JP2949702B2 - 2-oxoindoline derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2-oxoindoline derivative which has an excellent antagonistic effect on cholecystokinin and is useful for prevention and treatment of pancreatic disorders and gastrointestinal diseases, and a process for producing the same. .

[0002]

2. Description of the Related Art Cholecystokinin (CCK) is a brain / intestinal peptide present in gastrointestinal tissues and the central nervous system, is known as a substance involved in controlling pancreatic enzyme secretion and regulating appetite, and promoting colon motility. It is thought to have actions such as promoting gallbladder contraction, promoting pancreatic enzyme secretion, and suppressing gastric emptying. Further, since cholecystokinin coexists with dopamine in the central nervous system, it is considered that cholecystokinin has a role related to the function of the dopaminergic system.

[0003] Many antagonistic substances have been studied so far as being effective for the prevention or treatment of pancreatic disorders and gastrointestinal diseases, etc., as substances having an antagonistic action against cholecystokinin. For example, amino acid derivatives such as benzotrypto are known as cholecystokinin antagonists, but their effects are relatively weak, and their effects are short-lived, unstable, and poorly absorbed. It is not always satisfactory in point.

[0004] Non-peptide antagonists are disclosed in
Japanese Patent Publication No. 111774 discloses a benzodiazepine compound,
JP-A-2-28181 discloses a thienoazepine compound. Further, JP-A-64-68369 discloses a compound of the formula (V)

[0005]

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[0006] β-carboline derivatives have been disclosed.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel 2-oxoindoline derivative which exhibits more excellent antagonism to cholecystokinin, is useful as a medicament, a pharmacologically acceptable salt thereof, and a process for producing the same. Is what you do.

[0008]

According to the present invention, there is provided a compound of the formula (I)

[0009]

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(However, ring A is a substituted or unsubstituted benzene ring, R ¹ is a hydrogen atom, a cycloalkyl group, a substituted or unsubstituted aryl group, a nitrogen-containing heterocyclic group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group. Cyclic group, a heterocyclic group containing a nitrogen atom and an oxygen atom, a heterocyclic group containing a nitrogen atom and a sulfur atom, a lower alkoxy group, an optionally esterified carboxyl group, a cyano group, a lower alkylthio group, a lower An alkylsulfinyl group, a lower alkylsulfonyl group, an oxiranyl group or a 2- (lower alkylthio) -1-hydroxyethyl group, R ² is a substituted or unsubstituted aryl group,

[0011]

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A substituted or unsubstituted nitrogen-containing heterocyclic monocyclic group, a substituted or unsubstituted nitrogen-containing heterobicyclic group,

[0013]

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(Where n represents 1 or 2), an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, a heterocyclic group containing a nitrogen atom and an oxygen atom, or a nitrogen atom and a sulfur atom A heterocyclic group containing an atom, R ³ represents a substituted or unsubstituted lower alkyl group, Q represents a single bond or a lower alkylene group, and Y represents a single bond, a lower alkylene group or a lower alkenylene group. ), A pharmaceutically acceptable salt thereof, and a method for producing the same.

The object (I) of the present invention has an excellent cholecystokinin antagonism and is useful for preventing pancreatic disorders and gastrointestinal disorders.
It is a pharmaceutical compound useful as a therapeutic agent.

[0016] Specific examples of the subject matter of the present invention, in formula (I), ring A is a lower alkyl group and a lower alkoxy may be substituted with a group selected from the group benzene ring; R ¹ is a hydrogen atom A cycloalkyl group; a halogen atom,
Aryl group optionally substituted by a group selected from lower alkyl group, hydroxy group and lower alkoxy group; nitrogen-containing heterocyclic group; oxygen-containing heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and oxygen atom A heterocyclic group containing a nitrogen atom and a sulfur atom; a lower alkoxy group; a carboxyl group which may be esterified; a cyano group; a lower alkylthio group; a lower alkylsulfinyl group; a lower alkylsulfonyl group; An oxiranyl group; or a 2- (lower alkylthio) -1-hydroxyethyl group; an aryl group in which R ² may be substituted with a group selected from a halogen atom, a hydroxy group and a lower alkoxy group;

[0017]

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A nitrogen-containing heteromonocyclic group or a nitrogen-containing heterobicyclic group which may be substituted with a group selected from a formyl group, a lower alkoxycarbonyl group and a cyano-lower alkyl group;

[0019]

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Wherein n represents 1 or 2; an oxygen-containing heterocyclic group; a sulfur-containing heterocyclic group; a heterocyclic group containing a nitrogen atom and an oxygen atom; A heterocyclic group containing a sulfur atom; a compound wherein R ³ is a lower alkyl group which may be substituted with a group selected from a carboxyl group, a cyano group and a tetrazolyl group which may be esterified.

Examples of the aryl group include a phenyl group and a naphthyl group. Examples of the nitrogen-containing heteromonocyclic group include a pyridyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidyl group and a pyridazinyl group. Examples of the nitrogen-containing heterobicyclic group include an indolyl group, a quinolyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, a benzimidazolyl group, and a quinoxalinyl group. As the nitrogen-containing heterocyclic group, a pyrrolyl group,
Pyridyl group, imidazolyl group, pyrazolyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, indolyl group,
Quinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, benzimidazolyl group, quinoxalinyl group, carbazolyl group, carbolinyl group or formula

[0022]

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(Where n represents 1 or 2). Examples of the oxygen-containing heterocyclic group include a furyl group, a benzofuranyl group, a cumaryl group, a chromenyl group, and a chromanyl group. As the sulfur-containing heterocyclic group,
A thienyl group, a benzothiophenyl group or a thianthrenyl group. Examples of the heterocyclic group containing a nitrogen atom and an oxygen atom include a morpholinyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group and an isobenzooxazolyl group. Examples of the heterocyclic group containing a nitrogen atom and a sulfur atom include a thiazolyl group, an isothiazolyl group, a benzothiazolyl group and an isobenzothiazolyl group.

[0024] Among the objects of the present invention, drug efficacy on preferred compounds of the general formula (I), the benzene ring is substituted with a group ring A is selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom A phenyl group substituted with a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group; a phenyl group substituted with R ² by a group selected from a halogen atom and a lower alkoxy group; a naphthyl group; An indolyl group; an isoquinolyl group; a benzimidazolyl group;

[0025]

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Wherein n represents 1 or 2; a lower alkyl group in which R ³ may be substituted by a group selected from a carboxyl group, a cyano group and a tetrazolyl group; and Y is a single bond Or a compound that is a lower alkenylene group.

More preferred compounds from the pharmacological effect are those represented by formula (I), wherein ring A is a benzene ring substituted at the 5- or 6-position with a group selected from a lower alkyl group and a lower alkoxy group, R ¹ is a halogen atom, A phenyl group substituted with a group selected from a lower alkyl group and a lower alkoxy group, R ²
Is a naphthyl group, an indolyl group, an isoquinolyl group, a benzimidazolyl group or a formula

[0028]

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(Where n represents 1 or 2), a lower alkyl group in which R ³ is substituted by a group selected from a carboxyl group and a tetrazolyl group, Q is a single bond, Y is
Is a compound having a single bond.

The most preferred compound from the pharmacological effect is a benzene ring in which ring A in the general formula (I) is substituted at the 6-position with a group selected from a lower alkyl group and a lower alkoxy group.
A compound in which R ¹ is a halogenophenyl group, R ² is an isoquinolyl group, and R ³ is a carboxyl lower alkyl group.

The target compound (I) may have optical isomers based on asymmetric carbon atoms, and the present invention includes both of these optical isomers and mixtures thereof.

The object of the present invention can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Pharmaceutically acceptable salts include acid addition salts with inorganic or organic acids, and salts with inorganic bases, organic bases or amino acids, for example, hydrochloride, sulfate, hydrobromide, methane Sulfonate, fumarate, maleate,
Examples thereof include alkali metal (sodium, potassium, etc.) salts, methylamine salts, diethylamine salts, triethylamine salts, and salts with lysine.

In the object (I) of the present invention, when R ¹ is an esterified carboxyl group and / or R ³ is a carboxyl group-substituted lower alkyl group which is esterified, examples of the ester residue Is a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group,
Examples thereof include a phenacyl group and the like, and a lower alkyl group is particularly preferable.

The target substance (I) and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and are usually administered to mammals, including humans, in capsules, microcapsules, or the like. Tablets, granules, powders, troches, syrups,
It can be administered in conventional pharmaceutical compositions such as aerosols, inhalants, solutions, injections, suspensions, emulsions, suppositories and the like.

The pharmaceutical composition according to the present invention comprises excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc .; Binders such as polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch and the like; for example, starch, carboxymethylcellulose, calcium salts of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium hydrogen carbonate, calcium phosphate, citrate Disintegrants such as calcium acid salt;
Lubricants such as magnesium stearate, talc, sodium lauryl sulfate; fragrances such as citric acid, menthol, glycine, orange powder; sodium benzoate, sodium bisulfite, methyl paraben,
Preservatives such as propylparaben; stabilizers such as citric acid, sodium citrate, acetic acid; suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersants; aqueous diluents such as water; Various organic or inorganic carrier substances commonly used in medicine, such as base waxes such as fats, polyethylene glycols, white kerosene, etc., can be included.

The dose of the object (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the age, body weight, conditions and administration method of the patient, but is usually 0.01 mg / k / day.
g to 50 mg / kg.

According to the present invention, the desired 2-oxoindoline derivative (I) can be obtained by the method (A): General formula (II)

[0038]

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Wherein the rings A, R ¹ , R ³ and Q have the same meanings as described above, or a salt thereof, and a compound of the general formula (III)

[0040]

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(Wherein R ² and Y have the same meanings as described above), by reacting with a carboxylic acid compound, a reactive derivative thereof or a salt thereof, or by the method (B): General formula (IV)

[0042]

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Wherein the rings A, R ¹ , R ² , Q and Y have the same meaning as described above, or a salt thereof with R ³
By reacting with an alkylating agent corresponding to

The reactive derivative of the compound (III) includes acid halides, active esters, and acid anhydrides, and is preferably an acid halide such as acid chloride.

As the alkylating agent corresponding to R ³ used in the reaction with compound (IV), for example, R ³ -X ¹ (X ¹ represents a halogen atom, and R ³ has the same meaning as described above) An alkyl halide compound represented by the formula: CH ₂ = CH-R ³¹ (where R ³¹ is R ³
A substituted or unsubstituted lower alkyl group having 2 carbon atoms).

As the salts of the compounds (II) and (IV), for example, salts with inorganic acids such as hydrochloric acid and sulfuric acid can be used. As the salt of the compound (III), in addition to the salt with the above-mentioned inorganic acid, for example, a salt with an inorganic base such as an alkali metal salt can be used.

Method (A): The reaction of the amine compound (II) or a salt thereof with the carboxylic acid compound (III), a reactive derivative thereof or a salt thereof can be easily carried out by a conventional method. For example, the reaction between the amine compound (II) or a salt thereof and the reactive derivative of the carboxylic acid compound (III) or the salt thereof is carried out in a solvent, if necessary, in the presence of a deoxidizing agent, from the boiling point of the solvent used under cooling. Performed at temperatures up to.

The solvent to be used is not particularly limited as long as it is a solvent inert to the reaction. For example, water, alcohols such as methanol, ethanol, propanol and butanol;
Ethers such as tetrahydrofuran, diethyl ether and dioxane; esters such as methyl acetate and ethyl acetate; hydrocarbons such as petroleum ether, hexane and cyclohexane; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; benzene, toluene, Aromatic hydrocarbons such as xylene; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethyl sulfoxide; and a mixed solvent thereof can be used.

