JPH0873444A - Benzodiazepine derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new compound as a medicine having selective cholecystokinin-B antagonistic activity, useful for treating anorexia, irritable intestine syndrome, anxiety, schizophrenia, etc. CONSTITUTION: This compound, a benzodiazepine derivative, is expressed by formula I (R<1> is an aryl; R<2> is an aryl; R<3> is a lower al-kylthio (lower) alkyl, lower alkoxy (lower) alkyl, arylsulfinyl (lower) alkyl, etc.), e.g. N-[(3RS)-2,3- dihydro-5-(2-fluorophenyl)--1-(phenylsulfinylmethyl)-2-oxo-1H-1,4-benz odiazepin-3- yl]-N'-(3-methylphenyl)urea. The compound of formula I is obtained by reaction between a compound of formula II, reactive derivative at its amino group therefrom, or salt thereof and a compound of formula HOOC-NH-R<2> , reactive derivative therefrom, or salt thereof, in a solvent (e.g. THF) under cooling or heating.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzodiazepine derivative having a selective cholecystokinin-B (CCK-B) antagonism and a pharmaceutically acceptable salt thereof.

[0002]

OBJECT OF THE INVENTION An object of the present invention is to provide a novel compound useful as a selective CCK-B antagonist.
Specifically, disorders of the appetite control system (eg, anorexia), diseases related to intestinal smooth muscle hyperactivity (eg, irritable bowel syndrome, sphincter spasticity, etc.), anxiety, psychosis (eg,
As a preventive and / or therapeutic drug for schizophrenia, etc.,
Furthermore, it is to provide a novel benzodiazepine derivative useful as an analgesic and a pharmaceutically acceptable salt thereof.

[0003]

The benzodiazepine derivative of the present invention comprises:
Formula (I) below

[0004]

[Chemical 4]

[Wherein R ¹ is an aryl group optionally substituted by one or more suitable substituents, R ² is an aryl group optionally substituted by one or more suitable substituents, R 2 ³ is a lower alkylthio (lower) alkyl group, lower alkoxy (lower) alkyl group, arylsulfinyl (lower) alkyl group, formula:

[0006]

[Chemical 5]

(Wherein R ⁴ represents an aryl group, R ⁵ represents a carboxy group, a protected carboxy group or a pyrrolidinylcarbonyl group, respectively), or a group represented by the formula:

[0008]

[Chemical 6]

Wherein R ⁶ is a lower alkyl group or an aryl group, R ⁷ is hydrogen, a carboxy group, a protected carboxy group, or a hetero-bridged ring carbonyl group having at least one nitrogen atom, A Means a lower alkylene group) and a pharmaceutically acceptable salt thereof.

[0010]

DESCRIPTION OF THE STRUCTURE OF THE INVENTION Suitable pharmaceutically acceptable salts of the target compound (I) are conventional non-toxic salts, and examples thereof include alkali metal salts (eg sodium salt, potassium salt, etc.). ), An alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), ammonium salt,
Organic base salts (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.), organic acid salts (eg formate salt, acetate salt, trifluoroacetate salt, malein) Acid salt, tartrate salt, methanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, etc.), inorganic acid salt (eg, hydrochloride, hydrobromide salt, sulfate salt, phosphate salt, etc.), salt with amino acid (For example, arginine salt, aspartate, glutamate, etc.) and the like are included. In the above and subsequent description of this specification, preferred examples and specific examples of various definitions included in the scope of the present invention will be described in detail below.

Suitable "aryl group" includes phenyl, naphthyl and the like. Suitable "substituent" in "aryl group optionally substituted by one or more appropriate substituents" is hydroxy, protected hydroxy (eg acyloxy described below), nitro, lower Alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, tertiary pentyloxy, hexyloxy, etc.), amino, protected amino (eg, acylamino described below) , Lower alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl etc.), halogen (eg chlorine, bromine, fluorine, iodine etc.) Etc. Suitable "acyl group" in the above "acyloxy" and "acylamino"
Examples thereof include aliphatic acyl and acyl containing an aromatic ring or a heterocycle.

Preferable examples of the acyl group include lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, oxalyl, succinyl etc.); lower alkoxycarbonyl (eg methoxycarbonyl, ethoxy). Carbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl,
Pentyloxycarbonyl, hexyloxycarbonyl etc.); lower alkanesulfonyl (eg mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl etc.); arenesulfonyl (eg benzenesulfonyl, tosyl etc.); aroyl (eg benzoyl, toluoyl, Xyloyl, naphthoyl,
Phthaloyl, indanecarbonyl etc.); ar (lower) alkanoyl (eg phenylacetyl, phenylpropionyl etc.); ar (lower) alkoxycarbonyl (eg benzyloxycarbonyl, phenethyloxycarbonyl etc.) and the like. “Lower” means 1 to 6 carbon atoms unless otherwise specified.

Preferable "lower alkylthio (lower) alkyl group" includes, for example, methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like. Suitable "lower alkoxy (lower) alkyl group" is:
Examples thereof include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl and the like.

Suitable "arylsulfinyl (lower) alkyl group" includes, for example, phenylsulfinylmethyl, phenylsulfinylethyl, phenylsulfinylpropyl, naphthylsulfinylmethyl, naphthylsulfinylethyl, naphthylsulfinylpropyl and the like. Suitable "protected carboxy group" includes esterified carboxy group, and the following may be referred to for "esterified carboxy group".

Preferable examples of esterified ester moiety of carboxy group include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester and the like. Lower alkyl esters, which may be substituted by one or more suitable substituents, and examples thereof include lower alkanoyloxy (lower) alkyl esters [eg acetoxymethyl ester, propionyloxy. Methyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1- (or 2-) acetoxyethyl ester, 1
-(Or 2- or 3-) acetoxypropyl ester, 1- (or 2-or 3-or 4-) acetoxybutyl ester, 1- (or 2-) propionyloxyethyl ester, 1- (or 2-or 3) -) Propionyloxypropyl ester, 1- (or 2
-) Butyryloxyethyl ester, 1- (or 2
-) Isobutyryloxyethyl ester, 1- (or 2-) pivaloyloxyethyl ester, 1- (or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester Ester, 3,3-dimethylbutyryloxymethyl ester, 1- (or 2-) pentanoyloxyethyl ester and the like]; lower alkanesulfonyl (lower) alkyl ester (for example, 2-mesylethyl ester and the like);
Mono (or di or tri) halo (lower) alkyl ester (eg 2-iodoethyl ester, 2,2,2
-Trichloroethyl ester and the like); lower alkoxycarbonyloxy (lower) alkyl ester [eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tertiary butoxycarbonyloxymethyl ester, 1- (or 2-) methoxycarbonyloxyethyl ester, 1- (or 2-) ethoxycarbonyloxyethyl ester, 1- (or 2-) isopropoxycarbonyloxyethyl ester, etc.]; phthalidylidene (lower) alkyl ester; or (5-
Lower alkyl-2-oxo-1,3-dioxole-4
-Yl) (lower) alkyl ester [eg (5-methyl-2-oxo-1,3-dioxol-4-yl)
Methyl ester, (5-ethyl-2-oxo-1,3-
Dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)
Ethyl ester etc.]; lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester etc.): ar optionally substituted by one or more suitable substituents (lower ) Alkyl ester [eg benzyl ester, 4-methoxybenzyl ester, 4-
Nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc.]; 1 Aryl ester which may be substituted by the above appropriate substituents (for example, phenyl ester, 4-chlorophenyl ester, tolyl ester, tertiary butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); Examples thereof include diester. For the suitable “lower alkyl group”, those mentioned above may be referred to.

