JPH0940557A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition which has excellent antagonistic action against cholecystokinin and is effective for prevention and therapy of pancreatic disorder, gastrointestinal diseases and appetite satiation diseases. SOLUTION: This medicinal composition contains, as an active ingredient, 2-oxoindoline derivative of the formula (ring A is benzene ring; R<1> is H, a cycloalkyl, an aryl, a nitrogen-containing heterocyclic group, ant oxygen- containing heterocyclic group, a sulfur-containing heterocyclic group; R<2> is an aryl; R<3> is a lower alkyl; Q is a single bond, a lower alkylene; Y is a single bond, a lower alkylene, a lower alkenylene) or its salt, typically (S)-3-[1-(2-fluoro- phenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-6-methoxy-2-oxo-1 H-indol-3- yl]propionic acid. The dose is 0.01-50mg/kg/day and it is given orally or parenterally.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[0002]

Cholecystokinin (CCK) is a brain / intestinal peptide existing in gastrointestinal tissues and the central nervous system,
It is known as a substance related to regulation of pancreatic enzyme secretion and appetite regulation, and is considered to have actions such as promotion of colonic motility, contraction of gallbladder, promotion of pancreatic enzyme secretion, and suppression of gastric emptying (drug・ News and Perspectives (Drug News & Perspectives) 7 (2), PP87-95, M
arch, 1994). Moreover, cholecystokinin coexists with dopamine in the central nervous system, and is therefore considered to have a role related to the function of the dopaminergic system (Trends in Pharmacologic Science (Trends i
n Pharmacological Science), 12, PP232-236, 199
1).

[0003] A number of antagonistic substances have been studied so far, because they are effective in the prevention or treatment of pancreatic disorders, gastrointestinal disorders, other digestive system disorders, etc. Has been done. For example, amino acid derivatives such as benzotrypt are known as cholecystokinin antagonists, but their action is relatively weak,
In addition, it is not always satisfactory in terms of short duration of action, instability, and poor absorption.

[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 formula (V).

[0005]

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[0006] β-carboline derivatives have been disclosed.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition containing a novel 2-oxoindoline derivative having an excellent antagonism against cholecystokinin as an active ingredient.

[0008]

The present invention provides a compound of formula (I)

[0009]

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(Wherein 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 heterocycle Cyclic group, heterocyclic group containing nitrogen atom and oxygen atom, heterocyclic group containing nitrogen atom and sulfur atom, lower alkoxy group, optionally esterified carboxyl group, cyano group, lower alkylthio group, lower Alkylsulfinyl group, lower alkylsulfonyl group, oxiranyl group or 2- (lower alkylthio) -1-hydroxyethyl group, R ² is a substituted or unsubstituted aryl group, formula

[0011]

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A group represented by: a substituted or unsubstituted nitrogen-containing heteromonocyclic group, a substituted or unsubstituted nitrogen-containing heterobicyclic group, a formula

[0013]

[Chemical 12]

(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, or a nitrogen atom and sulfur. A heterocyclic group containing an atom, R ³ is a substituted or unsubstituted lower alkyl group, Q is a single bond or a lower alkylene group, and Y is a single bond, a lower alkylene group or a lower alkenylene group. And a 2-oxoindoline derivative (I) represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The 2-oxoindoline derivative (I) and its pharmacologically acceptable salts, which are the active ingredients of the present invention, have an excellent cholecystokinin antagonism, and therefore the pharmaceutical composition of the present invention has an anti-cholecyst effect. As a kinin antagonist,
Prevention of pancreatic disorders, gastrointestinal disorders or appetite regulation disorders
It is useful as a therapeutic agent.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION As a specific example of the 2-oxoindoline derivative (I) which is the active ingredient of the present invention, in the general formula (I), ring A is a group selected from a lower alkyl group and a lower alkoxy group. An optionally substituted benzene ring; R ¹ is a hydrogen atom; a cycloalkyl group; a halogen atom,
Aryl group which may be substituted with 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; an optionally esterified carboxyl group; 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 group represented by: 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; or a nitrogen atom and Heterocyclic group containing a sulfur atom; R ³ is a lower alkyl group optionally substituted with a group selected from an esterified carboxyl group, a cyano group and a tetrazolyl group; Q is a single bond; Examples of the compound include an alkylene group; Y is a single bond; a lower alkylene group; or a lower alkenylene group.

The compound (I) which is preferable in terms of efficacy is preferably a benzene ring in which ring A may be substituted with a group selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom; a cycloalkyl group; a halogen atom, a lower atom. An aryl group which may be substituted with a group selected from an alkyl group and a lower alkoxy group; an optionally esterified carboxyl group;
Lower alkylthio group; or 2- (lower alkylthio)-
1-hydroxyethyl group; R ² is an aryl group which may be substituted with a group selected from a halogen atom, a hydroxy group and a lower alkoxy group; a nitrogen-containing heterobicyclic group;

[0022]

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(Wherein n represents 1 or 2); an oxygen-containing heterocyclic group; or a sulfur-containing heterocyclic group; a carboxyl group or a cyano group in which R ³ may be esterified. And a lower alkyl group optionally substituted with a group selected from a tetrazolyl group; Q is a single bond; or a lower alkylene group; Y is a single bond; or a lower alkenylene group.

Compound (I) which is more preferable from the viewpoint of efficacy is ring A
Is a benzene ring substituted with a group selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom; a cycloalkyl group; may be substituted with a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group Aryl group; R ² is an aryl group which may be substituted with a group selected from a halogen atom, a hydroxy group and a lower alkoxy group; a nitrogen-containing heterobicyclic group;

[0025]

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(Wherein n represents 1 or 2); an oxygen-containing heterocyclic group; or a sulfur-containing heterocyclic group; a carboxyl group or a cyano group in which R ³ may be esterified. And a lower alkyl group optionally substituted with a group selected from a tetrazolyl group; Q is a single bond; or a lower alkylene group; Y is a single bond; or a lower alkenylene group.

Compound (I) which is more preferable in terms of efficacy is ring A
Is a benzene ring which may be 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 is substituted with a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group. Optionally substituted phenyl group; R ² is naphthyl group; halogenophenyl group; indolyl group; quinolyl group; isoquinolyl group; formula

[0028]

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(Wherein n represents 1 or 2); benzothiophenyl group; benzofuranyl group; or coumaryl group; R ³ may be substituted with an optionally esterified carboxyl group. A compound in which Q is a single bond; or a lower alkylene group; Y is a single bond.

Compound (I) which is more preferable in terms of efficacy is ring A
Is a benzene ring substituted with a lower alkoxy group, R ¹ is a halogenophenyl group or a cyclohexyl group, R ² is an indolyl group, a quinolyl group or an isoquinolyl group, and R ³ is a lower group substituted with an optionally esterified carboxyl group. An alkyl group, Q is a single bond, and Y is a single bond. Of these, ring A is a benzene ring substituted with a lower alkoxy group, R ¹ is a halogenophenyl group, R ² is an isoquinolyl group, and R ³ is a lower group which may be substituted with an optionally esterified carboxyl group. A compound in which an alkyl group, Q is a single bond, and Y is a single bond is preferable.

In the general formula (I), when ring A has a substituent, the substitution position of the substituent on ring A is specified by the following indolin ring position number (the same applies hereinafter).

[0032]

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Accordingly, the substituents on ring A are at the 4-position, 5
It exists in the 6th, 7th and 7th positions. Among them, from the viewpoint of efficacy, in the general formula (I), the 5-position or 6-position of the ring A is
Compounds in which the position is substituted are preferred.

Examples of the cycloalkyl group include cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups and other cycloalkyl groups having 3 to 7 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group. As the nitrogen-containing heteromonocyclic group, a pyridyl group, a pyrrolyl group, an imidazolyl group,
Examples thereof include a pyrazolyl group, a pyrazinyl group, a pyrimidyl group and a pyridazinyl group. As the nitrogen-containing heterobicyclic group,
Examples thereof 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, 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. Group, carbazolyl group, carborinyl group or formula

[0035]

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(Wherein n represents 1 or 2). Examples of the oxygen-containing heterocyclic group include furyl group, benzofuranyl group, coumaryl group, chromenyl group and chromanyl group. As the sulfur-containing heterocyclic group,
Examples thereof include thienyl group, benzothiophenyl group and 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 isobenzoxazolyl 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.

The compound (I) may have optical isomers based on an asymmetric carbon atom at the 3-position of the indoline ring, but the present invention includes any of these optical isomers and mixtures thereof.

