WO2003091213A1

WO2003091213A1 - Novel amide derivatives or salts thereof

Info

Publication number: WO2003091213A1
Application number: PCT/JP2003/005198
Authority: WO
Inventors: Kenichi Onda; Takayuki Suzuki; Ryota Shiraki; Yasuhiro Yonetoku; Takashi Ogiyama; Tatsuya Maruyama; Kazuhiro Momose
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 2002-04-25
Filing date: 2003-04-23
Publication date: 2003-11-06
Also published as: AU2003227360A1; JPWO2003091213A1

Abstract

It is intended to provide compounds of the following general formula (I) which are glycogen phosphorylase inhibitors and useful as remedies and preventives for insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), insulin resistant disease and obesity. Namely, glycogen phosphorylase inhibitors characterized by having an indole ring, etc. bonded to a ring A (an aryl ring or an aromatic heterocycle) via an amide bond and the ring A having a hydroxyethylene moiety as a substituent. It is still preferable that the glycogen phosphorylase inhibitors are characterized in that the above-described ring A has a dihydroxyethylene moiety as a substituent. (I) wherein each substituent is as defined in claim 1.

Description

Specification

Novel amide derivative or salt thereof

Technical field

The present invention relates to a novel amide derivative or a salt thereof, particularly a novel amide derivative or a amide derivative in which an indole ring or a chenobilol ring is bonded to an aryl or aromatic hetero ring having a hydroxyethylene moiety as a substituent via an amide bond. About its salt. Further, the present invention relates to a medicine, particularly to an amide derivative or a salt thereof which is a glycogen phosphorylase inhibitor. The compound of the present invention is useful for treating and preventing insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulin resistance disease, and obesity. Background art

The global diabetes population is projected to exceed 135 million (1995) and to increase to 300 million by 2025 (King HJ, Diabetes Care 21; 1414). -1431, 1998), and the social demands for progress in the treatment of this disease are very large. At present, the mainstay of diabetes treatment is the application of hypoglycemic drugs, which may result in lowering the rate of glycemic control, leading to diabetic neuropathy, retinopathy, nephropathy, and other diabetic complications and mortality. It has been revealed. However, there is a keen need for the creation of a drug that can control blood sugar more sophisticatedly, and the development of a highly useful antidiabetic drug having a new mechanism is desired.

According to recent elucidation of diabetes mellitus, dysfunction of kidney ^ cells and enhanced glucose release from the liver greatly contribute to the development and progression of diabetes (Wi thers DJ, Endocr i no l ogy 141; 1917-1921, 2000) ₀ Glucose release from the liver is strictly controlled by the relative regulation of glucagon and insulin, but in diabetic conditions, the absolute lack of insulin ( Insufficient relative action (type 1 diabetes mellitus: insulin-dependent diabetes mellitus) and increased relative hepatic glucose output due to lack of relative action (type 2 diabetes mellitus: non-insulin-dependent diabetes mellitus), resulting in a hyperglycemic state. Hepatic glucose release is expressed as the sum of two pathways: hepatic glycogen degradation and gluconeogenesis. In diabetic conditions, it has been reported that the hepatic glycogen decomposition system is enhanced (Tayek JA, Am. J. Physio, 270; E709-E717, 1996, Diraison F, Diabeto). Iogia 41; 212-220, 1998). It has also been reported that suppression of hepatic glycogen degradation normalizes the enhancement of hepatic glucose release in diabetic patients (Hell erste in MK, J. Clin. Invest. 100; 1305-1319, 1997, Pimenta, Diabeto Iogia 37; 697-702, 1994) _{0 From} these facts, it is considered that the enhancement of hepatic glycogen degradation contributes to the diabetic condition.

Hepatic glycogen is degraded to glycosyl-1-phosphate by glycogen phosphorylase (EG 2.4.1.1) and then converted to glucose (glycemia) by transphosphorylation monophosphorylation. Released into the blood, raising blood sugar. The glycogen phosphorylase inhibitor inhibits the above-mentioned glycogen decomposition reaction and suppresses glucose release (sugar release) from the liver. As a result, it has been reported that it shows a hypoglycemic effect in humans and diabetic animals (Tradway J. Diabetes 50 Supp 1.2; A133-A134, 2001, art in WH, Proc. At USA 95; 1776-1781, 1998). Conventionally, various compounds described in Patent Documents 1 to 3 below are known as glycogen phosphorylase inhibitors.

Patent Document 1 describes that a compound represented by the following general formula is used as a glycogen phosphorylase inhibitor in the treatment of diabetes and the like. The feature of the compound is that a chenobilol ring or the like is bonded to an ethylene moiety through an amide bond.

(Refer to the gazette for symbols in the formula)

Further, Patent Document 2 describes that a compound represented by the following general formula is used as a glycogen phosphorylase inhibitor for the treatment of a glycogen phosphorylase-dependent disease. The feature of the compound is that an indole ring or the like is bonded to an ethylene moiety through an amide bond.

(Refer to the gazette for symbols in the formula)

Patent Document 3 describes that a compound represented by the following general formula is used as a glycogen phosphorylase inhibitor for the treatment of diabetes and the like. The feature of the compound is that an indole ring or the like is bonded to a methylene moiety via an amide bond.

(See the gazette for symbols in the formula.) On the other hand, compounds in which an indole ring or the like is directly bonded to an aryl moiety via an amide bond

As (when a = 0), the compound described in Patent Document 4 is known. However, the use of the compound is a PDEIV (phosphodiesterase IV) inhibitor, and there is no disclosure or suggestion of the use as a glycogen phosphorylase inhibitor. The features of the compound are that an indole ring or the like is bonded to an aryl moiety directly via an amide bond or across methylene, and that the indole ring or the like has a substituent such as alkoxy or alkylene-aryl.

Glycogen phosphorylase inhibitors are excellent treatment and prevention agents for insulin-dependent diabetes mellitus (type 1 diabetes), non-insulin-dependent diabetes mellitus (type 2 diabetes), insulin resistance disease, and obesity. It is expected as. Therefore, there is a strong demand for the creation of a compound having a glycogen phosphorylase inhibitory action, which has a different chemical structure from the above-mentioned known compounds, and which has a more excellent effect.

