) aniline

Acetic acid (42 ml) was added to 4-trifluoromethoxyaniline (25.0 g, 141.1 mmol), and the mixture was stirred under ice-water cooling. Acetic anhydride (53.4 ml, 564.6 mmol) was added to this solution, and the mixture was warmed to room temperature and stirred for 30 minutes. After cooling to 0 ° C., 96% sulfuric acid (4.4 ml) and 70% nitric acid (7.5 ml) were added, and the mixture was returned to room temperature and stirred for 3 hours. The reaction solution was stirred under ice-water cooling, water (200 ml) was added, and the precipitated solid was collected by filtration.
To a solution of the obtained solid in methanol (125 ml), 5N aqueous sodium hydroxide solution (35 ml) was added and stirred for 30 minutes. The reaction solution was stirred under ice-water cooling, water (200 ml) was added, and the precipitated solid was collected by filtration. The solid was dried under reduced pressure at 50 ° C. to give the title compound (24.53 g, 78%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.03 (d, 1H, 4.0 Hz), 7.28 (dd, 1H, J = 8.0, 4.0 Hz), 6.85 (d, 1H, J = 8.0 Hz), 6.15 ( brs, 2H).

Reference Example 8-2
1- [2-Nitro-4- (trifluoromethoxy) phenyl] propan-2-one

A solution of copper chloride (17.82 g, 132.52 mmol) in isopropenyl acetate (120 ml) was heated to 40 ° C., and a solution of the compound of Reference Example 8-1 (24.53 g, 110.43 mmol) in isopropenyl acetate (80 ml) was added. In addition, isobutyl nitrite (17.0 ml, 143.56 mmol) was further added dropwise, and the mixture was stirred at 40 ° C. for 4 hours. Toluene (100 ml) and 1N hydrochloric acid aqueous solution (140 ml) were added to the reaction solution, and the mixture was separated. The organic layer was washed with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml), water (100 ml) and saturated brine (100 ml), then dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. did. The obtained residue was purified by silica gel column chromatography to obtain the title compound (20.59 g, 71%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.01 (d, 1H, J = 4.0 Hz), 7.47 (dd, 1H, J = 8.0, 4.0 Hz), 7.33 (d, 1H, J = 8.0 Hz), 4.15 (s, 2H), 2.35 (s, 3H).

Reference Example 8-3
2-Methyl-6- (trifluoromethoxy) -1H-indole

The title compound was synthesized in the same manner as in Reference Example 2-2 using the compound of Reference Example 8-2 (13.77 g, 82%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.93 (brs, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.16 (brs, 1H), 7.30 (dd, 1H, J = 8.0, 2.0 Hz ), 6.22 (brs, 1H), 2.45 (s, 3H).

Reference Example 9
6- (Difluoromethoxy) 2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 8 using 4-difluoromethoxyaniline (1.07 g, 35%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.89 (brs, 1H), 7.46 (d, 1H, J = 8.0 Hz), 7.09 (d, 1H, J = 4.0 Hz), 6.90 (dd, 1H, J = 8.0, 4.0 Hz), 6.69-6.31 (m, 1H), 6.22 (brs, 1H), 2.45 (s, 3H).
LC-MS: RT 2.15 min., M / z 198 (M + 1)

Reference Example 10
7-Chloro-2-methyl-1H-indole

To an isopropenyl magnesium bromide THF solution (0.5 mol / l, 50 ml, 25.0 mmol), THF (50 ml) was added and cooled to −40 ° C. To this solution was added 2-chloronitrobenzene (1.31 g, 8.3 mmol) in THF (25 ml), and the mixture was stirred at −40 ° C. for 1 hour. After returning to room temperature, an aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and liquid separation. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (0.714 g, 52%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.09 (brs, 1H), 7.40 (d, 1H, J = 7.6 Hz), 7.10 (dd, 1H, J = 7.6, 0.8 Hz), 6.99 (dd, 1H , J = 7.6, 7.6 Hz), 6.26 (brs, 1H), 2.48 (s, 3H).