Suitable "heterobridge ring" in "heterobridge ring carbonyl group having at least one nitrogen atom" is, in addition to nitrogen, a bridge ring group containing heteroatoms such as oxygen and sulfur. Is included. Preferred examples of the above-mentioned “heterobridged ring carbonyl group having at least one nitrogen atom” include, for example, (2-azabicyclo [2.2.
1] hept-2-yl) carbonyl, (2-azabicyclo [2.2.2] oct-2-yl) carbonyl, (2
-Azabicyclo [2.2.1] hept-5-ene-2-
Yl) carbonyl, (2-azabicyclo [2.2.2]
Oct-5-en-2-yl) carbonyl, (2,5-
Diazabicyclo [2.2.1] hept-2-yl) carbonyl, (2,5-diazabicyclo [2.2.2] oct-2-yl) carbonyl, (2,5-diazabicyclo [2.2.1]) Hept-5-en-2-yl) carbonyl, (2,5-diazabicyclo [2.2.2] oct-
5-en-2-yl) carbonyl, (3-azabicyclo [3.2.1] oct-3-yl) carbonyl, (3-
Azabicyclo [3.2.2] non-3-yl) carbonyl, (6-azabicyclo [3.2.1] oct-6-yl) carbonyl, (6-azabicyclo [3.2.2] non-6- Yl) carbonyl, (3,6-diazabicyclo [3.2.1] oct-3-yl) carbonyl, (3,6)
6-diazabicyclo [3.2.2] non-3-yl) carbonyl, (3,6-diazabicyclo [3.2.1] oct-6-yl) carbonyl, (3,6-diazabicyclo [3.2. 2] Non-6-yl) carbonyl, (3-
Azabicyclo [3.2.1] oct-6-en-3-yl) carbonyl, (3-azabicyclo [3.2.2] non-6-en-3-yl) carbonyl, (6-azabicyclo [3. 2.1] oct-2-en-6-yl) carbonyl, (6-azabicyclo [3.2.2] non-2-
En-6-yl) carbonyl, (3,6-diazabicyclo [3.2.1] oct-6-en-3-yl) carbonyl, (3,6-diazabicyclo [3.2.2] non-
6-en-3-yl) carbonyl, (3,6-diazabicyclo [3.2.1] oct-2-en-6-yl) carbonyl, (3,6-diazabicyclo [3.2.2] non- 2-en-6-yl) carbonyl etc. are mentioned.

Suitable "lower alkylene group" includes, for example, a straight chain or branched chain having 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, Pentamethylene,
Hexamethylene and the like can be mentioned.

Preferred examples of the target compound (I) are as follows. R ¹ is an aryl group which may have at least one halogen atom, R ² is an aryl group which may have at least one lower alkyl group, and R ³ is Lower alkylthio (lower) alkyl group, lower alkoxy (lower) alkyl group, arylsulfinyl (lower) alkyl group, formula:

[0019]

[Chemical 7]

(Wherein R ⁴ represents an aryl group, R ⁵ represents a carboxy group, an esterified carboxy group or a pyrrolidinylcarbonyl group, respectively),
Or expression:

[0021]

Embedded image

(Wherein R ⁶ is a lower alkyl group or an aryl group, R ⁷ is hydrogen, a carboxy group, an esterified carboxy group or (3-azabicyclo [3.2.2]).
Non-3-yl) carbonyl group, A is a group represented by a lower alkylene group). The method for producing the object compound (I) of the present invention is described in detail below. Manufacturing method 1 :

[0023]

[Chemical 9]

Where R ¹ , R ² and R ³ are as previously defined. Compound (I) or a salt thereof can be produced by reacting compound (II) or a reactive derivative at the amino group thereof or a salt thereof with compound (III) or a reactive derivative thereof or a salt thereof. .

Suitable reactive derivatives at the amino group of compound (II) include Schiff base type imino compounds obtained by reacting compound (II) with carbonyl compounds such as aldehydes and ketones or their enamine type tautomerism. Compound; a silyl derivative obtained by reacting compound (II) with a silyl compound such as N, N-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide; reacting compound (II) with phosphorus trichloride, phosgene, etc. Derivatives and the like obtained by

Suitable reactive derivatives of compound (III) include acid halides, acid anhydrides, active amides, active esters, isocyanates and the like. Suitable examples thereof include acid chloride, acid azide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid. , Alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonate, aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid Mixed anhydrides with acids such as (eg benzoic acid); symmetrical anhydrides; amides, tetrasubstituted imidazoles, dimethylpyrazoles, triazoles or active amides with tetrazole;
Or active ester (eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH
₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, phenyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester , Phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc., or N-hydroxy compound (for example, N, N-dimethylhydroxyl). Amine, 1-hydroxy-2- (1
H) -pyridone, N-hydroxysuccinimide, N-
Ester with hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc., formula: R ² —N═C═O
(In the formula, R ² is as described above) and the like are included.

These reactive derivatives are appropriately selected depending on the type of compound (III). Compounds (II) and (III
Examples of suitable salts of) include those exemplified as the salts of compound (I).

This reaction is carried out with water, acetone, dioxane,
It is usually carried out in a conventional solvent such as acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, or other organic solvent that does not adversely influence the reaction. These conventional solvents may be mixed with water before use.

When compound (III) is used in the above reaction in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N '
-Morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide, N-ethyl-
N '-(3-dimethylaminopropyl) carbodiimide, N, N-carbonylbis- (2-methylimidazole), N, N'-carbonyldiimidazole, pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexyl Imine, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride,
Thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt, 1- (P-Chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, N, N-dimethylformamide, a conventional condensing agent such as the commonly known Vilsmeier reagent obtained by reacting with thionyl chloride, phosgene, phosphorus oxychloride and the like. It is preferred to carry out the reaction in the presence of

This reaction is carried out by using an inorganic or organic base such as alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. Can also be performed in the presence of. The reaction temperature is not particularly limited and is usually under cooling or heating.