The deoxidizing agent optionally used includes organic bases such as triethylamine, pyridine, picoline and N-methylmorpholine; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate, sodium hydrogencarbonate; Examples thereof include alkali metal carbonates such as potassium carbonate and the like, preferably triethylamine, pyridine and the like. Among the aqueous solvents, sodium hydrogen carbonate, potassium carbonate and the like are preferable.

The reaction between the amine compound (II) or its salt and the free carboxylic acid compound (III) or its salt can be carried out in a solvent in the presence of a dehydrating agent.

As the dehydrating agent, those used for amide synthesis are preferable, for example, dicyclohexylcarbodiimide, N
-Ethyl-N′-diethylaminopropylcarbodiimide hydrochloride, N-methyl-2-chloropyridinium iodide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, BOP reagent [benzotriazol-1-yloxy Tris- (dimethylamino) phosphonium hexafluorophosphate], diphenylphosphate azide (DPPA) and the like.

If desired, an active ester reagent such as 1-hydroxybenzotriazole may be used in combination with a dehydrating agent.

As the solvent, those mentioned above can be preferably used. The reaction suitably proceeds from under cooling to under heating.

Since this reaction proceeds without racemization, an optically active target substance can be obtained by using an optically active raw material.

Method (B): Compound (IV) or a salt thereof and R ³
Can be carried out by a conventional method. For example, the reaction of compound (IV) or a salt thereof with an alkyl halide compound or alkene compound suitably proceeds in a solvent in the presence of a base. Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and 1,8-diazabicyclo [5,4,0 And organic bases such as undec-7-ene. Examples of the solvent include amides such as N, N-dimethylformamide and N, N-dimethylacetamide, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and dichloroethane, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, Dioxane,
Toluene and a mixed solvent thereof can be used. The reaction is performed under cooling to heating, for example, at 0 ° C to 100 ° C.
It proceeds favorably at a temperature of

The target substance (I) of the present invention can also be produced by interconverting the target substance obtained as described above into another target substance by a conventional method. Such an interconversion reaction between the target substances may be appropriately selected according to the type of the functional group of the compound, and can be carried out, for example, as in the following (a) or (b).

Method (a): The target product (I) in which Q is a lower alkylene group is the same as the target product (I) in which Q is a single bond and R ¹ is a hydrogen atom, except that the group: -Q ¹ -R ¹ (Wherein Q ¹ represents a lower alkylene group, and R ¹ has the same meaning as described above). This reaction can be carried out in the same manner as in the above method (B).

Method (b): R ¹ is a carboxyl group and / or
Target product (I) wherein R ³ is a carboxyl lower alkyl group
Can be produced by removing the ester residue of the corresponding target compound (I) in which the carboxyl group is esterified. The removal of the ester residue can be carried out by treating the target compound (I) in which the carboxyl group is esterified with an acid or an alkali reagent in a solvent and hydrolyzing it. Examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and inorganic or organic acids such as trifluoroacetic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Examples of the alkali reagent include an inorganic base such as an alkali metal hydroxide (eg, sodium hydroxide and potassium hydroxide).

Examples of the solvent include water, methanol,
Ethanol, isopropanol, acetone, acetonitrile, hexane, cyclohexane, benzene, toluene, chloroform, dichloromethane, dichloroethane,
Examples thereof include dioxane, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, and a mixed solvent thereof. The reaction suitably proceeds at a temperature from under cooling to the boiling point of the solvent used.

Further, the object (I) of the present invention can be mutually converted by a conventional method as described below.

For example, the target compound (I) in which R ¹ is a lower alkylthio group can be oxidized to a corresponding sulfinyl or sulfonyl compound. The target product (I) in which R ¹ is an oxiranyl group can be treated with an alkali metal lower alkyl sulfide to obtain the target product in which R ¹ is a 2- (lower alkylthio) -1-hydroxyethyl group. In this case, when R ³ is an esterified carboxyl lower alkyl group, it is simultaneously hydrolyzed to a carboxy lower alkyl group.

The target product (I) wherein R ² is an N-lower alkoxycarbonyl-substituted nitrogen-containing heteromonocyclic group or nitrogen-containing heterobicyclic group may be deacylated in the same manner as in the method (b). Can be a target product wherein R ² is an N-unsubstituted nitrogen-containing heteromonocyclic group or nitrogen-containing heterobicyclic group, and further a mixed acid anhydride or cyano lower obtained from formic acid and acetic anhydride. By treating with an alkane (eg, acrylonitrile), the N-position of the nitrogen-containing heteromonocyclic group or the nitrogen-containing heterobicyclic group can be formylated or cyano-lower alkylated.

The target compound (I) in which R ³ is a cyano lower alkyl group can be treated with tributyltin azide (Bu ₃ SnN ₃ ) to give a corresponding tetrazole form, or treated with a lower alkanol acid. To obtain the corresponding lower alkoxycarbonyl compound.

The target compound (I) in which a lower alkoxy group is present in at least one substituent of the ring A, R ¹ , R ² and R ³ is treated with a Lewis acid such as boron tribromide to give the corresponding hydroxy compound And further treated with a lower alkyl halide or the like to obtain a lower alkoxy compound.

Compound (I) wherein Y is lower alkenylene
Can be reduced to a target product wherein Y is a lower alkylene group.

Each of the above-mentioned interconversion reactions of the target product proceeds without racemization. If an optically active substance is used as a raw material, an optically active target product can be obtained.

After completion of the reaction, the 2-oxoindoline derivative produced by the above-mentioned production method can be isolated from the reaction mixture by an ordinary method, and can be purified according to an ordinary method, if desired. For example, after the completion of the reaction, if necessary, after decomposing the excess reagent or removing the reaction solvent, the desired product is extracted with a soluble solvent,
Alternatively, it can be collected by adding an appropriate solvent to precipitate. Further, if necessary, it can be purified by column chromatography, recrystallization or the like.

Amine compound (II) as a raw material of the present invention
Is represented by the general formula (VI)

[0069]

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(Wherein ring A has the same meaning as described above), and if necessary, a group having the amino group: -QR ¹ (wherein Q and R ¹ have the same meaning as described above) )), Followed by reaction with oxalyl halide,
General formula (VII) obtained

[0071]

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Wherein the rings A, R ¹ and Q have the same meaning as described above, are treated with hydroxyamine and then reduced to give a compound of the general formula (VIII)

[0073]

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(Wherein rings A, R ¹ and Q have the same meanings as described above), and if necessary, the amino group is protected and reacted with an alkylating agent in the same manner as in method (B). When the amino group is protected, it can be produced by removing the protecting group.

Compound (VII), which is 4- (lower alkoxy) -2,3-dihydro-1H-indole-2,3-dione, can be obtained by reacting 3- (lower alkoxy) aniline with RM Soll et al., J. Org.Chem., 53, 2844 (198
8)] According to the method described above, 3 ′-(lower alkoxy)-
2,2-dimethylpropionanilide, which can be produced by lithiation of the ortho position of the anilide compound, treatment with diethyl oxalate, and further ring closure.

Compounds in which Q is a lower alkylene group (VI
II) is a compound (VI) in which the group: -QR ¹ is a hydrogen atom.
To the nitrogen atom of the indoline ring position 1 II), groups in the same manner as (a) Method: -Q ² -R ¹ (where, Q ² represents a lower alkylene group, R ¹ is the same as defined above. ) Can be introduced.

The starting compound (IV) is a compound (VII)
I) can be produced by reacting with compound (III) in the same manner as in method (A).

Expression

[0079]

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The starting compound represented by the formula is

[0081]

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[H. Rapoport et al, J. Am. Chem. So
c., 80, 5574 (1958)] can be produced by hydrolysis in the same manner as in the method (b).

The target compound (I) of the optically active substance can be produced by reacting an optically active amine compound (II) or a salt thereof with a carboxylic acid compound (III), a reactive derivative or a salt thereof. it can.

The optically active form of the amine compound (II) can be obtained by forming an optical resolving agent and a diastereomer salt from the racemic amine compound (II) according to a conventional method and performing optical resolution. As the optical resolving agent, a conventional resolving agent can be used, and for example, optically active dibenzoyltartaric acid can be used.

In the present specification, the lower alkyl group and lower alkoxy group mean those having 1 to 6 carbon atoms, preferably those having 1 to 4 carbon atoms. A lower alkanoyl group is one having 2 to 6 carbon atoms, preferably 2 to 2 carbon atoms.
It means four things. The cycloalkyl group means one having 3 to 9 carbon atoms, preferably one having 3 to 6 carbon atoms. The lower alkylene group means one having 1 to 8 carbon atoms, preferably one having 1 to 5 carbon atoms. The lower alkenylene group means one having 2 to 6 carbon atoms, preferably one having 2 to 4 carbon atoms. As a halogen atom,
Chlorine, bromine, fluorine and iodine, preferably chlorine and fluorine.

Further, the compounds represented by the general formulas (I), (II) and (I)
In V), (VII) and (VIII), when the substitution position of the substituent on ring A is specified, it is specified by the position number of the following indoline ring.

[0087]

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[0088]

EXAMPLES The present invention will be described below in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Example 1 (1) 3-amino-1-pentyl-2,3-dihydro-1H-indol-2-one hydrochloride (2.84 g), sodium hydrogencarbonate (2.24 g), chloroform (30 ml), water (3)
0 ml of the mixture was cooled with water under an argon atmosphere, and 2.80 g of methylene chloride 2.80 g of 3,4-dichlorobenzoyl chloride was added.
0 ml solution is added dropwise. The reaction mixture is stirred under water cooling for 30 minutes and at room temperature for 30 minutes, then diluted with water and extracted with chloroform.

After washing and drying the chloroform layer, the solvent is distilled off. The residue was recrystallized from ethyl acetate-hexane,
4.06 g of 3,4-dichloro-N- (2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl) benzamide are obtained as colorless crystals. Melting point: 1
25-126 ° C, IR (Nujol) (cm ^-1 ): 3280,17
25, 1635, 1610, MS (m / z): 390 (M ⁺ ).
, 374, 372, 217 (base).

(2) 3.56 g of this product, 4.1 ml of methyl acrylate, 3.82 g of potassium carbonate, 70 ml of acetone
Is stirred at room temperature under argon atmosphere overnight.
The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed, dried, and the solvent is distilled off. The obtained crude crystals were recrystallized from ethyl acetate-hexane,
3- [3- (3,4-dichlorobenzoylamino)-
2,3-dihydro-2-oxo-1-pentyl-1H-
Indole-3-yl] propionic acid methyl ester,
That is, 3- (3,4-dichlorobenzoylamino)-
3- (2-methoxycarbonylethyl) -1-pentyl-1H-indole-2 (3H) -one, 3.96 g
Is obtained as colorless crystals. Melting point: 84-114 ° C, IR
(Nujol) (cm ^-1 ): 3330, 1735, 1705, 16
60, MS (m / z): 476 (M ⁺ ), 173 (base).

Example 2 (1) 3-amino-2,3-dihydro-1H-indol-2-one hydrochloride (15.05 g), 3,4-dichlorobenzoyl chloride (17.20 g), methylene chloride (300)
ml of triethylamine 1 under an argon atmosphere.
A solution of 6.5 g of methylene chloride in 50 ml is added dropwise with stirring under ice cooling. The mixture is returned to room temperature, stirred for 30 minutes, added with 100 ml of water and further stirred for 2 hours. The precipitated crystals were collected by filtration, washed and recrystallized from dimethylformamide-water to give 3,4-dichloro-N- (2,3-dihydro-2-oxo-1H-indol-3-yl) benzamide. 9 g are obtained as colorless needles. Melting point: 283-285 ° C (decomposition), IR
(Nujol) (cm ^-1 ): 3280, 3160, 3100, 17
10, 1690, 1635, MS (m / z): 322 & 3
20 (M ⁺ ), 147 (base).