Reference Example 11
2,7-Dimethyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 10 using 2-methylnitrobenzene (0.514 g, 43%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.78 (brs, 1H), 7.37 (d, 1H, J = 8.0 Hz), 7.01-6.97 (m, 1H), 6.92 (d, 1H, J = 7.2 Hz ), 6.23 (brs, 1H), 2.47 (s, 6H).

Reference Example 12
6,7-Dichloro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 10 using 2,3-dichloronitrobenzene (0.931 g, 56%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.10 (brs, 1H), 7.32 (d, 1H, J = 8.4 Hz), 7.13 (d, 1H, J = 8.4 Hz), 6.23 (brs, 1H), 2.46 (s, 3H).

Reference Example 13
6-Chloro-7-fluoro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 10 using 2-fluoro-3-chloronitrobenzene (0.477 g, 31%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.08 (brs, 1H), 7.17 (d, 1H, J = 8.4 Hz), 7.01 (dd, 1H, J = 8.4, 6.4 Hz), 6.22 (brs, 1H ), 2.45 (s, 3H).

Reference Example 14
6-Chloro-2,7-dimethyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 10 using 2-methyl-3-chloronitrobenzene (0.518 g, 35%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (brs, 1H), 7.26 (d, 1H, J = 8.4 Hz), 7.07 (d, 1H, J = 8.4 Hz), 6.19 (s, 1H), 2.49 (s, 3H), 2.45 (s, 3H).

Reference Example 15
6,7-Difluoro-2-methyl-1H-indole

Reference Example 15-1
1,2-difluoro-3-nitrobenzene

A solution of trifluoroacetic anhydride (45 ml, 326 mmol) in methylene chloride (94 ml) was added to aqueous hydrogen peroxide (28 ml, 285 mmol), and the mixture was stirred at 0 ° C. for 2 hours. To this solution was added 2,3-difluoroaniline (5.0 g, 38.7 mmol) in methylene chloride (50 ml), and the mixture was stirred at 0 ° C. for 30 minutes. After returning to room temperature, the mixture was stirred overnight. The reaction solution was extracted with chloroform and water (200 ml) and separated. The organic layer was washed twice with water (200 ml) and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (5.18 g, 84%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.88-7.85 (m, 1H), 7.52-7.50 (m, 1H), 7.28-7.20 (m, 1H).

Reference Example 15-2
6,7-Difluoro-2-methyl-1H-indole

The title compound was synthesized in the same manner as in Reference Example 10 using the compound of Reference Example 15-1 (433 mg, 31%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.05 (brs, 1H), 7.14-7.11 (m, 1H), 6.90-6.84 (m, 1H), 6.19 (brs, 1H), 2.44 (s, 3H) .
Reference Example 16
(6-Chloro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The compound of Reference Example 5 (20.0 g, 120.8 mmol) was dissolved in chloroform (350 ml) and stirred under ice water cooling. Diethylaluminum chloride hexane solution (1.06 mol / l, 171 ml, 181.2 mmol) was added dropwise to this solution, and the mixture was stirred at 0 ° C. for 30 minutes. A solution of 4-methoxybenzoyl chloride (30.9 g, 181.2 mmol) in chloroform (120 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water (200 ml) and 1N aqueous sodium hydroxide solution (600 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (2000 ml) and separated. The organic layer was washed with water (1000 ml) and saturated brine (1000 ml), dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the precipitated solid was filtered to obtain the title compound (29.2 g, 81%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.40 (brs, 1H), 7.78 (d, 2H, J = 8.8 Hz), 7.35-7.31 (m, 2H), 7.06 (dd, 1H, J = 8.4, 2.0 Hz), 6.95 (d, 2H, J = 8.8 Hz), 3.90 (s, 3H), 2.56 (s, 3H).


