JPH06502620A - benzodiazepine derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Technical field This invention relates to novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof. and its use as a medicine.

Background technology Some benzodiazepine derivatives are described, for example, in European Patent Publication No. 349949. It is well known as described in U.S. Pat. No. 4,820,834.

Detailed description of the invention This invention relates to novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof. It is related to.

More specifically, the present invention is a cholecystokinin (CCK) antagonist; vomiting, pancreatitis, disorders of appetite control system, pain, insulinoma, gastroparesis, pancreatic Related to visceral cancer, gallbladder disease (acute cholecystitis, stones, etc.), intestinal smooth muscle hyperactivity Diseases (irritable bowel syndrome, sphincter spasms), hyperinsulinemia, indigestion, vomiting Novel benzodiazepine derivatives useful for the treatment and/or prevention of It relates to pharmaceutically acceptable salts thereof.

The benzodiazepine derivative according to the present invention can be represented by the following formula (I). .

E (I + 1. ni ° is 泽 yo'trio indicating τ1 and 91 (υgoodsu 亙 system; nest color) Yolkohan1〕Jo, R2 is a hydrogen atom or a halogen, R3 is an aryl group which may have one or more suitable substituents, and R4 is a suitable substituent. an aryl group which may have at least one group, an aryl group which may have one or more suitable substituents; (lower)alkenyl group, aryl which may have one or more suitable substituents Amino group, heteromonocyclic group which may have one or more suitable substituents, quinolyl group, i Soquinolyl group, cinnolinyl group, indolyl group, or quinoxalinyl group, and A represents a lower alkylene group. − However, when R4 is an indolyl group, (i) R' has one or more suitable substituents. R3 represents a herophenyl group, or (ii) R' is an imidazolyl group which may have one or more suitable substituents; 3 is a herophenyl group, and A represents ethylene.

According to the present invention, the novel benzodiazepine derivative (I) is represented by the following formula: It can be manufactured using a manufacturing method.

or in its amino group or its reactive derivative or its reactive derivative or its reactive derivative or its Their salts or their salts (I) or its salt (Ia) or its salt (Ib) or its salt Christmas Day (Ic) or its salt (Id) or its salt Manufacturing method A or its salt or its salt (I) or its salt Dharma Festival or its salt or its salt (If) or its salt In the formula, R', R'', R'', R' and A are the same as above, Represents a heterocyclic group having a mino group, and this heterocyclic group has one or more suitable substituents. This heterocyclic group may have one or more suitable substituents, R7 a has an al(lower) alkenyl group having a nitro group, and R'b has an amino group Al(lower) alkenyl group, and X represents an acid residue.

Starting materials (U) and (rV) can be produced by the following production method.

- modulo Δ (■) or its salt (II) or its salt election day (■) (■) or in its amino group or its reactive derivative or its reactive derivative or its reactive derivative or its These salts or those salts (TV) or its salt In the formula, R', R'', R'', R' and A are respectively the same as above, and R7 is a protected atom. Represents a mino group.

The starting material (■) or its salt is as described in Production Methods 1 to 3.6 and 7 below. method or a method similar thereto.

If the group has a tautomer, the group may have tautomers. The equilibrium of various tautomers can be expressed by the following equation.

Both of the above two tautomers are included within the scope of the present invention. This statement and request Compounds containing such tautomeric groups may conveniently be expressed as groups of formula (A). Let it be expressed in the following expression.

, the group may have tautomers, and such tautomers Equilibrium can be expressed as:

Both of the above two tautomers are included within the scope of the present invention. This statement and request Compounds containing such a tautomeric group may conveniently contain the group (C) within the scope of interest. Let us express it in terms.

Preferred pharmaceutically acceptable salts of the target compound (I) include substantially non-toxic salts. salts and alkali metal salts (e.g. sodium salts, potassium salts, etc.) metal salts, alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.) , ammonium salts, organic base salts (e.g. trimethylamine salt, triethylamine salt) salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N’-dibe organic acid salts (e.g. acetate, malate, alcohol stone salt, methanesulfonate, benzenesulfonate, formate, toluenesulfonate chlorates, trifluoroacetates), inorganic acid salts (e.g. hydrochlorides, bromates, sulfates), salts with amino acids (e.g. arginine salts, asparagine salts), salts with amino acids (e.g. arginine salts, asparagine salts, salts, glutamates, etc.).

In the above and in the description that follows in this specification, various definitions are given. All preferred examples are within the scope of this invention, and their details are described below. This will be explained below.

The term "lower" shall mean groups containing 1 to 6 carbon atoms, unless otherwise specified.

Preferred "heterocyclic groups" include oxygen, sulfur, nitrogen, etc. Included are saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing a ro atom.

Particularly preferred heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, imidazolyl , pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, Dihydropyridazinyl, tetrahydrobyridazinyl, triazolyl (even if 1. 2.4-triazolyl, LH-1,2,3-triazolyl, etc.), tetrazolyl (e.g. IH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazilyl (e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro Nitrogen containing 1 to 4 nitrogen atoms, such as Heteromonocyclic group consisting of a saturated 3- to 8-membered ring; for example, pyrrolidinyl, imidazolidinyl saturated 3- to 4-nitrogen atoms, such as Heteromonocyclic group consisting of an 8-membered ring; for example, indolyl, isoindolyl, indolini isoindolinyl, intridinyl, benzimidazolyl, quinolyl, iso Quinolyl, imidazolyl, benzotriazolyl, tetracylopyridyl, tetracysyl Lopyridazinyl (such as tetracylo[1,5-bl pyridazinyl), Condensation of unsaturation containing 1 to 5 nitrogen atoms, such as dorotriazolopyridazinyl, etc. heterocyclic groups such as oxasilyl, inoxasilyl, dihydroisoxa Silyl, oxadiazolyl (e.g. 1°2.4-oxadiazolyl, 1,3. 1-2 such as 4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) Heteromonocyclic group consisting of an unsaturated 3- to 8-membered ring containing 5 oxygen atoms; for example, morpholin Saturated 3- to 3- to 3- to 3- to 3- to 3-saturated nitrogen atoms containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as Heteromonocyclic group consisting of an 8-membered ring; for example, benzoxacylyl, benzoxadiazole An unsaturated condensed compound containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as lyle. heterocyclic groups such as 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl , thiadiazolyl (e.g. l, 2,4-thiadiazolyl, 1,3,4-thiadiazolyl) azolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.) What kind of unsaturated 3- to 8-membered ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms? A heteromonocyclic group consisting of; For example, 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiadiazolyldyl. Heteromonocyclic group consisting of a saturated 3- to 8-membered ring containing children; for example, one member such as furyl a heteromonocyclic group consisting of an unsaturated 3- to 8-membered ring containing an oxygen atom; Consists of an unsaturated 3- to 8-membered ring containing one sulfur atom, such as chenyl heteromonocyclic group; For example, one or two sulfur groups such as benzothiazolyl, benzothiadiazolyl, etc. An unsaturated fused heterocyclic group containing a nitrogen atom and 1 to 3 nitrogen atoms, such as: is included.

"Heterocyclic group which may have one or more suitable substituents" and "Heterocyclic group which may have one or more suitable substituents" As a preferable "substituent" in the term "heteromonocyclic group which may have the following is a protected amino acid, oxo, hydroxy, as exemplified below, Protected lower alkyls as shown (e.g. methyl, ethyl, propyl) , isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl , tertiary pentyl, hexyl, etc.).

Preferred "protected amino" includes acylamino and the like.

Preferred "protected iminos" include acyl, mono (or di or tri) ) phenyl (lower) alkyl (e.g. trityl), tetrahydropyranyl etc. are included.

As the preferred "acyl moiety" in the words "acyl" and "acylamino" includes aliphatic acyls and acyls containing aromatic or heterocycles.