(2) To a solution of 23.0 g of this product and 7.52 g of ethyl acrylate in 130 ml of dimethyl sulfoxide,
Under an argon atmosphere, 10 g of potassium carbonate is added under ice cooling and stirring. After returning to room temperature and stirring for 1 hour, dilute with ice water. The precipitated crystals were collected by filtration and crystallized from ethyl acetate-hexane to give 3
-[3- (3,4-dichlorobenzoylamino) -2,
26.33 g of 3-dihydro-2-oxo-1H-indol-3-yl] propionic acid ethyl ester are obtained as a colorless powder. Melting point: 227-228 ° C, IR (Nujo
l) (cm ^-1 ): 3350, 3320, 3280, 1740,
1710, 1655, 1625, MS (m / z): 422 &
420 (M ⁺ ).

Example 3 (1) 1.22 g of 3-amino-2,3-dihydro-1-pentyl-1H-indol-2-one hydrochloride,
0.93 g of 2,3,4-tetrahydronaphthalene-2-carboxylic acid, 1-hydroxybenzotriazole 0.7
1 g of a mixture of 2 g and 40 ml of methylene chloride under ice-cooling.
1.10 g of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added. After the reaction mixture was stirred for 1 hour under ice cooling, 1.0 ml of triethylamine was added, and the mixture was stirred for 2 hours under ice cooling and further for 2 hours at room temperature.
After completion of the reaction, the solvent is distilled off under reduced pressure, the residue is diluted with ethyl acetate, washed and dried, and the solvent is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N- (2,3-
1.36 g of dihydro-2-oxo-1-pentyl-1H-indol-3-yl) -1,2,3,4-tetrahydronaphthalene-2-carboxamide are obtained as colorless crystals. Melting point: 127-132 ° C, IR (Nujol) (c
m- ¹ ): 3280, 1725, 1640, 1610, MS
(m / z): 376 (M ⁺ ), 218 (base), 147, 31.

(2) This product was treated in the same manner as in Example 1- (2) to give 3- [2,3-dihydro-2-oxo-1-
Pentyl-3- (1,2,3,4-tetrahydro-2-
Naphthylcarbonylamino) -1H-indole-3-
Yl] propionic acid methyl ester. Melting point: 17
2-179 ° C.

Example 4 2.70 g of 3,4-dichloro-N- (2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl) benzamide, 1.30 g of acrylonitrile, 30 ml of acetone, A mixture of 1.46 g of potassium carbonate is stirred for 1 hour at room temperature under an argon atmosphere. After the acetone has been distilled off, the mixture is treated with water and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off, and the residue is crystallized from ethyl acetate-hexane to give N- [3- (2-cyanoethyl) -2,3-dihydro-2-oxo-1-oxo. 2.28 g of pentyl-1H-indol-3-yl] -3,4-dichlorobenzamide are obtained as colorless crystals. Melting point: 79-84 ° C, IR (Nujol) (cm ^-1 ): 3340,2
325, 1700, 1655, 1610, MS (m / z):
445 & 443 (M ⁺ ).

Example 5 3-amino-2,3-dihydro-6-methoxy-1-pentyl-1H-indol-2-one hydrochloride 1 g, β-
To a mixture of 683 mg of naphthylcarbonyl chloride and 15 ml of methylene chloride was added 0.1 ml of triethylamine under ice-cooling.
98 ml is added dropwise and stirred at room temperature for 1 hour. In the reaction solution,
Water and chloroform were added, and the chloroform layer was separated,
After washing and drying, the solvent is distilled off under reduced pressure. The residue was dissolved in 10 ml of dimethyl sulfoxide, and 0.3 ml of ethyl acrylate was added.
8 ml and 500 mg of potassium carbonate are added, and the mixture is stirred at room temperature for 30 minutes under an argon atmosphere. Ethyl acetate,
Water is added, the organic layer is separated, washed and dried, and the solvent is distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane,
1.55 g of ethyl 3- [2,3-dihydro-6-methoxy-3- (2-naphthalenecarbonyl) amino-2-oxo-1-pentyl-1H-indol-3-yl] propionate are obtained. Melting point: 156-159C,
IR (Nujol) (cm ^-1 ): 3260, 1735, 1690,
1650, 1620, MS (m / z): 502 (M ⁺ ), 4
5.

Example 6 3-amino-2,3-dihydro-6-methoxy-1-pentyl-1H-indol-2-one hydrochloride (1 g), indole-2-carboxylic acid (570 mg), methylene chloride (20)
680 m of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride under ice-cooling.
g, 1-hydroxybenzotriazole (480 mg) and triethylamine (0.73 ml) were added, and the mixture was stirred at room temperature for 2.5 hours.

Water and ethyl acetate are added to the reaction solution, the organic layer is separated, washed, dried, and the solvent is distilled off. The residue is dissolved in dimethyl sulfoxide (10 ml), ethyl acrylate (0.38 ml) and potassium carbonate (485 mg) are added, and the mixture is stirred at room temperature for 1.5 hours. Water and ethyl acetate were added to the reaction solution, the organic layer was separated, washed, dried, and the solvent was distilled off under reduced pressure to give 3- [2,3-dihydro-3- (1H-indol-2-ylcarbonyl). There are obtained 1.72 g of amino-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester.

Example 7 (1) 3-Amino-1- (4-fluorophenyl)-
2,3-dihydro-6-methoxy-1H-indole-
2.00 g of 2-one hydrochloride, 1.33 g of sodium isoquinoline-3-carboxylate, 0.88 g of 1-hydroxybenzotriazole were added to 10 m of anhydrous dimethylformamide.
1- (1-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.49 g) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction mixture was extracted by pouring ethyl acetate-tetrahydrofuran (2: 1), and the extract was washed.
After drying, the mixture is filtered, and the filtrate is concentrated. The residue was ethyl acetate
Powdered from tetrahydrofuran and N- [1- (4-
2.60 g of (fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide are obtained. Melting point 21
9-220 ° C.

(2) This product 200 mg, 4-bromobutyric acid ethyl ester 275 mg, dimethylformamide 4 m
l of potassium carbonate 195 under an argon atmosphere.
mg and stirred for 15 hours at room temperature. Thiourea 71
Add mg and stir for an additional 24 hours. The reaction solution is poured into water and extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (2: 1)].
4- [1- (4-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinylcarbonylamino) -6
-Methoxy-2-oxo-1H-indol-3-yl] butyric acid ethyl ester 140 mg is obtained as a caramel. IR (Nujol) (cm ^-1 ): 3380, 1740, 167
5,1625, MS (m / z): 541 (M ⁺ ), 476,4.
26, 156, 128 (base).

Examples 8-42 The corresponding starting compounds were treated in the same manner as in any of Examples 1 to 7, to obtain the compounds shown in Tables 1 to 6.

[0103]

[Table 1]

[0104]

[Table 2]

[0105]

[Table 3]

[0106]

[Table 4]

[0107]

[Table 5]

[0108]

[Table 6]

Example 43 (1) 3-Amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indole hydrochloride (2.00 g) was added to a solution of 2.00 g of dimethyl sulfoxide in 40 ml of dimethyl sulfoxide. .85 ml and potassium carbonate 1.94
g and stirred at room temperature for 3 hours under an argon atmosphere.
The reaction solution is extracted with ethyl acetate, and the extract is washed and dried.
The insolubles are removed by filtration, and the filtrate is concentrated. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1: 1)] to give 3- [3-amino-2,
1.36 g of 3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester are obtained as a pale yellow oil.

(2) This product and 5,6-dihydro-4H-
Pyrrolo [3,2,1-ij] quinoline-2-carboxylic acid was treated in the same manner as in Example 3- (1) to give 3- {3-
[(5,6-dihydro-4H-pyrrolo [2,3,1-i
j] quinolin-2-yl) carbonyl] amino-2,3
To give -dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl} propionic acid ethyl ester.

Examples 44-60 The corresponding starting compounds were treated in the same manner as in Example 43 to give
The compounds described in Tables 9 to 10 are obtained.

[0112]

[Table 7]

[0113]

[Table 8]

[0114]

[Table 9]

Example 61 3- [3- (3,4-dichlorobenzoylamino)-
2,3-dihydro-2-oxo-1H-indole-3
-Yl] propionic acid ethyl ester 1.06 g, 3-
1.0 g of phenylpropyl bromide, potassium carbonate 1.
A mixture of 10 g and 16 ml of acetone is refluxed overnight.
The solvent is distilled off, the residue is extracted with ethyl acetate, washed, dried, and then the solvent is distilled off. The residue was crystallized from isopropyl ether-hexane to give 3- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-2-oxo-1.
-(3-phenylpropyl) -1H-indole-3-
Yl] propionic acid ethyl ester 1.25 g is obtained as a colorless solid. Melting point: 119.5-121.5 ° C, IR
(Nujol) (cm ^-1 ): 3320, 1730, 1700, 16
60, 1615, FAB-MS (m / z): 541 & 539
(MH ⁺ ).

Examples 62 to 74 The corresponding starting compounds were treated in the same manner as in Example 61 to give the first compound.
The compounds described in Tables 0 to 11 are obtained.

[0117]

[Table 10]

[0118]

[Table 11]

Example 75 3- [3- (3,4-Dichlorobenzoylamino)-
2,3-dihydro-1- (3-methylthiopropyl)-
To a solution of 2-oxo-1H-indol-3-yl] propionic acid ethyl ester (2.05 g) in chloroform (80 ml) was added 1.22 g of metachloroperbenzoic acid under ice-cooling and stirring, followed by stirring at room temperature overnight. The solvent is distilled off from the reaction solution,
The mixture is extracted with ethyl acetate, and the extract is washed, dried, filtered, and dried under reduced pressure.

The residue was subjected to silica gel column chromatography [ethyl acetate-hexane (1: 2) -chloroform-
Methanol (20: 1)] to give 3- [3-
(3,4-dichlorobenzoylamino) -2,3-dihydro-1- (3-methylsulfinylpropyl) -2-
Oxo-1H-indol-3-yl] propionic acid ethyl ester (sulfinyl compound, small Rf) and 3- [3
-(3,4-dichlorobenzoylamino) -2,3-dihydro-1- (3-methylsulfonylpropyl) -2-
[Oxo-1H-indol-3-yl] propionic acid ethyl ester (sulfonyl compound, large Rf) is obtained. The sulfinyl compound is recrystallized from ethyl acetate-isopropyl ether to give 1.07 g as colorless prisms. Melting point: 154-159 ° C, IR (Nujol) (cm ^-1 ): 322
0, 1720, 1655, 1610, FAB-MS (m /
z): 527 & 525 (MH ⁺ ).

Example 76 In Example 75, 3- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-1- (3-methylsulfonylpropyl) obtained by separation by silica gel column chromatography. ) -2-Oxo-1H-indol-3-yl] propionic acid ethyl ester (sulfonyl compound, large Rf) is recrystallized from ethyl acetate-hexane to give 592 mg as colorless needles. Melting point: 106
-108 ° C, IR (Nujol) (cm ^-1 ): 3360,173
0,1660,1615, FAB-MS (m / z): 543
& 541 (MH ⁺ ).

Example 77 3- [1- (t-butoxycarbonylmethyl) -3-
(3,4-dichlorobenzoylamino) -2,3-dihydro-2-oxo-1H-indol-3-yl] propionic acid ethyl ester 700 mg methylene chloride 20
5 ml of trifluoroacetic acid was added to
Stir for hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 2- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-3- (2
-Ethoxycarbonylethyl) -2-oxo-1H-indol-1-yl] acetic acid (651 mg) is obtained as colorless prisms. Melting point: 219-220 ° C, IR (Nujol)
(cm ^-1 ): 3280,1735,1720,1705,1
670, 1610, FAB-MS (m / z): 481 & 47
9 (MH ⁺ ).