Reference Example 17
(5-Methoxy-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using 2-methyl-5-methoxy-1H-indole (231 mg, 78%).
LC-MS: RT 2.08 min., M / z 296 (M + 1)

Reference Example 18
1H-Indol-3-yl (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using indole (84 mg, 34%).
LC-MS: RT 2.06 min., M / z 252 (M + 1)

Reference Example 19
(2,5-Dimethyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using 2-methyl-5-methoxyindole (124 mg, 44%).
LC-MS: RT 2.20 min., M / z 280 (M + 1)

Reference Example 20
(6-Methoxy-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using the compound of Reference Example 1 (251 mg, 85%).
LC-MS: RT 2.10 min., M / z 296 (M + 1)

Reference Example 21
(6-Bromo-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using 6-bromoindole (259 mg, 78%). LC-MS: RT 2.27 min., M / z 330 (M + 1), 332 (M + 3)

Reference Example 22
(4-Methoxyphenyl) [2-methyl-6- (trifluoromethoxy) -1H-indol-3-yl] methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 8 (4.37 g, 90%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.66 (brs, 1H), 7.78 (d, 2H, J = 8.8 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.18 (brs, 1H), 7.00-6.94 (m, 3H), 3.87 (s, 3H), 2.56 (s, 3H).

Reference Example 23
(6-Bromo-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 6 (4.44 g, 90%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.50 (brs, 1H), 7.77 (d, 2H, J = 8.8 Hz), 7.46 (brs, 1H), 7.29 (d, 1H, J = 8.6 Hz), 7.18 (dd, 1H, J = 8.6, 1.8), 6.95 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.55 (s, 3H).

Reference Example 24
3-[(4-Methoxyphenyl) carbonyl-2-methyl-1H-indole-6-carbonitryl

The title compound was synthesized using Reference Example 3 in the same manner as Reference Example 16 (225 mg, 81%).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ12.41 (brs, 1H), 7.90 (s, 1H), 7.65 (d, 2H, J = 8.0 Hz), 7.45-7.37 (m, 2H), 7.05 (d, 2H, J = 8.0 Hz), 3.85 (s, 3H), 2.46 (s, 3H).

Reference Example 25
(6,7-Dichloro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized using Reference Example 12 in the same manner as Reference Example 16 (557 mg, 69%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.54 (brs, 1H), 7.77 (d, 2H, J = 8.8 Hz), 7.25 (d, 1H, J = 8.4 Hz), 7.15 (d, 1H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.59 (s, 3H).

Reference Example 26
(2,7-Dimethyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 11 (441 mg, 84%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.30 (brs, 1H), 7.80 (d, 2H, J = 8.8 Hz), 7.25-7.23 (m, 1H), 7.02-6.97 (m, 2H), 6.96 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.62 (s, 3H), 2.51 (s, 3H).

Reference Example 27
(6-Chloro-7-fluoro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 13 (155 mg, 19%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.58 (brs, 1H), 7.77 (d, 2H, J = 9.2 Hz), 7.11 (d, 1H, J = 8.8 Hz), 7.03 (dd, 1H, J = 8.8, 6.4), 6.95 (d, 2H, J = 9.2 Hz), 3.89 (s, 3H), 2.58 (s, 3H).

Reference Example 28
(6-Chloro-2,7-dimethyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 14 (489 mg, 54%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.31 (brs, 1H), 7.76 (d, 2H, J = 8.8 Hz), 7.16 (d, 1H, J = 8.4 Hz), 7.06 (d, 1H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.59 (s, 3H), 2.52 (s, 3H).

Reference Example 29
(6,7-Difluoro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 16 using Reference Example 15 (88 mg, 12%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.45 (brs, 1H), 7.66 (d, 2H, J = 8.8 Hz), 7.05-7.00 (m, 1H), 6.83-6.78 (m, 3H), 3.79 (s, 3H), 2.45 (s, 3H).

Reference Example 30
(6-Fluoro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The compound of Reference Example 4 (346 mg, 2.32 mmol) was dissolved in methylene chloride (10 ml) and stirred under ice-water cooling. To this solution was added dropwise a dimethylaluminum chloride hexane solution (1.04 mol / l, 3.34 ml, 3.47 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. 4-Methoxybenzoyl chloride (593 mg, 3.47 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water (10 ml) and 1N aqueous sodium hydroxide solution (50 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate and separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the precipitated solid was filtered to obtain the title compound (547 mg, 83%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 8.47 (brs, 1H), 7.78 (d, 2H, J = 8.8 Hz), 7.39 (dd, 1H, J = 8.8, 5.6 Hz), 7.01 (dd, 1H , J = 8.8, 2.3 Hz), 6.95 (d, 2H, J = 8.8 Hz), 6.87-6.82 (m, 1H), 3.89 (s, 3H), 2.52 (s, 3H).