Preferred examples of the acyl include lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (and For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cycarbonyl Chlopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarboyl Nyl, tertiary butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl (such as carbonyl); lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); benzenesulfonyl (e.g. benzenesulfonyl, tosyl), niaroyl (and For example, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indan carbonyl, etc.); al(lower) alkanoyl (e.g. phenylacetyl, carbonyl, etc.); phenylpropionyl); al(lower) alkoxycarbonyl (e.g. benylpropionyl); (dyloxycarbonyl, phenethyloxycarbonyl, etc.).

Acyl moieties such as those mentioned above are halogens (e.g. chlorine, bromine, fluorine and iodine) , amino, protected amino (e.g. lower alkanoylamino, phenylthio It may have one or more suitable substituents such as ureido, etc.).

Preferred "acid residues" include halogens and the like.

Preferred "halogens" include chlorine, bromine, fluorine and iodine.

Preferred “aryl” and [al(lower)alkenyl] and “arylami The "aryl moiety" in the word "ノ" includes phenyl, naphthyl, etc. Ru. "aryl which may have one or more suitable substituents", "aryl which may have one or more suitable substituents" "al(lower)alkenyl which may have at least one suitable substituent" and "al(lower)alkenyl which may have one or more suitable substituents" Preferred "substituents" in the term arylamino J that may have include Hydroxy, protected hydroxy such as those exemplified below, nitro, lower alkoxy (e.g. methoxy, ethoxy, propoxy, impropoxy, butoxy, (tertiary butoxy, pentyloxy, tertiary pendeloxy, hexyloxy, etc.) , Amino protected lower alkyl as exemplified above (e.g. methyl, ether) Chyl, propyl, isopropyl, isobutyl, secondary butyl, tertiary butyl, penyl pentyl, tertiary pentyl, hexyl, etc.), halogens such as those listed above. be caught.

The preferred "lower alkenyl moiety" in the term "al(lower) alkenyl" is vinyl, allyl, 1-propenyl, 1-12- or 3-butenyl, 1- ．． 2-. 3- or 4-pentenyl, 1-. 2-. 3-. 4- or 5-hexa Includes nil, etc.

Preferred "heteromonocyclic groups" include heterocyclic groups such as oxygen atoms, sulfur atoms, nitrogen atoms, etc. Included are saturated or unsaturated heteromonocyclic groups containing one or more terror atoms. Especially preferred Examples of heteromonocyclic groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrolyl, etc. Zolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazi Nyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (and For example, 1.2.4-triazolyl, LH-1,2,3-triazolyl, 2H-1, 2,3-)riazolyl), tetrazolyl (e.g. IH-tetrazolyl, 2 H-tetrazolyl), dihydrotriazinyl (e.g. 4,5-dihydro- 1,2,4-triazinyl, 2,5-dihydro-1,2,4-)riazinyl, etc. ), etc. A heteromonocyclic group consisting of an unsaturated 3- to 8-membered ring containing 1 to 4 nitrogen atoms, such as ; For example, pyrrolidinyl, imidazolidinyl, piperazinyl, etc. A heteromonocyclic group consisting of a saturated 3- to 8-membered ring containing 1 to 4 nitrogen atoms; for example, oxa Silyl, inoxasilyl, dihydroinoxasilyl, oxadiazolyl For example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1.2 ．． 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as 5-oxadiazolyl, etc. Heteromonocyclic group consisting of an unsaturated 3- to 8-membered ring containing atoms; for example, morpholinyl, etc. consisting of a saturated 3- to 8-membered ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as heteromonocyclic groups such as 1,3-thiazolyl, 1,2-thiazolyl, thiazolini thiadiazolyl (e.g. 1,2.4-thiadiazolyl, 1.3.4-thiadiazolyl) diazolyl, 1.2.5-thiadiazolyl, 1.2.3-thiadiazolyl, etc.) An unsaturated 3- to 8-membered ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as A heteromonocyclic group consisting of; For example, 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl. A heteromonocyclic group consisting of a saturated 3- to 8-membered ring containing one acid such as furyl, etc. A heteromonocyclic group consisting of a saturated 3- to 8-membered ring containing elementary atoms; For example, a hetero compound consisting of an unsaturated 3- to 8-membered ring containing one sulfur atom, such as chenyl. Monocyclic group; Examples include heteromonocyclic groups such as.

Preferred "lower alkylene" includes methylene, ethylene, trimethylene, and tether. Linear or branched such as tramethylene, pentamethylene, hexamethylene, etc. and those having 1 to 6 carbon atoms, particularly preferably 1 to 4 carbon atoms. carbon atoms.

As a more preferable "heterocyclic group" in the term "heterocyclic group having an imino group" is, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyryl. dazinyl, tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-t Riazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-)riazolyl ), tetrazolyl (e.g. IH-tetrazolyl, 2H-tetrazolyl), etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-triazinyl) 1-4, such as dinyl, 2,5-dihydro-1,2,4-triazinyl etc. Heteromonocyclic group consisting of an unsaturated 3- to 8-membered ring containing nitrogen atoms; for example, pyrrolidi 1 to 4 nitrogens such as nyl, imidazolidinyl, piperidyl, piperazinyl, etc. A heteromonocyclic group consisting of a saturated 3- to 8-membered ring containing atoms; etc. are included.

More preferred examples of the target compound (I) are as follows.

R' is a heterocyclic group (more preferably an unsaturated 3- to 8-membered group having 1 to 4 nitrogen atoms) a heteromonocyclic group consisting of a ring, most preferably tetrazolyl or imidazolyl) These may have ~3 (more preferably 1) suitable substituents. [more preferably tetrazolyl or imidazolyl, each of which is a protected imidazolyl] most preferably mono(di or tri)phenyl (lower ) tetrazolyl or imidazolyl which may have alkyl], or sia of; R2 is a hydrogen atom; R3 is an aryl group which may have 1 to 3 (more preferably 1) suitable substituents. (more preferably phenyl) [more preferably phenyl or herophenyl] ] ; R4 is an aryl group which may have 1 to 3 (more preferably 1) suitable substituents. (more preferably phenyl or naphthyl) [more preferably phenyl or naphthyl] naphthyl, each containing one or two selected from the group consisting of halogen and amino; optionally with substituents, most preferably naphthyl, dihalophenyl or halide phenyl having rogene and amino], 1 to 3 suitable substituents (more preferably Al(lower) alkenyl [more preferably phenyl(lower) alkenyl] class) alkenyl] [More preferably, it may have an amino group or a nitro group. phenyl (lower) alkenyl; most preferably nitrophenyl (lower) alkenyl; nyl or aminophenyl (lower) alkenyl], Aryl amine optionally having 1 to 3 (more preferably 1) suitable substituents (more preferably phenylamino) [more preferably lower alkyl or Phenylamino optionally containing rogene; most preferably lower alkylphenyl ruamino or herophenylamino], with 1 to 3 suitable substituents (more preferably is a heteromonocyclic group (more preferably pyridyl or tetra hydropyridazinyl) [more preferably having a pyridyl or oxo group good tetrahydropyridazinyl; most preferably pyridyl or with an oxo group; tetrahydropyridazinyl], Quinolyl, isoquinolyl, cinnolinyl, indolyl or quinoxalinyl and Beauty A is lower alkylene (more preferably C, -C4 alkylene), provided that R4 is When you are in drill, (i) R’ is tetrazolyl R3 is herophenyl, or (ii) R’ has mono(di or tri)-phenyl(lower) alkyl; imidazolyl, which may be R3 is herophenyl, A is ethylene.

The method for producing the object compound (I) and the starting materials of this invention will be explained in detail below.

Manufacturing method 1: Compound (I) or a salt thereof is a compound (n) or its reactivity at an amino group. a derivative or a salt thereof, and a compound (m) or a reactive derivative thereof or its salt; It can be produced by reacting these salts.

Preferred reactive derivatives of the amino group of compound (n) include aldehydes and Obtained by reacting a carbonyl compound such as a ketone with compound (II) Schiff salt-type imino or its enamine-type tautomer; silyl such as methylsilyl)acetamide, N-trimethylsilylacetamide, etc. Silyl derivative obtained by reacting a compound with compound (n); trichloride Derivatives etc. obtained by reacting phosphorus, phosgene, etc. with compound (n) is included.