Patent Document 1 Japanese Patent Application Laid-Open No. 2000-13-1131

Patent Literature 2 Tokiohei 1 1-5 0 0 4 4 5

Patent Literature 3 Japanese Patent Publication No. Hei 10-0-5 1 1 6 8 7

Patent Document 4 International Publication No. 0 1/6 4 6 3 9 Pamphlet Disclosure of the Invention

Under the state of the art in which a glycogen phosphorylase inhibitor in which an indole ring or a chenopyrrole ring binds to an alkylene (methylene, ethylene, etc.) moiety via an amide bond exists, the present inventors have proposed the substitution of a nitrogen atom of an amide. Focusing on the group, we conducted intensive research. As a result, instead of the indole ring or the chenobilol ring being bonded to the alkylene (methylene, ethylene, etc.) moiety via the amide bond, the ring is bonded to the ring A (aryl or aromatic hetero ring), and the ring A is formed. The inventors have found that a novel amide derivative represented by the following general formula (I) or a salt thereof, which always has a hydroxyethylene moiety as a substituent, has a more excellent glycogen phosphorylase inhibitory action, and completed. That is, the present invention relates to an amide derivative represented by the following general formula (I) or a salt thereof, and a dalycogen phosphorylase inhibitor containing the same as an active ingredient, particularly an agent for treating or preventing diabetes.

The compound of the present invention and the compounds described in Patent Documents 1 to 4 They differ from the compounds described in Patent Documents 1 to 4 in that they have an A ring (aryl or aromatic hetero ring) having a ethylene moiety as a substituent. Further, the compound of Patent Document 4 differs from the compound of the present invention also in that it has a substituent such as alkoxy or alkylene-aryl on the indole ring or the like.

(The symbols in the above formula have the following meanings, respectively.

Ring A: Aryl, or 5 to 1 to 4 heteroatoms selected from N, S, O

6-membered aromatic heterocycle,

Ring B: benzene or thiophene,

R ^{1 to} R ⁹ : identical or different, hydrogen atom, halogen atom, lower alkyl, -OH, -0 -lower alkyl, aryl, -0-aryl, -C (= 0) -lower alkyl, -CH (OH ) - lower alkyl, -C (= 0) - Ariru, - CH (OH) - Ariru, - lower alkylene _{- OH, - NH 2, -} N0 2, - CN, - COOH, = 0, -C (= 0)-O-lower alkyl, halogen-substituted lower alkyl, -0-halogen-substituted lower alkyl, -lower alkylene-aryl, -0-lower alkylene-aryl, -0-lower alkylene-COOH, -0-lower alkylene- C (= 0) - 0- lower alkyl, - 0- lower alkylene - C (= 0) - NH 2, -O- lower alkylene - C (= 0) -NH- lower alkyl, - 0- lower alkylene - C (= 0) -N (lower alkyl) ₂ , or -NH-C (= 0) -aryl,

R ¹⁰ : hydrogen atom or lower alkyl,

R ¹¹ : hydrogen atom, lower alkyl, or -lower alkylene-aryl,

R ^{12 to} R ¹⁵ : the same or different, hydrogen atom, -OH, halogen atom, lower alkyl, mono-lower alkyl, halogen-substituted lower alkyl, -lower alkylene-OH, -0-aryl, N, S, 5- or 6-membered aromatic heteroatom having 1-4 heteroatoms selected from O Ring, - lower alkylene - Ariru, - lower alkylene - CO OH, - lower alkylene - C (= O) - O- lower alkyl, - lower alkylene _{- C (= 0) -NH 2} , - lower alkylene - C (= 0) _ NH-lower alkyl, -C (= 0) -lower alkyl, -O-C (= 0) -lower alkyl, -CH (0H) -lower alkyl, -CH (OH) -aryl, -lower alkylene - C (= 0) - N ( lower § alkyl) _2, or - C (= 0) -0- lower alkyl, - COOH, -C (= 0 ) - NH 2, - lower § alkylene - OH, halogen atom, a lower alkyl, -O- lower _{alkyl, - OH, - NH 2,} - N0 2, optionally substituted with a substituent selected from -CN Ariru,

However, R ¹³ and R ¹⁴ may be combined with a carbon atom to form = 0 or cycloalkyl, and R ¹³ , R ¹⁴ and R ¹⁵ may be combined with a carbon atom to form aryl, or Lower alkynyl may be formed. )

Particularly preferably, the ring A is benzene, thiazol, pyrazine, pyrimidine or pyridine.

Further, among the general formula (I), an amide derivative represented by the following general formula (II) or a salt thereof is more preferable.

(The symbols in the above formula have the following meanings, respectively.

A ring: aryl, or a 5- or 6-membered aromatic hetero ring having 1 to 4 hetero atoms selected from N, S, O,

R ^{16 to} R ²⁴ : identical or different, hydrogen atom, halogen atom, lower alkyl, -OH, -0-lower alkyl, aryl, -0-aryl, -c (= o) -lower alkyl, -c (= o) - § reel, -CH (OH) - Ariru, - lower alkylene _{- OH, - NH 2, -NO} 2, - CN, - COOH, -C (= 0) -0- lower alkyl, halogen substituted lower alkyl , -0-halogen substituted lower alkyl, -lower alkylene-aryl, -0-lower alkylene-aryl, -0- Lower alkylene - COOH, - O-lower alkylene - C (= 0) -0- lower alkyl, - 0- low grade alkylene _{- C (= 0) -NH 2} , - O- lower alkylene - C (= 0) - N H -lower alkyl, -0-lower alkylene-C (= 〇) -N (lower alkyl) ₂ , or -NH-C (= 〇) -aryl, R ²⁵ and R ²⁶ : same or different, Hydrogen atom, or lower alkyl,

R ^{27 to} R ²⁹ : the same or different, hydrogen atom, lower alkyl, -lower alkylene-5- or 6-membered aromatic hetero having 1 to 4 hetero atoms selected from OH, aryl, N, S, O ring, - lower alkylene - Ariru, - lower alkylene - COOH, - lower alkylene emissions - C (= 0) - 0- lower alkyl, - lower alkylene - C (= 0) - NH 2, - lower alkylene - C 0 = O) -NH-lower alkyl or -lower alkylene-C (= 0) -N (lower alkyl) ₂ ) Particularly preferably, ring A is benzene, thiazole, pyrazine, pyrimidine or pyridine. Ring A is most preferably benzene.