Reference Example 31
(7-Fluoro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The compound of Reference Example 7 (760 mg, 5.60 mmol) was dissolved in 1,4-dioxane (10 ml), and zinc chloride (1.53 g, 11.2 mmol) was added and stirred. To this solution was added 4-methoxybenzoyl chloride (593 mg, 3.47 mmol) in 1,4-dioxane (7 ml), and the mixture was heated at 80 ° C. for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and separated. The organic layer was washed with water, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the precipitated solid was filtered to obtain the title compound (760 mg, 47%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.51 (brs, 1H), 7.79 (d, 2H, J = 8.8 Hz), 7.17 (d, 1H, J = 8.0 Hz), 7.00-6.87 (m, 4H ), 3.90 (s, 3H), 2.60 (s, 3H).

Reference Example 32
(2-Methyl-1H-indol-3-yl) (4-methylphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 31 using 2-methylindole (3.05 g, 61%).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ7.53 (d, 2H, J = 8.0 Hz), 7.38 (d, 1H, J = 7.1 Hz), 7.33 (d, 1H, J = 7.1 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.11 (dd, 1H, J = 7.1, 7.1 Hz), 7.01 (dd, 1H, J = 7.1, 7.1 Hz), 2.41 (s, 3H), 2.40 (s , 3H).

Reference Example 33
(4-Methoxyphenyl) (2-methyl-1H-indol-3-yl) methanone

The title compound was synthesized in the same manner as in Reference Example 31 using 2-methylindole (3.10 g, 58%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.67 (brs, 1H), 7.80 (d, 2H, J = 8.8 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 8.0, 8.0), 7.08 (dd, 1H, J = 8.0, 8.0), 6.95 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H), 2.56 (s, 3H).

Reference Example 34
(4-Methoxyphenyl) [2-methyl-6- (trifluoromethyl) -1H-indol-3-yl] methanone

The title compound was synthesized in the same manner as in Reference Example 31 using the compound of Reference Example 2 (583 mg, 87%).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ12.29 (brs, 1H), 7.70 (s, 1H), 7.66 (d, 2H, J = 8.0 Hz), 7.50 (d, 1H, J = 8.0 Hz ), 7.33 (d, 1H, J = 8.0 Hz), 7.05 (d, 2H, J = 8.0 Hz), 3.85 (s, 3H), 2.45 (s, 3H).

Reference Example 35
(7-Chloro-2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 31 using the compound of Reference Example 10 (557 mg, 43%).
¹ H NMR (CDCl ₃ , 400 MHz) δ8.66 (brs, 1H), 7.76 (d, 2H, J = 8.8 Hz), 7.32 (d, 1H, J = 7.6), 7.17 (dd, 1H, J = 7.6, 0.8 Hz), 7.01 (dd, 1H, J = 7.6, 7.6 Hz), 6.93 (d, 2H, J = 8.8 Hz), 3.87 (s, 3H), 2.58 (s, 3H).

Reference Example 36
[6- (Difluoromethoxy) 2-methyl-1H-indol-3-yl) (4-methoxyphenyl) methanone

The title compound was synthesized in the same manner as in Reference Example 31 using the compound of Reference Example 9 (190 mg, 75%).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ11.95 (brs, 1H), 7.64 (d, 2H, J = 8.0 Hz), 7.36-6.99 (m, 5H), 6.88 (d, 1H, J = 8.0 Hz), 3.84 (s, 3H), 2.40 (s, 3H).
Reference Example 37
2-{[4- (Bromomethyl) benzyl] oxy} -2-methylpropionic acid methyl ester

Sodium hydride (4.80 g, 110 mmol) was added to a solution of methyl 2-hydroxyisobutyrate (11.8 g, 100 mmol) in THF (200 ml) at 0 ° C. and stirred for 1 hour. Separately, p-xylene dibromide (26.4 g, 100 mmol) was dissolved in THF (200 ml) and stirred at 70 ° C. The sodium alkoxide solution was added dropwise and stirred for 2 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and separated. The organic layer was washed with water, dried over magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (13.5 g, 43%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.29 (s, 4H), 4.41 (s, 2H), 4.38 (s, 2H), 3.68 (s, 3H), 1.44 (s, 6H).