Preferred salts of compound (n) and (I[[) include salts of compound (I); Examples can be mentioned.

Preferred reactive derivatives of compound (I[l) include acid halides, acid anhydrides, active These include natural amides, active esters, incyanates, etc. A good example of this is acid chlorides, acid azides; substituted phosphoric acids (e.g. dialkyl phosphates, phenyl phosphates); phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), di- Alkyl phosphites, sulfites, thiosulfates, alkanesulfonic acids (e.g. methane sulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonate, aliphatic carboxylic acid ( For example, bivaric acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloro (e.g. acetic acid) or aromatic carboxylic acids (e.g. benzoic acid) Acid anhydride; Symmetrical acid anhydride; Imidazole 54 snow exchange imidazole, dimethylpyrazo activated amides with triazoles, triazoles or tetrazoles; or activated esters ( For example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH-)2N=CH-1 ester, vinyl ester, propargyl ester para, paranitrophenyl ester, 2,4-dinitrophenyl ester, tric Lorophenyl ester, pentachlorophenyl ester, mesylphenyl ester phenylazophenyl ester, phenylthioester, paranitrophenyl ruthioester, paracresyl thioester, carboxymethyl thioester, Pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthio esters, etc.), or N-hydroxy compounds (e.g. N,N-dimethylhydro Roxylamine, 1-hydroxy-2-(LH)-pyridone, N-hydroxys succinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide 1-hydroxy-6-chloro-IH-benzotriazole, etc.) Formula R' -N=C=O (wherein R' may have one or more suitable substituents) This includes isocyanates represented by (representing aryl).

This reaction involves water, acetone, dioxane, acetonitrile, chloroform, and chloride. Methylene, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethyl Formamide, pyridine or other commonly used materials that do not adversely affect the reaction. It is usually carried out in a solvent. These conventional solvents may be mixed with water. do not have.

When compound (111) is used in the reaction as a free acid or its salt, the reaction The reaction is N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N '-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4- diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbo Diimide, N, N'-diisopropylcarbodiimide; N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide: N,N-carbonylbis-( 2-methylimidazole); pentamethyleneketene-N-cyclohexylimine ; diphenylketene-N-cyclohexylimine: ethoxyacetylene: 1-a Rukoxy-1-chloroethylene; trialkyl phosphorous acid; polyethyl phosphate; Isopropyl phosphate: phosphorus oxychloride (POCl, ): phosphorus trichloride; thiochloride oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxy Benzisoxazinium salt; 2-ethyl-5-(methasulfophenyl)isoo Inner salt of xazolium hydroxide; 1-(parachlorobenzenesulfonyloxy )-6-chloro-LH-benzotriazole; thionyl chloride, phosgene, oxy Obtained by reacting phosphorus chloride with N,N-dimethylformamide. It is preferably carried out in the presence of a conventional condensing agent, such as Vilsmeier's reagent.

This reaction involves alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine It can also be carried out in the presence of an inorganic or organic base such as. Reaction temperature is controlled However, it is usually carried out under cooling or heating.

Folding: Compound (Ib) or a salt thereof is an imino protecting group of compound (Ia) or a salt thereof. It can be produced by causing an elimination reaction. Preferred method for this reaction includes common reactions such as hydrolysis, reduction, etc.

(i) Hydrolysis: Hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.

Preferred bases include alkali metals (e.g. sodium, potassium, etc.) hydroxides or carbonates or bicarbonates, trialkylamines (e.g. trimene). thylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo[4 ,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, ■, inorganic bases such as 8-diazabicyclo[5,4,0]undec-7-ene, etc. and organic bases.

Preferred acids include organic acids such as formic acid, acetic acid, propionic acid, trichloro acetic acid, trifluoroacetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid) , hydrogen chloride, hydrogen bromide, etc.).

Such as trihaloacetic acids (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) The elimination reaction using isic acid is performed using a cation scavenger (e.g. anisole, phenol). etc.) is preferably carried out.

This reaction involves water, alcohol (e.g. methanol, ethanol, etc.), N.

N-dimethylformamide, methylene chloride, tetrahydrofuran, mixtures thereof Presence of solvents such as solvents or other solvents that do not adversely affect this reaction Usually done below. Liquid bases and acids can also be used as solvents. reaction The temperature is not critical, and it is usually carried out under cooling or under heating.

(ii) Reduction: Reduction is carried out according to conventional methods including chemical reduction and catalytic reduction. For chemical reduction The preferred reducing agents used are metals (e.g. tin, zinc, iron, etc.) or compounds (e.g. chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g. chromium chloride, chromium acetate, etc.) Formic acid, acetic acid, propionic acid, trifluoroacetic acid, para-toluenesulfonic acid, salt acid, hydrobromic acid, etc.).

Preferred catalysts used for catalytic reduction include platinum-based catalysts (e.g. platinum). platinum foil, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum palladium-based catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium carbon, colloidal palladium, palladium - barium sulfate, palladium - barium carbonate, etc.), nickel-based catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt-based catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron-based catalysts (reduced iron, Raney iron, etc.), etc.), copper-based catalysts (e.g. reduced copper, Raney copper, Ullmann copper, etc.). Examples include catalysts for Reduction can be done using water, methanol, ethanol, propatool, N,N-dimethylformamide, tetrahydrofuran, or mixtures thereof It is usually carried out in a conventional solvent which does not adversely affect the reduction reaction.

If the above acids used in chemical catalysts are in liquid form, they can be used as a solvent. It can also be used.

The reaction temperature for this reduction is not critical, and it is usually carried out under cooling or heating.

Manufacturing method: Compound (Id) or a salt thereof can be obtained by subjecting compound (Ic) or a salt thereof to a reduction reaction. It can be manufactured by This reduction reaction was carried out in the same manner as in Production Method 2 above. It can be done.

Luxury beans: Compound (I) or a salt thereof is a combination of compound (IV) or a salt thereof and compound (V) or can be produced by reacting its salts.

Preferred salts of compounds (IV) and (V) include, for example, the salt of compound (1). Salts such as those shown can be mentioned.

This reaction is usually carried out in the presence of a base. - Preferred bases include alkaline Potassium metal hydrides (e.g. sodium hydride), alkali metal hydroxides ( (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.) (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g. (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetates (such as (e.g., sodium acetate, potassium acetate, etc.), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal phosphorus hydrogen salts Inorganic bases such as (disodium hydrogen phosphate, dicalcium hydrogen phosphate, etc.) , and trialkylamines (e.g. trimethylamine, triethylamine) ), picoline, N-methylpyrrolidine, N-methylmorpholine, etc. Contains bases.

This reaction involves alcohols (e.g. methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or is usually carried out in a conventional solvent such as any other solvent that does not adversely affect the reaction. It will be done.

The reaction temperature for this reaction is not critical (it is usually carried out under cooling or heating.

Commentary: Compound (If) or a salt thereof is a combination of compound (Ie) or a salt thereof and compound (V 1) or a salt thereof.

Preferred salts of compounds (re) and (If) include salts of compound m (I) Salts such as those exemplified can be mentioned.

Preferred salts of compound ('/I) include alkali metal salts (e.g. sodium salt, potassium salt, etc.).

This reaction consists of 1-methyl-2-pyrrolidinone, N,N-dimethylformamide, Dichloromethane, ethylene chloride or others that do not adversely affect the reaction This is usually carried out in a conventional solvent such as a solvent such as .

The reaction temperature for this reaction is not critical (it is usually carried out with or without heating).

Manufacturing Δ The compound (formerly or its salt) is a compound (■) or its salt whose amino protecting group is removed by reaction. It can be obtained by making it correspond.

Preferred salts of compound (■) include those exemplified as the salt of compound (I). can be lost.

Elimination reactions include hydrolysis, reduction, Edman method (phenylinthiocyanate method), etc. This can be done according to any conventional method. For hydrolysis, acids or bases may Examples include methods using hydrazine and the like. These methods depend on the type of protecting group. is selected and the withdrawal is performed.