Further, as specific compounds, 5-chloro-N- [4- (1,2-dihydroxyethyl) phenyl] -1H-indole-2- 2-propuloxamide, 5-chloro-N- [4- (1,2-dihydroxyethyl) -2,5-difluorofurnyl] -1H-indole-2 -caprolupoxamide, 5-chloro mouth

-N- [4- (1,2-dihydroxyethyl) -2,3,5,6-tetrafluorophenyl] -1H-indole-2-hexolpoxamide, 5-chloro-N- [4- ( 1-hydroxyethyl) phenyl]-1H-indole-2 -carboxamide, 5-chloro-N- [5- (1,2-dihydroxyethyl) pyridine-2-yl] -1H-indole- 2-carboxamide, 2,3-dichloro-N- [4- (1,2-dihydroxyethyl) phenyl] -1 4H-thieno [3,2-b] pyrrol-5-caprolupoxamide, 2, 3-dichloro

-N- [4- (1,2-dihydroxyethyl) -2,6-difluorophenyl] -4H-thieno [3,2-b] pyrrol-5-hexolpoxamide is preferred. Hereinafter, the compound of the present invention will be described in detail.

In the definition of the general formula in this specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Accordingly, "lower alkyl" includes, for example, straight chain or branched such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl. And alkyl. Among them, those having 1 to 3 carbon atoms are preferred, and methyl and ethyl are particularly preferred.

"Lower alkylene" includes methylene, ethylene, propylene, butylene and the like, It may be a branched lower alkylene. Methylene and ethylene are particularly preferred.

The term "aryl" means an aromatic hydrocarbon ring containing a condensed ring, and includes aryl having 6 to 14 carbon atoms. Benzene, naphthalene and anthracene are preferred.

"-Lower alkylene-aryl" means a compound in which the above alkylene is bonded to the above lower alkylene, and specific examples include benzyl, phenyl and the like. Benzyl is particularly preferred.

As the `` 5- or 6-membered aromatic heterocyclic ring having 1-4 heteroatoms selected from N, S, O '', 1-3 heteroatoms selected from N, S, O, It means a 5- or 6-membered aromatic hetero ring having 1 to 4 in total. Specific examples include furan, thiophene, pyrrole, pyridine, oxazole, thiazole, isothiazole, imidazole, virazole, tetrazole, pyrazine, pyrimidine, pyridazine, and triazine. Thiazole, pyrazine, pyrimidine and pyridine are particularly preferred.

Further, when the substituent in the formula is = o, it may mean a heterocycle in which a nitrogen atom has been oxidized, such as pyridineoxide ォ pyrimidineoxide.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine, chlorine, and bromine are preferred.

“Halogen-substituted lower alkyl” means the above-mentioned lower alkyl substituted with the above-mentioned halogen atom. Particularly, lower alkyl substituted with a fluorine atom is preferable. Further the preferred - is CF _3.

"Cycle mouth alkyl" means cycloalkyl having 3 to 8 carbon atoms.

"Lower alkynyl" means those having 2 to 6 carbon atoms, preferably acetylinyl. When ring B or A ring is a 5-membered ring, each R ⁵ and R ^9, or R ^{2 4} may that we do not exist.

Further, the compound of the present invention includes a mixture of various stereoisomers such as tautomers and optical isomers, and an isolated compound.

The compound of the present invention may form an acid addition salt. Further, depending on the type of the substituent, a salt with a base may be formed. Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid Acid addition salts with acidic amino acids such as acid, inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; organic bases such as methylamine, ethylamine and ethanolamine; basic amino acids such as lysine and orditin And ammonium salts.

The compounds of the present invention also include hydrates, various pharmaceutically acceptable solvates and polymorphs. Needless to say, the compound of the present invention is not limited to the compounds described in Examples below, but may be a derivative represented by the general formula (I) or (II) and a pharmaceutically acceptable derivative thereof. It includes all salts.

The compounds of the present invention also include all compounds that are metabolized in vivo and converted into the above general formula (I) or (II), or compounds converted into salts thereof, so-called prodrugs. Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med. 5:21 57-21 61 (1 985) and Hirokawa Shoten, 1990, “Development of Drugs”. The groups described in Vol. ₇ , Molecular Design, pp. 163-198 are listed.

The compounds of the present invention and their pharmaceutically acceptable salts can be produced by applying various known synthetic methods, utilizing characteristics based on the basic structure or the types of substituents. At that time, depending on the type of the functional group, it is necessary to replace the functional group with an appropriate protecting group, that is, a group that can be easily converted to the functional group at the stage of a raw material or an intermediate. May be. Thereafter, the desired compound can be obtained by removing the protecting group, if necessary. Examples of such a functional group include a hydroxyl group and a carboxyl group. Examples of such a protective group include, for example, Greene and Wuts, “Protective Groups in Organic Synthesis” No. 2 The protecting groups described in the edition can be mentioned.

(Manufacturing method)

Hereinafter, a typical production method of the compound of the present invention will be described.

Manufacturing method 1

()

(I)

(Wherein, ρ ^ ~Β ^{1 5,} A ring, B ring the same as supra, X is meant hydroxyl, a leaving group or a leaving atom such as a lower alkoxy group, or a halogen atom)

This reaction is a reaction in which the compound (II) and the compound (III) are reacted as they are or in a solvent, and then, if necessary, the protecting group is removed to obtain the compound of the present invention. Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone and acetate, ethers such as dioxane, tetrahydrofuran and diglyme, methanol and ethanol. And alcohols such as isopropanol, acetonitrile, dimethylformamide, dimethylsulfoxide, water, and a mixed solvent thereof, which are appropriately selected according to various reaction conditions.

Here, when X is a hydroxyl group, a method of reacting in the above solvent in the presence of a condensing agent can be applied. Examples of the condensing agent include N, N'-dicyclocarbodiimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, 1,1, -carbonyldiimidazole, diphenylphosphoryl azide and the like. .

When X is a lower alkoxy group, a method in which the reaction is carried out as it is or in the above-mentioned solvent under heating or under reflux with heating can be applied.