In the compound (I), when R ¹ is an esterified carboxyl group and / or R ³ is an esterified carboxyl group-substituted lower alkyl group, examples of the ester residue include a lower alkyl group. Group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group, a phenacyl group and the like, and the lower alkyl group is particularly preferable.

The 2-oxoindoline derivative (I), which is the active ingredient of the present invention, can be used in medicinal use either in free form or in the form of a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include an acid addition salt with an inorganic acid or an organic acid, and a salt with an inorganic base, an organic base or an amino acid, for example, hydrochloride, sulfate, hydrobromide, methane. Examples thereof include sulfonates, fumarates, maleates, alkali metal (sodium, potassium, etc.) salts, methylamine salts, diethylamine salts, triethylamine salts, salts with lysine and the like.

Further, the 2-oxoindoline derivative (I) and its salt, which are the active ingredients of the present invention, are interpreted to include any of their inner salts, adducts, complexes, solvates or hydrates. Should be.

Compound (I) and its pharmacologically acceptable salt can be administered orally or parenterally. The dose varies depending on the patient's age, body weight, condition or administration method, but is usually 0.01 mg / kg to 50 mg / kg per day.

The compound (I) and its pharmacologically acceptable salts are generally used in mammals including humans in capsules, microcapsules, tablets, granules, powders, troches, and
Syrup, aerosol, inhalant, solution, injection, suspension,
It can be administered in the form of conventional pharmaceutical compositions such as emulsions, suppositories and the like. The pharmaceutical composition is, for example, an excipient such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc .; for example, cellulose, methyl cellulose, hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, Binders such as gum arabic, polyethylene glycol, sucrose, starch; eg starch,
Disintegrators such as carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium hydrogen carbonate, calcium phosphate, calcium citrate; lubricants such as magnesium stearate, talc, sodium lauryl sulfate; Fragrances such as citric acid, menthol, glycine, orange powder; preservatives such as sodium benzoate, sodium hydrogen sulfite, methylparaben, propylparaben; stabilizers such as citric acid, sodium citrate, acetic acid; Suspending agents such as pyrrolidone and aluminum stearate; Dispersants; Aqueous diluents such as water; Pharmaceutical agents such as cocoa butter, polyethylene glycol, base waxes such as white kerosene Various organic or inorganic carrier substances commonly used as can contain.

The 2-oxoindoline derivative (I), which is the active ingredient of the present invention, is obtained by the method (A): the general formula (II).

[0044]

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

[0046]

[Chemical 21]

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

[0048]

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(Wherein ring A, R ¹ , R ² , Q and Y have the same meanings as described above) or a salt thereof is converted into R ³
Can be produced by reacting with an alkylating agent corresponding to.

Examples of the reactive derivative of the compound (III) include acid halides, active esters and acid anhydrides, preferably acid halides such as acid chlorides.

The alkylating agent corresponding to R ³ used in the reaction with the compound (IV) is, 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 CH ₂ = CH-R ³¹ (R ³¹ is R ³
Examples thereof include an alkene compound represented by a substituted or unsubstituted lower alkyl group having a carbon number of 2 less.

As the salts of compounds (II) and (IV), salts with inorganic acids such as hydrochloric acid and sulfuric acid can be used. Further, as the salt of the compound (III), in addition to the salt with the above-mentioned inorganic acid, 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 a salt thereof is carried out in a solvent, if necessary in the presence of a deoxidizing agent, and after cooling, the boiling point of the solvent used Done at temperatures up to.

The solvent used is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include alcohols such as water, 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 and toluene, Aromatic hydrocarbons such as xylene; amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dimethylsulfoxide, and mixed solvents thereof can be used.

As the deoxidizing agent used as necessary, 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, etc., preferably triethylamine, pyridine, etc. In the water-containing solvent, sodium hydrogencarbonate, potassium carbonate, etc. are preferable.

The reaction of the amine compound (II) or its salt with 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], diphenylphosphoric acid azide (DPPA) and the like. If desired, an active ester reagent such as 1-hydroxybenzotriazole may be used in combination with the 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 compound can be obtained by using an optically active raw material.

Method (B): Compound (IV) or its salt and R ³
The reaction with the alkylating agent corresponding to 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 an 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]. ] Organic bases such as undeca-7-ene are mentioned. As the solvent, 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, 0 ° C to 100 ° C.
Suitably proceeds at the temperature of.

The compound (I) which is the active ingredient of the present invention is
It can also be produced by subjecting the compound obtained as described above to interconversion into another compound which is the active ingredient of the present invention by a conventional method. The interconversion reaction between such compounds may be appropriately selected according to the type of functional group of the compound, and can be carried out, for example, as shown in (a) or (b) below.

Method (a): The compound (I) in which Q is a lower alkylene group is the compound (I) in which Q is a single bond and R ¹ is a hydrogen atom, and the group: -Q ¹ -R ¹ (Q ¹ represents a lower alkylene group, and R ¹ has the same meaning as described above.), And can be produced by reacting an alkylating agent corresponding to the 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
Compound (I) in which R ³ is a carboxyl lower alkyl group
Can be produced by removing the ester residue of the corresponding compound (I) in which the carboxyl group is esterified. The removal of the ester residue can be carried out by treating the compound (I) in which the carboxyl group is esterified with an acid or alkaline reagent in a solvent to hydrolyze the compound. 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. In addition, examples of the alkaline reagent include inorganic bases such as alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide).

As the solvent, for example, 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 compound (I) which is the active ingredient of the present invention can be converted into each other by a conventional method as described below.

For example, the compound (I) in which R ¹ is a lower alkylthio group can be oxidized to give the corresponding sulfinyl or sulfonyl compound. Further, the compound (I) in which R ¹ is an oxiranyl group can be treated with an alkali metal lower alkyl sulfide to give a compound 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 form a carboxy lower alkyl group.

Compound (I) in which R ² is a N-lower alkoxycarbonyl-substituted nitrogen-containing heteromonocyclic group or nitrogen-containing heterobicyclic group can be deacylated in the same manner as in method (b). , R ² can be a compound in which R ² is an N-unsubstituted nitrogen-containing heteromonocyclic group or nitrogen-containing heterobicyclic group, and further a mixed acid anhydride obtained from formic acid and acetic anhydride or a cyano lower alkane ( N-position of the nitrogen-containing heteromonocyclic group or the nitrogen-containing heterobicyclic group can be formylated or cyano lower alkylated by treatment with acrylonitrile or the like).

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

The compound (I) in which a lower alkoxy group is present in at least one substituent of ring A, R ¹ , R ² and R ³ is treated with a Lewis acid such as boron tribromide to give a corresponding hydroxy compound. Further, it can be 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 compound in which Y is a lower alkylene group.

The interconversion reaction of the above compounds proceeds without any racemization, and an optically active compound can be obtained by using an optically active substance as a raw material.

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

Amine compound (II) which is a raw material of the present invention
Is the general formula (VI)

[0074]

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(Wherein ring A has the same meaning as described above), the amino group optionally has a group: -Q-R ¹ (wherein Q and R ¹ have the same meanings as described above). .) And then reacted with oxalyl halide,
General formula (VII) obtained

[0076]

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(Wherein ring A, R ¹ and Q have the same meaning as described above), the compound represented by the general formula (VIII) is treated with hydroxyamine and then reduced.

[0078]

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(Wherein rings A, R ¹ and Q have the same meanings as described above), and if desired, the amino group is protected and reacted with an alkylating agent in the same manner as in the method (B). Then, 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, was prepared by converting 3- (lower alkoxy) aniline into the literature [Journal of Organics]. Chemistry (J. Org. Chem.), 53, 2844 (1988), RM Soll et
al.] according to the method described in 3 '-(lower alkoxy)-
2,2-dimethylpropionanilide can be produced by lithiation of the ortho position of the anilide compound, treatment with diethyl oxalate, and further ring closure.

Compounds (VI in which Q is a lower alkylene group)
II) is a compound (VI) in which the group: —Q—R 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 also be introduced to manufacture.

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

Expression

[0084]

[Chemical formula 26]

The starting compound represented by the formula is

[0086]

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[Journal of the American Chemical Society (J. Am. Chem. Soc.), Vol. 80,
P5574 (1958), H. Rapoport et al] can be produced by hydrolysis in the same manner as in the method (b).