Among these methods, substituted or unsubstituted alkoxycarbonyl, e.g. Tertiary pentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl) ), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl Rubonyl, aralkyl (e.g. trityl), substituted phenylthio, substituted substituted aralkylidene, substituted alkylidene, interchanged cycloalkylidene The most common and preferred method for removing protecting groups such as This is the solution.

Preferred acids include formic acid, trifluoroacetic acid, benzenesulfonic acid, paratol Contains organic or inorganic acids such as ensulfonic acid, hydrochloric acid, etc. The best acids are vacuum Acids that can be easily removed from the reaction mixture by conventional methods such as distillation, e.g. These include formic acid, trifluoroacetic acid, and hydrochloric acid. These acids are the protecting groups that are removed. are selected depending on the type of

The elimination reaction using trifluoroacetic acid may be carried out in the presence of anisole.

Hydrolysis using hydrazine removes phthaloyl and succinyl type amino protecting groups. Generally used when

Detachment using a base is useful when removing acyl groups such as trifluoroacetyl. used. Preferred bases include inorganic bases and organic bases.

Reductive elimination can be performed, for example, on haloalkoxycarbonyls (e.g. trichloroethoxy carbonyl), substituted or unsubstituted aralkoxycarbonyl (e.g. (2-pyridyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. It is commonly used when leaving. Preferred reduction methods include, for example, hydrogen Boronide reduction with alkali metals (e.g. sodium borohydride), gold genus (e.g. tin, zinc, iron, etc.) or their metals and metal salt compounds (e.g. chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g. acetic acid, (propionic acid, hydrochloric acid, etc.); and catalytic reduction.

Preferred catalysts include conventional catalysts such as Raney nickel, platinum oxide, palladium oxide, This includes um-carbon, etc.

Among the protective groups, the acyl group can generally be removed by hydrolysis. especially , halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl groups are copper Desorption is usually accomplished by treatment with heavy metals such as , zinc, etc.

This reaction can be performed using water, chloroform, methylene chloride, alcohol (e.g. methanol), water, ethanol, etc.), tetrahydrofuran, or other materials that do not adversely affect this reaction. The process is normally carried out in a conventional solvent such as other solvents.

The reaction temperature is not limited and may be appropriate depending on the type of amino protecting group and the above-mentioned removal method. You can choose the method according to your needs, but usually it is done under cooling or gentle heating (mild). carried out under conditions. Among the protecting groups, the acyl group derived from α-amino acid is It can be removed using the Edman method.

sudden departure Compound (TV) or its salt reacts with compound (■) or its amino group. a reactive derivative or a salt thereof, and a compound (In) or a reactive derivative thereof or can be produced by reacting their salts.

This reaction is carried out in substantially the same manner as Production Process 1, and therefore the reaction method and reaction For the applicable conditions, refer to Manufacturing Method 1 above.

The target compound (I) and its pharmaceutically acceptable salts are CCK antagonists; Therefore, it is useful as a therapeutic agent for vomiting, pancreatitis, etc.

Furthermore, the objective compound (I) and its pharmaceutically acceptable salts are gastrin antagonists. It is expected to have an effect on ulcers, gastric hypersecretion, Zollinger-El It is also expected to be useful as a treatment and/or preventive drug for lison syndrome, etc. .

In order to clarify the usefulness of target compound (1), the pharmacological activities of representative compounds are shown below. show.

[I] Test compound: (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-[(E) -3-(2-aminophenyl)propenoylamino]-5-(2-fluorophe )-28-1,4-benzodiazepine-2-one dihydrochloride [hereinafter referred to as test compound Object A].

[Test 11: CCK receptor antagonism in isolated guinea pig gastric fundus cylinder.

■Narrow way Ring tube strips obtained from guinea pig stomachs were soaked in Kreves' bicarbonate solution (NaC 1; 118mM, KCI; 4.8mM, KH, PO4; 1.2mM.

MgSO4; 1.2mM, CaC1z; 2.5mM%NaHCO3; 2 5mM, glucose; 11mM and bovine serum albumin; 0.1%). The cells were suspended in an organ culture bath kept at 37°C and aerated with 95% 0□ and 5% CO2. Ta.

The strip was equilibrated for 60 minutes at an initial tension of 0.5 g, during which time the bath contents were changed every 15 minutes. It was replaced with Equiaxial muscle contraction was measured using a force transducer. . CCK-8 (3,2 x 10-'M) was added to the bath solution and the contraction force was measured.

After washing and removing CCK-8, the test muscle was released for approximately 15 minutes until the contractile force reached a plateau. Test compound A (IXIO-'M) was then added, and after 5 minutes CCK-8 was added to measure the muscle contraction force. CCK antagonism is observed in the absence of test compound A. It was calculated by comparing the muscle contraction force induced by CCK in the presence of CCK.

”Gatenephew − Suppression rate (%): 89.9 The objective compound (I) and its pharmaceutically acceptable salts can be prepared in capsules, microorganisms, etc. capsules, tablets, granules, powders, troches, syrups, aerosols, inhalers, solutions In the form of conventional pharmaceutical compositions such as liquids, injections, suspensions, emulsions, herbal medicines, etc. can be applied to mammals including humans, but the most preferred form of administration is injection. It is a liquid.

The pharmaceutical composition of this invention contains various organic or inorganic carriers. (Such carriers include excipients such as sucrose, starch, salt, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate binders (cellulose, methyl cellulose, hydrocarbon, etc.), binders (cellulose, methyl cellulose, Xypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic.

polyethylene glycol, sucrose, starch), disintegrants (e.g. starch, carbon carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydride Roxypropyl starch, sodium glycol starch, sodium bicarbonate calcium phosphate, calcium citrate, etc.), lubricants (such as stearin), magnesium acid, talc, sodium lauryl sulfonate, etc.), sweeteners (such as e.g. citric acid, menthol, glycine, orange powder, etc.), preservatives (e.g. Sodium benzoate, sodium bisulfite, methylparaben, propylparaben stabilizers (e.g. citric acid, sodium citrate, acetic acid, etc.), suspending agents (e.g. citric acid, sodium citrate, acetic acid), agents (e.g. methylcellulose, polyvinylpyrrolidone, aluminum stearate) dispersants, aqueous diluents (e.g. water), base waxes (cocoa butter, etc.), dispersants, aqueous diluents (e.g. water), -, polyethylene glycol, white petrolatum, etc.).

This active ingredient is usually administered at a dose of 0.01 mg/kg to 50 mg/kg. kg is administered 1-3 times per day.

The preparations and examples below are merely for the purpose of illustrating the invention in more detail. It is given.

Yasuhiro Ashi 1 (3R3)-3-phthalimido-5-(2-fluorophenyl)-1,3-dihydrogen Dro-28-1,4-benzodiazepin-2-one (21,17 g), N - dimethylformamide (400 ml) solution under nitrogen atmosphere while cooling in a water bath. Sodium hydride (2.0 g, 60% suspension in mineral oil) was added in portions. Mixed liquid The mixture was stirred for 0.5 hour under the same conditions and further stirred for 1 hour at room temperature. Cool the mixture in a water bath Then, to this was added chloroacetonitrile (3,48 ml) of N,N-dimethylforma. Mido (5 ml) solution was added dropwise. Stir the mixture at the same temperature for 1 hour and then at room temperature overnight. did. Acetic acid (3.5 g) was added to the reaction mixture under cooling, and the resulting mixture was diluted with ethyl acetate. and water with stirring. Add the mixture to an aqueous solution of sodium bicarbonate. The pH was adjusted to 7.5. Filter the formed crystals and wash with chilled ethyl acetate. and (3RS)-3-phthalimido-1-cyanomethyl-1,3-dihydro- 5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one ( 20.9 g) was obtained.

mp: 260℃ (decomposition) IR (Nujol): 2160.1776, 1725.1700.1604 cm” NMR (DMSO-d6.δ): 5.15 (2H, ABq, J =24.6Hz, 17.8t(z), 5.83(LH,s).