When X is a halogen atom, a method of reacting in the solvent in the presence of a base can be applied. Specific examples of the base include sodium carbonate, potassium carbonate such as potassium carbonate, sodium hydrogen carbonate, potassium carbonate such as potassium hydrogen carbonate, triethylamine, diisopropylethylamine, pyridine, and the like. Organic amines and the like. Manufacturing method 2

(I)

(Wherein, R ^{1 to} R ¹⁵ , A ring and B ring mean the same as those described above)

This reaction is a reaction in which R ¹² is added to compound (IV) as it is or after addition in a solvent, and the protecting group is removed as required to obtain the compound of the present invention. This sodium water borohydride For R ^{1 2} is hydrogen atom, lithium borohydride, hydrogen Kaboku Increment butoxy aluminum lithium and diisobutylaluminum hydride, lithium, sodium, by reaction with a - reducing agent such as zinc An inventive compound can be obtained. When R ¹² is an alkyl group or the like, the compound of the present invention can be obtained by a reaction using an alkyl metal or the like. Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane, tetrahydrofuran and diglyme, alcohols such as methanol, ethanol and isopropanol, and acetates. Examples thereof include tolyl, dimethylformamide, dimethylsulfoxide, water, and a mixed solvent thereof, which is appropriately selected according to various reaction conditions.

Manufacturing method 3

(I)

This reaction is a reaction in which CR ¹³ R ¹⁴ R ¹⁵ is added to compound (V) as it is or after it is added in a solvent, followed by removal of a protecting group as required to obtain the compound of the present invention. When CR R ¹ ⁴ R ¹⁵ is an alkyl group can be obtained the compound of the present invention by reaction with a an alkyl metal. Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane, tetrahydrofuran, and diglyme, acetonitrile, dimethylformamide, and a mixed solvent thereof. Is appropriately selected according to the conditions.

Manufacturing method 4

(I) (Wherein, R ^{1 to} R ¹⁵ , A ring and B ring mean the same as those described above)

This reaction is a reaction for oxidizing compound (VI) in a solvent and then removing a protecting group as required to obtain a compound of the present invention in which R ¹⁵ is a hydroxyl group.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone and acetone, ethers such as dioxane, tetrahydrofuran and diglyme, and methanol and ethanol and isopropanol. Alcohols, acetonitrile, dimethylformamide, dimethylsulfoxide, water, or a mixed solvent thereof may be mentioned, but may be appropriately selected according to various reaction conditions. Here, examples of the oxidizing agent include osmium tetroxide, hydrogen peroxide, potassium permanganate, and the like. If necessary, a co-oxidizing agent such as N-methylmorpholine-N-oxide-trimethylamine-N-oxide is used. Can also be added.

(Production method of raw material compounds)

(II)

(Wherein, R ^{1 to} R ⁵ , R ¹ °, X and B rings mean the same as above)

The starting compound (II) is commercially available or can be obtained by a known method, for example,

Synthes is, 222 (1980), J. Chem. Soc., 7185 (1965), Heterocyc Ies, 3402), 2349 (1992), J. Chem. Soc., Perk in Trans 1, 2189 (1984), J. Heterocyclic Ghem., 21.215 (1984). ⁸ R ¹² R ¹³

(VII) (ill)

(Wherein, R ^{6 to} R ⁹ , R ¹¹ to R ¹⁵ , and the A ring mean the same as described above)

This reaction is a reaction in which R ¹² is added to compound (VII) as it is or after addition in a solvent, followed by removal of a protecting group as required to obtain a starting compound (Ml). The reaction conditions are the same as in the reaction for producing the compound of the present invention from compound (IV) (Production method 2). Manufacturing method 3

(VIII)

(Wherein, R ^{6 to} R ⁹ , R ^{11 to} R ¹⁵ , and the A ring mean the same as described above)

In this reaction, 0 ^{13 14 15} is added to compound (VIII) as it is or after addition in a solvent, and then, if necessary, the protecting group is removed to obtain the starting compound (Ml). The reaction conditions are the same as those for the reaction for producing the compound of the present invention from compound (V) (Production method 3). Manufacturing method 4

(IX) (X)

(Wherein, R ^{6 to} R ⁹ , R ¹¹ to R ¹⁵ , and A ring are the same as those described above, and Y represents a halogen atom, a trifluoromethanesulfonyl group, or an acyl group)

This reaction is a synthesis method particularly when R ¹⁵ in the intermediate (III) is a hydroxyl group. In compound (IX), when Y is a halogen atom or a trifluoromethanesulfonyl group, Angew. Chem. Int. Ed. Engl., 25, 508 (1986) and J. Am. Chem. Soc., 106, 4630 ( The compound can be converted to the corresponding compound (X) by the method described in 1984) or a method analogous thereto. When Y is an acyl group in the compound (IX), the method described in Org. Synth., 751 (1973) or Am. Chem. Soc., 90, 6816 (1968) or a method analogous thereto. Compound

(X). This compound (X) is compounded by the oxidation reaction described above.

(XI). Further, the nitro group of the compound (XI) can be led to the intermediate (III) by catalytic hydrogenation or reduction reaction such as metal reduction.

(ll)

(VII)

(IV)

(Wherein, R ^{1 to} R ¹¹ , R ^{13 to} R ¹⁵ , ring A and ring B have the same meanings as described above.) In this reaction, compound (VII) is condensed with compound (VII) and optionally protected In this reaction, the group is removed to obtain the starting compound (IV). The reaction conditions are the same as in the reaction for producing the compound of the present invention from compounds (II) and (III) (Production method 1).

Manufacturing method 6

(ll)

(VIII)

(V) (Wherein, R ^{1 to} R ¹² , ring A and ring B mean the same as those described above)

This reaction is a reaction in which the compound (VIII) is condensed with the compound (II), and then, if necessary, the protecting group is removed to obtain the starting compound (V). The reaction conditions are the same as in the reaction (Production method 1) for obtaining the compound of the present invention from compounds (II) and (III).

Manufacturing method 7

(Wherein, Ρ ^ ~Ρ¾ ^14, Α ring, B ring is the same as defined above)

This reaction is a reaction in which the compound (XII) is condensed with the compound (II) and, if desired, the protecting group is removed to obtain the starting compound (VI). The reaction conditions are the same as in the reaction (Production method 1) for obtaining the compound of the present invention from compounds (II) and (III). Furthermore, some ^: compounds contained in the compound of the present invention are compounds obtained by the above method.

It can also be produced from (I) by arbitrarily combining steps commonly known to those skilled in the art such as alkylation, acylation, oxidation, reduction, hydrolysis and the like.