Compound (III) or its reactive derivative,
Alternatively, those salts can be produced by substantially the same method as the production examples described later. Manufacturing method 2A:

[0032]

[Chemical 10]

Where R ¹ , R ² and R ⁴ are as previously defined, and R ⁵ _a means a protected carboxy group. Compound (Ia) or a salt thereof can be produced by subjecting compound (IV) or a salt thereof to a reaction for eliminating a carboxy protecting group. Compounds (IV) and (I
Suitable salts of a) may be the same as the salts of compound (I).

This reaction is usually carried out by a conventional method such as hydrolysis or reduction. (I) Hydrolysis: Hydrolysis is preferably performed in the presence of an acid or a base. Suitable bases include the bases mentioned above (eg sodium hydroxide etc.).

Suitable acids include organic acids such as formic acid,
Examples thereof include acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.).

Acidic hydrolysis with a Lewis acid such as trihaloacetic acid (eg trichloroacetic acid, trifluoroacetic acid, etc.) is usually facilitated by the addition of a cation scavenger (eg phenol, anisole etc.).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methylene chloride, alcohol (eg methanol, ethanol etc.), tetrahydrofuran, dioxane, acetone etc., or a mixture thereof. . Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited and is usually under cooling or heating.

(Ii) Reduction: The reduction method is carried out according to conventional methods such as chemical reduction and catalytic reduction. Suitable reducing agents used for the above chemical reduction include metals (eg zinc, zinc amalgam etc.) or chromium compound salts (eg chromium chloride, chromium acetate etc.) and organic acids (eg formic acid, acetic acid, propionic acid). , Trifluoroacetic acid, p-toluenesulfonic acid) or inorganic acids (eg hydrochloric acid, hydrobromic acid, etc.)
Is a combination of.

Further, as a suitable catalyst used for the catalytic reduction, a palladium-based catalyst (for example, palladium sponge, palladium black, palladium oxide, palladium-charcoal,
Colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, palladium hydroxide-charcoal, etc., nickel-based catalysts (for example, reduced nickel, nickel oxide, Raney nickel, etc.), platinum-based catalysts (platinum plate, platinum sponge, platinum black, colloid) Examples include conventional catalysts such as platinum, platinum oxide, platinum wire, etc.). This reduction is preferably carried out in the vicinity of neutrality.

This reaction adversely affects reactions such as water, alcohols (eg methanol, ethanol, propanol etc.), dioxane, tetrahydrofuran, acetic acid, buffer solutions (eg phosphate buffer, acetate buffer etc.) etc. In conventional solvents, or mixtures thereof. The reaction temperature is not particularly limited, but it is usually performed under cooling or heating. The elimination reaction can be selected depending on the type of carboxy protecting group to be eliminated. Manufacturing method 2B :

[0041]

[Chemical 11]

Wherein R ¹ , R ² , R ⁶ and A are as defined above and R ⁷ _a means a protected carboxy group. This reaction is substantially the same as the above-mentioned production method 2A. As the suitable salts of the compounds (V) and (Ib), those exemplified for the compound (I) may be referred to. Manufacturing method 3A :

[0043]

[Chemical 12]

Where R ¹ , R ² and R ⁴ are as previously defined. Compound (Ic) or a salt thereof is produced by reacting compound (Ia) or a reactive derivative thereof at a carboxy group or a salt thereof with compound (VI) or a reactive derivative at an imino group thereof or a salt thereof. be able to. Compound (I
Suitable reactive derivatives at the carboxy group of a) include the same ones as exemplified in the above-mentioned production method 1.

The preferred reactive derivative at the imino group of the compound (VI) can be appropriately selected from the reactive derivative at the amino group exemplified in the above-mentioned production method 1. As for suitable salts of the compounds (Ia), (VI) and (Ic), those exemplified for the compound (I) may be referred to. This reaction is usually performed in the presence of a base or a conventional condensing agent.

Suitable bases include alkali metal hydrides (eg sodium hydride, potassium hydride etc.), alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides ( For example, magnesium hydroxide, calcium hydroxide, etc., alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates (eg, hydrogen carbonate) Sodium, potassium hydrogen carbonate, etc.), alkali metal acetates (eg sodium acetate, potassium acetate etc.), alkaline earth metal phosphates (eg magnesium phosphate,
Inorganic bases such as calcium phosphate), alkali metal hydrogen phosphate (eg, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), trialkylamines (eg, trimethylamine, triethylamine, etc.), picoline, N
Examples include organic bases such as -methylpyrrolidine and N-methylmorpholine. As the suitable condensing agent, the same ones as exemplified in the above production method 1 can be mentioned.

This reaction is usually carried out in alcohol (eg methanol, ethanol etc.), benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether, or another solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited, but it is usually performed under cooling or heating. Manufacturing method 3B :

[0048]

[Chemical 13] (Wherein R ¹ , R ² , R ⁶ and A are as defined above,

[0049]

Embedded image

Means a heterobridged cyclic group having at least one nitrogen atom). This reaction is substantially the same as the above-mentioned production method 3A. Compound (Ib), (VII
) And (Id) as suitable salts, those exemplified for the compound (I) may be referred to. Next, a method for producing the starting material will be described below. Manufacturing method A

[0051]

[Chemical 15]

Where R ¹ , R ³ and X are as previously defined, and R ⁹ means a protected amino group.
Compound (X) or a salt thereof can be obtained by reacting compound (VIII) or a salt thereof with compound (IX) or a salt thereof. For details, refer to Production Example 1 and Production Example 6-2 described later. Manufacturing method B

[0053]

Embedded image

Where R ¹ , R ³ and R ⁹ are as previously defined. Compound (II) or a salt thereof can be obtained by subjecting compound (X) or a salt thereof to an elimination reaction of an amino-protecting group. Specifically, Production Example 2 described later
-2, 6-3 and 7-4 may be referred to. Manufacturing method C

[0055]

[Chemical 17]

Where R ¹ , R ³ and R ⁹ are as previously defined. Compound (X) or a salt thereof can be obtained by subjecting compound (II) or a salt thereof to an amino protection reaction. For details, refer to Production Example 6-1 described later.

The object compound (I) and pharmaceutically acceptable salts thereof are selective CCK-B antagonists. Furthermore,
The object compound (I) and pharmaceutically acceptable salts thereof have a gastrin antagonistic action and are also useful as therapeutic agents and / or preventive agents for ulcer, gastric hypersecretion, Zollinger-Ellison syndrome and the like. Be expected.