Example 78 (1) 3- [2,3-dihydro-6-methoxy-3-
(2-naphthalenecarbonyl) amino-2-oxo-1
-Phenyl-1H-indol-3-yl] propionic acid ethyl ester (2.37 g) in methylene chloride (20 ml) was added dropwise under cooling with about 2.5 ml of boron tribromide.
Stir at room temperature for hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The extract was evaporated to dryness under reduced pressure to give 3- [2,3-dihydro-6-hydroxy-3- (2-naphthalenecarbonyl) amino-2-oxo-1-phenyl-1H-indol-3-yl] propionic acid. Obtain the ethyl ester.

(2) 63.3% sodium hydride 3 in a solution of 2.15 g of this product in 20 ml of dimethylformamide
After adding 30 mg and stirring, 0.35 m of ethyl iodide was added.
Add l. After stirring at room temperature for 2.5 hours, the reaction solution is washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography [ethyl acetate-hexane (1:
2)] to give 3- [6-ethoxy-2,3-dihydro-3- (2-naphthalenecarbonyl) amino-2-.
Oxo-1-phenyl-1H-indol-3-yl]
928 mg of ethyl propionate are obtained as colorless needles. Melting point: 195-196 ° C, IR (Nujol)
(cm ^-1 ): 3420, 1750, 1730, 1640, ¹
620, 1540, MS (m / z): 522 (M ⁺ ), 155
(base).

Example 79 3- [3- (2-t-butoxycarbonyl-1,2,2,3)
3,4-tetrahydro-3-isoquinolinyl) carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 6.79 g in a 75 ml ethyl acetate solution. Under ice cooling, hydrochloric acid gas is added until saturation, and the mixture is stirred at 0 ° C. for 2.5 hours. After evaporation of the solvent, the residue is suspended in isopropyl ether. The suspension was filtered to give 3- [2,3-dihydro-2-oxo-1-pentyl-3- (1,2,2
3,05-tetrahydro-3-isoquinolinyl) carbonylamino-1H-indol-3-yl] propionic acid ethyl ester hydrochloride (6.05 g) is obtained as a pale yellow amorphous solid. IR (Nujol) (cm ^-1 ): 3180, 172
5,1690,1610, FAB-MS (m / z): 478
(MH ⁺ ), 132 (base).

Example 80 0.66 g of formic acid and 1.35 g of acetic anhydride were mixed, and 50
Heat for 15 minutes at ° C.

After cooling, 15 ml of anhydrous methylene chloride, 0.68 g of sodium formate and 3- [2,3-dihydro-2
-Oxo-1-pentyl-3- (1,2,3,4-tetrahydro-3-isoquinolinyl) carbonylamino-1
[H-Indol-3-yl] propionic acid ethyl ester hydrochloride (1.70 g) in methylene chloride (15 ml) was added, and the mixture was stirred at room temperature overnight. The reaction solution is neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The extract was washed, dried, filtered, concentrated and concentrated to give 3- [3- (2
-Formyl-1,2,3,4-tetrahydro-3-isoquinolinyl) carbonylamino-2,3-dihydro-2
-Oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 1.72 g is obtained as a pale yellow amorphous solid. IR (Nujol) (cm ^-1 ): 328
0, 1720, 1655, 1610, FAB-MS (m /
z): 506 (MH ⁺ ), 160 (base).

Example 81 3- [2,3-dihydro-3-[(E) -3- (3-methoxyphenyl) -2-propenoylamino] -2-oxo-1-pentyl-1H-indole- 3-yl] propionic acid ethyl ester 1.64 g of methylene chloride 3
2 ml of boron tribromide is added dropwise to the 0 ml solution under ice cooling. The mixture was stirred for 1 hour under ice cooling, then poured into ice water,
Extract with chloroform. After drying the extract, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (1: 1)] to give 3-
[2,3-dihydro-3-[(E) -3- (3-hydroxyphenyl) -2-propenoylamino] -2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 1.53 g are obtained as a colorless amorphous solid. IR (Nujol) (cm ^-1 ): 3280,170
5,1660,1610, FAB-MS (m / z): 465
(MH ^<+> ), 302, 256, 228, 147 (base).

Example 82 3- [2,3-dihydro-3-[(E) -3- (2-methoxyphenyl) -2-propenoylamino] -2-oxo-1-phenyl-1H-indole- The 3-yl] propionic acid ethyl ester was treated in the same manner as in Example 81 to give 3- [2,3-dihydro-3-[(E) -3- (2
-Hydroxyphenyl) -2-propenoylamino]-
2-oxo-1-phenyl-1H-indol-3-yl] propionic acid ethyl ester is obtained as a colorless solid. IR (Nujol) (cm ^-1 ): 3280, 1740, 171
0,1610, FAB-MS (m / z): 470 (M ⁺ ), 9
One.

Example 83 3- [3- (3,4-Dichlorobenzoylamino) -1
-(2-oxiranylmethyl) -2,3-dihydro-2
-Oxo-1H-indol-3-yl] propionic acid ethyl ester (1.635 g) in ethanol (24 ml), 15% aqueous sodium methyl sulfide solution (12 ml)
And stirred at 50 ° C. for 3 hours. After concentrating the reaction solution,
Acidify with 0% hydrochloric acid and extract with ethyl acetate. The extract is washed, dried, filtered and concentrated. The residue was subjected to silica gel column chromatography [chloroform-methanol (1
0: 1)] and recrystallized from ethyl acetate-hexane to give 3- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-1- (3-methylthio-2-).
1.52 g of (hydroxypropyl) -2-oxo-1H-indol-3-yl] propionic acid are obtained as colorless needles. Melting point: 168.5-169.5 ° C, IR (Nujo
l) (cm ^-1 ): 3400, 3300, 1710, 1650,
1615, FAB-MS (m / z): 499 & 497 (M
H ⁺ ).

Example 84 3- [2,3-dihydro-3-[(E) -3- (2-methoxyphenyl) -2-propenoylamino] -2-oxo-1-phenyl-1H-indole- A mixture of 719 mg of 3-yl] propionic acid ethyl ester, 100 mg of 10% palladium-carbon, 20 ml of ethanol and 6 ml of tetrahydrofuran is stirred overnight under a hydrogen gas atmosphere of 1 atm. The reaction solution was filtered, and the solvent was distilled off from the filtrate to give 3- [2,3-dihydro-3- [3- (2-
700 mg of methoxyphenyl) propanoylamino] -2-oxo-1-phenyl-1H-indol-3-yl] propionic acid ethyl ester are obtained as an amorphous solid.

Example 85 3- [3- (3,4-Dichlorobenzoylamino)-
2,3-dihydro-2-oxo-1-pentyl-1H-
A mixture of 3.89 g of methyl indole-3-yl] propionate, 16 ml of a 2N aqueous sodium hydroxide solution and 100 ml of methanol is heated to reflux for 40 minutes. After cooling the reaction mixture to room temperature, the solvent is distilled off under reduced pressure. The residue is diluted with water, adjusted to pH 4 with 10% aqueous hydrochloric acid, and extracted with chloroform. After washing and drying the extract, the solvent is distilled off. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 3- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-2-oxo-1-.
3.34 g of pentyl-1H-indol-3-yl] propionic acid are obtained as colorless crystals. Melting point: 202-2
04 ° C, IR (Nujol) (cm ^-1 ): 3260, 1730, ¹
675, 1660, FAB-MS (m / z): 463 (M
H ⁺ ), 173 (base).

Example 86 3- [3- (3,4-Dichlorobenzoylamino)-
2,3-Dihydro-2-oxo-1- (3-phenylpropyl) -1H-indol-3-yl] propionic acid ethyl ester (1.20 g), ethanol (20 ml), tetrahydrofuran (5 ml) were mixed with a 4N sodium hydroxide solution. 5 ml and 5 ml of water are added and stirred at room temperature for 7 hours. The reaction solution is concentrated under reduced pressure, diluted with water, made acidic with 10% hydrochloric acid, and extracted with ethyl acetate. After drying the extract, the solvent was distilled off, and the residue was recrystallized from ethanol-ethyl acetate to give 3- [3- (3,4-dichlorobenzoylamino).
This gives 1.09 g of 2,3-dihydro-2-oxo-1- (3-phenylpropyl) -1H-indol-3-yl] propionic acid as colorless needles. Melting point: 242
-243 ° C, IR (Nujol) (cm ^-1 ): 3285,171
5,1690,1675,1615, FAB-MS (m /
z): 513 & 511 (MH ⁺ ).

Example 87 3- [3- (2-Formyl-1,2,3,4-tetrahydro-3-isoquinolinyl) carbonylamino-2,3
-Dihydro-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 1.70
To a solution of g in 30 ml of ethanol, 3.79 ml of 1N sodium hydroxide is added and stirred at room temperature for 4 hours. After concentration of the reaction solution, the residue is dissolved in water, washed with diethyl ether, acidified with 10% hydrochloric acid, and extracted with ethyl acetate.
The ethyl acetate layer was further extracted with an aqueous sodium hydrogen carbonate solution, and the extract was subjected to a nonionic adsorption resin (trade name: HP-2).
0, manufactured by Mitsubishi Kasei Corporation) and eluted with water and a mixed solution of water and methanol (1: 1). Lyophilize the eluate and add
-[3- (2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl) carbonylamino-2,3-
1.24 g of sodium dihydro-2-oxo-1-pentyl-1H-indol-3-yl] propionate are obtained as a pale yellow powder. IR (Nujol) (cm ^-1 ): 3680-
2400 (br), 1710, 1660, 1610, F
AB-MS (m / z): 522 (MNa ⁺ ), 500 (MH ⁺ ,
base).

Examples 88-162 The corresponding starting compounds were treated in the same manner as in any of Examples 85-87, to give the compounds described in Tables 12 to 22.

[0136]

[Table 12]

[0137]

[Table 13]

[0138]

[Table 14]

[0139]

[Table 15]

[0140]

[Table 16]

[0141]

[Table 17]

[0142]

[Table 18]

[0143]

[Table 19]

[0144]

[Table 20]

[0145]

[Table 21]

[0146]

[Table 22]

Example 163 N- [3- (2-cyanoethyl) -2,3-dihydro-
2-oxo-1-pentyl-1H-indol-3-yl] -3,4-dichlorobenzamide 2.00 g, tributyltin azide (Bu ₃ SnN ₃ ) 3.0 g and toluene 1.
5 ml of the mixture is heated and stirred at 110 ° C. for 3 hours. After cooling, a 6.4% hydrochloric acid-ethanol 50 ml solution was added,
Stir at room temperature for 30 minutes. After evaporating the solvent, ethyl acetate and then a saturated aqueous solution of potassium fluoride are added, and the insoluble matter is removed by filtration. The ethyl acetate layer is separated, washed, and concentrated. The residue is dissolved in a 5% aqueous sodium hydroxide solution and washed with diethyl ether. After acidifying the aqueous layer with 10% hydrochloric acid,
After extraction with ethyl acetate, washing and drying, the solvent is distilled off. The residue was recrystallized from ethyl acetate to give N- {2,3-dihydro-2-oxo-1-pentyl-3- [2- (1H-tetrazol-5-yl) ethyl] -1H-indole-
1.72 g of 3-yl @ -3,4-dichlorobenzamide
As colorless needles. Melting point: 142-147 ° C, I
R (Nujol) (cm ^-1 ): 3340,1705,1655,1
675, 1615, FAB-MS (m / z): 489 & 48
7 (MH ⁺ ).