The compound of the present invention thus produced can be isolated and purified by a known method, for example, extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like. When the compound of the present invention has an asymmetric carbon, optical isomers exist. These optical isomers can be separated by a conventional method such as fractional crystallization for recrystallization with an appropriate salt or column chromatography. Industrial applicability

The compound of the present invention has a glycogen phosphorylase inhibitory action, and its action is adapted to diseases such as diabetes (insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes)). , Insulin resistance disease, and obesity. The excellent glycogen phosphorylase inhibitory activity of the compound of the present invention was confirmed by the following test methods.

1) Glycogen phosphorylase (GP) inhibitory test

The procedure for measuring the GP activity is as follows. The reaction was performed using a 96-well plate. 45 mM potassium phosphate, 0.24% glycogen, 1.6 mM magnesium chloride, 120 iM ethylenediaminetetraacetic acid trisodium, 22.5 M S-NADP, 4 10 ^_4 % -glucose 1,6-diphosphate, glucose-6-phosphate mixing the aqueous solution of acid dehydrogenase one peptidase 385Un it / and phosphonium Darco Mutter peptidase 77Unit / L, and a pH of 6.8 (Reaction Cocktai l) ₀ measurement Weng fruits, by averaging the values of 3 Ueru identical conditions Calculated. Each compound subjected to the reaction was dissolved in dimethyl sulfoxide, and added at a rate of 10 L per 1 ゥ: c. After adding 26.5 iL of the above-mentioned aqueous solution (Reaction Cocktail) to each well, the human liver-type GP protein solution (GP protein is dissolved in 40 mM; 8 glycerol phosphate, 80 mM cysteine (pH 6.8)) 23.5 L each, and reacted at room temperature. The GP enzyme reaction was detected by the increase in absorbance at 340 nm (SPEGTRAmax, Molecular Device, Sunnyvale, GA). The GP inhibitory activity of the test compound was evaluated by the percentage (%) of the reaction in the absence of the compound added to the reaction in the L (control). The concentration of the test compound that inhibited the control reaction by 50% (IC ₅₀ value) ). As a result, the compound of the present invention exhibited a strong glycogen phosphorylase (GP) inhibitory action equal to or higher than that of a conventional glycogen phosphorylase inhibitor. The IC ₅₀ values of representative compounds of the present invention are shown in Table 1 below. table 1

Compound IC ₅₀ (/ iM) Compound IC ₅₀ () Example 1 0.90 Example 38 0.28

Example 57 0.25 Example 62 0.40 2) Hypoglycemic effect measurement test

Six-week-old male G57BL / KsJ-db / db mice (CLEA Japan, Tokyo) were used for the experiments after a one-week acclimation period. Under non-fasting condition, 10 L of blood was collected from the tail vein, immediately mixed with 100 mL of a 0.33 M aqueous solution of perchloric acid, mixed and stirred, centrifuged (3000 rptn, 10 minutes), and the sugar concentration in the supernatant

(Blood glucose level) was measured using Glucose GI Test Co. Reagent (Wako Pure Chemical Industries, Osaka). Based on the weight and blood glucose level at that time, mice were allocated to each group (6 animals each) so as to be even. The next day, the test compound was orally administered to each of the assigned groups using a probe. At a certain time after the oral administration, blood was collected in the same manner as described above, and the blood glucose level was measured. The hypoglycemic effect of the test compound was evaluated by measuring the blood glucose level of the test compound administration group relative to the blood glucose level of the solvent group. As a result, the compound of the present invention showed a strong hypoglycemic effect. Therefore, the compound of the present invention exhibits a strong glycogen phosphorylase (GP) inhibitory action at least as high as that of a conventional glycogen phosphorylase inhibitor, and has a strong hypoglycemic action, so that it can be used as a pharmaceutical composition, particularly as an antidiabetic agent Useful. Pharmaceutical compositions containing one or more of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be used as carriers, excipients, and other additives commonly used for pharmaceuticals. It is prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc., and administered orally or parenterally.

Symptoms of patients clinical dose applied for human Bok of the compounds of the present invention, body weight, but is appropriately determined in consideration of age and gender, etc., the usual adult daily oral 0. 1~5 0 0 m _g The parenteral dose is 0.01 to 100 mg, which can be administered once or in several divided doses. Since the dose varies under various conditions, an amount smaller than the above dose range may be sufficient.

As the solid composition for oral administration of the compound of the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl. Pyrrolidone, mixed with magnesium aluminate metasilicate. The composition should be prepared according to the usual methods Additives other than 3 05198, for example, lubricants such as magnesium stearate and disintegrants such as calcium cellulose glycolate; It may contain a stabilizing agent such as acetic acid, a solubilizing agent such as glutamic acid or aspartic acid or a solubilizing agent. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a film of gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as Contains purified water and ethyl alcohol. The composition may contain, in addition to the inert diluent, solubilisers, solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (trade name).

Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizers or solubilizers. . These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can be used by dissolving them in sterile water or a sterile solvent for injection before use. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the production method of the compound of the present invention will be specifically described with reference to examples of the compound of the present invention. The starting compounds of the compounds of the present invention also include novel compounds, and these production methods are described as reference examples.

Reference example 1

Dissolve 780 mg of 5-chloroindole-2-hydroxyluponic acid and 976 mg of 2,3,5,6-tetrafluoro-4-promoline phosphorus in 15 ml of pyridine, and add phosphorus oxychloride at -25 ° C. 41 ml were added and the reaction mixture was stirred at room temperature for 12 hours. 20 ml of water was added to the reaction mixture, and the insoluble material was removed by filtration. The medium was distilled off under reduced pressure. 20 ml of a 1 M aqueous sodium hydroxide solution was added to the obtained residue, and the mixture was extracted with 30 ml of ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid is dried, washed with diisopropyl ether, and treated with N- (4-bromo-2,3,5,6-tetrafluorophenyl) -5-chloro-1H-india

This gave 825 mg of l-2-carboxamide.

In the same manner as in Reference Example 1, the compounds of Reference Examples 2 to 17 were obtained.

Reference Example 18

Dissolve 800 mg of 5-chloro-N-[(4-hydroxymethyl) phenyl] -1H-indole-2-caproloxamide in 10 ml of dimethyl sulfoxide, add 1.48 ml of triethylamine and 847 mg of sulfur trioxide pyridine complex, and add at room temperature. Stir for 1 hour. Water was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain 671 mg of 5-chloro-N-[(4-formylphenyl) -1H-indole-2-carboxamide.