In order to clarify the usefulness of the objective compound (I), the pharmacological activity of its representative compound is shown below. [I] Test compound: N-[(3RS) -2,3-dihydro-1- (2-methylthioethyl) -5- (2-fluorophenyl) -2-oxo-1H-1,4-benzodiazepine-3. -Yl] -N '-(3-methylphenyl) urea [hereinafter referred to as test compound] [II] test: [ ¹²⁵ I] CCK-8 binding to guinea pig cerebral cortex membrane.

Test Method After decapitating and killing the guinea pig, the cerebral cortex was taken out,
It was put into a small amount of 50 mM Tris-HCl buffer (pH 7.4) and finely chopped. Add this to 20 volumes of buffer,
Homogenized with a glass-Teflon homogenizer.
The resulting strip was centrifuged at 30,000 xg (16000 rpm) for 10 minutes. The pellets obtained in this way were
The suspension was resuspended in the above buffer using a Teflon homogenizer and centrifuged at 30,000 xg for 10 minutes. This washing step was repeated two more times. The final pellet (membrane) thus obtained was suspended in the following incubation solution so that the final protein concentration would be 4 mg / ml, to give a membrane preparation. All of these series of operations are 0-4 ° C.
I went there. Incubation solution composition: 10 mM HEPES (pH 6.5) 5 mM MgCl ₂ 1 mM EGTA 130 mM NaCl 0.25 mg / ml bacitracin The obtained membrane preparation was frozen and stored (-80 ° C), and thawed before use.

(Ii) Receptor Binding Assay The membrane preparation (containing 400 μg of protein) contains or does not contain the above-mentioned test compound (1 × 10 ⁻⁶ M),
Incubation solution (500 μl) containing 50 pM ¹²⁵ I-CCK-8 in a plastic test tube at 37 ° C.
And incubated for 60 minutes with shaking. To measure non-specific binding, 1 μM CCK-8 was added. Each measurement was performed twice. The reaction was stopped by filtering the reaction mixture through a Whatman GF / B glass filter. After washing the filter with 50 mM Tris-HCl buffer (pH 7.4) containing 0.1% BSA (bovine serum albumin), the radioactivity of the filter was counted. The specific binding amount was calculated by subtracting the non-specific binding amount from the total binding amount. The effect of test compound is specific to ¹²⁵ I
The rate of inhibition (%) of CCK-8 binding was evaluated.

Test Results Inhibition rate (%): 98.5 The target compound (I) and its pharmaceutically acceptable salts are capsules, microcapsules, tablets, granules, powders, troches, syrups, aerosols, inhalants, solution,
It can be applied to mammals including human in the form of conventional pharmaceutical composition such as injection solution, suspension, emulsion and the like.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier such as various organic carriers or inorganic carriers. Such carriers include excipients such as sucrose, starch, mannitol, sorbit,
Lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binders (cellulose, methyl cellulose, hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, acacia, polyethylene glycol, sucrose, starch, etc.),
Disintegrants (eg starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium hydrogen carbonate, calcium phosphate, calcium citrate, etc.), lubricants (eg magnesium stearate, talc, sodium lauryl sulfate, etc.) ), Fragrances (eg citric acid, menthol, glycine, orange powder etc.), preservatives (eg sodium benzoate, sodium bisulfite, methylparaben, propylparaben etc.), stabilizers (eg citric acid, sodium citrate, etc.)
Acetic acid, etc.), suspending agents (eg methylcellulose, polyvinylpyrrolidone, aluminum stearate etc.), dispersants, aqueous diluents (eg water etc.), base waxes (eg cocoa butter, polyethylene glycol, white petrolatum etc.).

The dosage of the drug of the present invention depends on the type of dosage form,
It may be appropriately determined in consideration of the type of treatment, administration method, age and weight of patient, symptom of patient, etc., but the effective dose of the active ingredient is usually 0.01 mg / kg to 50 mg / kg. It is administered in the range of 1 to 4 times per day.

The following Production Examples and Examples are provided for the purpose of showing the present invention in more detail. Production Example 1 Sodium hydride (60% suspension of mineral oil, 0.22 g)
N, N-dimethylformamide (20 ml) suspension of (3RS) -2,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-1H-1 was added thereto while cooling in ice-cooling. , 4-Benzodiazepin-2-one (2.00 g) was added portionwise in a nitrogen atmosphere. The mixture was stirred under the same conditions for 0.5 hours and then at room temperature for 2 hours. The obtained mixed solution was cooled in an ice bath, and thereto, a solution of sodium iodide (0.82 g) and chloromethyl benzenesulfenate (0.87 g) in N, N-dimethylformamide (5 ml) was sequentially added. Added little by little. The mixture was stirred at the same temperature for 1 hour and then at room temperature overnight. Acetic acid (0.5
g) was added while cooling in an ice bath, and the residue obtained by concentration under reduced pressure was purified by column chromatography packed with silica gel (eluent: chloroform) to give (3RS) -2,3-dihydro as colorless solid crystals. -5- (2-fluorophenyl) -1-phenylsulfinylmethyl-3-
Phthalimide-1H-1,4-benzodiazepine-2-
On (2.03 g) was obtained. NMR (CDCl ₃ , δ): 5.23 (1H, m), 5.51 (1H, m), 5.
96 (1H, s), 7.00 ~ 7.60 (13H, m), 7.76 (2H, m), 7.9
2 (2H, m)

Production Example 2-1 The following compound (colorless solid crystal) was obtained in substantially the same manner as in Production Example 1. (3RS) -2,3-Dihydro-5- (2-fluorophenyl) -1- (2-methyl-2-propenyl) -3-
Phthalimide-1H-1,4-benzodiazepine-2-
ON NMR (DMSO-d ₆ , δ): 1.50 (3H, s), 4.47 (1H, d,
J = 15Hz), 4.72 (1H, s), 4.77 (1H, d, J = 15Hz), 4.80
(1H, s), 5.78 (1H, s), 7.2 ~ 8.1 (12H, m)

Production Example 2-2 (3RS) -2,3-dihydro-5- (2-fluorophenyl) -1- (2-methyl-2-propenyl) -3-
Phthalimide-1H-1,4-benzodiazepine-2-
On (860 mg) of tetrahydrofuran (30 ml)
While stirring the solution at room temperature, a tetrahydrofuran solution (3 ml) of hydrazine monohydrate (89 mg) was added dropwise thereto. The mixture was stirred at room temperature for 3 hours, then at the solvent reflux temperature for 1 hour, the obtained precipitate was filtered, and the filtrate was concentrated. Ethyl acetate (200 ml) was added to the residue to dissolve the residue, and the mixture was extracted with 1N hydrochloric acid (100 ml). The obtained aqueous layer was neutralized with sodium carbonate and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give (3RS) -3-amino-2,3-dihydro-5-as a colorless compound.
(2-Fluorophenyl) -1- (2-methyl-2-propenyl) -1H-1,4-benzodiazepin-2-one (380 mg) was obtained. NMR (DMSO-d ₆ , δ): 1.48 (3H, s), 4.41 (1H, s),
4.43 (1H, d, J = 15Hz), 4.67 (1H, s), 4.73 (1H, s),
4.74 (1H, d, J = 15Hz), 7.0 ~ 7.8 (8H, m)