Example 1
2-{[4-({6-Fluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

Example 1-1
2-{[4-({6-Fluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionate methyl

Acetone (2 ml) and cesium carbonate (345 mg, 1.05 mmol) were added to the compound of Reference Example 30 (100 mg, 0.35 mmol) and stirred, and then acetone (1 mg of the compound of Reference Example 38 (117 mg, 0.39 mmol) was added. ml) solution was added and stirred at 50 ° C. for 3 hours. The reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (163 mg, 92%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.39-7.34 (m, 3H), 6.99 (d, 2H, J = 8.2 Hz), 6.95 (d, 2H , J = 8.8 Hz), 6.98 (dd, 1H, J = 9.4, 2.3 Hz), 6.84 (ddd, 1H, J = 9.4, 9.4, 2.3 Hz), 5.31 (s, 2H), 4.43 (s, 2H) , 3.89 (s, 3H), 3.75 (s, 3H), 2.49 (s, 3H), 1.50 (s, 6H).

Example 1-2
2-{[4-({6-Fluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The compound of Example 1-1 (163 mg, 0.32 mmol) was dissolved in methanol (3 ml) and THF (3 ml), 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 4 and a half hours. To the reaction solution was added 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate-hexane was added to the obtained residue, and the precipitated solid was filtered to obtain the title compound (127 mg, 80%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.37 (dd, 1H, J = 8.8, 5.3 Hz), 7.32 (d, 2H, J = 8.2 Hz), 7.01 (d, 2H, J = 8.2 Hz), 6.95 (d, 2H, J = 8.8 Hz), 6.91 (dd, 1H, J = 9.4, 2.3 Hz), 6.85 (ddd, 1H, J = 9.4, 9.4, 2.3 Hz), 5.32 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 2.50 (s, 3H), 1.55 (s, 6H).

Example 2
2-{[4-({5-methoxy-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 17 (80 mg, 80%).
LC-MS: RT 2.36 min., M / z 502 (M + 1)

Example 3
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 18 (76 mg, 83%).
LC-MS: RT 2.35 min., M / z 458 (M + 1)

Example 4
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -2,5-dimethyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 19 (90 mg, 93%).
LC-MS: RT 2.45 min., M / z 486 (M + 1)

Example 5
2-{[4-({6-Methoxy-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 20 (85 mg, 85%).
LC-MS: RT 2.35 min., M / z 502 (M + 1)

Example 6
2-{[4-({6-Bromo-3-[(4-methoxyphenyl) carbonyl] -1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 21 (93 mg, 87%).
LC-MS: RT 2.48 min., M / z 536 (M + 1), 538 (M + 3)

Example 7
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 33 (43 mg, 46%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.82 (d, 2H, J = 8.8 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.25 ( d, 1H, J = 8.0 Hz), 7.17-7.14 (m, 1H), 7.11-7.07 (m, 1H), 7.03 (d, 2H, J = 8.0 Hz), 6.95 (d, 2H, J = 8.8 Hz ), 5.40 (s, 2H), 4.49 (brs, 2H), 3.89 (s, 3H), 2.54 (s, 3H), 1.55 (s, 6H).


Example 8
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -2-methyl-6- (trifluoromethyl) -1H-indol-1-yl} methyl) benzyl] oxy} -2-methyl Propionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 34 (149 mg, 92%).
LC-MS: RT 2.58 min., M / z 540 (M + 1)

Example 9
2-{[4-({6-Chloro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 16 (36.88 g, 84%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.80 (d, 2H, J = 8.0 Hz), 7.34-7.32 (m, 3H, J = 8.0 Hz), 7.24 (d, 1H, J = 4.0 Hz), 7.06 (dd, 1H, J = 8.0, 4.0 Hz), 7.01 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.0 Hz), 5.35 (s, 2H), 4.50 (s, 2H ), 3.90 (s, 3H), 2.52 (s, 3H), 1.56 (s, 6H).