7.2-8.1 (12H, m) Ai Kendan (3R3)-3-phthalimido-1-cyanomethyl-1,3-dihydro-5=( 2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (20, 0g), sodium azide (8,43g) and triethylamine hydrochloride (8,43g) 92g) in N-methyl-2-pyrrolidone (350ml) was stirred. Heated at 145°C for 3.5 hours. After cooling to room temperature, the mixture was diluted with 5% hydrochloric acid (50% 0 ml) and then cooled. The formed precipitate is collected by filtration, washed several times with cold water, and reduced. When dried under pressure with pentoxide, (3RS)-3-phthalimide-1゜3- Dihydro-5-(2-fluorophenyl)-1[(LH-tetrazol-5-y ) methyl]-28-1,4-benzodiazepin-2-one (18,07 g) Obtained.

IR (Nujol): 1778.1?20.1693.1610 cm-' NMR (DMSO-d,, δ): 5.46 (2H, s), 5.85 (IH ,s), 7.2-8.0 (13H, m) Production Example 1 (3R5)-3-phthalimido-1,3-dihydro-5-(2-fluorophenyl )-1-((IH-tetrazol-5-yl)methylgo2H-1,4-ben Zodiazepin-2-one (18,07g) and trityl chloride (10,99g) was dissolved in N,N-dimethylformamide (330 ml), and triethyl A solution of amine (4.6 g) in N,N-dimethylformamide (LOML) was added to a water bath. The mixture was added under stirring while cooling. Stir the mixture at the same temperature for 20 minutes and then at room temperature overnight. did. Pour the reaction mixture into ice water (500 ml), collect the formed precipitate by filtration, and then add to water. After washing and drying over pentoxide under reduced pressure, (3R3)-3-phthalimide-1, 3-dihydro-5-(2-fluorophenyl)-1-[(1-trityl-IH- Tetrazol-5-yl) methylgol 2H-1,4-benzodiazepine-2-o (33.41 g) was obtained as a white powder.

IR (Nujol): 1778.1?23.1695.1610 crn- 'NMR (DMSO-d, δ): 5.56 (2H, ABq, J=16. 0Hz, 52.6Hz), 5.80 (IH, s).

6, 8-8.1 (27H, m) Manufacturing example A (3R3)-3-phthalimido-1-[(1-trityl-IH-tetrazole- 5-yl)methyl]-5-(2-fluorophenyl)-1,3-dihydro-2 H-1,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran (500 ml) P, hydrazine hydrate (1.90 g) was added to the suspension while stirring at room temperature. added. The mixture was stirred at the same temperature for 2 hours, and then refluxed for 2 hours with further stirring. anti The reaction mixture was cooled in a water bath, and the formed precipitate was filtered off. Combine filtrate and washing solution and evaporate The dried residue was stirred in ethyl acetate and filtered. Combine the filtrate and washing solution. When evaporated and dried, (3R3)-3-amino-1,3-dihydro-5-(2- fluorophenyl)-1-[(1-trityl-IH-tetrazol-5-yl) methyl]-28-1,4-benzodiazepin-2-one (14,43 g) was obtained.

IR (Nujol): 3350.1686.1597.760.700a m”NMR (CDCI,, δ): 2.95 (2H, br sL 4.62 (IH, s).

5.42 (2H, ABq, J: 19.6Hz, 15.8Hz), 6.8~7 ．． 6 (23H, m) execution sentence 2 The following compound was obtained in the same manner as in Production Example 4.

(3R3)-3-amino-1,3-dihydro-5-phenyl-1-[(1-tri methyl-IH-tetrazol-5-yl)methyl]-2F(-1,4-benzodia Zepin-2-one mp: 132-135℃ IR (Nujol): 3375.1680.1595.1575.1560 cm” NMR (CDC1, d, δ): 2.72 (2H, s), 4.55 (IH, s), 5.46 (2H, ABq, J=16Hz, 51Hz), 6 ．． 90-6.70 (6H, m), 7.15-7.50 (18H, m) Production example (3RS)-3-amino-1,3-dihydro-5-(2-fluorophenyl)- 1-[(1-trityl-IH-tetrazol-5-yl)methyl]-2H-1 , 4-benzodiazepin-2-one (11,54 g) and N-tertiary butoxycarp Bonyl-phenylalanine (5°42g) in N,N-dimethylformamide 76g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt The acid salt (3.91 g) and triethylamine (2.36 g) were heated to room temperature. I added it one by one. Stir the mixture at the same temperature for 4.5 hours, then add water (1 ．． 5 liters).

The mixed solution was adjusted to pH 8 with an aqueous sodium hydrogen carbonate solution, and the precipitate formed was collected by filtration and added to water. After washing and drying with pentoxide under reduced pressure, (3R)-3-[((2 S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino ]゛-1,3-dihydro-5-(2-fluorophenyl)-1-((1-) -Rhythyl-IH-tetrazol-5-yl)methylgo-2H-1,4-benzodi Azepin-2-one and (3S)-3-[((2S)-2-tert-butoxy cyclocarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro -5-(2-fluorophenyl)-1- [(1-) lythyl-IH-tetrazo 5-yl)methyl]-28-1.4-benzodiazepin-2-one (16.29 g) was obtained.

mp: 108-114℃ (decomposition) IR (Nujol): 3330, 1700, 1690, 1675.　 1610 am”NMR (DMSO-d6, δ): 1.28 (9H, s) , 2.65-2.9 (LH, m), 3.0-3.2 (LH, m).

4, 40 (LH, m), 5.33-5.41 (28, m), 5.39, 5. 40 (IH, eachd, J=8Hz), 5.58 (2H, ABq, J =16.8Hz, 82.2Hz).

6, 8-7.95 (14H, m), 9.25, 9.37 (IH, each d, J=8Hz) (3R)-3-[((2S)-2-tertiary-butoxycarbonylamino=3 -phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophore) phenyl)-1-[(1-1-lythyl-IH-tetrazol-5-yl)methy Lugault 2H-1.4-benzodiazepine-2-one and (3S)-3-[( (2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl) Amino]-1.

3-dihydro-5-(2-fluorophenyl)-1-[(1-trityl-LH -tetrazol-5-yl)methyl]-28-1.4-benzodiazepine-2- A mixture of (16.2 g) and 4N hydrochloric acid solution in ethyl acetate (200 ml) The mixture was stirred at room temperature for 5 hours. This mixture was concentrated under reduced pressure, and the residue was dissolved in methanol. (100 ml) and neutralized with ammonia in ethanol solution. This mixture was concentrated under reduced pressure and dried. This was used as an eluent (CHCl.:CH.OH=10 :1) was subjected to silica gel packed column chromatography. Target compound The fractions containing diisopropyl are combined and evaporated to dryness to give an amorphous mass, which is converted to When suspended in ether and collected by filtration, (3S)-3-[((2S)- 2-amino-3-phenylpropanoyl)amino]-1,3-dihydro-5- (2-fluorophenyl)-1-[(LH-tetrazol-5-yl)methyl Go2H-1,4-benzodiazepin-2-one (4.57 g) was obtained.

NMR (DMSO-d., δ): 2.91 (LH, dd, J=14. OHz. 8.4Hz), 3.20 (LH, dd, J≠SHz.

14, 0Hz), 4.13 (IH, dd, J=4Hz.8.4Hz), 5.26 (2H, ABQ.

J=15.4Hz, 31.6Hz), 5.39(IH, d, J=8.0 Hz), 7.1-7.35 (IOH, m), 7.52-7.66 (4H, m) , 7.96 (IH, d, J = 8.4Hz) 9.77 (LH, d, J: 8. 0Hz) When the fractions containing other target compounds are combined and evaporated to dryness, an amorphous mass is obtained. , when this is suspended in diisopropyl ether and collected by filtration, (3R)'- 3-[((2s)-2-amino-3-phenylpropanoyl)amino]-1,3 -dihydro-5-(2-fluorophenyl)-1-[(IH-tetrazole-5 -yl)methyl] -2H-1,4-benzodiazepin-2-one (4,76 g )was gotten.