Example 164 N- [3- (2-Cyanoethyl) -1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3 -0.647 g of isoquinolinecarboxamide was treated in the same manner as in Example 163 to give N- {1- (4-fluorophenyl)-
2,3-dihydro-6-methoxy-2-oxo-3-
[2- (1H-tetrazol-5-yl) ethyl] -1
0.252 g of H-indol-3-yl} -3-isoquinolinecarboxamide is obtained. Melting point 154-160 ° C Example 165 3- [2,3-dihydro-3- (1H-indole-2)
-Ylcarbonyl) amino-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 375 mg, acrylonitrile 530 mg, 1,
A mixture of 3 drops of 8-diazabicyclo [5,4,0] undec-7-ene (DBU) and 4 ml of dimethylformamide is stirred at 80 ° C. for 22 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. After washing and drying the extract,
Activated carbon treatment, and the solvent is distilled off under reduced pressure to obtain a caramel-like residue. A mixture of the obtained residue, 1.4 ml of 2N aqueous sodium hydroxide solution and 10 ml of methanol is stirred at room temperature for 20 hours. After methanol was distilled off from the reaction solution under reduced pressure, the solution was acidified with 10% aqueous hydrochloric acid and extracted with chloroform. After drying the extract, the solvent is distilled off under reduced pressure. The residue was recrystallized from diisopropyl ether to give 3- [3-
[1- (2-cyanoethyl) -1H-indole-2-
This gives 150 mg of [ylcarbonylamino] -2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid. Melting point 125 [deg.] C.

Example 166 (S) -3-Amino-1- (4-fluorophenyl)-
2,3-Dihydro-5-methoxy-3-methyl-2-oxo-1H-indole and 5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2-carboxylic acid were carried out By treating in the same manner as in Example 3- (1) or Example 7- (1), (S) -N- [1- (4-fluorophenyl)
-2,3-dihydro-5-methoxy-3-methyl-2-
Oxo-1H-indol-3-yl] -5,6-dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2
-Obtaining carboxamide. Melting point: 223-224 ° C.
[Α] ²⁵ _D : +58.33 (c = 0.240, chloroform).

Examples 167 to 171 The following compounds were obtained by treating corresponding starting compounds in the same manner as in Example 166.

Example 167: (S) -N- [1- (2-
Fluorophenyl) -2,3-dihydro-3-methyl-
2-oxo-1H-indol-3-yl] -5,6-
Dihydro-4H-pyrrolo [3,2,1-ij] quinoline-2-carboxamide. Melting point: 194-195 ° C,
[Α] ²⁵ _D : + 127.8 ° (c = 0.374, chloroform).

Example 168: (S) -N- [1- (4-
Fluorophenyl) -2,3-dihydro-5-methoxy-3-methyl-2-oxo-1H-indol-3-yl] -1H-indole-2-carboxamide. Melting point:
287-288 ° C., [α] ²⁵ _D : + 90.95 ° (c =
0.376, chloroform).

Example 169: (S) -N- [1- (4-
Fluorophenyl) -2,3-dihydro-5-methoxy-3-methyl-2-oxo-1H-indol-3-yl] -4,5-dihydropyrrolo [3,2,1-hi] indole-2- Carboxamide. Melting point: 277-278
° C, [α] ²⁵ _D : + 42.30 ° (c = 0.312, chloroform).

Example 170: (+)-N- [3- (2-
Cyanoethyl) -1- (4-fluorophenyl) -2,
3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide. [Α] ²⁵ _D : + 80.53 ° (c = 0.226, chloroform).

Example 171: (-)-N- [3- (2-
Cyanoethyl) -1- (4-fluorophenyl) -2,
3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide. [Α] ²⁵ _D : −80.70 ° (c = 0.228, chloroform).

Example 172 (+)-N- [3- (2-cyanoethyl) -1- (4-
Fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide 1.88 g of methanol 20
Hydrochloric acid gas is passed through the ml solution under ice cooling until saturation, and the mixture is stirred at room temperature for 30 minutes. 140 μl of water is added to the reaction solution and left for 7 days. The reaction solution is concentrated, and an aqueous solution of sodium hydrogen carbonate and then ethyl acetate are added to the obtained residue for extraction. The organic layer is separated, dried, filtered and concentrated. The residue was subjected to silica gel column chromatography [hexane-
Ethyl acetate (1: 1)] to give (+)-3- {1
-(4-Fluorophenyl) -2,3-dihydro-3-
1.84 g of [(3-isoquinolinyl) carbonylamino] -6-methoxy-2-oxo-1H-indol-3-yl} propionic acid methyl ester are obtained as a colorless amorphous solid. [Α] ²⁵ _D : + 53.41 ° (c =
0.468, chloroform).

Example 173 (-)-N- [3- (2-cyanoethyl) -1- (4-
Fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide was treated as in Example 172 to give (-)-3- {1 -(4-fluorophenyl)-
2,3-Dihydro-3-[(3-isoquinolinyl) carbonylamino] -6-methoxy-2-oxo-1H-indol-3-yl} propionic acid methyl ester is obtained. [Α] ²⁵ _D : −53.81 ° (c = 0.446, chloroform).

Example 174 (+)-3- {1- (4-fluorophenyl) -2,3
-Dihydro-3-[(3-isoquinolinyl) carbonylamino] -6-methoxy-2-oxo-1H-indol-3-yl} propionic acid methyl ester 1.80 g
Then, 4.21 ml of 1N sodium hydroxide is added to a solution of the above in 20 ml of ethanol, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated, and the residue is purified with a nonionic adsorption resin (trade name: HP-2).
0, manufactured by Mitsubishi Kasei Co., Ltd.) and (+)-3-
{1- (4-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonylamino] -6
1.64 g of sodium -methoxy-2-oxo-1H-indol-3-yl} propionate are obtained as a colorless powder. [Α] ²⁵ _D : + 72.94 ° (c = 0.41)
4, methanol).

Example 175 (-)-3- {1- (4-fluorophenyl) -2,3
-Dihydro-3-[(3-isoquinolinyl) carbonylamino] -6-methoxy-2-oxo-1H-indol-3-yl} propionic acid methyl ester was treated in the same manner as in Example 174 to give (-) -3- {1- (4-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonylamino] -6-methoxy-2
-Oxo-1H-indol-3-yl} sodium propionate is obtained. [Α] ²⁵ _D : −72.41 ° (c =
0.406, methanol).

Example 176 (1) 3-Amino-1- (2-fluorophenyl)-
2,3-dihydro-6-methoxy-1H-indole-
To 210 ml of a dimethyl sulfoxide solution of 70.00 g of 2-one hydrochloride are added 29.90 ml of acrylonitrile and 62.70 g of potassium carbonate, and the mixture is stirred at room temperature overnight under an argon gas atmosphere. The reaction solution obtained is poured into water and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 70.70 g of 3- [3
-Amino-1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] propanenitrile is obtained as a brown oil.

(2) 3- [3-amino-1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-
2-oxo-1H-indol-3-yl] propanenitrile 70.70 g of crude product
and a solution of 51.21 g of (+)-dibenzoyltartaric acid monohydrate in 150 ml of ethyl acetate is added dropwise to the solution under ice-cooling. The crystals were collected by filtration, washed with ethyl acetate, and washed with 3- [3-amino-1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-.
2-oxo-1H-indol-3-yl] propanenitrile (+)-dibenzoyl tartrate (41.13 g)
As pale yellow crystals. This product is dissolved in 180 ml of methanol under heating, concentrated, and the resulting residue is triturated with ethyl acetate to obtain 34.02 g of the above salt as colorless crystals (yield: 22%). [Α] ²⁵ _D +5
0.0 ° (c = 0.420, methanol). Melting point 155
-157 ° C.

(3) 34.02 g of 3- [3-amino-
1- (2-fluorophenyl) -2,3-dihydro-6
-Methoxy-2-oxo-1H-indol-3-yl] propanenitrile (+)-dibenzoyl tartrate in a mixed solvent of aqueous potassium carbonate and ethyl acetate,
Dissolve under stirring. The ethyl acetate layer is separated, washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
After filtration, the filtrate is concentrated under reduced pressure to give 15.44 g of a colorless oil. The above oil was dissolved in 100 ml of anhydrous dimethylformamide, and 10.19 g of 3-isoquinolinecarboxylic acid sodium salt, 6.41 g of 1-hydroxybenzotriazole and 10.92 g of N-ethyl-
N′-Diethylaminopropylcarbodiimide hydrochloride is added under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction is poured into water and the mixture is extracted with ethyl acetate.

The organic layer was washed successively with dilute hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
85 g of (+)-N- [3- (2-cyanoethyl) -1
-(2-fluorophenyl) -2,3-dihydro-6
Methoxy-2-oxo-1H-indol-3-yl]
-3-isoquinolinecarboxamide is obtained as a pale yellow oil.

Example 177 23.85 g of (+)-N- [3- (2-cyanoethyl) -1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H- Indole-3
-Yl] -3-isoquinolinecarboxamide The crude product is dissolved in 80 ml of anhydrous methanol, hydrogen chloride gas is saturated under ice cooling until saturated, and 1.71 ml of water is added. The reaction solution is heated to reflux for 1 hour, cooled, and concentrated under reduced pressure. The residue is neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is separated, washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration,
The filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (ethyl acetate: hexane (1: 1).
1, volume) and 22.30 g of (+)-3-
[1- (2-Fluorophenyl) -2,3-dihydro-
3- (3-Isoquinolinyl) carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester is obtained as a pale yellow amorphous solid (yield: 91% (Example 176 (2 ))))). DI-MS (m / z) 513 (MH +), 426
156,128 (base). [Α] ²⁵ _D + 66.2 ° (c
= 0.402, chloroform).

Example 178 62.53 g of (+)-3- [1- (2-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo- 1
H-Indol-3-yl] propionic acid methyl ester was dissolved in 576 ml of methanol, and the solution
6.78 ml of 3N-NaOH aqueous solution is added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was
Acidify with aqueous citric acid solution and extract with ethyl acetate. The organic layer was separated, washed sequentially with water and saturated saline,
Add 15 g of activated carbon and dry over anhydrous sodium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain (+)
-3- [1- (2-Fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-
6-Methoxy-2-oxo-1H-indol-3-yl] propionic acid is obtained as an oil [[α] ²⁵ _D +8
0.3 ° (c = 0.426, chloroform)]. 7.36 g of sodium carbonate and 200 ml of water are added to the product to form a solution. The solution is concentrated to dryness under reduced pressure, 500 ml of acetonitrile is added to the residue, and after heating and dissolution, insolubles are removed by filtration. After cooling, crystals precipitated from the filtrate were collected by filtration, and 60.07 g of (+)-3- [1-
(2-fluorophenyl) -2,3-dihydro-3-
Sodium (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl] propionate is obtained as a colorless solid (yield: 95
%). 206-211 ° C. FAB-MS (m / z)
522 (MH +), 177, 23 (base). [Α] ²⁵ _D +8
9.7 ° (c = 0.406, methanol).

Example 179 11.47 g of (+)-3- [1- (2-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo- 1
[H-indol-3-yl] propionic acid;
g of potassium carbonate, 5 ml of water and 20 ml of acetonitrile are added to form a solution. This solution is concentrated to dryness under reduced pressure, 100 ml of acetonitrile is added to the residue, and after heating and dissolution, insolubles are removed by filtration. Concentrate the filtrate,
Dissolve the residue by heating in 100 ml of acetonitrile,
After cooling, the precipitated crystals were collected by filtration, and 10.91 g of (+)
-3- [1- (2-Fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-
6-Methoxy-2-oxo-1H-indol-3-yl] propionic acid potassium salt is obtained as a colorless solid. 275-277 ° C (decomposition). FAB-MS (m / z)
576 (MK ⁺ ), 538 (MH ⁺ ), 192, 39 (bas
e). [Α] ²⁵ _D + 91.8 ° (c = 0.438, methanol).