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

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

In the present specification, the lower alkyl group and the lower alkoxy group mean those having 1 to 6 carbon atoms, preferably those having 1 to 4 carbon atoms. The lower alkanoyl group has 2 to 6 carbon atoms, preferably 2 to 6 carbon atoms.
It means 4 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,
Examples include chlorine, bromine, fluorine and iodine, preferably chlorine and fluorine.

Experimental Example 1 [Cholecystokinin Receptor Binding Action] After removing the pancreas of SD male rat, 50 mM Tris-HCl buffer (pH 7.5, 0.01% soybean trypsin inhibitor) was added and homogenized. The homogenate was filtered through gauze and centrifuged at 50,000 xg for 10 minutes, and the resulting pellet was incubated with incubation medium (5
0 mM Tris-HCl (pH 7.5), 5 mM magnesium chloride, 5 mM dithiothreitol, 0.14 mg / ml
Bacitracin, 0.2% bovine serum albumin (BSA),
0.01% soybean trypsin inhibitor) was added to prepare a pancreatic membrane specimen. All of the above operations were performed under ice cooling.

Membrane preparation in a polyethylene tube, ¹²⁵ I-C
An incubation medium containing CK-8 (50 pM) and a test compound was added, and the mixture was incubated at 25 ° C for 90 minutes. Membrane-bound ¹²⁵ I-CCK-8 washes (5
0 mM Tris-HCl, 0.01% BSA, pH 7.5,4
C) was added and the cells were separated by washing and filtering using a cell harvester, and the radioactivity of the bound fraction on the filter was measured with a γ-counter. The specific binding amount was calculated from the radioactivity of the binding fraction on the filter, and the specific binding was 50%.
The concentration of each compound to be suppressed (IC ₅₀ value) was calculated.

The results are shown in Tables 1 to 7 below.

[0094]

[Table 1]

[0095]

[Table 2]

[0096]

[Table 3]

[0097]

[Table 4]

[0098]

[Table 5]

[0099]

[Table 6]

[0100]

[Table 7]

Experimental Example 2 [Effects on exocrine pancreas (intraduodenal administration)] SD male rats (2-3 animals per group) were fasted for 16 to 20 hours, and then urethane (1.2 g / kg, sc) was used. I was anesthetized with. Then, a polyethylene tube (SP31, manufactured by Natsume Seisakusho) was inserted and fixed into the pancreatic duct at the opening of the duodenum, and pancreatic juice was extracted. A cannula was inserted and fixed in the duodenum. The experiment was started at least 1 hour after the surgery, and the pancreatic juice was collected at 30-minute intervals and the weight thereof was measured.

After confirming that the pancreatic juice secreted within 1 hour from the start of the experiment was almost constant, CCK-8 (0.3 μg
/ Kg / hr) was administered from the right femoral vein at a rate of 0.73 ml / hr. Two hours after the administration of CCK-8, the test compound was administered via the intraduodenal cannula. Each sample compound was suspended in a solution prepared by adding Tween 80 to distilled water.

The amount of pancreatic juice increased by the administration of CCK-8, that is, (the amount of pancreatic juice for 30 minutes immediately before the administration of the sample)-(CCK-8
After administration of the sample (dose: 10 mg / kg or 1 mg / kg) with 100% of the pancreatic juice volume for 30 minutes before administration as 100%,
The maximum inhibition rate (E) was calculated from the amount of pancreatic juice when the CCK-8-induced exocrine pancreas was maximally suppressed. Exocrine pancreatic secretion suppressive action,
Based on the maximum inhibition rate (E) thus obtained, the following display was made.

When 60 ≦ E <90 ++ 90 ≦ E ++ The results are shown in Tables 8 to 11 below.

[0105]

[Table 8]

[0106]

[Table 9]

[0107]

[Table 10]

[0108]

[Table 11]

Experimental Example 3 [Action on exocrine pancreas (intravenous administration)] In the same manner as in Experiment 2, CCK-8 (0.3 μg / kg / h)
r) was administered from the right femoral vein at a rate of 0.73 ml / hr. After the secretion of pancreatic juice after the start of CCK-8 administration became almost constant, the test compound was administered through the left femoral vein. Each compound was dissolved or suspended in 75% N, N-dimethylformamide.

In the same manner as in Experiment 2, the specimen was 10 mg / kg.
The maximum inhibition rate (E) after administration was calculated. The pancreatic exocrine inhibitory effect is based on the maximum inhibitory rate (E) thus obtained,
It was displayed in the same manner as in Experiment 2.

The results are shown in Tables 12 to 13 below.

[0112]

[Table 12]

[0113]

[Table 13]

Experimental Example 4 [Action on Pancreatitis Induced by Cerulein] Male Wister rats, each group consisting of 6 rats, were used for the experiment after fasting for about 18 hours. Test compound or vehicle (vehi
cle) (0.5% Tween80, 5ml / kg) was orally administered.
After the minute, 20 μg / kg of cerulein or physiological saline was subcutaneously administered (1 ml / kg) four times every hour. Three hours after the last administration of cerulein, blood was collected from the abdominal vena cava under ether anesthesia, centrifuged, and amylase activity in serum was measured.

A monotest amylase (Boehringer Mannheim Yamanouchi) was used for measuring the enzyme activity in serum.
The ED ₅₀ value (dose that suppresses the increase in amylase activity in serum by 50%) of each compound was calculated from the logarithmic regression line.

The results are shown in Table 14 below.

[0117]

[Table 14]

Production Example 1 (1) 3-Amino-1-pentyl-2,3-dihydro-1H-indol-2-one hydrochloride 2.84 g, sodium hydrogen carbonate 2.24 g, chloroform 30 ml, water 3
To 0 ml of the mixture, water-cooled under an argon atmosphere, 3,4-dichlorobenzoyl chloride 2.80 g of methylene chloride 2 was added.
Add 0 ml solution 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 the chloroform layer is washed and dried, the solvent is distilled off. The residue was recrystallized from ethyl acetate-hexane to give 3,
4-dichloro-N- (2,3-dihydro-2-oxo-
4.06 g of 1-pentyl-1H-indol-3-yl) benzamide are obtained as colorless crystals. Melting point: 125
-126 ° C, IR (Nujol) (cm ^-1 ): 3280, 172
5,1635,1610, 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
The mixture is stirred at room temperature under an argon atmosphere overnight.
The insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, washed and dried, and then 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, ¹
660, MS (m / z): 476 (M ⁺ ), 173 (bas
e).

Production 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
Triethylamine 1 in 1 ml suspension under 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 and stirred for 30 minutes, 100 ml of water is added, and the mixture is 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 22. 9 g are obtained as colorless needles. Melting point: 283-285 ° C (decomposition), IR
(Nujol) (cm ^-1 ): 3280,3160,3100,1
710, 1690, 1635, MS (m / z): 322 &
320 (M ⁺ ) and 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 with stirring under ice cooling. After returning to room temperature and stirring for 1 hour, the mixture is diluted 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 colorless powder. Melting point: 227-228 ° C, IR (Nujo
l) (cm ^-1 ): 3350, 3320, 3280, 174
0,1710,1655,1625, MS (m / z): 4
22 & 420 (M ⁺ ).

Production Example 3 (1) 1.22 g of 3-amino-2,3-dihydro-1-pentyl-1H-indol-2-one hydrochloride, 1,
2,3,4-Tetrahydronaphthalene-2-carboxylic acid 0.93 g, 1-hydroxybenzotriazole 0.7
To a mixture of 2 g and 40 ml of methylene chloride, under ice cooling, 1-
Add 1.10 g of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture is stirred under ice cooling for 1 hour, 1.0 ml of triethylamine is added, and the mixture is stirred under ice cooling for 2 hours and further at room temperature for 2 hours.
After completion of the reaction, the solvent is distilled off under reduced pressure, the residue is diluted with ethyl acetate, washed and dried, and then 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) (cm
^-1 ): 3280, 1725, 1640, 1610, MS
(M / z): 376 (M ⁺ ), 218 (base), 147, 3
One.

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

Production 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 distilling off acetone, the mixture is treated with water and extracted with ethyl acetate. The ethyl acetate layer was washed and dried, the solvent was distilled off, and the residue was crystallized from ethyl acetate-hexane to give N- [3- (2-cyanoethyl) -2,3-dihydro-2-oxo-1- 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,
2325, 1700, 1655, 1610, MS (m /
z): 445 & 443 (M ⁺ ).