Example 10
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 22 (41 mg, 57%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.80 (d, 2H, J = 8.0 Hz), 7.42 (d, 2H, J = 12.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.12 ( s, 1H), 7.03-6.95 (m, 5H), 5.37 (s, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 2.52 (s, 3H), 1.55 (s, 6H).

Example 11
2-{[4-({6-Bromo-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 23 (126 mg, 99%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.39 (d, 1H, J = 1.6), 7.32 (d, 2H, J = 8.1 Hz), 7.27 (d , 1H, J = 8.4 Hz), 7.18 (dd, 1H, J = 8.4, 1.6 Hz), 7.00 (d, 2H, J = 8.1 Hz), 6.95 (d, 2H, J = 8.8 Hz), 5.34 (s , 2H), 4.50 (s, 2H), 3.89 (s, 3H), 2.51 (s, 3H), 1.55 (s, 6H).

Example 12
2-{[4-({6-Cyano-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 24 (168 mg, 98%).
LC-MS: RT 2.41 min., M / z 497 (M + 1)

Example 13
2-{[4-({7-Fluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 31 (380 mg, 78%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.31 (d, 2H, J = 8.0), 7.18 (d, 1H, J = 7.6), 7.01 (d, 2H, J = 8.0), 6.99-6.93 (m, 3H), 6.86-6.81 (m, 1H), 5.57 (s, 2H), 4.48 (s, 2H), 3.89 (s, 3H), 2.48 (s, 3H), 1.54 (s, 6H).

Example 14
2-{[4-({7-Chloro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 35 (250 mg, 99%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.39 (dd, 1H, J = 8.0, 0.8), 7.31 (d, 2H, J = 8.0), 7.11 ( dd, 1H, J = 7.6, 0.8), 7.00 (d, 1H, J = 8.0 Hz), 7.01-6.93 (m, 4H), 5.87 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 2.42 (s, 3H), 1.54 (s, 6H).

Example 15
2-{[4-({6,7-dichloro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 25 (238 mg, 99%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, 2H, J = 8.8 Hz), 7.34-7.31 (m, 3H), 7.18 (d, 1H, J = 8.4), 6.96-6.93 (m, 4H), 5.87 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 2.42 (s, 3H), 2.43 (s, 3H), 1.55 (s, 6H).

Example 16
2-{[4-({3-[(4-Methoxyphenyl) carbonyl] -2,7-dimethyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 26 (79 mg, 74%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.81 (d, 2H, J = 8.8 Hz), 7.34-7.31 (m, 3H), 6.99-6.87 (m, 6H), 5.63 (s, 2H), 4.49 (s, 2H), 3.88 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H), 1.55 (s, 6H).

Example 17
2-{[4-({6-Chloro-7-fluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methyl Propionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 27 (105 mg, 83%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.4 Hz), 7.11 (d, 1H, J = 8.4 Hz), 7.04- 7.00 (m, 4H), 6.94 (d, 2H, J = 8.8 Hz), 5.54 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 2.47 (s, 3H), 1.55 (s , 6H).

Example 18
2-{[4-({6-Chloro-3-[(4-methoxyphenyl) carbonyl] -2,7-dimethyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 28 (152 mg, 58%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.23 (d, 1H, J = 8.8 Hz), 7.10 ( d, 1H, J = 8.8 Hz), 6.95-6.91 (m, 4H), 5.62 (s, 2H), 4.50 (s, 2H), 3.89 (s, 3H), 2.58 (s, 3H), 2.41 (s , 3H), 1.56 (s, 6H).

Example 19
2-{[4-({6,7-Difluoro-3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 29 (87 mg, 52%).
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.77 (d, 2H, J = 8.8 Hz), 7.36-7.31 (m, 3H), 7.14-7.10 (m, 1H), 7.01 (d, 1H, J = 8.0 Hz), 6.96-6.87 (m, 3H), 5.53 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 2.47 (s, 3H), 1.55 (s, 6H).