Production Example 3 The following crude compound was obtained in substantially the same manner as in Production Example 1 and Production Example 2-2. The crude product was subjected to preparative thin layer chromatography to give one spot and was used in the next reaction without further purification. (3RS) -3-amino-2,3-dihydro-5- (2
-Fluorophenyl) -1- (2-methylthioethyl)
-1H-1,4-benzodiazepin-2-one

Production Example 4 The following crude compound was obtained in substantially the same manner as in Production Example 1 and Production Example 2-2. The crude product was subjected to preparative thin layer chromatography to give one spot and was used in the next reaction without further purification. (3RS) -3-amino-2,3-dihydro-1- (2
-Ethoxyethyl) -5- (2-fluorophenyl)-
1H-1,4-benzodiazepin-2-one

Production Example 5 The following compounds were obtained in substantially the same manner as in Production Example 1 and Production Example 2-2. (3RS) -3-amino-2,3-dihydro-5- (2
-Fluorophenyl) -1- (2-phenyl-2-propenyl) -1H-1,4-benzodiazepin-2-one NMR (CDCl ₃ , δ): 2.20 to 2.80 (2H, b), 4.58 (1
H, s), 4.80 (1H, d, J = 16Hz), 5.12 (1H, s), 5.39 (1
H, d, J = 16Hz), 5.47 (1H, s), 6.96 (13H, m)

Production Example 6-1 (3RS) -3-amino-2,3-dihydro-5- (2
-Fluorophenyl) -1H-1,4-benzodiazepin-2-one (7.66 g), triethylamine (9.
31 g) and a catalytic amount of hydroxylamine hydrochloride in methylene chloride (200 ml) with stirring at room temperature while di-tertiary butyl dicarbonate (9.31 g) was added thereto.
Methylene chloride (5 ml) solution of was added dropwise. After stirring this mixed solution for 4.5 hours under the same conditions, the solvent was distilled off and the obtained residue was dissolved in ethyl acetate and washed several times with water.
After drying this over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crystals. The crystals were treated with diethyl ether, collected by filtration, washed with ether and dried under reduced pressure to give (3RS) -3-tertiary butoxycarbonylamino-2,3-dihydro as white crystalline powder. -5
-(2-Fluorophenyl) -1H-1,4-benzodiazepin-2-one (10.13 g) was obtained. mp: 205-206 ℃ IR (nujol): 3330, 3180, 3060, 1700 (sh),
1670, 1605, 1510, 1481, 1450, 1397, 1365, 1330, 127
0, 1250, 1220, 1170, 1060, 1010, 958, 891, 819, 77
2, 756, 677 cm ^-1 NMR (CDCl ₃ , δ): 1.49 (9H, s), 5.33 (1H, d, J =
8.5Hz), 6.40 (1H, d, J = 8.5Hz), 6.95 ~ 7.75 (8H, m),
8.89 (1H, s) Mass (m / z): 370 (M ⁺ +1), 314, 253

Production Example 6-2 (3RS) -3-tertiary butoxycarbonylamino-
2,3-dihydro-5- (2-fluorophenyl) -1
H-1,4-benzodiazepin-2-one (738.0
(mg) was dissolved in dry dimethylformamide (10 ml), and then sodium hydride (9
2 mg) was added portionwise in several portions. After the addition was completed, the mixture was stirred at room temperature for 30 minutes, and after confirming that the bubbling of hydrogen gas was completed, it was ice-cooled again. In this solution, α
-Methyl bromophenylacetate (Purity: 97%, 566.
A solution of 8 mg) in dimethylformamide (1 ml) was added dropwise. After the completion of dropping, the mixture was stirred for 30 minutes under ice cooling. The mixture was further stirred at room temperature for 3 hours, the precipitated crystals were collected by filtration, washed with water and dried. The obtained crystalline powder was dissolved in chloroform and then purified by column chromatography packed with silica gel (eluent: chloroform). Fractions containing the target compound were combined and the solvent was distilled off under reduced pressure to give a foamy substance (3R
S) -1- (α-methoxycarbonylbenzyl) -3-
Tertiary butoxycarbonylamino-2,3-dihydro-
5- (2-Fluorophenyl) -1H-1,4-benzodiazepin-2-one (865.4 mg) was obtained.
This compound was used in the next reaction without further purification. IR (Film): 3400, 1745, 1710, 1682, 1605, 1
482, 1448, 1370, 1262, 1213, 1160, 754 cm ^-1 NMR (CDCl ₃ , δ): 4.46, 4.48 (9H, each s), 3.6
8, 3.86 (3H, each s), 5.41, 5.45 (1H, each d, J = eac
h 8.4Hz), 5.90, 6.17 (1H, each s), 6.40, 6.51 (1H,
each d, J = each8.4Hz), 6.95 ~ 7.75 (13H, m) Mass (m / z): 518 (M ⁺ +1)

Production Example 6-3 (3RS) -1- (α-methoxycarbonylbenzyl)
-3-Tertiary butoxycarbonylamino-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-
A solution of benzodiazepin-2-one (0.85 g) in methanol (16 ml) was stirred at room temperature while adding 4N thereto.
A solution of hydrogen chloride in ethyl acetate (6 ml) was added, and the mixture was stirred under the same conditions for 4 hours. Water and ethyl acetate were added to the residue obtained by evaporating the solvent under reduced pressure with vigorous stirring. A saturated aqueous solution of sodium hydrogen carbonate was added to this mixed solution to adjust the pH to 8. The separated organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give amorphous (3RS) -1- (α-methoxycarbonylbenzyl).
A diastereomeric mixture of -3-amino-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one (592.7 mg) was obtained. This compound was used in the next reaction without further purification. NMR (CDCl ₃ , δ): 2.32 (2H, broad), 3.74, 3.87 (3
H, each s), 4.64 (1H, broad), 5.91, 6.25 (1H, each
s), 7.0 ~ 7.7 (13H, m) Mass (m / z): 418 (M ⁺ +1)