Example 180 (1) 3-Amino-1- (4-fluorophenyl)-
2,3-dihydro-5-methoxy-1H-indole-
60 g of 2-one hydrochloride was converted to 200 m of dimethyl sulfoxide.
, and 43 g of potassium carbonate and then 20 ml of acrylonitrile were added to the solution.
Stir at room temperature. After 2 hours, 2 ml of acrylonitrile are added and stirring is continued overnight. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing the extract with saturated saline,
After drying over anhydrous magnesium sulfate and filtering, the solution is concentrated under reduced pressure. The precipitated crystals were collected by filtration, and 3- [3-
Amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo-1H-indole-
36.8 g of propanenitrile are obtained. Melting point 1
36-138 ° C. EI-MS (m / z) 325 (M ⁺ )
.

(2) 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2
-Oxo-1H-indol-3-yl] propanenitrile (43.7 g) and (-)-dibenzoyltartaric acid (40 g) are dissolved in ethyl acetate (300 ml) and left overnight at room temperature with gentle stirring. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give the desired product, 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo. -1H-indole-
26.4 g of [3-yl] propanenitrile (-)-dibenzoyl tartrate are obtained. 157-158.5 ° C.
[Α] ²⁰ _D + 64.91 ° (c = 0.228, methanol). EI-MS (m / z): 325 (M ⁺ ). IR (N
ujol) (cm-1): 1380, 1460, 1690, 174
0,2250.

(3) 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2
-Oxo-1H-indol-3-yl] propanenitrile (-)-dibenzoyl tartrate is added with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate, and the ethyl acetate layer is separated. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered.
Then the solvent is distilled off under reduced pressure. The residue was dissolved in dimethylformamide (800 ml), and isoquinoline-
40 g of sodium 3-carboxylate are added, and 27.4 g of 1-hydroxybenzotriazole and 39 g of N-ethyl-N'-diethylaminopropylcarbodiimide hydrochloride are further added under ice-cooling, followed by stirring. The solution is gradually brought to room temperature and stirred overnight.

The reaction solution is diluted with water and ethyl acetate, and the ethyl acetate layer is separated. The ethyl acetate layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered.

The solvent in the obtained solution was distilled off under reduced pressure.
(+)-N- [3- (2-cyanoethyl) -1- (4-
Fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide is obtained as an oil.
[Α] ²⁵ _D + 32.52 ° (c = 0.412, methanol).

Example 181 (+)-N- [3- (2-cyanoethyl) -1- (4-
160 g of (fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide is dissolved in 770 ml of methyl alcohol, and hydrochloric acid gas is added under ice cooling for about 2 hours. Inhale. Then, 6.6 ml of water is added and the reaction is heated to reflux for 1 hour. After returning to room temperature, the reaction solution is concentrated under reduced pressure, diluted with an aqueous solution of sodium hydrogen carbonate and ethyl acetate, and the organic layer is separated. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 2-
1: 1) to give (+)-3- [1- (4-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-5-methoxy-2-oxo-
Methyl [1H-indol-3-yl] propionate is obtained as an amorphous material. [Α] ²⁵ _D + 7.25 ° (c =
0.248, methanol).

Example 182 (+)-3- [1- (4-Fluorophenyl) -2,3
-Dihydro-3- (3-isoquinolinyl) carbonylamino-5-methoxy-2-oxo-1H-indole-
91 g of methyl 3-yl] propionate is dissolved in 800 ml of methyl alcohol, 300 ml of a 1N aqueous sodium hydroxide solution is added to this solution, and the mixture is stirred at room temperature. After 5 hours, the solvent is distilled off under reduced pressure, dilute hydrochloric acid and ethyl acetate are added to the residue, and the organic layer is separated. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The residue was acetonitrile-
By crystallizing from diisopropyl ether and collecting by filtration, 90.59 g of crystals are obtained. 10g of filtered material
Is dissolved in a 1.6 N aqueous potassium hydroxide solution, and HP-2
0 and freeze-dried. The obtained amorphous substance was crystallized from ethyl acetate to give (+)-3- [1- (4-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-5-methoxy- 8.29 g (0.3-0.6 hydrate) of potassium 2-oxo-1H-indol-3-yl] propionate are obtained. Melting point 28
0-286 ° C. [Α] ²⁵ _D + 13.07 ° (c = 0.
260, methanol). FAB-MS (m / z): 57
6 (MK ⁺ ), 538 (MH +). IR (Nujol) (cm-1): 15
20, 1570, 1670, 1730.

Reference Example 1 (1) To a solution of 65 ml (0.745 mol) of oxalyl chloride dissolved in 65 ml of dichloromethane was added 32.3 g of 4-methoxy-4'-fluorodiphenylamine.
(0.149 mol) dissolved in 120 ml of dichloromethane was added dropwise with stirring under ice cooling, and the mixture was stirred for 1 hour and 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, 120 ml of dichloromethane was added to the residue, and 23.9 g (0.179 mol) of aluminum chloride was added under ice-cooling, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was treated with 10% hydrochloric acid, and the precipitated crystals were separated by filtration, washed with water and then with diethyl ether, and dried to obtain red crystals.
1- (4-fluorophenyl) -2,3-dihydro-5
-Methoxy-1H-indole-2,3-dione 38.
7 g are obtained. 246-247 ° C.

(2) 13.55 g (0.05 mol) of this product, 10.43 g (0.15 mol) of hydroxyamine hydrochloride, 7.95 g (0.075 mol) of sodium carbonate, 500 ml of ethanol and 200 ml of water Is heated at reflux for 1 hour. After completion of the reaction, ethanol is distilled off under reduced pressure, water is added, and the precipitated crystals are separated by filtration. The obtained crystals were washed with water and dried to give 1- (4-fluorophenyl) as yellow crystals.
This gives 14.3 g of -2,3-dihydro-5-methoxy-1H-indole-2,3-dione-3-oxime. 217-219 ° C.

(3) 14.3 g (0.05 mol) of this product,
A mixture of 8.2 ml of concentrated hydrochloric acid, 3.0 g of 10% palladium-carbon and 500 ml of ethanol is subjected to a catalytic reduction reaction at room temperature under a hydrogen atmosphere overnight. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. To the residue obtained, a mixed solvent of acetone and diethyl ether was added to give 3-amino-1- (4
-Fluorophenyl) -2,3-dihydro-5-methoxy-1H-indol-2-one [= 3-amino-1-
(4-Fluorophenyl) -5-methoxy-1H-indole-2 (3H) -one] hydrochloride (12.4 g) is obtained.
170-175 ° C, IR (Nujol) (cm ^-1 ): 1740, MS
(DI, m / z): 272 (M ⁺ ).

Reference Examples 2 to 7 The corresponding starting compounds were treated in the same manner as in Reference Example 1 to give the following compounds.

Reference Example 2: 3-amino-1- (2-fluorophenyl) -2,3-dihydro-1H-indole-
2-one hydrochloride Melting point: 182 to 183 ° C, Reference Example 3: 3-amino-1-phenyl-2,3-dihydro-1H-indol-2-one hydrochloride. Melting point 90 [deg.] C.

Reference Example 4: 3-amino-1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-1H
-Indol-2-one hydrochloride. 160-161 ° C
(Disassembly).

Reference Example 5 3-amino-2,3-dihydro-6-methoxy-1-phenyl-1H-indole-2
-One hydrochloride. 172-175 ° C (decomposition).

Reference Example 6 3-amino-1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-1H
-Indol-2-one hydrochloride. 180 ° C (decomposition).

Reference Example 7 3-amino-1- (3-chlorophenyl) -2,3-dihydro-6-methoxy-1H-
Indole-2-one hydrochloride. Melting point 168-173 (decomposition).

Reference Example 8 (1) 2,3-dihydro-1H-indole-2,3
To a solution of 1.00 g of dione in dimethylformamide is added 270 mg of sodium hydride at room temperature. After stirring the reaction mixture at room temperature for 10 minutes, a solution of 2.10 g of pentyl bromide in 5 ml of dimethylformamide is added dropwise. After stirring the reaction mixture at room temperature for 20 minutes, water is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off. The residue is purified by silica gel column chromatography [ethyl acetate-hexane (1: 5)] to obtain 1.31 g of 2,3-dihydro-1-pentyl-1H-indole-2,3-dione as orange crystals. . Melting point: 50-51 ° C (2) 1.23 g of this product was treated in the same manner as in Reference Examples 1- (2) and (3) to give 3-amino-2,3-dihydro-1-pentyl-1H- 1.31 g of indole-2-one hydrochloride are obtained as colorless crystals (recrystallized from ethanol-diethyl ether). Melting point: 142-144 ° C. Reference Example 9 14.7 g of 2,3-dihydro-1H-indole-2,3-dione was treated in the same manner as in Reference Examples 1- (2) and (3) to give 3-amino. 16.9 g of -2,3-dihydro-1H-indol-2-one hydrochloride are obtained (recrystallized from ethanol-diethyl ether). Melting point: 199 [deg.] C.

Reference Example 10 (1) To a solution of 70.5 g of m-anisidine in 500 ml of a methylene chloride solution, 120 ml of triethylamine and 56.7 ml of acetic anhydride were added dropwise under ice cooling. After the completion of the dropwise addition, the reaction solution is washed and dried, and the insoluble matter is removed by filtration. The filtrate is concentrated and the resulting residue is recrystallized from hexane-ethyl acetate to give 80.9 g of N- (3-methoxyphenyl) acetamide as pale yellow needles. Melting point: 8
1-82 ° C (2) Sodium hydride 60% oil suspension 10.6
5 g are suspended in 100 ml of anhydrous dimethylformamide under an argon atmosphere. 40.00 g of this product in the suspension
Of dimethylformamide in 100 ml, and then 38.23 g of n-pentylpromide were added dropwise under ice cooling, the temperature was gradually raised from 0 ° C. to room temperature, and the mixture was stirred for 5 hours. The reaction solution is poured into water, and the precipitated oil is extracted with ethyl acetate.
After washing and drying the extract, the insoluble matter is removed by filtration. The filtrate is concentrated to give 67.76 g of N- (3-methoxyphenyl) -N-pentylacetamide as a pale yellow oil.

(3) This product 67.76 g of ethanol 2
To 100 ml of the solution, 100 ml of concentrated hydrochloric acid was added, and for 24 hours,
Heat to reflux. The reaction solution is concentrated, and the residue is extracted with chloroform. After making it alkaline with sodium bicarbonate,
The organic layer is separated, dried, and filtered to remove insolubles. The brown oil obtained by concentrating the filtrate was converted into a hydrochloride by treatment with ethanol-hydrochloric acid, and then recrystallized from acetone-isopropyl ether to give N-pentyl-m-anisidine hydrochloride 4
7.05 g are obtained as colorless needles. Melting point: 110-
112 ° C.

(4) 47.00 g of this product was used in Reference Example 1-
The same treatment as in (1) to (3) was carried out to give 3-amino-2,3
33.39 g of dihydro-6-methoxy-1-pentyl-1H-indol-2-one hydrochloride are obtained as colorless needles (recrystallized from acetone). Melting point: 178-1
80 ° C.

Reference Examples 11 to 13 The corresponding starting compounds were treated in the same manner as in Reference Example 10 to obtain the following compounds.

Reference Example 11: 3-amino-2,3-dihydro-5-methoxy-1-pentyl-1H-indole-
2-one hydrochloride. Melting point: 163-165C.