Production Example 5 3-Amino-2,3-dihydro-6-methoxy-1-pentyl-1H-indole-2-one hydrochloride 1 g, β-
A mixture of 683 mg of naphthylcarbonyl chloride and 15 ml of methylene chloride was added to triethylamine (0.1%) under ice cooling.
98 ml is added dropwise, and the mixture is stirred at room temperature for 1 hour. In the reaction solution,
Add water and chloroform, separate the chloroform layer,
After washing and drying, the solvent is distilled off under reduced pressure. The residue was dissolved in 10 ml of dimethyl sulfoxide, and ethyl acrylate 0.3
8 ml and potassium carbonate 500 mg are added, and the mixture is stirred under an argon atmosphere at room temperature for 30 minutes. Ethyl acetate,
Water is added, the organic layer is separated, washed and dried, and then the solvent is distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane,
1.55 g of ethyl ethyl 3- [2,3-dihydro-6-methoxy-3- (2-naphthalenecarbonyl) amino-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid are obtained. Melting point: 156-159 ° C,
IR (Nujol) (cm ^-1 ): 3260, 1735, 169
0, 1650, 1620, MS (m / z): 502
(M ⁺ ), 45.

Production Example 6 3-Amino-2,3-dihydro-6-methoxy-1-pentyl-1H-indole-2-one hydrochloride 1 g, indole-2-carboxylic acid 570 mg, methylene chloride 20
To a mixture of ml, 680 m of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride under ice cooling.
g, 1-hydroxybenzotriazole 480 mg, and triethylamine 0.73 ml are added, and the mixture is stirred at room temperature for 2.5 hours. Water and ethyl acetate are added to the reaction solution, the organic layer is separated, washed and dried, and then the solvent is distilled off. The residue is dissolved in 10 ml of dimethyl sulfoxide, 0.38 ml of ethyl acrylate and 485 mg of potassium carbonate 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 and dried, and the solvent was evaporated under reduced pressure to give 3- [2,3-dihydro-3- (1H-indol-2-ylcarbonyl). 1.72 g of amino-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester are obtained.

Production Example 7 (1) 3-Amino-1- (4-fluorophenyl)-
2,3-dihydro-6-methoxy-1H-indole-
2-one hydrochloride 2.00 g, sodium isoquinoline-3-carboxylate 1.33 g, 1-hydroxybenzotriazole 0.88 g anhydrous dimethylformamide 10 m
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.49 g) is added under ice-cooling, and the mixture is stirred for 30 minutes. Ethyl acetate-tetrahydrofuran (2: 1) was poured into the reaction solution for extraction, and the extract was washed,
After drying, it is filtered and the filtrate is concentrated. The residue is ethyl acetate
Powdered from tetrahydrofuran to give 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) 200 mg of this product, 275 mg of 4-bromobutyric acid ethyl ester, 4 m of dimethylformamide
1 of a mixture of potassium carbonate 195 under an argon atmosphere.
Add mg and stir at room temperature for 15 hours. Thiourea 71
Add mg and stir for a further 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
140 mg of -methoxy-2-oxo-1H-indol-3-yl] butyric acid ethyl ester are obtained as caramel. IR (Nujol) (cm ^-1 ): 3380, 1740, 16
75, 1625, MS (m / z): 541 (M ⁺ ), 47
6, 426, 156, 128 (base).

Production Examples 8-42 The corresponding starting material compounds are treated in the same manner as in Production Examples 1 to 7 to obtain the compounds shown in Tables 15 to 20.

[0130]

[Table 15]

[0131]

[Table 16]

[0132]

[Table 17]

[0133]

[Table 18]

[0134]

[Table 19]

[0135]

[Table 20]

Production Example 43 (1) 3-amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indole hydrochloride 2.00 g of dimethylsulfoxide 40 ml solution was added with ethyl acrylate. 0.85 ml and potassium carbonate 1.94
g, and the mixture is stirred under an argon atmosphere at room temperature for 3 hours.
The reaction solution is extracted with ethyl acetate, and the extract is washed and dried.
Insoluble matter is filtered off 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,
3-Dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid ethyl ester 1.36 g is 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 Production Example 3- (1) to give 3- {3-
[(5,6-Dihydro-4H-pyrrolo [2,3,1-i
j] quinolin-2-yl) carbonyl] amino-2,3
-Dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl} propionic acid ethyl ester is obtained.

Production Examples 44-60 The corresponding starting compound was treated in the same manner as in Production Example 43 to give the second compound.
The compounds listed in Tables 1 to 23 are obtained.

[0139]

[Table 21]

[0140]

[Table 22]

[0141]

[Table 23]

Production Example 61 3- [3- (3,4-dichlorobenzoylamino)-
2,3-dihydro-2-oxo-1H-indole-3
-Yl] propionic acid ethyl ester 1.06 g, 3-
Phenylpropyl bromide 1.0 g, 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 and 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-
1.25 g of ethyl] propionic acid ethyl ester is obtained as a colorless solid. Melting point: 119.5-121.5 ° C, IR
(Nujol) (cm ^-1 ): 3320, 1730, 1700, ¹
660, 1615, FAB-MS (m / z): 541 & 5
39 (MH ⁺ ).

Production Examples 62-74 The corresponding starting compound was treated in the same manner as in Production Example 61 to give the second
The compounds shown in Tables 4 to 25 are obtained.

[0144]

[Table 24]

[0145]

[Table 25]

Production Example 75 3- [3- (3,4-dichlorobenzoylamino)-
2,3-dihydro-1- (3-methylthiopropyl)-
To a solution of 2.05 g of 2-oxo-1H-indol-3-yl] propionic acid ethyl ester in 80 ml of chloroform, 1.22 g of metachloroperbenzoic acid is added under ice-cooling stirring, and the mixture is stirred at room temperature overnight. The solvent was distilled off from the reaction solution,
Extract with ethyl acetate, wash, dry and filter the extract, and dry under reduced pressure. The residue was separated by silica gel column chromatography [ethyl acetate-hexane (1: 2) -chloroform-methanol (20: 1)] to give 3- [3- (3,3.
4-dichlorobenzoylamino) -2,3-dihydro-
1- (3-methylsulfinylpropyl) -2-oxo-1H-indol-3-yl] propionic acid ethyl ester (sulfinyl derivative, 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, Rf large) obtain. The sulfinyl compound is recrystallized from ethyl acetate-isopropyl ether to obtain 1.07 g as colorless prism crystals. Melting point: 154-159 ° C, IR (Nujol) (cm ^-1 ): 322
0,1720,1655,1610, FAB-MS (m /
z): 527 & 525 (MH ⁺ ).

Production Example 76 3- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-1- (3-methylsulfonylpropyl) obtained by isolation by silica gel column chromatography in Production Example 75. ) -2-Oxo-1H-indol-3-yl] propionic acid ethyl ester (sulfonyl compound, Rf large) is recrystallized from ethyl acetate-hexane to obtain 592 mg as colorless needle crystals. Melting point: 106
-108 ° C, IR (Nujol) (cm ^-1 ): 3360,173
0, 1660, 1615, FAB-MS (m / z): 54
3 & 541 (MH ⁺ ).

Production 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
To the ml solution, add 5 ml of trifluoroacetic acid,
Stir for hours. The reaction solution was dried under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to give 2- [3- (3,4-dichlorobenzoylamino) -2,3-dihydro-3- (2
651 mg of -ethoxycarbonylethyl) -2-oxo-1H-indol-1-yl] acetic acid are obtained as colorless prism crystals. Melting point: 219-220 ° C, IR (Nujol)
(Cm ^-1 ): 3280, 1735, 1720, 1705,
1670, 1610, FAB-MS (m / z): 481 &
479 (MH ⁺ ).

Production Example 78 (1) 3- [2,3-dihydro-6-methoxy-3-
(2-naphthalenecarbonyl) amino-2-oxo-1
To a solution of 2.37 g of -phenyl-1H-indol-3-yl] propionic acid ethyl ester in 20 ml of methylene chloride, about 2.5 ml of boron tribromide was added dropwise under cooling.
Stir at room temperature for hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The extract was dried 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) 20 m of dimethylformamide of 2.15 g of this product
To the 1 solution, 330 mg of 63.3% sodium hydride was added, and after stirring, 0.35 ml of ethyl iodide was added.
After stirring at room temperature for 2.5 hours, the reaction solution was washed and dried,
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
928 mg of -Naphthalenecarbonyl) amino-2-oxo-1-phenyl-1H-indol-3-yl] propionic acid ethyl ester are obtained as colorless needles. Melting point: 195-196 ° C, IR (Nujol) (cm ^-1 ): 342
0, 1750, 1730, 1640, 1620, 154
0, MS (m / z): 522 (M ⁺ ), 155 (base).