Reference Example 19

N- (4-Bromo-2,3,5,6-tetrafluorophenyl) -5-culo-1H-indole-2-carboxamide 240 mg and vinyltriptyltin 542 mg in 1,4-dioxane 3 ml And 131 mg of tetrakistriphenylphenylphosphine palladium and 72 mg of lithium chloride were added under argon atmosphere, and the reaction mixture was heated to reflux for 8 hours. After returning the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Hexane (10 ml) was added to the obtained residue, and the mixture was extracted with acetonitrile (20 ml). The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (eluent: ethyl acetate: hexane = 6: 4) to give 5-chloro-N- (2,3,5,6-tetrafluoro-ethyl). 180 mg of 4-vinylphenyl) -1H-indole-2-carboxamide were obtained.

In the same manner as in Reference Example 19, the compounds of Reference Examples 20 to 32 were obtained.

Reference Example 33

7.00 g of methyltriphenylphosphonium bromide was suspended in 140 ml of tetrahydrofuran, and 19.5 ml of sodium bis (trimethylsilyl) amido-tetrahydrofuran solution was added thereto under ice-cooling under an argon atmosphere, and the reaction mixture was stirred at room temperature for 2.5 hours. A solution of 5.00 g of 3-benzyloxy-4-nitrobenzaldehyde in 20 ml of tetrahydrofuran was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, 200 ml of water was added to the residue obtained, and the mixture was extracted with 500 ml of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is applied to a silica gel column. Purification by chromatography (eluent; hexane: ethyl acetate = 5: 1) gave 1.69 g of 3-benzyloxy-4-nitrostyrene.

Reference example 34

N- (4-Promo-2--2-butanol) -5-coguchi-1H-indole-2-caproloxamide 2.55 g, iron powder 1.76 g and ammonium chloride 0.34 in a mixture of ethanol 150 m I And 25 ml of water were added, and the mixture was heated under reflux for 12 hours. After concentrating the reaction mixture, dimethylformamide was added, the insolubles were removed by filtration, the solvent was distilled off under reduced pressure, the residue obtained was washed with getyl ether, dried and dried to give N- (2-amino-4-bromophenyl). 1.36 g of -5-Chloro-1H-indole-2-force lipoxamide were obtained.

In the same manner as in Reference Example 34, the compound of Reference Example 35 was obtained. Example 1

760 mg of 1- (4-aminophenyl) ethane-1,2-diol, 970 mg of 5-chloroindole-2-caprolonic acid, 970 mg of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride 1.09 g A mixture of 880 mg of 1-hydroxybenzotriazole was dissolved in 20 ml of dimethylformamide, and the mixture was stirred at room temperature for about 8 hours. The solvent was distilled off under reduced pressure, and 80 ml of water was added to the residue obtained. The precipitated crystals were washed with 20 ml of water and dried to obtain 1.70 g of crude crystals. The obtained crude crystals were washed with ethyl acetate to obtain 1.05 g of N- [4- (1,2-dihydroxyethyl) phenyl) -5-chloro-1H-indole-2-carboxamide.

In the same manner as in Example 1, the compounds of Examples 2 to 56 were obtained.

Example 57

167 mg of 5-Hokuguchi-1H-indole (4-acetylphenyl) -2-carboxamide was dissolved in a mixture of 167 mg of methanol, 20 m of tetrahydrofuran, 20 m of tetrahydrofuran and dimethylformamide ΊΟπιΙ, and 26 mg of sodium borohydride was added. Stir for 5 hours. The solvent was distilled off under reduced pressure, and 80 ml of water was added to the residue obtained. The precipitated crystals were washed with water and dried to obtain crude crystals. The obtained crude crystals were washed with chloroform to give 58 mg of 5-chloro-1H-indole [4- (1-hydroxyethyl) phenyl] -2-hydroxylpoxamide.

As in Example 57, the compounds of Examples 58 to 59 were obtained.

Example 60

Suspension of 43mg of magnesium in 4ml of tetrahydrofuran, iodine pieces and cyclopro A solution of 0.46 ml of pilbromide in 2.5 ml of tetrahydrofuran was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was added to a solution of 175 mg of 5-chloro-1H-indole- (4-formylphenyl) -2-carboxamide in 4 ml of tetrahydrofuran under ice-cooling, followed by stirring at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixed solvent of 2-propanol and methanol was added to the obtained residue, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent; chloroform-form) to give 58 mg of 5-chloro-1H-indole [4- (cyclopropylhydroxymethyl) phenyl] -2-fluorophenol. Obtained.

In the same manner as in Example 60, the compound of Example 61 was obtained.

Example 62

A mixture of 1.02 ml of osmium tetroxide (0.080.0-butanol solution) and 140 mg of N-methylmorpholine-N-oxide was dissolved in tetrahydrofuran-water (4: 1, 20 ml), and 5-chloro-N- 180 mg of (2,3,5,6-tetrafluoro-4-vinylphenyl) -1H-indole-2-carboxamide was added, and the mixture was stirred at room temperature for 28 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (eluent; chloroform: methanol = 19: 1), washed with diisopropyl ether, and washed with diisopropyl ether. 43 mg of [4- (1,2-dihydroxyxethyl) -2,3,5,6-tetrafluorophenyl] -1H-indole-2-carboxamide was obtained.

In the same manner as in Example 62, the compounds of Examples 63 to 95 were obtained.

Example 96

N- [2-Benzyloxy-4-(1,2-dihydroxyethyl) phenyl] -5-chloro-1H-indole-2-hexoloxamide 1.96 g is treated with tetrahydrofuran 80m and dimethylformamide The mixture was dissolved in 40 ml, and 200 mg of 10% palladium activated carbon was added, followed by stirring under a hydrogen atmosphere for 1.5 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure. The residue obtained was washed with chloroform, dried and dried. N- [4- (1,2-dihydroxyxethyl) -2-hydroxyphenyl] -5-chloro-1H 1.03 g of indole-2-carboxamide was obtained.

The compounds of Examples 97 to 99 were obtained in the same manner as in Example 96.