Reference Example 12: 3-Amino-2,3-dihydro-7-methoxy-1-pentyl-1H-indole-
2-one hydrochloride. Melting point: 184.5-187C.

Reference Example 13 3-Amino-2,3-dihydro-6-ethyl-1-pentyl-1H-indole-2
-One hydrochloride. Melting point: 157-159 ° C Reference Example 14 (1) N- (3-ethylphenyl) acetamide 11
g, copper powder 9 g, potassium carbonate 19.8 g and m-bromoanisole 26.7 g are stirred at 200 ° C. for 3 days. The insoluble matter is removed by filtration from the reaction solution, and the filtrate is purified by silica gel column chromatography [ethyl acetate-hexane (1: 3)]. To the obtained substance, 16.6 g of potassium hydroxide, 8.7 ml of water, 170 ml of ethanol
And heat to reflux for 1 hour. The solvent was distilled off from the reaction solution, water and ethyl acetate were added to the residue, and the organic layer was separated.
After washing and drying, the solvent was distilled off to give N- (3-ethylphenyl) -N- (3-methoxyphenyl) amine 15.0.
8 g are obtained as an oil. IR (Nujol) (cm ^-1 ): 3
400, 1600, 1490, 1460, MS (m / z):
227 (M ⁺ base).

(2) This product was treated in the same manner as in Reference Examples 1- (1) to (3) to give 3-amino-1- (3-ethylphenyl) -2,3-dihydro-6-methoxy- 1H-Indol-2-one hydrochloride is obtained as a foam.

Reference Examples 15 and 16 The corresponding starting compounds were treated in the same manner as in Reference Example 14 to give the following compounds.

Reference Example 15: 3-Amino-2,3-dihydro-6-methoxy-1- (3-methoxyphenyl) -1
H-Indol-2-one hydrochloride. IR (Nujol) (cm
^-1 ): 1730, 1630, 1600, 1470, 13
80, MS (m / z): 284 (M ⁺ ), 255 (base).

Reference Example 16: 3-amino-6-ethyl-1
-(4-Fluorophenyl) -2,3-dihydro-1H
-Indol-2-one hydrochloride. Melting point: 213-215
° C.

Reference Example 17 (1) To a suspension of 8 g of sodium borohydride in 300 ml of dichloroethane, 45 ml of acetic acid was added dropwise over 1 hour under ice cooling. To the mixture, m-anisidine 17.48 was added.
g and 16 ml of cyclohexanone in dichloroethane 50
ml solution is added slowly and stirred at room temperature for 40 minutes. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. After washing and drying the extract, silica gel column chromatography [ethyl acetate-hexane (1:
5)] to give 29.37 g of cyclohexyl- (3-methoxyphenyl) amine as an oil. I
R (Neat) (cm ^-1 ): 3400, 2920, 2850, ¹
615, 1510, 1500, 1450, MS (m / z):
205 (M ⁺ ), 162.

(2) This product is referred to as Reference Examples 1- (1) to (3)
To give 3-amino-1-cyclohexyl-
2,3-dihydro-6-methoxy-1H-indole-
This gives 2-one hydrochloride. Melting point: 185 [deg.] C.

Reference Example 18 The corresponding starting compound was treated in the same manner as in Reference Example 17, to give 3-amino-1-cyclopentyl-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride. Melting point: 183-185C.

Reference Example 19: (1) 2,2-dimethyl-N- (3-methoxyphenyl) propanamide [RM Soll et al, Journal of O.
rganic Chemistry, 53, 2844 (1988))
To a solution of 5.75 g of tetrahydrofuran in 100 ml, 43 ml of a 1.6 Mn-butyllithium hexane solution was added dropwise with water cooling under an argon atmosphere. After stirring the mixture under ice cooling for 2 hours, 18 ml of diethyl oxalate is added, and the mixture is stirred at room temperature for 2 hours. After adding water to the reaction solution and extracting with ethyl acetate, the extract is washed and dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (5: 1)] and recrystallized from ethyl acetate-hexane to give 2- (2,2-dimethylpropanoylamino) -6-methoxybenzene-α −
2.86 g of oxoacetic acid ethyl ester are obtained as pale yellow crystals. Melting point: 99-100 [deg.] C.

(2) This product 2.85 g, concentrated hydrochloric acid 30 m
1, a mixture of 30 ml of ethanol is heated under reflux for 2.5 hours. The solvent is distilled off from the reaction solution. The residue is diluted with water, made basic with sodium hydrogen carbonate and extracted with chloroform. After washing and drying the extract, the solvent is distilled off.
The residue was digested with chloroform, treated with diisopropyl ether and hexane, and the precipitated crystals were collected by filtration.
3-dihydro-4-methoxy-1H-indole-2,
1.49 g of 3-dione are obtained as orange crystals. Melting point:
198-200 ° C.

(3) This product was treated in the same manner as in Reference Example 8- (1) to give 2,3-dihydro-4-methoxy-1-pentyl-1H-indole-2,3-dione. Melting point: 80-82 ° C (4) This product was treated in the same manner as in Reference Examples 1- (2) and (3) to give 3-amino-2,3-dihydro-4-methoxy-1-pentyl-1H- Indole-2-one hydrochloride is obtained. Melting point: 130-136 [deg.] C.

Reference Example 20 (1) 3-Amino-1- (4-fluorophenyl)-
2,3-dihydro-5-methoxy-1H-indole-
4.00 g (0.013 mol) of 2-one hydrochloride were suspended in 80 ml of anhydrous dichloroethane, and 2.69 g (0.0182 mol, 1.4 equivalents) of phthalic anhydride were added under an argon atmosphere.
Was added all at once, followed by 2 ml of triethylamine (0.014
3 mol) are added dropwise over 10 minutes. Then 10 at room temperature
After stirring for an additional minute, reflux on the oil bath overnight. Excess phthalic anhydride is decomposed by adding 20 ml of triethylamine and 2 ml of methanol and refluxing for 20 minutes. After the reaction mixture is concentrated under reduced pressure, it is extracted with ethyl acetate. The ethyl acetate layer is washed and dried.

The residue obtained by distilling off ethyl acetate was recrystallized from hexane-ethyl acetate to give 3- (1,2).
-Dihydro-1,3-dioxoisoindol-2-yl) -1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-1H-indol-2-one 4.5
0 g are obtained as colorless crystals. Melting point: 208.5-21
0.0 ° C, IR (Nujol) (cm ^-1 ): 1730, 1715, 1495, 140
0, 1225, 1210, 750, 715, MS (DI, m / e): 402 (M ⁺ , ba
se), 227, 184, 76.

(2) In a solution of 4.50 g (0.0112 mol) of this product in 80 ml of acetone, under an argon atmosphere, 4.64 g (0.0336 mol) of potassium carbonate and 1.39 ml of methyl iodide (0.039 mol) were added. 0.0224 mol) and vigorously stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure is extracted with ethyl acetate. The ethyl acetate layer is washed with water and then with a saturated saline solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was recrystallized from ethyl acetate-hexane to give 3- (1,2-dihydro-
1,3-dioxoisoindol-2-yl) -1-
(4-fluorophenyl) -2,3-dihydro-5-methoxy-3-methyl-1H-indol-2-one
22 g are obtained as pale yellow crystals. Recrystallization from mother liquor gives an additional 0.70 g of the title compound. Melting point: 20
7-208 ° C, IR (Nujol) (cm ^-1 ): 1725, 1515, 1490,
1220, 1040, 835, 715, 655, 560, 520, 475, MS (DI,
m / z): 416 (M ⁺ , base), 401 (M ⁺ -Me), 373, 343, 241,
226, 198.

(3) 447 μl of hydrazine hydrate was added to a solution of 3.20 g (0.00768 mol) of this product in a mixed solvent of 30 ml of tetrahydrofuran and 30 ml of ethanol.
(0.00922 mol) is added dropwise at room temperature. After stirring overnight, 20 ml of tetrahydrofuran and 20 ml of ethanol were added.
ml and 447 μl of hydrazine hydrate, respectively.
Heat to reflux for hours. After cooling the reaction mixture to room temperature,
The precipitated insoluble matter is separated by filtration, and the filtrate is concentrated to obtain a residue.
This residue is dissolved in ethyl acetate. The filtrate obtained by filtering off insolubles was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography [chloroform: ethyl acetate (1: 1).
1)] to give 3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-3-
2.10 g of methyl-1H-indol-2-one are obtained as colorless needles. Melting point: 163-164 ° C, IR (Nu
jol) (cm ^-1 ): 1710, 1610, 1490, 12 25, 1200, 1000,
835, 715, 655, 560, 520, 475, FAB-MS (m / z): 287 (MH
^{+), 286 (M +)} , 270 (M + -NH 2 base), 258 (M + -CO).

Reference Example 21 3-amino-1- (4-fluorophenyl) -2,3-
1.2 g of acrylonitrile was added to a suspension of 5.00 g of dihydro-6-methoxy-1H-indol-2-one hydrochloride in 30 ml of dimethyl sulfoxide under an argon atmosphere.
And 4.48 g of potassium carbonate, and stirred at room temperature for 9 hours. The reaction solution is poured into water and extracted with ethyl acetate. The extract is washed, dried, filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1: 1)] to give 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-2-. Oxo-1H-indole-3-
Yl] propanenitrile is obtained as a pale yellow oil.

Reference Example 22 3-Amino-1- (4-fluorophenyl) -2,3-
Optical Resolution of Dihydro-5-methoxy-3-methyl-1H-indol-2-one (1) dl-form 3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-3 9.26 g of -methyl-1H-indol-2-one and 11.72 g of dibenzoyl-L-tartaric acid (hereinafter referred to as DBT) are dissolved by heating together with 80 ml of ethyl acetate. After the ethyl acetate was distilled off, 40 ml of ethyl acetate was added again, and 20 ml of diisopropyl ether was added while heating. After cooling, the precipitated crystals were collected by filtration, washed with diisopropyl ether-ethyl acetate (1: 1 v / v), and dried to give 7.71 g of the corresponding (S) -form (-)-DBT salt as a colorless powder. obtain. Melting point: 164.5-167 [deg.] C (decomposition). [Α] _D ²⁵ :-
78.12 ° (c = 0.896, methanol), optical purity: 99.7% ee (measured by optical activity HPLC described later).

Free base: (S) -3-amino-1- (4
-Fluorophenyl) -2,3-dihydro-5-methoxy-3-methyl-1H-indol-2-one Melting point:
160-161 ° C. [Α] _D ²⁵ : -72.38 ° (c
= 1.014, chloroform).

(2) The filtrate was concentrated, the residue was extracted with ethyl acetate, treated with an aqueous solution of sodium hydrogen carbonate, washed with water and then with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. I do. Dibenzoyl-D in residue
Add 6.45 g of tartaric acid and heat dissolve with 20 ml of ethyl acetate. After cooling, the precipitated crystals were collected by filtration, washed with 30 ml of isopropyl ether-ethyl acetate (1: 1 v / v), and dried to give the corresponding (R) -form of the colorless powder (+)-.
8.31 g of DBT salt are obtained. Melting point: 163.0-164
° C (decomposition) [α] _D ²⁵ : + 76.29 ° (c = 0.928, methanol), optical purity: 99.9% ee (measured by optical activity HPLC described later).

Free base: (R) -3-amino-3-methyl-1- (4-fluorophenyl) -5-methoxy-
2,3-dihydro-1H-indol-2-one Melting point: 160-161 ° C. [Α] _D ²⁵ : + 74.05 °
(C = 1.426, chloroform).

(3) The absolute configuration was determined by determining the 3
It is performed by X-ray structural analysis of-(p-toluenesulfonyl) amino derivative.