NMR (DMSO-d,, δ): 3.0-3.17 (LH, m), 3.5 7-3.64 (IH, m), 3.0-4.1 (2H.

broad), 4.21 (IH, t, J=4.2Hz), -5,19 (2H , ABq.

J=15.6Hz, 70.1Hz), 5.38(LH, d, J=8.3H z), 7.16-7.4 (IOH, m), 7.51-7.67 (4H, m) , 7.97 (LH, d, J=8.2Hz).

9.78 (LH, d, J=8.3Hz) Execution Day <3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino ]-1,3-dihydro-5-(2-fluorophenyl)-1-[(LH-tetra sol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4 , 57g) and triethylamine (Q, 974g) in a dry tetrahydrofuran solution. Phenyl isothiocyanate was added to the solution in Lan (45 ml) under stirring at room temperature. (2.54 g) was added. This mixture was stirred at room temperature for 2 hours and then at 50'C for 1 hour. After stirring, IN-hydrochloric acid (9.64 ml) was added to the reaction mixture under cooling. Mixed liquid Concentration under reduced pressure gave a residue, which was extracted with ethyl acetate. Wash the extract twice with water and dried using magnesium sulfate. The amorphous mass obtained by removing the solvent under reduced pressure ( 7.23g) was powdered by stirring in diisopropyl ether for 3 hours. did. The resulting powder was collected by filtration and washed with diisopropyl ether to give (3 S)-3-[((2S)-2-(N'-(phenyl)thioureido)-3-ph phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl) )-1-[(LH-tetrazol-5-yl)methyl]-2H-1,4-ben Zodiazepin-2-one (5.63 g) was obtained.

The product obtained above was suspended in tetrahydrofuran (35 ml), and 4N-salt was added thereto. A solution of the acid in ethyl acetate (33.5 ml) was added dropwise while cooling with ice. Add this mixture at 5 o'clock. Stir for 3 hours and evaporate to dryness under reduced pressure to obtain a viscous oil, which is dissolved in ethyl acetate for 3 hours. It was washed by stirring for a while. The obtained powder was collected by filtration and dried under reduced pressure ( 3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1- [(LH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepi ion-2-one hydrochloride (2.91 g) was obtained.

[α] 30° = + 36.36’″ (C = 0.495. CH, OH) The following compound was obtained in the same manner as in Production Example 8.

(3R)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1 -[(LH-tetrazol-5-yl)methyl]-2H-1,4-benzodiaze Pin-2-one hydrochloride.

[α] 30° = + 33.46° (C = 0.505. CH30H) Theory of theft conviction (3RS)-3-amino-1,3-dihydro-5-(2-fluorophenyl)- 28-1,4-benzodiazepin-2-one (2,0 g) in methylene chloride (30 g) ml) suspension was cooled in a water bath and stirred with triethylamine (1.61 g). dripped. Add 2-naphthoyl chloride (1.52 g) to this mixture under the same conditions. was added and stirred at the same temperature for 2 hours. The formed precipitate is collected by filtration and treated with methylene chloride or and water. When the collected crystals are dried with pentoxide under reduced pressure, (3R S)-3-(2-naphthoylamino)-5-(2-fluorophenyl)-1,3 -dihydro-2H-1,4-benzodiazepin-2-one (2.33 g) was obtained. It was.

NMR (DMSO-d,, δ): 5.60 (IH, d, J = 7.71 (z ), 7.22-7.39 (5H, m), 7.54-7.6U (5H, m), 7.99-8.11 (4H, m), 8.72 (IH, s).

9.74 (LH, d, J=7.7Hz), 11.05 (LH, m) MASS (m/e): 423 (M”) Manufacturing example top soil The following compound was obtained in the same manner as in Production Example 10.

m (3R5)-3-(3-quinolylcarbonylamino')-5-(2-fluoro lophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one IR (Nujou): 3600.1695.1670.1610.1590 ．． 1515 cm-'NMR (DMSO-d,, δ): 5.59 (LH, d , J=7.6Hz), 7.23-7.40 (5H, m).

7.61-7.76 (4H, ml, 7.67-7.94 (IH, m), 8.1 ~8.16 (2H.

ml, 9.09 (IH, s), 9.40 (IH, d, J = 2.1Hz), 10.1 (IH, d, J=7.6Hz), 11.08 (LH, 5) (2) (3RS)-3-(3,4-dichlorobenzoylamicar 5-(2-”fluorocarbon lophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one NMR (DMSO-d, δ): 5.49 (IH, d, J = 7.6Hz) , 7.2-8.02 (llH, +n), 8.21 (IHCs).

9.93 (LH, d, J=7.6Hz), 11.03 (LH, s) MASS (m/e) + 442 (M”) Large example (3S)-1,3-dihydro-5-(2-fluorophenyl)-3-amino-1 -[(1-tritylimidazol-4-yl)methyl]-2H-1,4-benzo diazepin-2-one (1.0 g) in N,N-dimethylformamide (10 m l) To the solution, (E)-3-(2-nitrophenyl)propenoic acid (330 mg), 1-Hydroxybenzotriazole (230 mg), N-ethyl-N'-(3 -dimethylaminopropyl)carbodiimide hydrochloride (320mg) and Torie Thylamine (170 mg) was added sequentially with stirring at room temperature. This mixture is heated for 3 hours. Stir 1 and set aside overnight. Stir the reaction mixture into the ethyl acetate and water mixture. The separated organic phase was washed twice with water and then dried. Remove the solvent under reduced pressure. Upon removal, an amorphous residue was obtained, which was purified by column chromatography packed with silica gel. It was purified by matography using chloroform as the eluent. The fraction containing the target substance When combined and evaporated to dryness, an amorphous mass is obtained, which is crushed and diisopropyl Stir in ether for several hours. Filter collection, washing with diisopropyl ether and when dried under reduced pressure, (3S)-1,3-dihydro-1-[(1-trithi limidazol-4-yl)methyl]-3-[(E)-3-(2-nitrophe propenoylamino]-5-(2-fluorophenyl)-2H-1,4 -Benzodiazepin-2-one (1.16 g) was obtained.

NMR (CDCI,, δ): 5.07 (28, brs), 5.66-5 ．． 7 (IH, m), 6.49-8.14 (32H, +n) Kashidendan The following compound was obtained according to the same method as in Example 1.

(1) (3S)-1,3-dihydro-1-[(1-tritylimidazole-4- yl)methyl]-3-[(2-amino-4-chlorobenzoyl)amino]-5 -(2-fluorophenyl)-28-1,4-benzodiazepin-2-one NMR (CDCI, δ): 5.06 (2H, d, J = 3.7Hz), 5.62-5.68 (3H, ml.

6, 63-8.04 (29H, m) MASS (m/e): 502(M”-2431(2)(3RS)-1,3- Dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-[ (2,3,4,5-tetrahydro-3-year-old xopyridazin-6-yl)carbonyl Ruamino”J-5-(2-fluorophenyl)-2H-1,4-benzodiaze Pin-2-one (3) (3R3)-1,3-dihydro-1-[(1-trityl- midazol-4-yl)methyl]-3-(3,4-dichlorobenzoylamino )-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-o NMR (CDC1,, δ): 5.02 (LH, d, J=15Hz), 5.12 (IH, d, J=15Hz).

5.67 (LH, d, J near, 8Hz), 6.85-8.04 (298, m) (4) (3RS)-1,3-dihydro-1-[(1-tritylimidazole- 4-yl)methyl]-3-(3-quinolylcarbonylamino)-5-(2-ph (fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (CDC 1,, δ): 5.01-5.18 (2H, m), 5.78 (IH, d, J=7.8Hz), 6.87~8.26(30H,m), 8.72(it( , d, J=1.9Hz), 9.44 (LH, d, J=2.2Hz) MAS S (m/e): 504 (M”-243), 424 (5) (3R3)-1,3- Dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-( 2-quinoxalinylcarbonylamino)-5-(2-fluorophenyl)-2H -1,4-benzodiazepin-2-one (6) (3R8)-1,3-dihydro- 1-[(1-tritylimidazol-4-yl)methyl]-3-(4-cinnoly Nylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-ben Zodiazepine-2-one NMR (CDC1, δ): 5.09 (2H, s) , 5.80 (LH, d, J=7.8Hz), 6.116~8.09 (2 8HCm).