Example 100

N- [4- (1,2-dihydroxyl) -2-hydroxyphenyl] -5-chloro-1H-indole 98 mg 2-Carboxamide (304 mg) was dissolved in 2-butanone (10 ml), potassium carbonate (600 mg) and 4-bromobutyrate (305 mg) were added, and the mixture was stirred at 80 ° C for 7 hours. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was added with 100 ml of water and extracted with 200 ml of ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chromate form: methanol = 20: 1) to give 4- {2-[(5-chloro-1H-indole-2--2-propanol) amino]. -5- (1,2-Dihydroxyxethyl) phenoxy} ethyl butyrate 308 mg was obtained.

In the same manner as in Example 100, the compounds of Examples 101 to 103 were obtained.

Example 104

Dissolve 250 mg of 4-ethyl 2- (2-[(5-cu-mouth-1H-indole-2- 2-propanol) amino] -5- (1,2-dihydroxyethyl) phenoxy} butyrate in 7 ml of 1,4-dioxane Then, 3 ml of a 4M hydroxylation solution was added and the mixture was stirred at room temperature for 3.5 hours. Under ice-cooling, 1M hydrochloric acid was added to the reaction mixture to adjust the pH to 5, the mixture was stirred at room temperature, and the solvent was distilled off under reduced pressure. 50 ml of water was added to the residue, and the precipitated crystals were dried and 219 mg of 4- {2-[(5-chloro-1H-indole-2-carbonyl) amino] -5- (1,2-dihydroxyxethyl) phenoxy} butyric acid was obtained. I got

In the same manner as in Example 104, the compounds of Examples 105 to 110 were obtained.

Example 111

5-Cross-N- [5- (1,2-dihydroxyethyl) pyridine-2-yl] -1H-indole-2-force 100 mg of lipoxamide was suspended in 6 ml of dimethylformamide, and 70% / 148 mg of 7-chloroperbenzoic acid and 6 ml of methylene chloride were added, and the mixture was stirred at room temperature for 6.5 hours. Then, 74 mg of 70% ^ lo-perbenzoic acid was added, and the mixture was stirred at room temperature for 15 hours. The precipitate was collected by filtration, washed with chloroform and ethanol, and treated with 5-chloro-N- [5- ( There was obtained 62 mg of 1.2-dihydroxyethyl) -1-oxoxidepyridine-2-yl] -1H-indole-2-caproloxamide.

Example 112

Methyl 4-((11 ^ / 21 ^)-2- {4-[(5-ku-guchi-1H-indole-2-carbonyl) amino] phenyl} -1,2-dihydroxyethyl) benzoate 66 mg was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (16 ml) was added, and the mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 1.5 hours. Further, 16 mg of lithium aluminum hydride was added, and the mixture was stirred at 0 ° C for 30 minutes, and then stirred at room temperature for 1.5 hours. Further, 16 mg of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 3.5 hours. After adding 1 M hydrochloric acid to the reaction mixture, add 40 ml of ethyl acetate, and add 1 M hydrochloric acid. Washed with 20 ml of hydrochloric acid. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: formanol = 9: 1). Further, the obtained solid was washed with methanol, and 5-chloro-i4-[(1RS / 2RS) -1,2-dihydroxy-2- (4-hydroxymethylphenyl) ethyl] phenyl 1H-indole -32 mg of 2-force lupoxamide were obtained.

Example 113

125 mg of 5-N- [4- (1,2-dihydroxyethyl) fu: Lnyl] -1H-indole-2-carboxamide is dissolved in 5 ml of pyridine, 40 juM of acetic anhydride is added, and the mixture is added at room temperature. Stirred for hours. The solvent was distilled off under reduced pressure, 20 ml of water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with 1M hydrochloric acid, water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 50: 1) to give 2- (4- (5-kuguchi-1H) 53 mg of -indole-2-yl) proponyl] amino} phenyl) -2-hydroxyacetate were obtained.

Example 114

AD-mix— dissolve 8700 mg in ί-butanol-water (1: 1, 5 ml) and add 5-chloro-N-[(2,3,5,7-tetrafluoro- mouth-4-vinyl) phenyl ] -1H-indole-2-carboxamide (184 mg) was added, and the mixture was stirred at 0 ° C for 24 hours. Further, methanesulfonamide (48 mg) was added, and the mixture was stirred at 0 ° C for 28 hours. Add AD-mix-j 81.05g and ί-butanol-water (1: 1, 5ml), stir at 0 ° C for 89 hours, add AD-mixH.75g, and add at 0 ° C for 23 hours Stirred. Finally, 1.75 g of AD-mix and 1-butanol-water (1: 1, 5 ml) were added, and the mixture was stirred at 0 ° C. for 3 hours, and then 5.5 g of sodium sulfite was added. After extracting the reaction mixture with 120 ml of ethyl acetate, the organic layer was washed with 40 ml of a 1M aqueous sodium hydroxide solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 15: 1) to give 5-chloro-4-{[(1R) -1,2-dihydroxyethyl]- 2,3,5,6-tetrafluoro} phenyl-1H-indole-2-carboxamide 127 mg was obtained. (79% e.e. CHIRALPAK AD-H (DA I SEL CHEM I GAL I ND., LTD))

Example 115

AD-mix-Dissolve 700mg in ί-butanol-water (1: 1, 5ml) and give 5-chloro-N-[(2,3,5,7-tetrafluoro-4--4-vinyl) phenyl] 184 mg of -H-indole-2-forcelupoxamide was added, and the mixture was stirred at 0 ° C for 24 hours. Further, add methanesulfonamide (48 mg) and stir at 0 ° C for 28 hours. Stirred. Add AD-mix-α.05 g and ί-butanol-water (1: 1, 5 ml), stir at 0 ° C for 89 hours, add AD-mix- 1.75 g, and add 0 ° C For 23 hours. Finally, 1.75 g of AD-mix and -butanol-water (1: 1, 5ιτιΙ) were added, and the mixture was stirred at 0 ° G for 48 hours, and then 5.5 g of sodium sulfite was added. After extracting the reaction mixture with 120 ml of ethyl acetate, the organic layer was washed with 80 ml of 1 M hydrochloric acid and 40 ml of 1 M aqueous sodium hydroxide solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 15: 1) to give 5-kuguchi-4- (1S) -1,2-dihydroxyxethyl] -2. , 3,5,6-tetrafluoro} phenyl-1H-indole-2-carboxamide (136 mg) was obtained. (70 ° / .ee: CHIRALPAK AD-HCDAISEL CHEMICAL IND., LTD)) The structural formulas and physicochemical properties of the reference example compound and the example compound are shown in Appended Tables 2 and 3. Further, the compounds shown in Table 4 can be easily produced in substantially the same manner as in the methods described in the above Examples and Production Methods, or by applying slight modifications obvious to those skilled in the art from those methods. it can. The symbols in the table have the following meaning.