Production Example 7-1 A solution of ethyl diethoxyphosphoryl acetate (12.45 g) in tetrahydrofuran (120 ml) was cooled in an ice bath under ice cooling.
With stirring, add sodium hydride (60% of mineral oil
Suspension, 2.23 g) was added in small portions. After the addition is complete
The mixture was stirred at room temperature for 0.5 hr, acetophenone (6.07 g) was added dropwise, and the mixture was refluxed for 2.5 hr with further stirring. Tetrahydrofuran was distilled off from this reaction mixture under reduced pressure, and water and ethyl acetate were added to the residue obtained with vigorous stirring. The separated organic layer and the extract from the aqueous layer were combined and washed twice with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a yellow oily substance. This was purified by distillation under reduced pressure to give an EZ mixture of ethyl 3-phenyl-2-butenoate (8.21 g) as a colorless oil. bp: 115 to 120 ° C./7 to 8 mmHg E: Z = 11: 1 (by NMR analysis) IR (Neat): 1710, 1624, 1440, 1340, 1270, 1160,
1040, 870, 764, 690 cm ^-1 NMR (CDCl ₃ , δ): 1.04, 1.32 [3H (1:11), each t,
J = 8.6Hz], 2.17, 2.58 [3H (1:11), each d, J = 1.5Hz,
1.3Hz], 3.99,4.21 [2H (1:11), each q, J = 8.6Hz], 5.9
1, 6.13 [1H (1:11), each q, J = 1.5Hz, 1.3Hz], 7.1-7.5
(5H, m) Mass (m / z): 191 (M ⁺ +1)

Production Example 7-2 EZ mixture of ethyl 3-phenyl-2-butenoate (1.90 g) and N-bromosuccinimide (2.14)
To a solution of g) in carbon tetrachloride (50 ml) was added a catalytic amount of benzoyl peroxide (60 mg). The mixture was refluxed for 10 hours with stirring.

After the precipitate thus obtained was filtered off, the filtrate and the washing solution were combined and the solvent was distilled off to obtain an oily substance. This oily substance was purified by column chromatography packed with silica gel (eluent: n-hexane). Fractions containing the desired compound were combined and the solvent was removed under reduced pressure to an EZ mixture of ethyl 4-bromo-3-phenyl-2-butenoate as a colorless oil (about 10: 1 by NMR analysis. , 1.67 g) was obtained. IR (Neat): 1705, 1620, 1574, 1490, 1445, 1365,
1340, 1281,1215, 1170, 1140 (sh), 1046, 1017, 87
9, 766,690 cm ^-1 NMR (CDCl ₃ , δ): 1.32, 1.34 [3H (1:10), each t,
J = 7.1Hz], 4.21, 4.26 [2H (1:10), each q, J = 7.1Hz],
4.98 (2H, s), 6.14, 6.21 [1H (1:10), t, s, J = 1.3Hz],
7.25 ~ 7.6 (5H, m) Mass (m / z): 269 (M ⁺ ), 271 (M ⁺ +2)

Production Example 7-3 The following compound (amorphous) was obtained in substantially the same manner as in Production Example 6-2. (3RS) -1- (E-2-phenyl-3-ethoxycarbonyl-2-propenyl) -3-tertiary butoxycarbonylamino-2,3-dihydro-5- (2-fluorophenyl) -1H-1 , 4-benzodiazepin-2-one IR (film, cm ^-1 ): 3410, 1701, 1672, 1624, 1
605, 1490, 1448, 1368, 1214, 1170, 1020, 750 NMR (CDCl ₃ , δ): 1.35 (3H, t, J = 7.1Hz), 1.45
(9H, s), 4.28 (2H, q, J = 7.1Hz), 5.19 (1H, d, J = 8.5H
z), 6.07 (2H, ABq, J = 16.5Hz, 59.8Hz), 6.16 (1H, s),
6.45 (1H, d, J = 8.5Hz), 6.84 ~ 7.7 (13H, m) Mass (m / z): 558 (M ⁺ +1)

Production Example 7-4 (3RS) -1- (E-2-phenyl-3-ethoxycarbonyl-2-propenyl) -3-tertiary butoxycarbonylamino-2,3-dihydro-5- (2 A solution of -fluorophenyl) -1H-1,4-benzodiazepin-2-one (1.82g) in trifluoroacetic acid (20ml) was stirred in an ice bath for 0.5 hours and then at room temperature for another 1 hour. It was stirred. After trifluoroacetic acid was distilled off under reduced pressure, the obtained residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and further washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a solid. After treating this with diisopropyl ether,
The crystals were collected by filtration to obtain white crystalline powder (3R
S) -1- (E-2-phenyl-3-ethoxycarbonyl-2-propenyl) -3-amino-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine-2 -On (1.36 g) was obtained. This compound was used in the next reaction without further purification. mp: 151-153 ° C IR (nujol): 3380, 3300, 1703, 1677, 1624,
1604, 1575, 1460 (sh), 1448, 1370, 1180, 1038, 88
7, 770, 760, 700 cm ^-1 NMR (CDCl ₃ , δ): 1.36 (3H, t, J = 7.1Hz), 2.45
(2H, s), 4.29 (2H, q, J = 7.1Hz), 4.42 (1H, s), 6.11
(2H, ABq, J = 16.7Hz, 49.9Hz), 6.17 (1H, s), 6.55 ~
7.7 (13H, m) Mass (m / z): 458 (M ⁺ +1)

Example 1 (3RS) -3-Amino-2,3-dihydro-5- (2-fluorophenyl) -1-phenylsulfinylmethyl-1H-1 was prepared in substantially the same manner as in Preparation Example 2-2. , 4
-Benzodiazepin-2-one was obtained, which was then treated in substantially the same manner as in Example 4 without purification to give the following compound. N-[(3RS) -2,3-dihydro-5- (2-fluorophenyl) -1-phenylsulfinylmethyl-2
-Oxo-1H-1,4-benzodiazepin-3-yl] -N '-(3-methylphenyl) urea mp: 194-195 ° C IR (KBr): 3344, 1681, 1648, 1560, 1485 cm ^-1 NMR. (DMSO-d ₆ , δ): 2.23 (3H, s), 5.27 (1H, d,
J = 7.0Hz), 5.44 (1H, d, J = 13Hz), 5.89 (1H, d, J = 13H
z), 6.73 (1H, d, J = 7.0Hz), 7.08 ~ 7.82 (17H, m), 8.9
0 (1H, s)

Example 2 The following crude product was obtained in substantially the same manner as in Example 4. This was purified by flash chromatography packed with silica gel [eluent (chloroform: ethyl acetate = 10: 1)] and crystallized from chloroform-diisopropyl ether to give a white solid. N-[(3RS) -2,3-dihydro-5- (2-fluorophenyl) -1- (2-methyl-2-propenyl)
-2-oxo-1H-1,4-benzodiazepine-3-
Il] -N '-(3-methylphenyl) urea mp: 196-197 ° C IR (KBr): 3330, 1679, 1649, 1612, 1560, 1486,
1449 cm ^-1 NMR (DMSO-d ₆ , δ): 2.24 (3H, s), 4.47 (1H, d,
J = 17Hz), 4.71 (1H, s), 4.78 (1H, d, J = 17Hz), 4.78
(2H, s), 5.30 (1H, d, J = 10Hz), 6.74 (1H, d, J = 9Hz),
7.0 ~ 7.8 (12H, m), 9.00 (1H, s)