8.4'J-8,66 (2H, m), 9.54 (IH, 5) (7) (3RS ) -1,3-dihydro-1-[(1-tritylimidazol-4-yl)methy ]-3-(1-isoquinolylcarbonylamino)-5-(2-fluorophore )-2H-1,4-benzodiazepin-2-one NMR (CDC1, δ) : 5.11 (2H, s), 5.78 (LH, d, J=8.3Hz), 6 ．． 89-7.89 (28H, m)B 8.05 (IH, d, J=8.2Hz), 8.59 (LH, d, J=5. 5Hz), 9.52-9.56 (LH, m), 9.93 (LH, d, J: 8.2Hz)(8)(3R3)-1,3-dihydro-1-[(1-tritylimi dazol-4-yl)methyl]-3-nicotinoylamino-5-(2-fluoro phenyl)-28-1,4-benzodiazepine-2-one NMR (CDCI) 2. δ): 4.99-5.16 (4H, m), 5.71 (IH, d, J= 7.7Hz).

6, 85-9.18 (28H, m) Great Nagiden (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl ) methyl]-3-amino-5-(2-fluorophenyl)-2H-1,4-be Add trichloride to a solution of nzodiazepin-2-one (1.0 g) in methylene chloride (10 ml). Ethylamine (340 mg) and 2-naphthoyl chloride (320 mg) were added sequentially. added. This mixture was stirred for 1.5 hours, and the reaction mixture was washed with water and dried. solvent Removal under reduced pressure yielded an amorphous residue, which was packed with silica gel. It was purified by column chromatography using chloroform as an eluent. object Combining the fractions containing the oil and evaporating to dryness yields an oil, which is then dried under reduced pressure. (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl ) methyl] -3-(2-naphthoylamino)-5-(2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (1,21 g) was obtained.

NMR (CDC1, δ): 5.03 (2H, d, J=15Hz), 5. 15 (2H, d, J=15Hz), 5.79 (IH, dB J=8Hz), 6.89-8.07 (29H, m), 8.22 (IH, d, J=8Hz).

8.47 (IH, s) It is difficult to apply (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl ) methyl]-3-amino-5-(2-fluorophenyl)-2H-1,4-be Solution of nzodiazepin-2-one (1.5 g) in tetrahydrofuran (23 ml) To this, methatolyl isocyanate (0.35 g) was added at room temperature with stirring. this The mixture was stirred under the same conditions for 2 hours. The crude product is obtained by removing the solvent from the reaction mixture under reduced pressure. By recrystallizing this from ethyl acetate and tetrahydrofuran, pure (3 R3)-1,3-dihydro-1-[(1-tritylimidazol-4-yl)methyl Chil]-3-[3-(3-methylphenyl)ureido]-5-(2-fluoro Lophenyl)-2H-1,4-benzodiazepin-2-one (1,47 g) was obtained. It was done.

NMR (DMSO-d, δ): 2.24 (3H, s), 4.85 (IH, d, J=14JHz), 5.24-5.33 (2H.

01), 6.67-7.68 (29H, m), 7.91 (IH, d, J= 8.2Hz).

8,97 (IH,s) 衷し伍田 Iron powder (1.1g) and ammonium chloride (0.13g) are mixed with water (2.5ml). (3S)-1,3-dihydro -1-[(1-)lythylimidazol-4-yl)methyl]-3-[(E)- 3-(2-nitrophenyl)propenoylamino]-5-(2-fluorophenylamino) -2H-1,4-benzodiazepin-2-one (1.1 g) was added under stirring. The mixture was added dropwise and refluxed. Added ethanol (7.5 ml) and water (2.5 ml) Thereafter, the mixture was refluxed for 1.5 hours while stirring. Filter the reaction mixture through Celite. The filtrate was washed several times with warm ethanol. Reduce ethanol from filtrate and wash solution Removed under pressure. A saturated aqueous solution of sodium bicarbonate (100 ml) was added to the residual mixture. was added and extracted with ethyl acetate (loOml). Washed with water and dried with magnesium condensate sulfate The extract was evaporated to dryness to give an amorphous residue, which was evaporated with diisopropyl ether. (3S)-1,3-dihydro-1-[ (1-tritylimidazol-4-yl)methyl]-3-[(E)-3-(2 -aminophenyl)propenoylamino] -5-(2-fluorophenyl)- 2H-1,4-benzodiazepin-2-one (0.98 g) was obtained.

NMRfcDcl,, δ): 3.71-4.07 (2H, br d), 5 ．． 06 (2H, s), 5.68 (LH, d, J = 8Hzj.

6, 47-7.99 (32H, m) IMss (m/e): 476 (M”-260) Kashidendan- (3S)-1,3-dihydro-1-[(1-tritylimidazol-4-yl) methyl]-3-[(E)-3-(2-aminophenyl)propenoylamino] -5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-o (0.49 g) in N,N-dimethylformamide (4.9 ml), N-hydrochloric acid (3.4 ml) was added with stirring while cooling in a water bath. 50% of this mixture The mixture was warmed to ℃ and stirred for 1 hour. After cooling to room temperature, water and acetic acid were added to the reaction mixture. Ethyl was added under stirring. Adjust this mixture to pH 8 with an aqueous sodium hydrogen carbonate solution. I arranged it. The separated organic phase is washed with water, dried and the solvent is removed under reduced pressure to obtain a The crystalline residue was ground up and stirred in diisopropyl ether for several hours. filtration collection After washing with diisopropyl ether and drying under reduced pressure, (3S)-1,3- dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-amino phenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1 4-Benzodiazepin-2-one (350 mg) was obtained.

A solution of the product obtained above in chloroform (10 ml) was added with ethyl acetate of 20% hydrochloric acid under cooling. Nord solution (5 ml) was added. The resulting yellow transparent solution was dried under reduced pressure to remove the residue. It was ground and stirred in diisopropyl ether for several hours. Then filter collection, diiso After washing with propyl ether and drying under reduced pressure, (3S)-1,3- Dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-ami nophenyl)propenoylamino]-5-(2-fluorophenyl)-2H- 1. Yellow powder (234 mg) of 4-benzodiazepine-2-one dihydrochloride was obtained. It was.

IR (Nujol): 3650~3050.270 (1~2150.166 0.1605 cm-'NMR (CDC1,, δ): 3.8-4.8 (2H , b), 5.15-5.56 (3H, ml, 7.04-7.81 (18H.

ml, 9.03 (LH, s), 9.43 (LH, d, J = 8Hz) MAS S (m/e): 494 (M"-73), 476% Following a method similar to Example 6, the following compound was obtained.

(1) (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-[ (2-amino-4-chlorobenzoyl)amino]-5-(2-fluorophenyl )-2H-1,4-benzodiazepine-2-one mp: 180-220℃ (Disassembly) IR (Nujol): 3500-3000.1675.1640 cm-1 HMR (CDCIs, δ): 4.93 (IH, d, J=15Hz), 5. 20 (LH, d, J = 15Hz), 5.25-5.69 (3H, ml, 6 ．． 62-6.67 (2H, m), 6.98-7.26 (6H, m).

7.4 (1-7.69 (5H, m), 7.89-7.91 (2H, m) MAS S (a+/e): 502 (M”) (2) (3RS)-1,3-dihydro -1-(4-imidazolylmethyl)-3-[(2,3,4,5-tetrahydro- 3-year-old xoviridazin-6-yl)carbonylamino]-5-(2-fluoro phenyl)-2H-1,4-benzodiazepine-2-one dihydrochloride mp: 230-240℃ (decomposition) IR (Nujol): 36513-3050.2650.2200.167 0.1610.1500 cm-'NMR (DMSO-d,, δ): 2.4 1-2.88 (4H, m), 5.20 (IH, d, J=16Hz), 5. 42 (IH, dB J=16Hzl, 5.43 (LH, d, J near, 8Hz), 7.15-7. 78 (9H, m).