Measurement of optical purity HPLC conditions Column: Optipac XC 3.9 × 300 mm (manufactured by Waters) Elution solvent: hexane-isopropanol (50/50 v
/ v) Flow rate: 0.5 ml / min Detection wavelength: UV 254 nm Under the above conditions, the dl form is separated. Retention time (R) form: 9.27 minutes (S) form: 15.80 minutes.

Reference Example 23 dl-form 3-amino-1- (2-fluorophenyl)-
2,3-dihydro-3-methyl-1H-indole-2
The -one is treated in the same manner as in Reference Example 22 to obtain the following compound.

(R) Form (-)-DBT salt: melting point 167.
5 to 169.5 ° C., [α] _D ²⁰ : −60.14 ° (c
= 0.562, methanol), 99.3% ee. Free base: (R) -3-amino-1- (2-fluorophenyl) -2,3-dihydro-3-methyl-1H-indol-2-one [α] _D ²⁰ : + 63.33 ° (c
= 0.960, chloroform).

(S) Form (+)-DBT salt: melting point 165.
5 to 167 ° C., [α] _D ²⁰ : + 59.51 ° (c =
0.578, methanol), 99.2% ee. Free base: (S) -3-amino-3-methyl-1- (2
-Fluorophenyl) -2,3-dihydro-1H-indol-2-one [α] _D ²⁰ : −63.46 ° (c
= 0.936, chloroform).

Reference Example 24 The dl form of 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-
[1H-Indol-3-yl] propanonitrile is treated in the same manner as in Reference Example 22 to obtain the following compound.

(-)-DBT salt: melting point 175-177
° C, [α] _D ²⁵ : -67.94 ° (c = 0.836,
Methanol), 99.9% ee.

(+)-DBT salt: melting point 169-170
° C., [α] _D ²⁵ : + 62.14 ° (c = 0.856,
Methanol), 99.9% ee.

[0218]

The compound of the present invention and a salt thereof have excellent cholecystokinin antagonistic activity and an excellent inhibitory effect on pancreatic exocrine secretion, and therefore prevent or prevent digestive diseases such as pancreatic disorders and gastrointestinal disorders. Useful as a therapeutic. Examples of pancreatic disorders include acute pancreatitis, chronic pancreatitis, pancreatic cancer and the like. Gastrointestinal disorders include irritable bowel syndrome,
Reflux esophagitis, indigestion and the like. Further, other digestive diseases include biliary colic and the like. In addition, since the compounds of the present invention have low toxicity, they can be used as pharmaceuticals with high safety when used as pharmaceuticals.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 405/12 209 C07D 405/12 209 409/12 209 409/12 209 471/06 471/06 487/06 487/06 // A61K 31/00 601 A61K 31/00 601 601N 643 643D 31/40 31/40 31/415 31/415 31/435 31/435 31/44 31/44 31/47 31/47 31/495 31/495 31 / 535 31/535 (56) References JP-A-7-48349 (JP, A) JP-A-6-41126 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 209 / 40 C07D 401/06 C07D 401/12 C07D 403/12 C07D 405/06 C07D 405/12 C07D 409/12 C07D 471/06 C07D 487/06 CA (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. A compound of the general formula (I) (However, ring A is a lower alkyl group or a lower alkoxy group.
Et chosen benzene ring which may be substituted with a group, R ¹ is
Hydrogen atom; cycloalkyl group; halogen atom, lower alkyl
Selected from a kill group, a hydroxy group and a lower alkoxy group
Aryl group optionally substituted with a nitrogen-containing heterocyclic ring
Formula group; oxygen-containing heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and
Heterocyclic groups containing nitrogen and oxygen atoms; nitrogen and sulfur atoms
Containing heterocyclic group; lower alkoxy group; esterified
Optionally carboxyl group; cyano group; lower alkylthio
E group; lower alkylsulfinyl group; lower alkylsulfinyl group
A honyl group, an oxiranyl group; or 2- (lower alkylthio)
E) -1-hydroxyethyl group , R ² is a halogen atom,
Substituted with a group selected from droxy group and lower alkoxy group
An aryl group which may be represented by the formula : A group represented by the following: formyl group, lower alkoxycarbonyl
And a group selected from a cyano lower alkyl group
A nitrogen-containing heteromonocyclic group or a nitrogen-containing heterobicyclic group
Cyclic group; formula (Where n represents 1 or 2); an oxygen-containing group
Heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and oxygen atom
Containing heterocyclic groups; or hetero containing nitrogen and sulfur atoms
Cyclic group , R ³ is a carboxyl which may be esterified
Group, a group selected from a cyano group and a tetrazolyl group
An optionally substituted lower alkyl group , Q represents a single bond or a lower alkylene group, and Y represents a single bond, a lower alkylene group or a lower alkenylene group. Or a pharmacologically acceptable salt thereof. 2. An aryl group is a phenyl group or a naphthyl group, and a nitrogen-containing heteromonocyclic group is a pyrrolyl group, a pyridyl group, an imidazolyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidyl group or a pyridazinyl group, and a nitrogen-containing heterobicyclic group. Is an indolyl group, a quinolyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, a benzimidazolyl group, a quinoxalinyl group, a nitrogen-containing heterocyclic group is a pyrrolyl group, a pyridyl group, an imidazolyl group, a pyrazolyl group, a pyrazinyl group, a pyrimidyl group, a pyridazinyl group An indolyl group, a quinolyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, a benzimidazolyl group, a quinoxalinyl group, a carbazolyl group, a carbolinyl group or a compound of the formula (Where n represents 1 or 2), the oxygen-containing heterocyclic group is a furyl group, a benzofuranyl group, a cumaryl group, a chromenyl group or a chromanyl group, and the sulfur-containing heterocyclic group is a thienyl group or a benzoyl group. A thiophenyl group or a thianthrenyl group, a heterocyclic group containing a nitrogen atom and an oxygen atom is a morpholinyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group or an isobenzooxazolyl group, and a heterocyclic group containing a nitrogen atom and a sulfur atom The compound according to claim 1 , wherein the formula group is a thiazolyl group, an isothiazolyl group, a benzothiazolyl group or an isobenzothiazolyl group. 3. A benzene ring in which ring A is substituted with a group selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom; a cycloalkyl group; or a halogen atom, a lower alkyl group and a lower alkoxy group. A phenyl group substituted with a group; a phenyl group substituted with a group in which R ² is selected from a halogen atom and a lower alkoxy group; a naphthyl group;
An indolyl group; an isoquinolyl group; a benzimidazolyl group; or a formula Wherein n represents 1 or 2; R ³ is a lower alkyl group optionally substituted with a group selected from a carboxyl group, a cyano group and a tetrazolyl group; Y is a single bond; or The compound according to claim 2, which is a lower alkenylene group. 4. Ring A is a benzene ring substituted at the 5- or 6-position with a group selected from a lower alkyl group and a lower alkoxy group, and R ¹ is a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group. A substituted phenyl group, wherein R ² is a naphthyl group, an indolyl group, an isoquinolyl group, a benzimidazolyl group or a compound of the formula (Where n represents 1 or 2), a lower alkyl group in which R ³ is substituted with a group selected from a carboxyl group and a tetrazolyl group, Q is a single bond, and Y is a single bond. A compound according to claim 3 . 5. A benzene ring in which ring A is substituted at the 6-position with a group selected from a lower alkyl group and a lower alkoxy group, R ¹
There halogenophenyl group, R ² is isoquinolyl group, a compound of claim 4, wherein R ³ is a carboxyl-lower alkyl group. 6. A compound of the general formula (II) (However, ring A is a lower alkyl group or a lower alkoxy group.
Et chosen benzene ring which may be substituted with a group, R ¹ is
Hydrogen atom; cycloalkyl group; halogen atom, lower alkyl
Selected from a kill group, a hydroxy group and a lower alkoxy group
Aryl group optionally substituted with a nitrogen-containing heterocyclic ring
Formula group; oxygen-containing heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and
Heterocyclic groups containing nitrogen and oxygen atoms; nitrogen and sulfur atoms
Containing heterocyclic group; lower alkoxy group; esterified
Optionally carboxyl group; cyano group; lower alkylthio
E group; lower alkylsulfinyl group; lower alkylsulfinyl group
Honi group, oxiranyl group, or 2- (lower alkylthio
E) a 1-hydroxyethyl group , R ³ is esterified
Carboxyl group, cyano group and tetrazolyl
Lower alkyl which may be substituted with a group selected from groups
And the group Q represents a single bond or a lower alkylene group. And a salt thereof with a compound of the general formula (III): (However, R ² is a halogen atom, a hydroxy group,
Aryl which may be substituted with a group selected from a xy group
A group represented by the formula : A group represented by the following: formyl group, lower alkoxycarbonyl
And a group selected from a cyano lower alkyl group
A nitrogen-containing heteromonocyclic group or a nitrogen-containing heterobicyclic group
Cyclic group; formula (Where n represents 1 or 2); an oxygen-containing group
Heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and oxygen atom
Containing heterocyclic groups; or hetero containing nitrogen and sulfur atoms
A cyclic group , Y represents a single bond, a lower alkylene group or a lower alkenylene group. ), A reactive derivative thereof or a salt thereof, and if necessary, a product is converted into a pharmaceutically acceptable salt thereof by a general formula (I). (However, the rings A, R ¹ , R ² , R ³ , Q and Y have the same meanings as described above.) Or a pharmaceutically acceptable salt thereof. 7. A compound of the general formula (IV) (However, ring A is a lower alkyl group or a lower alkoxy group.
Et chosen benzene ring which may be substituted with a group, R ¹ is
Hydrogen atom; cycloalkyl group; halogen atom, lower alkyl
Selected from a kill group, a hydroxy group and a lower alkoxy group
Aryl group optionally substituted with a nitrogen-containing heterocyclic ring
Formula group; oxygen-containing heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and
Heterocyclic groups containing nitrogen and oxygen atoms; nitrogen and sulfur atoms
Containing heterocyclic group; lower alkoxy group; esterified
Optionally carboxyl group; cyano group; lower alkylthio
E group; lower alkylsulfinyl group; lower alkylsulfinyl group
A honyl group, an oxiranyl group; or 2- (lower alkylthio)
E) -1-hydroxyethyl group , R ² is a halogen atom,
Substituted with a group selected from droxy group and lower alkoxy group
An aryl group which may be represented by the formula : A group represented by the following: formyl group, lower alkoxycarbonyl
And a group selected from a cyano lower alkyl group
A nitrogen-containing heteromonocyclic group or a nitrogen-containing heterobicyclic group
Cyclic group; formula (Where n represents 1 or 2); an oxygen-containing group
Heterocyclic group; sulfur-containing heterocyclic group; nitrogen atom and oxygen atom
Containing heterocyclic groups; or hetero containing nitrogen and sulfur atoms
A cyclic group , Q represents a single bond or a lower alkylene group, and Y represents a single bond, a lower alkylene group or a lower alkenylene group. ) Or a salt thereof with an alkylating agent corresponding to R ^3, and if necessary, converting the product into a pharmaceutically acceptable salt thereof. (However, R ³ is a carboxyl which may be esterified
Group, a group selected from a cyano group and a tetrazolyl group
Represents a lower alkyl group which may be a ring A, R ¹ ,
R ² , Q and Y have the same meaning as described above. )) Or a pharmacologically acceptable salt thereof. 8. (+)-3- [1- (2-Fluorophenyl) -2,3-dihydro-3- (3-isoquinolyl)
Carbonylamino-6-methoxy-2-oxo-1H-
Indole-3-yl] propionic acid or a pharmaceutically acceptable salt thereof. 9. The (+)-3- [1- (2-fluorophenyl) -2,3-dihydro-3- (3-isoquinolyl)
Carbonylamino-6-methoxy-2-oxo-1H-
Indole-3-yl] sodium propionate.