Example 3 The following compound was obtained in substantially the same manner as in Example 4. N-[(3RS) -2,3-dihydro-1- (2-methylthioethyl) -5- (2-fluorophenyl) -2-
Oxo-1H-1,4-benzodiazepin-3-yl]
-N '- (3- methylphenyl) urea mp: 233 ~236 ℃ IR (KBr ): 3311, 1674, 1643, 1561, 1491 cm -1 NMR (DMSO-d 6, δ): 1.96 (3H, s) , 2.23 (3H, s), 2.4
3 (1H, m), 2.50 (1H, m), 4.00 (1H, m), 4.45 (1H, m),
5.25 (1H, d, J = 6.0Hz), 6.73 (1H, d, J = 6.0Hz), 7.08
~ 7.80 (12H, m), 8.94 (1H, s) Mass (m / z): 476 (M ⁺ ) C ₂₆ H ₂₅ FN ₄ O ₂ S: (theoretical value) C. 65.53%, H. 5.29%, N. 1
1.76% (actual value) C. 64.93%, H. 5.25%, N. 11.51%

Example 4 (3RS) -3-amino-2,3-dihydro-1- (2
-Ethoxyethyl) -5- (2-fluorophenyl)-
1H-1,4-benzodiazepin-2-one (400m
To a solution of g) in dry methylene chloride (20 ml) was added dropwise a solution of 3-methylphenylisocyanate (172 mg) in dry methylene chloride (5 ml) at room temperature under a nitrogen atmosphere. After stirring this mixed solution at room temperature overnight, the obtained precipitate was collected by filtration to obtain a crude product. This was recrystallized from a mixed solution of methylene chloride and diisopropyl ether and purified to obtain a colorless crystalline solid. When this was dried under reduced pressure, N-[(3RS) -2,3-dihydro-1- (2-ethoxyethyl) -5- (2-fluorophenyl) -2-oxo-1H-1,4-benzodiazepine- 3-yl] -N '-(3-methylphenyl) urea (340 mg) was obtained. mp: 220-222 ° C (decomposition) IR (KBr): 3310, 1674, 1644, 1614, 1489 cm ^-1 NMR (DMSO-d ₆ , δ): 0.90 (3H, t, J = 7Hz), 2.24 (3
H, s), 3.27 (2H, m), 3.40 (2H, t, J = 5Hz), 3.98 (1H, m),
4.40 (1H, m), 5.26 (1H, d, J = 10Hz), 6.74 (1H, d, J = 10H
z), 7.08 ~ 7.80 (12H, m), 8.98 (1H, s)

Example 5 The following compound was obtained in substantially the same manner as in Example 4. N-[(3RS) -2,3-dihydro-5- (2-fluorophenyl) -1- (2-phenyl-2-propenyl) -2-oxo-1H-1,4-benzodiazepine-
3-yl] -N '-(3-methylphenyl) urea mp: 205-207 ° C IR (KBr): 3314, 1678, 1650, 1614, 1561, 1492,
1450,1211 cm ^-1 NMR (DMSO-d ₆ , δ): 2.14 (3H, s), 4.90 (1H, d,
J = 18Hz), 5.10 (1H, s), 5.30 (1H, d, J = 8Hz), 5.42 (1
H, d, J = 18Hz), 5.48 (1H, s), 6.74 (1H, d, J = 8Hz),
6.92 ~ 7.85 (17H, m), 8.95 (1H, s) Mass (m / z): 520 (M ⁺ +2), 412 (M ⁺ -106) C ₃₂ H ₂₇ FN ₄ O ₂ : (theoretical value) C. 74.11%, H. 5.25%, N. 1
0.80% (actual value) C. 73.75%, H. 5.31%, N. 10.61%

Example 6 In substantially the same manner as in Example 4, the following diastereomeric mixture (4: 1 to 5: 1 by NMR analysis, white crystalline powder) was obtained. N-[(3RS) -2,3-dihydro-1- (α-methoxycarbonylbenzyl) -5- (2-fluorophenyl) -2-oxo-1H-1,4-benzodiazepine-
3-yl] -N ′-(3-methylphenyl) urea mp: 208-212 ° C. (decomposition) IR (nujol, cm ⁻¹ ): 3310, 1746, 1678, 1645,
1610, 1560, 1488, 1450, 1374, 1210, 1165, 770, 72
4,690 NMR (CDCl ₃ , δ): 1.43, 1.67 (3H, each s), 3.6
8, 3.82 (3H, each s), 5.70, 5.73 (1H, each d, J = 8.1
Hz), 5.93 ~ 6.13 (1H, each s), 6.8 ~ 7.75 (19H, m) Mass (m / z): 551 (M ⁺ +1)

Example 7 The following compound was obtained in substantially the same manner as in Example 4. N-[(3RS) -2,3-dihydro-1- (E-2-
Phenyl-3-ethoxycarbonyl-2-propenyl)
-5- (2-fluorophenyl) -2-oxo-1H-
1,4-benzodiazepin-3-yl] -N '-(3-
Methylphenyl) urea mp: 251 to 253.5 ° C IR (nujol): 3300, 1700, 1670, 1641, 1610,
1560, 1510, 1490, 1459 (sh), 1447, 1375, 1295, 121
5, 1185, 1025,880, 772, 750 (sh), 695 cm ^-1 NMR (DMSO-d ₆ ,, δ): 1.30 (3H, t, J = 7.1Hz), 2.23
(3H, s), 4.25 (2H, q, J = 7.1Hz), 5.14 (1H, d, J = 8.4
Hz), 5.95 (2H, ABq, J = 15.7Hz, 29.8Hz), 6.19 (1H,
s), 6.41 (1H, t, J = 6.1Hz), 6.74 (1H, d, J = 6.2Hz),
7.0 ~ 7.65 (16H, m), 8.91 (1H, s) Mass (m / z): 591 (M ⁺ +1)

Example 8 N-[(3RS) -2,3-dihydro-1- (α-methoxycarbonylbenzyl) -5- (2-fluorophenyl) -2-oxo-1H-1,4-benzodiazepine-
3-yl] -N '-(3-methylphenyl) urea (53
5.6 mg) of diastereomeric compound was suspended in a mixture of methanol (22 ml) and tetrahydrofuran (8 ml) at room temperature while stirring, and 1N sodium hydroxide (3.6 ml) was added thereto. . The mixture was stirred under the same conditions overnight and then 1N sodium hydroxide (1.
2 ml) was added and the mixture was further stirred for 8 hours.