Example 20
2-{[4-({6- (Difluoromethoxy) -3-[(4-methoxyphenyl) carbonyl] -2-methyl-1H-indol-1-yl} methyl) benzyl] oxy} -2-methylpropion acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 36 (93 mg, 98%).
LC-MS: RT 2.44 min., M / z 538 (M + 1)

Reference Example 38
2-Methyl-2-{[4-({6-fluoro-3-[(4-methylphenyl) carbonyl] -1H-indol-1-yl} methyl) benzyl] oxy} propionic acid

The title compound was synthesized in the same manner as in Example 1 using the compound of Reference Example 32 (53 mg, 58%).
¹ H NMR (CDCl ₃ , 400 MHz) δ7.71 (d, 2H, J = 8.8 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.25- 7.24 (m, 3H), 7.18-7.14 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (d, 2H, J = 8.0 Hz), 5.40 (s, 2H), 4.49 (s, 2H) , 2.54 (s, 3H), 2.45 (s, 3H), 1.55 (s, 6H).
Test example 1
Evaluation of PPARα or γ agonist activity
Preparation of reporter plasmid A gene fragment encoding the ligand binding region of human PPARα (including amino acid residues 167-468) or the ligand binding region of human PPARγ (including amino acid residues 204-505) The gene fragment obtained is inserted into the multicloning site of the expression vector-pM (Clontech) containing the DNA binding region of yeast GAL4 protein, and the GAL4 protein DNA binding region and human PPARα or γ ligand binding region are fused. A vector-plasmid expressing the protein was obtained.

  As the reporter plasmid, a pGL3-basic vector (Promega) containing a firefly luciferase gene, into which a GAL4 protein response element UAS and a rabbit β globin promoter were inserted, was used.

For correction of transformation efficiency, plasmid pβgal control (Clontech) containing lacZ gene was used.
Luciferase assay COS-1 cells were obtained by using phenol red-free Dulbecco's modified Eagle medium (DMEM) (Gibco) containing 5% activated carbon / dextran-treated fetal bovine serum (Gibco) in the presence of 5% carbon dioxide, Cultured at 37 ° C. COS-1 cells were seeded in a 24-well plate at a density of 5 × 10 ⁴ cells / well and cultured overnight. The medium was replaced with 5% activated carbon / dextran-treated fetal bovine serum-free medium, and 5 μl of GAL4-PPARα, γ expression plasmid, 50 ng of reporter plasmid, and 350 ng of pβgal control were added to each lipofectamine plus reagent (well). Transfected with Gibco). After culturing for 4 hours, the medium was replaced with a medium containing 5% activated carbon / dextran-treated fetal bovine serum, and this compound was added to final concentrations of 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, and 10 μM. After culturing for 24 hours, the cells were lysed using the cell lysate attached to the luciferase assay system (Promega), and the luciferase activity was measured with a luminometer using the attached luciferase measurement reagent. did. β-galactosidase activity was measured using a β-galactosidase enzyme measurement system (Promega), and the transformation efficiency was corrected.

As PPARα and γ agonist activity, the relative activity of each compound was calculated when the luciferase activity of the well to which the solvent (DMSO) was added was 1. The EC ₅₀ was calculated by linear regression using two adjacent concentrations sandwiching the concentration that activated 50% of the maximum relative activity of each compound. That is, the logarithm of the common logarithm of the concentration was X, the relative activity was Y, and two adjacent concentrations sandwiching the concentration that activated 50% of the maximum relative activity of each compound were used to perform linear regression to the equation Y = aX + b. EC ₅₀ was calculated by substituting 50% of the maximum relative activity of each compound into the obtained formula. However, if the relative activity of the compound is less than 10% of the maximum activity value of pioglitazone as a positive control at any of the above concentrations, the PPARγEC ₅₀ should be> 10 μM.

Test example 2
The test substance described in the Examples is dissolved or suspended in a 0.5% carbomethylcellulose solution, and the final dosage is 7 mg to 8 weeks old male db / db mice. (1) 30 mg of the Example compound of Patent Document 1 / Kg, (2) Example compounds of the present invention were orally administered by gavage once a day for 2 weeks so as to be 10 mg / kg. On the last day, the blood collected from the tail vein was immediately subjected to deproteinization treatment by adding perchloric acid, and then the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries). This is shown in Table 4 below.