Production Example 79 3- [3- (2-t-butoxycarbonyl-1,2,2
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 75 ml of ethyl acetate solution, Under ice-cooling, hydrochloric acid gas was added until saturation, and the mixture was stirred at 0 ° C for 2.5 hours. After evaporating the solvent, the residue is suspended in isopropyl ether. The suspension is filtered to give 3- [2,3-dihydro-2-oxo-1-pentyl-3- (1,2,2
6.05 g of 3,4-tetrahydro-3-isoquinolinyl) carbonylamino-1H-indol-3-yl] propionic acid ethyl ester hydrochloride are obtained as a pale yellow amorphous solid. IR (Nujol) (cm ^-1 ): 3180, 17
25, 1690, 1610, FAB-MS (m / z): 4
78 (MH ⁺ ) and 132 (base).

Production Example 80 0.66 g of formic acid and 1.35 g of acetic anhydride were mixed to give 50
Heat at 15 ° C for 15 minutes. After cooling, anhydrous methylene chloride 15m
1, 0.68 g of sodium formate and 3- [2,3-dihydro-2-oxo-1-pentyl-3- (1,2,3,3
A solution of 1.70 g of 4-tetrahydro-3-isoquinolinyl) carbonylamino-1H-indol-3-yl] propionic acid ethyl ester hydrochloride in 15 ml of methylene chloride is added, and the mixture is stirred at room temperature overnight. The reaction mixture is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract is washed, dried, filtered and concentrated to give 3- [3
-(2-formyl-1,2,3,4-tetrahydro-3
-Isoquinolinyl) carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indole-3
1.72 g of -yl] propionic acid ethyl ester are obtained as a pale yellow amorphous solid. IR (Nujol) (cm ^-1 ):
3280, 1720, 1655, 1610, FAB-M
S (m / z): 506 (MH ⁺ ), 160 (base).

Production 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 methylene chloride 3
2 ml of boron tribromide was added dropwise to the 0 ml solution under ice cooling. The mixture was stirred under ice cooling for 1 hour and 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): 46
5 (MH ⁺ ), 302, 256, 228, 147 (bas
e).

Production Example 82 3- [2,3-dihydro-3-[(E) -3- (2-methoxyphenyl) -2-propenoylamino] -2-oxo-1-phenyl-1H-indole- 3-Yl] propionic acid ethyl ester was treated as in Preparation 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, 17
10, 1610, FAB-MS (m / z): 470
(M ⁺ ), 91.

Production 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 solution, 15% sodium methyl sulfide aqueous solution 12 ml
And stirred at 50 ° C. for 3 hours. After concentrating the reaction solution, 1
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 then 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, 165
0,1615, FAB-MS (m / z): 499 & 497.
(MH ⁺ ).

Production Example 84 3- [2,3-Dihydro-3-[(E) -3- (2-methoxyphenyl) -2-propenoylamino] -2-oxo-1-phenyl-1H-indole- A mixture of 3-yl] propionic acid ethyl ester 719 mg, 10% palladium-carbon 100 mg, ethanol 20 ml, and tetrahydrofuran 6 ml is stirred overnight under a hydrogen gas atmosphere of 1 atm. The reaction solution is filtered, the solvent is distilled off from the filtrate, and 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.

Production Example 85 3- [3- (3,4-dichlorobenzoylamino)-
2,3-dihydro-2-oxo-1-pentyl-1H-
A mixture of 3.89 g of indole-3-yl] propionic acid methyl ester, 16 ml of 2N aqueous sodium hydroxide solution, and 100 ml of methanol is heated under reflux for 40 minutes. After cooling the reaction mixture to room temperature, the solvent is evaporated 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,
1675, 1660, FAB-MS (m / z): 463 (M
H ⁺ ), 173 (base).

Production 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 was added to a mixed solution of 4N sodium hydroxide 1. Add 5 ml and 5 ml of water and stir at room temperature for 7 hours. The reaction solution is concentrated under reduced pressure, diluted with water, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. After the extract was dried, the solvent was evaporated and the residue was recrystallized from ethanol-ethyl acetate to give 3- [3- (3,4-dichlorobenzoylamino).
1.09 g of 2,2,3-dihydro-2-oxo-1- (3-phenylpropyl) -1H-indol-3-yl] propionic acid are obtained 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 ⁺ ).

Production 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
3.79 ml of 1N sodium hydroxide is added to a 30 ml solution of g in ethanol, and the mixture is stirred at room temperature for 4 hours. The reaction solution is concentrated, 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 solution of sodium hydrogen carbonate, and the extract was mixed with a nonionic adsorption resin (trade name: HP-2
0, manufactured by Mitsubishi Kasei Co., Ltd.) and eluted with water and a water-methanol (1: 1) mixture. Lyophilize the eluate to 3
-[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,
FAB-MS (m / z): 522 (MNa ⁺ ), 500 (MH
⁺ , base).

Production Examples 88-162 The corresponding starting material compounds are treated in the same manner as in Production Examples 85-87 to obtain the compounds shown in Tables 26 to 36.

[0160]

[Table 26]

[0161]

[Table 27]

[0162]

[Table 28]

[0163]

[Table 29]

[0164]

[Table 30]

[0165]

[Table 31]

[0166]

[Table 32]

[0167]

[Table 33]

[0168]

[Table 34]

[0169]

[Table 35]

[0170]

[Table 36]

Production Example 163 N- [3- (2-cyanoethyl) -2,3-dihydro-
A mixture of 2.00 g of 2-oxo-1-pentyl-1H-indol-3-yl] -3,4-dichlorobenzamide, 3.0 g of tributyltin azide (Bu ₃ SnN ₃ ) and 1.5 ml of toluene was heated at 110 ° C. Heat and stir for 3 hours. After cooling, a 6.4% hydrochloric acid-ethanol 50 ml solution is added, and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled off, ethyl acetate and then a saturated potassium fluoride aqueous solution are added, and the insoluble matter is filtered off. The ethyl acetate layer is separated, washed and then concentrated. The residue is dissolved in 5% aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer is acidified with 10% hydrochloric acid, extracted with ethyl acetate, washed and dried, and the solvent is evaporated. The residue was recrystallized from ethyl acetate to give N- {2,3-
Dihydro-2-oxo-1-pentyl-3- [2- (1
H-tetrazol-5-yl) ethyl] -1H-indol-3-yl} -3,4-dichlorobenzamide 1.
72 g are obtained as colorless needles. Melting point: 142-147
° C, IR (Nujol) (cm ^-1 ): 3340, 1705, 16
55, 1675, 1615, FAB-MS (m / z): 4
89 & 487 (MH ⁺ ).

Production 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 as in Preparation 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 Production 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,
It is treated with activated carbon 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 under reduced pressure from the reaction solution, it 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-
150 mg of ylcarbonylamino] -2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl] propionic acid are obtained. Melting point 125 [deg.] C.

Production Example 166 (S) -3-amino-1- (4-fluorophenyl)-
Preparation of 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 By treating in the same manner as in Example 3- (1) or Production 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
To obtain a carboxamide. Melting point: 223-224 ° C,
[Α] ²⁵ _D : +58.33 (c = 0.240, chloroform).

Production Examples 167-171 The corresponding starting material compounds were treated in the same manner as in Production Example 166 to obtain the following compounds.

Production 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).

Production 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).

Production 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).

Production 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).

Production 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).

Production 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
The ml solution is bubbled with hydrochloric acid gas under ice cooling until saturated, and stirred at room temperature for 30 minutes. 140 μl of water is added to the reaction solution and the mixture is left for 7 days. The reaction solution is concentrated, and an aqueous sodium hydrogen carbonate solution and then ethyl acetate are added to the resulting residue for extraction. The organic layer is separated, dried, filtered and concentrated. The residue is subjected to silica gel column chromatography [hexane-
Ethyl acetate (1: 1)] and purified (+)-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).

Production 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 Preparation 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).

Production 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
4.21 ml of 1N sodium hydroxide is added to a solution of 20 ml of ethanol in, and the mixture is stirred overnight at room temperature. The reaction solution is concentrated, and the residue is treated with a nonionic adsorption resin (trade name: HP-2
0, manufactured by Mitsubishi Kasei Co., Ltd.) for desalting, 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).