From this reaction mixture, methanol and tetrahydrofuran were distilled off under reduced pressure to obtain an aqueous solution. 2N in this solution
After adding hydrochloric acid to make the mixture acidic, the mixture was extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give an oily substance. This was purified by column chromatography packed with silica gel [eluent: a mixture of chloroform and methanol (20: 1)]. After the fractions containing the desired compound were combined, the solvent was distilled off under reduced pressure to obtain N-
[(3RS) -2,3-Dihydro-1- (α-carboxybenzyl) -5- (2-fluorophenyl) -2-oxo-1H-1,4-benzodiazepin-3-yl]-
Diastereomeric mixture of N '-(3-methylphenyl) urea (NMR analysis 10: 1, 358.6 m
g) was obtained. mp: 236-236.5 ℃ (decomposition) IR (nujol): 3320, 1650, 1605, 1550, 1375,
1214, 750, 692 cm ^-1 NMR (DMSO-d ₆ , δ): 1.90, 2.24 (3H, each s), 5.
32 (1H, d, J = 8.6Hz), 5.79, 6.17 (1H, each s), 6.7
~ 8.0 (19H, m), 8.98, 9.13 (1H, each s)

Example 9 Using the compound obtained in Example 7, the following compound (crystalline powder) was obtained in substantially the same manner as in Example 8. N-[(3RS) -2,3-dihydro-1- (E-2-
Phenyl-3-carboxy-2-propenyl) -5-
(2-Fluorophenyl) -2-oxo-1H-1,4
-Benzodiazepin-3-yl] -N '-(3-methylphenyl) urea mp: 217 to 218 ° C (decomposition) IR (nujol): 3300, 2800 to 2300 (br), 1670,
1638, 1609, 1550, 1490, 1448, 1375, 1321, 1215, 11
60, 765,690 cm ^-1 NMR (DMSO-d ₆ , δ): 2.23 (3H, s), 5.15 (1H, d,
J = 8.4Hz), 6.06 (2H, ABq, J = 15.9Hz, 14.9Hz), 6.09 (1
H, t, J = 6.8Hz), 6.21 (1H, s), 6.73 (1H, d, J = 7.0H
z), 6.7 ~ 7.6 (16H, m), 8.03 (1H, d, J = 8.4Hz), 9.01
(1H, s) Mass (m / z): 563 (M ⁺ +1)

Example 10 N-[(3RS) -2,3-dihydro-1- (α-carboxybenzyl) -5- (2-fluorophenyl) -2
-Oxo-1H-1,4-benzodiazepin-3-yl] -N '-(3-methylphenyl) urea (188.5
a solution of 1-hydroxybenzotriazole (5 mg) and pyrrolidine (30 mg) with stirring at room temperature.
6.9 mg), 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride (80.7 mg)
And triethylamine (42.6 mg) were sequentially added.
The mixture was stirred overnight under the same conditions and then at 80 ° C. for another hour. The reaction mixture thus obtained was poured into water and adjusted to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted twice with ethyl acetate, the obtained extract was washed with water and then dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography packed with silica gel (eluent: chloroform).
Purified in. Fractions containing the desired compound were combined and evaporated to an oil to give an oil (163.8 mg). Treatment of this oil with cyclohexane gave N-[(3RS) -2,3-dihydro-1 as a white crystalline powder.
-[Α- (1-pyrrolidinylcarbonyl) benzyl]-
5- (2-fluorophenyl) -2-oxo-1H-
1,4-benzodiazepin-3-yl] -N '-(3-
Diastereomeric mixture of methylphenyl) urea (NM
According to R analysis, 15: 1,85 mg) was obtained. mp: 182-1835 ℃ IR (nujol): 3325, 1650, 1608, 1549, 1481,
1372, 1326, 1210, 770, 750, 695 cm ^-1 NMR (DMSO-d ₆ , δ): 1.82 (4H, br), 2.24 (3H,
s), 2.96 (1H, br), 3.56 (3H, br), 5.31 (1H, d, J = 8.
5Hz), 6.43 (1H, s), 6.76 (1H, d, J = 8.5Hz), 7.05 ~
7.75 (17H, m), 8.98 (1H, s) Mass (m / z): 590 (M ⁺ +1)

Example 11 The following compound was obtained in substantially the same manner as in Example 10. N-[(3RS) -2,3-dihydro-1- {E-2-
Phenyl-3- (3-azabicyclo [3.2.2] non-3-yl) carbonyl-2-propenyl} -5- (2
-Fluorophenyl) -2-oxo-1H-1,4-benzodiazepin-3-yl] -N '-(3-methylphenyl) urea mp: 170.5 to 172 ° C IR (nujol): 3300, 1673, 1641, 1610 , 1560,
1450, 1375, 1212, 765, 690 cm ^-1 NMR (DMSO-d ₆ , δ): 1.62 (8H, br d), 1.99 (1H,
br s), 2.09 (1H, br s), 2.23 (3H, s), 3.3 to 3.45 (1
H, m), 3.5 to 3.7 (2H, m), 3.9 to 4.05 (1H, m), 5.13 (1
H, d, J = 8.4Hz), 5.52 (2H, ABq, J = 15.9Hz, 87.3Hz), 6.2
7 (1H, t, J = 6.2Hz), 6.57 (1H, s), 6.73 (1H, d, J = 6.2
Hz), 6.95 to 7.65 (15H, m), 7.85 (1H, d, J = 6.2Hz), 8.92 (1
H, s) Mass (m / z): 670 (M ⁺ +1)

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/55 AED (72) Inventor Katsumi Ikuyo 1-6-13 Ebie, Fukushima-ku, Osaka (72) Inventor Sato Yuichi 4-52 Nakanoshima-cho, Suita City

Claims (1)

[Claims] 1. Formula (I): [Wherein R ¹ is an aryl group optionally substituted by one or more suitable substituents, R ² is an aryl group optionally substituted by one or more suitable substituents, and R ³ is a lower group. Alkylthio (lower) alkyl group, lower alkoxy (lower) alkyl group, arylsulfinyl (lower) alkyl group, formula: (Wherein R ⁴ represents an aryl group, R ⁵ represents a carboxy group, a protected carboxy group or a pyrrolidinylcarbonyl group, respectively), or a group represented by the formula: (In the formula, R ⁶ is a lower alkyl group or an aryl group, R ⁷ is hydrogen, a carboxy group, a protected carboxy group,
Or a hetero-bridged ring carbonyl group having at least one nitrogen atom, A means a group represented by A) and a pharmaceutically acceptable salt thereof.