The hypoglycemic effect was derived from the following formula.
Hypoglycemic action (%) = [{Vehicle blood glucose level (final day) −blood glucose level of test substance administration group (final day)} / Vehicle blood glucose level (final day)] × 100

Since the compound of the present invention is close to the structure of Example Nos. 40-2, 43, 44, 46, 47, 48, 49 among the Example compounds described in Patent Document 1, the pharmacological activity with these compounds We compared and examined.
Table 1 shows the relationship between the chemical structure and pharmacological activity, but the (R) -monomethyl group at the carboxylic acid α-position was converted to a dimethyl group with respect to the compound of Example No. 48 described in Patent Document 1. In the compound of Reference Example No. 38, which is a compound, the PPARγEC ₅₀ was improved by 2 times, and in the compound of Example No. 7 which was a compound in which the methyl group on benzoyl was converted to a methoxy group, the PPARγEC ₅₀ was further improved by 6 times. .
Further, as shown in Table 2, the (R) -monomethyl group at the α-position of the carboxylic acid was similarly applied to the compounds of Example Nos. 40-2, 43, 44, 46, 47, and 49 described in Patent Document 1. Was converted to a dimethyl group, and the methyl group on benzoyl was converted to a methoxy group, and PPARγEC ₅₀ was improved without exception, and the degree was between 3 times and> 14 times.

Furthermore, as shown in Table 3, other example compounds of the present invention also showed high PPARγEC ₅₀ values.

  As shown in Table 4 of Test Example 2, not only the example compounds described in Patent Document 1 but also the example compounds of the present invention were found to have a hypoglycemic action (anti-diabetic action) in diabetes model mice. In addition, the doses of Example Nos. 20, 34, 35, and 54 described in Patent Document 1 are 30 mg / kg, whereas the doses of Example Nos. 9, 10, and 13 of the present invention are 10 mg / kg. Nevertheless, it showed a stronger hypoglycemic effect.

As described above, by converting the (R) -monomethyl group at the carboxylic acid α-position to a dimethyl group and converting the methyl group on benzoyl to a methoxy group with respect to the compound described in Patent Document 1, PPARγEC ₅₀ is obtained. It has been found that it is clearly improved and exhibits a stronger anti-diabetic action even in a diabetic model mouse. It is not described in Patent Document 1 that such a structural change greatly improves the PPARγ affinity and the antidiabetic action, and it is completely unexpected from the conventional knowledge.

  The compound of the present invention can be used as a therapeutic agent for diabetes, a preventive agent, a blood glucose regulator or a therapeutic agent for hyperlipidemia and the like.

Claims (6)

Formula (1):
(In the formula, R ¹ does not exist, or one or more thereof exist, and each independently represents a halogen atom, an optionally substituted C ₁ -C ₈ alkyl, or an optionally substituted C ₁ -C. _{8 represents} alkoxy, optionally substituted amino, hydroxyl, cyano, nitro, carboxyl, optionally substituted acyl, optionally substituted non-aromatic heterocyclic, or optionally substituted carbamoyl R ² represents a hydrogen atom, an optionally substituted C ₁ -C ₈ alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, or a pharmaceutical thereof Top acceptable salt. Formula (2):
(Wherein, R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkoxy, substituted An optionally substituted amino, a hydroxyl group, cyano, nitro, carboxyl, an optionally substituted acyl, an optionally substituted non-aromatic heterocyclic ring, or an optionally substituted carbamoyl). A compound, or a pharmaceutically acceptable salt thereof. The following formula:
The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The pharmaceutical which contains the compound as described in any one of Claims 1-3, or those pharmacologically acceptable salts as an active ingredient. A PPARα, PPARγ, or PPARα / γ activation modulator comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. The therapeutic agent of diabetes or hyperlipidemia which contains the compound as described in any one of Claims 1-3, or those pharmacologically acceptable salts as an active ingredient.