Production 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 as in Preparation Example 174 to give (-) -3- {1- (4-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonylamino] -6-methoxy-2
-Sodium oxo-1H-indol-3-yl} propionate is obtained. [Α] ²⁵ _D : −72.41 ° (c =
0.406, methanol).

Production Example 176 (1) 3-Amino-1- (2-fluorophenyl)-
2,3-dihydro-6-methoxy-1H-indole-
To 210 ml of a dimethyl sulfoxide solution containing 70.00 g of 2-one hydrochloride, 29.90 ml of acrylonitrile and 62.70 g of potassium carbonate are added, and the mixture is stirred overnight at room temperature 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 brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to 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
70.70 g of the crude product of -oxo-1H-indol-3-yl] propanenitrile was dissolved in 250 ml of ethyl acetate, and to this solution was added 51.21 g of (+)-dibenzoyltartaric acid monohydrate in 150 ml of acetic acid. The solution dissolved in ethyl is added dropwise under ice cooling. The crystals were collected by filtration, washed with ethyl acetate, and then (S) -3- [3-amino-1- (2-
Fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl] propanenitrile (+)-dibenzoyl tartrate (41.13)
g) are obtained as pale yellow crystals. 180m under heating this product
After dissolving in 1 l of methanol and concentrating, the obtained residue is triturated with ethyl acetate to obtain 34.02 g of the above salt as colorless crystals (yield: 22%). [Α] ²⁵ _D +
50.0 ° (c = 0.420, methanol). Melting point 15
5-157 ° C.

(3) 34.02 g of (S) -3- [3-
Amino-1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H-indole-
3-yl] propanenitrile (+)-dibenzoyl tartrate is dissolved in a mixed solvent of an aqueous potassium carbonate solution and ethyl acetate with stirring. The ethyl acetate layer is separated, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give 15.44 g of colorless oil. The above oil was dissolved in 100 ml of anhydrous dimethylformamide, 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 solution is poured into water and the mixture is extracted with ethyl acetate. The organic layer was washed successively with diluted hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 23.85 g of (S) -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.

Preparation Example 177 23.85 g of (S) -N- [3- (2-cyanoethyl) -1- (2-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-1H- Indole-3
-Yl] -3-isoquinolinecarboxamide crude product is dissolved in 80 ml of anhydrous methanol, and hydrochloric acid gas is passed under ice cooling until it is saturated, and 1.71 ml of water is added. The reaction solution is heated under reflux for 1 hour, cooled and then concentrated under reduced pressure. The residue is neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is separated, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration,
The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate: hexane (1:
1, volume) and 22.30 g of (S) -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% (Production Example 176 (2 ) From the product)). DI-MS (m / z) 513 (MH +), 42
6,156,128 (base). [Α] ²⁵ _D + 66.2 °
(C = 0.402, chloroform).

PREPARATIVE EXAMPLE 178 62.53 g of (S) -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 cooled to 5 under ice-cooling.
Add 6.78 ml of 3N NaOH aqueous solution and stir overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was concentrated to 15
Acidify with aqueous citric acid solution and extract with ethyl acetate. The organic layer was separated, washed successively with water and saturated saline,
Add 15 g of activated carbon and dry over anhydrous sodium sulfate. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure, and (S)
-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 +7.
9.8 ° (c = 0.426, chloroform)]. 7.36 g of sodium carbonate and 200 ml of water are added to this product to make a solution. This solution is concentrated to dryness under reduced pressure, 500 ml of acetonitrile is added to the residue, and after heating and dissolution, the insoluble matter is removed by filtration. After cooling, the crystals precipitated from the filtrate were collected by filtration, and 60.07 g of (S) -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
%). Melting point 206-211 [deg.] C. FAB-MS (m / z)
522 (MH +), 177, 23 (base). [Α] ²⁵ _D +
89.7 ° (c = 0.406, methanol).

Preparation Example 179 11.47 g of (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo- 1
To H-indol-3-yl] propionic acid, 1.74
g potassium carbonate, 5 ml water and 20 ml acetonitrile are added to form a solution. The solution is concentrated to dryness under reduced pressure, 100 ml of acetonitrile is added to the residue, and the residue is dissolved by heating and then the insoluble matter is 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 (S)
-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. Melting point 275-277 [deg.] C (decomposition). FAB-MS (m / z)
576 (MK ⁺ ), 538 (MH ⁺ ), 192, 39 (bas
e). [Α] ²⁵ _D + 91.8 ° (c = 0.438, methanol).

Production Example 180 (1) 3-Amino-1- (4-fluorophenyl)-
2,3-dihydro-5-methoxy-1H-indole-
60 g of 2-one hydrochloride was added to 200 m of dimethyl sulfoxide
1 g, potassium carbonate 43 g and then acrylonitrile 20 ml were added to the solution,
Stir at room temperature. After 2 hours, add 2 ml of acrylonitrile and continue stirring overnight. The reaction solution is put 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 are collected by filtration, and 3- [3-
Amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo-1H-indole-
36.8 g of 3-yl] 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
43.7 g of -oxo-1H-indol-3-yl] propanenitrile and 40 g of (-)-dibenzoyltartaric acid are dissolved in 300 ml of ethyl acetate 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-3
26.4 g of -yl] propanenitrile (-)-dibenzoyl tartrate are obtained. Melting point 157-158.5 [deg.] C.
[Α] ²⁰ _D + 64.91 ° (c = 0.228, methanol). EI-MS (m / z): 325 (M ⁺ ). IR
(Nujol) (cm-1): 1380, 1460, 1690,
1740, 2250.

(3) 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2
Ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution are added to 125.1 g of -oxo-1H-indol-3-yl] propanenitrile (-)-dibenzoyl tartrate, and the ethyl acetate layer is separated. The ethyl acetate layer is washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure. The residue was dissolved in 800 ml of dimethylformamide, and isoquinoline-3 was added to this solution.
-Add 40 g of sodium carboxylic acid salt, and further add 27.4 g of 1-hydroxybenzotriazole and 39 g of N-ethyl-N'-diethylaminopropylcarbodiimide hydrochloride under ice cooling and stir. The solution is gradually warmed 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 brine, dried over anhydrous magnesium sulfate, and filtered. The solvent in the obtained solution was distilled off under reduced pressure, and (+)-
N- [3- (2-cyanoethyl) -1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl] -3-isoquinolinecarboxamide as an oily substance Get as. [Α] ²⁵ _D +
32.52 ° (c = 0.412, methanol).

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

Production 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 1N sodium hydroxide aqueous 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, diluted 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. Acetonitrile-
Crystallization from diisopropyl ether and filtration give 90.59 g of crystals. 10g of filtered material
Was dissolved in a 1.6N aqueous potassium hydroxide solution to give HP-2
And lyophilize. The amorphous material obtained 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):
1520, 1570, 1670, 1730.

Production Example 183 (+)-3- [1- (4-fluorophenyl) -2,3
-Dihydro-3- (3-isoquinolinyl) carbonylamino-5-methoxy-2-oxo-1H-indole-
5.62 g of methyl 3-yl] propionate is dissolved in 50 ml of methyl alcohol, 12 ml of 1N sodium hydroxide aqueous solution is added to this solution, and the mixture is stirred at room temperature overnight. After completion of the reaction, the solvent is distilled off under reduced pressure, diluted hydrochloric acid and ethyl acetate are added to the residue, and the organic layer is separated. This organic layer
After washing with saturated saline and drying over anhydrous magnesium sulfate,
Filter. The solvent is distilled off from the filtrate under reduced pressure. 12 ml of 1N aqueous sodium hydroxide solution and 300 ml of water
, HP-20 and freeze-dried. (+)-
3- [1- (4-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-5
5.32 g (1.5 hydrate) of sodium-methoxy-2-oxo-1H-indol-3-yl] propionate are obtained as an amorphous substance. [Α] ²⁰ _D +12.2
6 ° (c = 0.326, methanol). IR (Nujol)
(Cm ^-1 ): 1510, 1580, 1600, 1670,
1720, FAB-MS (m / z): 544 (M + Na), 5
56 (M + 2Na), 522 (M ⁺ ).

Reference Example 1 (1) 65 ml (0.745 mol) of oxalyl chloride
Was dissolved in 65 ml of dichloromethane, and 32.3 g of 4-methoxy-4'-fluorodiphenylamine (0.
A solution of 149 mol) dissolved in 120 ml of dichloromethane was added dropwise with stirring under ice cooling, and the mixture was stirred for 1 hour 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 filtered off, washed with water and then with diethyl ether, and dried to give red crystals, 1-
(4-Fluorophenyl) -2,3-dihydro-5-methoxy-1H-indole-2,3-dione 38.7 g
Get. 246-247 ° C.