R f.: Reference example number, Ex .: Example number, Structure: Structural formula, Data: Physical property data, NMR: Nuclear magnetic resonance spectrum (TMS internal standard), S: Mass spectrometry value, Ac: Acetyl

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Claims

The scope of the claims

1. An amide derivative represented by the following general formula (I) or a salt thereof c

(The symbols in the above formula have the following meanings, respectively.

Ring B: benzene or thiophene,

R ^{1 to} R ⁹ : same or different, hydrogen atom, halogen atom, lower alkyl, -OH, -O-lower alkyl, aryl, -0-aryl, -C (= 0) -lower alkyl, -CH (OH ) - lower alkyl, - C (= 0) - Ariru, -CH (OH) - Ariru, - lower alkylene _{- OH, - NH 2, -} N0 2, - CN, - COOH, = 0, -C (= 0) -O-lower alkyl, halogen-substituted lower alkyl, -O-halogen-substituted lower alkyl, -lower alkylene-aryl, -O-lower alkylene-aryl, -0-lower alkylene-COOH, -0-lower alkylene- C (= 〇) - 0- lower alkyl, -O- lower alkylene - C (= 0) - NH 2, -O- lower alkylene - C (= 0) - NH- lower alkyl, - O-lower alkylene - C (= 0) -N (lower alkyl) ₂ , or -NH-C (= 0) -aryl,

R ¹⁰ : hydrogen atom or lower alkyl,

R ¹ : hydrogen atom, lower alkyl, or -lower alkylene-aryl,

R ^{12 to} R ¹⁵ : the same or different, hydrogen atom, -OH, halogen atom, lower alkyl, -0-lower alkyl, halogen-substituted lower alkyl, -lower alkylene-OH, -O-aryl, N, S, 5- or 6-membered aromatic heterocycle having 1 to 4 heteroatoms selected from O, -lower alkylene-aryl, -lower alkylene-COOH, -lower alkylene -C (= O) -O-lower alkyl , -Lower alkylene- C (= 0) -NH, -lower alkylene- C (= 0) _ NH-lower alkyl, -C (= 0) -lower alkyl, -OC (= 0) -lower alkyl, -CH (OH) -lower alkyl, -CH (OH) -aryl, -lower alkylene-C (= 0) -N (lower § alkyl) _2, or - C (= 0) - O- lower alkyl, - COOH, - C (= 0) - NH 2, - lower § alkylene - OH, a halogen atom, a lower alkyl, -0- lower _{alkyl, -OH, - NH 2, -} N0 2, optionally substituted with a substituent selected from -CN Ariru,

However, R ¹³ and R ¹⁴ may be combined with a carbon atom to form = 0 or cycloalkyl, and R ¹³ , R ¹⁴ and R ¹⁵ may be combined with a carbon atom to be aryl or lower. Alkynyl may be formed. )

2. The compound according to claim 1, wherein the A ring is benzene, thiazole, pyrazine, pyrimidine, or pyridine.

3. An amide derivative represented by the following general formula (II) or a salt thereof.

(The symbols in the above formula have the following meanings, respectively.

R ^{16 to} R ²⁴ : identical or different, hydrogen atom, halogen atom, lower alkyl, -OH, -0-lower alkyl, aryl, -O-aryl, -c (= o) -lower alkyl, -c (= o) - § reel, -CH (OH) - Ariru, - lower alkylene _{- OH, -NH 2, - N0} 2, - CN, - COOH, - C (= 0) -0- lower alkyl, halogen substituted lower alkyl , -0-halogen-substituted lower alkyl, -lower alkylene-aryl, -0-lower alkylene-aryl, -0-lower alkylene-COOH, -0-lower alkylene-C (= 0) -0-lower alkyl,- O-low Grade alkylene _{- C (= 0) -NH 2} , - O- lower alkylene - C (= 0) -NH- lower alkyl, - 0- lower alkylene - C (= 0) - N ( lower alkyl) _2, or - NH-C (= 0) -aryl, R ²⁵ , and R ²⁶ : the same or different, a hydrogen atom, or lower alkyl,

R ^{27 to} R ^{29 are the} same or different, and are a 5- or 6-membered aromatic hetero atom having 1 to 4 hetero atoms selected from hydrogen atom, lower alkyl, -lower alkylene-OH, aryl, N, S, and O ring, - lower alkylene - Ariru, - lower alkylene - CO OH, - lower alkylene emissions -C (= 0) -0- lower alkyl, - lower alkylene _{- C (= 0) -NH 2} , - lower alkylene - C ( = 0) -NH-lower alkyl, or -lower alkylene- C (= 0) -N (lower alkyl) ₂ )

4. The compound according to claim 3, wherein ring A is benzene, thiazole, pyrazine, pyrimidine, or pyridine.

5. The compound according to claim 3, wherein the A ring is benzene.

6.5 5-clo-N- [4- (1,2-dihydroxyethyl) phenyl] -1H-indole-2-carboxamide, 5-clo-N- [4- (1,2-dihydroxy) -Ethyl) -2,5-difluorophenyl] -1H-indole-2- 2-propoxamide, 5-chloro-N- [4- (1,2-dihydroxyethyl) -2,3,5,6-tetra Fluorophenyl] -1H-indole-2- 2-propoxamide, 5-chloro-N- [4- (1-hydroxyxethyl) phenyl] -1Η-indole-2-carboxamide, 5-chloro-Ν- [5- (1,2-dihydroxyethyl) pyridine-2-yl] -1Η-indole-2-carboxamide, 2,3-dichloro-Ν- [4- (1,2-dihydroxyethyl) phenyl]- 4Η-thieno [3,2-b] pial-5-hexyl poloxamide, 2,3-dichloro-1 ^-[4- (1,2-dihydroxyethyl) -2,6-difluorophenyl Le-4H-thieno [3,2-b] pyrrole-5-carboxamide 2. The compound according to claim 1, wherein

7. A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient.

8. The pharmaceutical composition according to claim 1, which is a glycogen phosphorylase inhibitor.

9. The pharmaceutical composition according to claim 8, which is a therapeutic agent for diabetes.