(2) 13.55 g (0.05 mol) of this product, 10.43 g (0.15 g) of hydroxyamine hydrochloride
Mol), 7.95 g (0.075 mol) of sodium carbonate, 500 ml of ethanol, and 200 ml of water are heated to 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 are washed with water and dried to obtain 1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-1H-indole-2,3-dione-3-oxime (14.3 g) as yellow crystals. . 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 overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and a mixed solvent of acetone and diethyl ether was added to the residue to give 3-amino-1- (4
-Fluorophenyl) -2,3-dihydro-5-methoxy-1H-indol-2-one [= 3-amino-1-
12.4 g of (4-fluorophenyl) -5-methoxy-1H-indole-2 (3H) -one] hydrochloride are obtained.
Melting point 170-175 ° C, IR (Nujol) (cm ^-1 ): 1740, M
S (DI, m / z): 272 (M ⁺ ).

Reference Examples 2 to 7 The corresponding starting material compounds were treated in the same manner as in Reference Example 1 to obtain 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-indole-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. Melting point 160-161 ° C
(Disassembly).

Reference Example 5: 3-amino-2,3-dihydro-6-methoxy-1-phenyl-1H-indole-2
-One hydrochloride. Melting point 172-175 [deg.] C (decomposition).

Reference Example 6: 3-Amino-1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-1H
-Indol-2-one hydrochloride. Melting point 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, 270 mg of sodium hydride is added at room temperature. The reaction mixture is stirred at room temperature for 10 minutes, and then a solution of 2.10 g of pentyl bromide in 5 ml of dimethylformamide is added dropwise. The reaction mixture is stirred 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 used in Reference Examples 1- (2) and (3).
Treated in a similar manner to 3-amino-2,3-dihydro-1
-Pentyl-1H-indole-2-one hydrochloride 1.3
1 g is obtained as colorless crystals (recrystallized from ethanol-diethyl ether). Melting point: 142-144 ° C. Reference Example 9 2,3-dihydro-1H-indole-2,3-dione (14.7 g) 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 ° C.

Reference Example 10 (1) m-Anisidine 70.5 g in methylene chloride solution 5
120 ml of triethylamine and 56.7 ml of acetic anhydride are added dropwise to the 00 ml solution under ice cooling. After dropping,
The reaction solution is washed and dried, and the insoluble matter is filtered off. The filtrate is concentrated, and the obtained residue is recrystallized from hexane-ethyl acetate to obtain 80.9 g of N- (3-methoxyphenyl) acetamide as pale yellow needle crystals. Melting point: 81-
82 ° C (2) Sodium hydride 60% oil suspension 10.65
g is suspended in 100 ml of anhydrous dimethylformamide under an argon atmosphere. A solution of 40.00 g of this product in 100 ml of dimethylformamide, and then 38.23 g of n-pentylpromide were added dropwise to the suspension under ice cooling, and the temperature was gradually raised from 0 ° C. to room temperature and stirred for 5 hours. To do. The reaction solution is poured into water and the precipitated oily substance is extracted with ethyl acetate. The extract is washed and dried, and 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) 67.76 g of ethanol 20 of this product
100 ml of concentrated hydrochloric acid is added to the 0 ml solution, and the mixture is heated under reflux for 24 hours. The reaction solution is concentrated and the residue is extracted with chloroform. The mixture is made alkaline with sodium hydrogen carbonate, the organic layer is separated, dried and the insoluble matter is removed by filtration. The brown oily substance obtained by concentrating the filtrate was treated with ethanol-hydrochloric acid to give the hydrochloride, and then recrystallized from acetone-isopropyl ether to give N-pentyl-m-anisidine hydrochloride 47.
05 g are obtained as colorless needles. Melting point: 110-11
2 ° C.

(4) 47.00 g of this product was used in Reference Example 1-
3-amino-2,3 is treated in the same manner as in (1) to (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 material 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: 184.5-187 [deg.] C.

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, 9 g of copper powder, 19.8 g of potassium carbonate and 26.7 g of m-bromoanisole are stirred at 200 ° C. for 3 days. The insoluble matter is removed from the reaction solution by filtration, 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
Is added and the mixture is heated under 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 ):
3400, 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 obtain 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) Dichloroethane 3 containing 8 g of sodium borohydride
Under ice cooling, 45 ml of acetic acid was added dropwise to the 00 ml suspension over 1 hour. 17.48 g of m-anisidine was added to the mixture.
And cyclohexanone 16ml dichloroethane 50m
1 solution is added slowly and stirred for 40 minutes at room temperature. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution 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, 285
0, 1615, 1510, 1500, 1450, MS
(M / z): 205 (M ⁺ ), 162.

(2) This product was treated in the same manner as in Reference Examples 1- (1) to (3) to give 3-amino-1-cyclohexyl-.
2,3-dihydro-6-methoxy-1H-indole-
2-one hydrochloride is obtained. Melting point: 185 [deg.] C.

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

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 hexane solution of 1.6Mn-butyllithium was added dropwise under water cooling under an argon atmosphere. The mixture is stirred under ice cooling for 2 hours, 18 ml of diethyl oxalate is added, and the mixture is stirred at room temperature for 2 hours. Water is added to the reaction solution, extracted 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 ° C.

(2) 2.85 g of this product, 30 ml of concentrated hydrochloric acid,
A mixture of 30 ml of ethanol is heated to 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 to give 1.49 g of 2,3-dihydro-4-methoxy-1H-indole-2,3-dione as orange crystals. Get as. Melting point: 198-
200 ° C.

(3) This product is 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-indol-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 was suspended in 80 ml of anhydrous dichloroethane and 2.69 g (0.0182 mol, 1.4 eq) of phthalic anhydride was added at once under an argon atmosphere. After that, 2 ml of triethylamine (0.0
143 mol) is added dropwise over 10 minutes. Then, after stirring at room temperature for 10 minutes, the mixture is further refluxed on an oil bath overnight. Excess phthalic anhydride is decomposed by adding 2 ml of triethylamine and 2 ml of methanol and then refluxing for 20 minutes. The reaction mixture is concentrated under reduced pressure and then 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)
4.50 g of 2,2,3-dihydro-5-methoxy-1H-indol-2-one are obtained as colorless crystals. Melting point:
208.5-210.0 ° C, IR (Nujol) (cm ^-1 ): 173
0, 1715, 1495, 1400, 1225, 1210, 750,715, MS (DI,
m / e): 402 (M ⁺ , base), 227, 184, 76.

(2) To a solution of 4.50 g (0.0112 mol) of this product in 80 ml of acetone, under argon atmosphere, 4.64 g (0.0336 mol) of potassium carbonate was added.
And 1.39 ml (0.0224 mol) of methyl iodide are added and the mixture is vigorously stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue obtained is extracted with ethyl acetate. The ethyl acetate layer is washed with water and then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue 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 3.
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, 149
0, 1220, 1040, 835, 715, 655, 560, 520, 475, MS (D
I, m / z): 416 (M ⁺ , base), 401 (M ⁺ -Me), 373, 343,
241, 226, 198.

(3) 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, 447 μl of hydrazine hydrate was added.
(0.00922 mol) is added dropwise at room temperature. After continuing stirring overnight, 20 ml of tetrahydrofuran and 20 ml of ethanol
ml and 447 μl of hydrazine hydrate,
Heat to reflux for hours. After cooling the reaction mixture to room temperature,
The precipitated insoluble material is filtered off, and the filtrate is concentrated to give a residue.
This residue is dissolved in ethyl acetate. The insoluble material was filtered off and the obtained filtrate was concentrated under reduced pressure to give a residue, which was subjected to silica gel column chromatography [chloroform: ethyl acetate (1:
1)] and purified by 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, 1225, 1200, 1000,
835,715, 655, 560, 520, 475, FAB-MS (m / z): 287
(MH ⁺ ), 286 (M ⁺ ), 270 (M ⁺ -NH ₂ base), 258 (M ⁺ -C
O).

Reference Example 21 3-Amino-1- (4-fluorophenyl) -2,3-
To a suspension of 5.00 g of dihydro-6-methoxy-1H-indol-2-one hydrochloride in 30 ml of dimethyl sulfoxide, 1.2 ml of acrylonitrile under an argon atmosphere.
And 4.48 g of potassium carbonate are added, and the mixture is 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-
Yield] propanenitrile 3.48 g 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 of 3-amino-1- (4-fluorophenyl) -2,3-dihydro-5-methoxy-3 -Methyl-
9.26 g of 1H-indol-2-one and 11.72 g of dibenzoyl-L-tartaric acid (hereinafter referred to as DBT) are dissolved by heating 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 under 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 ° C (decomposition). [Α] _D ²⁵ : -7
8.12 ° (c = 0.896, methanol), optical purity: 99.7% ee (determined by optically active HPLC described later).

Free base: (S) -3-amino-1- (4
-Fluorophenyl) -2,3-dihydro-5-methoxy-3-methyl-1H-indole-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 sodium hydrogen carbonate solution, washed with water, then with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate,
The solvent is distilled off under reduced pressure. To the residue was added 6.45 g of dibenzoyl-D-tartaric acid, and the mixture was heated and dissolved 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 a colorless powder of the corresponding (R) form (+)-D.
8.31 g of BT salt are obtained. Melting point: 163.0 to 164 ° C
(Decomposition) [α] _D ²⁵ : + 76.29 ° (c = 0.928, methanol), optical purity: 99.9% ee (determined by optically active 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 3-
It is performed by X-ray structural analysis of a (p-toluenesulfonyl) amino derivative.

Measurement of Optical Purity HPLC Conditions Column: Optipac XC 3.9 × 300 mm (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 body is separated.

Retention time (R) body: 9.27 minutes (S) body: 15.80 minutes.

Reference Example 23 3-amino-1- (2-fluorophenyl)-of dl form
2,3-dihydro-3-methyl-1H-indole-2
The -one is treated as in Reference Example 22 to give 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 3- [3-amino-1- (4-fluorophenyl) -2,3-dihydro-6-methoxy-2-oxo-dll-form
1H-Indol-3-yl] propanonitrile is treated as in Reference Example 22 to give the following compound.

(-)-DBT salt: melting point 175-177
^{_{℃, [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.

[0242]

INDUSTRIAL APPLICABILITY The 2-oxoindoline derivative (I) and its pharmaceutically acceptable salt, which are the active ingredients of the present invention, are
It has an excellent cholecystokinin antagonism and exhibits an excellent pancreatic exocrine inhibitory effect. Moreover, since the compound of the present invention has low toxicity, it can be a highly safe drug when used as a drug. For example, (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo-1H-indol-3-yl] Sodium propionate or (+)-3- [1- (4-fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl)
Carbonylamino-5-methoxy-2-oxo-1H-
Oral administration of sodium indole-3-yl] propionate to rats at 1 g / kg did not change the general symptoms.

Therefore, the pharmaceutical composition of the present invention provides a pancreatic disorder such as acute pancreatitis, chronic pancreatitis, excessive pancreatic secretion, pancreatic cancer, insulinoma, hyperinsulinemia, irritable bowel syndrome, reflux esophagitis, excess gastric juice. Gastrointestinal disorders such as secretion, or other gastrointestinal disorders such as gallbladder pain, or nausea,
It is useful as a prophylactic or therapeutic drug for various symptoms such as vomiting, loss of appetite, and indigestion.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/445 A61K 31/445 31/47 ACJ 31/47 ACJ 31/495 31/495 31/535 31/535 // C07D 209/40 C07D 209/40 401/06 209 401/06 209 401/12 209 401/12 209 401/14 209 401/14 209 403/12 209 403/12 209 405/12 209 405 / 12 209 409/12 209 409/12 209 471/06 471/06 487/06 9271-4C 487/06

Claims (10)

[Claims] 1. A compound of the general formula (I) (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. 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,
Optionally esterified carboxyl group, cyano group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, oxiranyl group or 2
-(Lower alkylthio) -1-hydroxyethyl group, R ²
Is a substituted or unsubstituted aryl group, and has the formula: A group represented by, a substituted or unsubstituted nitrogen-containing heteromonocyclic group, a substituted or unsubstituted nitrogen-containing heterobicyclic group, a compound represented by the formula: (Provided that 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, R ³ is a substituted or unsubstituted lower alkyl group, Q is a single bond or a lower alkylene group, and Y is a single bond, a lower alkylene group or a lower alkenylene group. 2-)
A pharmaceutical composition comprising an oxoindoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 2. A benzene ring in which ring A may be substituted with a group selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom; a cycloalkyl group; a halogen atom,
Aryl group which may be substituted with 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; an optionally esterified carboxyl group; 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; A group represented by: 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; (However, 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; R ³ is a lower alkyl group optionally substituted with a group selected from an optionally esterified carboxyl group, a cyano group and a tetrazolyl group; Q is a single bond; or a lower alkylene group; Y is a single bond; lower alkylene group;
Alternatively, the pharmaceutical composition according to claim 1, which is a lower alkenylene group. 3. A benzene ring in which ring A may be substituted with a group selected from a lower alkyl group and a lower alkoxy group; R ¹ is a hydrogen atom; a cycloalkyl group; a halogen atom,
An aryl group which may be substituted with a group selected from a lower alkyl group and a lower alkoxy group; an optionally esterified carboxyl group; a lower alkylthio group; or 2
-(Lower alkylthio) -1-hydroxyethyl group; R ²
Is an aryl group which may be substituted with a group selected from a halogen atom, a hydroxy group and a lower alkoxy group; a nitrogen-containing heterobicyclic group; (Wherein n represents 1 or 2); an oxygen-containing heterocyclic group; or a sulfur-containing heterocyclic group; a carboxyl group, a cyano group and a tetrazolyl group in which R ³ may be esterified. The pharmaceutical composition according to claim 1, wherein a lower alkyl group optionally substituted with a group selected from: Q is a single bond; or a lower alkylene group; Y is a single bond; or a lower alkenylene group. 4. A benzene ring in which ring A may be 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. An aryl group which may be substituted with a group selected from: 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; a nitrogen-containing heterobicyclic group; Chemical 7] (Wherein n represents 1 or 2); an oxygen-containing heterocyclic group; or a sulfur-containing heterocyclic group; a carboxyl group, a cyano group and a tetrazolyl group in which R ³ may be esterified. The pharmaceutical composition according to claim 1, wherein a lower alkyl group optionally substituted with a group selected from: Q is a single bond; or a lower alkylene group; Y is a single bond; or a lower alkenylene group. 5. A benzene ring in which ring A may be 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 which may be substituted with a group selected from: R ² is a naphthyl group; a halogenophenyl group; an indolyl group; a quinolyl group;
Isoquinolyl group; Formula: (However, n represents 1 or 2); a benzothiophenyl group; a benzofuranyl group; or a coumaryl group;
The pharmaceutical composition according to claim 1, wherein R ³ is a lower alkyl group which may be substituted with an optionally esterified carboxyl group, Q is a single bond; or a lower alkylene group; Y is a single bond. 6. A benzene ring in which ring A is substituted with a lower alkoxy group, R ¹ is a halogenophenyl group or a cyclohexyl group, R ² is an indolyl group, a quinolyl group or an isoquinolyl group, and R ³ may be esterified. The pharmaceutical composition according to claim 1, wherein a lower alkyl group substituted with a carboxyl group, Q is a single bond, and Y is a single bond. 7. A benzene ring in which ring A is substituted with a lower alkoxy group, R ¹ is a halogenophenyl group, R ² is an isoquinolyl group, and R ³ is a lower alkyl group substituted with an optionally esterified carboxyl, The pharmaceutical composition according to claim 1, wherein Q is a single bond and Y is a single bond. 8. (S) -3- [1- (2-Fluorophenyl) -2,3-dihydro-3- (3-isoquinolinyl) carbonylamino-6-methoxy-2-oxo-1.
A pharmaceutical composition comprising H-indol-3-yl] propionic acid, an ester thereof or a pharmaceutically acceptable salt thereof as an active ingredient. 9. The pharmaceutical composition according to any one of claims 1, 2, 3, 4, 5, 6, 7 or 8, which is a cholecystokinin antagonist. 10. Acute pancreatitis, chronic pancreatitis, excessive pancreatic juice secretion,
A prophylactic / therapeutic agent for pancreatic cancer, insulinoma, hyperinsulinemia, irritable bowel syndrome, reflux esophagitis, excessive gastric secretion, colic pain, nausea, vomiting, loss of appetite, dyspepsia. The pharmaceutical composition according to 4, 5, 6, 7, 8 or 9.