8.58 (IH, d, J=7.8Hz), 9.02 (IH, s). 11.3 1 (LH, s).

14.67 (IH, br　s) MASS (m/e): 393 (M”-153) (3) (3RS)-1,3- Dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobenzoi Ruamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-one hydrochloride IIIp: 212-230°C (decomposition) IR (Nujol) : 3650.3150.2650 to 2000.1650.1600.1510 crn-'NMR (DMSO-d, δ): 5.20 (IH, d, J=1 6Hz), 5.43 (LH, d, J=16Hz), 5.61 (LHB d, J = 7.3Hzl, 7.19-7.82 (IOH, ml, 7.98 (L H, dd, J: 2Hz.

8Hz), 8.30 (LH, d, J=2Hz), 9.02 (LH, d, J=1.2Hz).

10.0 (IH, d, J=9.4Hz), 14.64 (IH, br s) N IASS (m/e) +521 (M”-37), 441 (4) (3R3)-1, 3-dihydro-1-(4-imidazolylmethyl)-3-(3-quinolylcarbonyl Ruamino”) -5-(2-fluorophenyl)-2H-1,4-benzodiaze Pin-2-one dihydrochloride mp: 230-233°C (decomposition) IR (Nujol): 3600-3100.2700-2100.1670 ．． 1610.1510 crn-'NMR (DMSO-d,, δ): 5.2 4(1)1. d, J=16Hz), 5.47(1)1. d, J=16 ．． 1) 1z), @5.71 (LH.

d, J=7.2Hz), 7.2-8.39 (13H, m), 9.05 (L H, d, J = 1.1Hz).

9.48 (LH, d, J: 1.8Hz), 9.60 (IH, d, J = 2H z), 10.36 (LH.

d, J4.2Hz), 14.72 (IH, br s) MASS (m/e): 504(M”-73), 424(5)(3RS)-1,3-dihydro-1-(4 -imidazolylmethyl)-3-(2-quinoxalinylcarbonylamino)-5- (2-Fluorophenyl)-2H-1,4-benzodiazepine-2-one hydrochloride mp: 205-220℃ (decomposition) IR (Nujol): 3B00~3050.2700~2000.1670 ．． 1600 cm-'NMR (DMSO-da, δ): 5.25 (LH, d , J=16.1Hz), 5.48 (IH, d, J:16.1Hz), 5 ．． U8 (1)1. d, J=7.8)1z), 7.18-8.35 (13H, m), 9.04 (LH, s).

9.53-9.61 (2H, m), 14.63 (LH, m) MASS (m/e ): 505(M′″-36), 425(6)(3RS)-1,3-dihydro -1-(4-imidazolylmethyl)-3-(4-cinnolinylcarbonylamine/ )-5-(2-fluorophenyl)di2H-1,4-benzodiazepine-2-o Nihydrochloride mp: 215-230℃ (decomposition) IR (Nujol): 3600-3100.2700-2100.1660 ．． 1610 cm-'NMR (DMSO-d,, δ): 5.21-5.72 (3)1. m), 7.18-8.61 (13H, m), 9.01 (IH, s ) B 9.48 (11(,s), 10.46(LH,d, J=7.1)1z), 14Jl (LH,br　s)MASS　(m/e)　:　505　(M”-73 ), 448(7)(3RS)-1,3-dihydro-1-(4-imidazolyl methyl)-3-(1-isoquinolylcarbonylamino)-5-(2-fluorophore (enyl)-2H-1,4-benzodiazepine-2-one dihydrochloride mp: 209 ~220℃ (decomposition) IR (Nujol): 3B00~3200.2700~2100.1670.1 610 cm-'NMRfDMsO-d,, δ): 5.2-5.55 (2H , ml, 5.67 (LH, d, J = 7.71 (z), 7.23 ~ 8.1X (13H, m), 8.67 (IH, d, J=5.6Hz), 9.03 (L H,s), 9.19 (LH.

d, J=8.4Hz), 9.9 (IH, d, J=7.7Hz), 14 ．． 62 (LH,br　s)MASS　(m/e)　:　504　(M”-73) , 424(8)(3RS)-1,3-dihydro-1-(4-imidazolylmethane) chill)-3-nicotinoylamino-5-(2-fluorophenyl)-2H-1, 4-Benzodiazepine-2-one dihydrochloride mp: 220-235℃ (decomposition) NMR (DMSO-d,, δ): 5.21(l)l, d, J=16.1 1 (z), 5.45 (IH, d, J: 16.IHz), @5.64 (LH, d, J near, 2Hz), 7.2-8.0 (IH, m), 8.76-9 ．． 04 (2H.

ml, 9.32 (LH, s), 10.32 (IH, d, J = 7.2Hz) .

14, 67 (IH, br　s) MASS (m/e): 454 (M”-73) (9) (3RS)-1,3-di Hydro-1-(4-imidazolylmethyl)-3-(2-naphthoylamino)- 5-(2-fluorophenyl)-2H-1゜4-benzodiazepine-2-one salt Acid acid mp: 220-230℃ (decomposition) IR (Nujol): 3600~3050.2800~2000.1690 ．． 1660.1610 cm-'NMR (DMSO-d,, δ): 5.22 (IH, d, J=16Hz), 5.45 (LH, d, J=16Hz), 5.70 (Lg.

d, J=7.4Hz), 7.19-8.1 (15H, m), 8.70 (LH , s), 9.03 (LH.

s), 9.78 (IH, d, J=7.4Hz), 14.61 (IH, br s) MASS (m/e): 503 (M”-37), 427 (10 )(3RS)-1,3-dihydro-1-(4-imidazolylmethyl)-3-[3 -(3-methylphenyl)ureido]-5-(2-fluorophenyl)-2H -1,4-benzodiazepine-2-one hydrochloride mp: 210-225°C (decomposition ) IR (Nujol): 3600-3050.1680.1610.1555 cm” NMR (DMSO-d, δ): 2.24 (3H, s), 5.06 ( 2H, s), 5.26 (IH, d, J: 8.4Hz).

6.74 (LH, d, J=6.6Hz), 6.87 (IH, s), 7.0 7-7.71 (13H, m).

8.02 (LH, d, J = 8.0Hz), 8.99 (IH, s) five plates (3R3)-1,3-dihydro-3-(3-quinolylcarbonylamino-5-( 2-fluorophenyl)-2H-1,'4-benzodiazepine-2-one (85 0 mg) and 1-trityl-4-(2-chloroethyl)imidazole-hydrochloride (9 N,N-dimethylformamide mixture with Sodium hydride (180 mg of a 60% suspension in mineral oil) was cooled to 0°C in a bath and stirred. ) and sodium iodide (3.98 g) were added. Leave this mixture at room temperature for 1.5 hours. , and further stirred at 60-65°C for 6 hours. Add acetic acid (2 ml) to this reaction mixture. The resulting mixture was stirred into a mixture of ethyl acetate (200 ml) and water (200 ml). Pour while stirring. This mixture was adjusted to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate. It was adjusted. The separated organic phase is washed with water and the solvent is removed under reduced pressure, leaving an amorphous residue. was obtained, and this was analyzed using column chromatography packed with silica gel. The product was purified using chloroform as an eluent. Combine fractions containing the target substance and evaporate to dryness An amorphous mass was obtained, which was dried under reduced pressure to form (3R3)-1,3-dihydrogen. Dro-1-[2-(1-1-ditylimidazol-4-yl)ethyl]-3- (3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1 , 4-benzodiazepin-2-one (750 mg) was obtained.

NMR (DMSO-d, δ): 2.49-2.65 (2H, ml, 3.8- 4.6 (2H, m), 5.62 (IH, d.

J=7.48Hz), 6.70(LH,s), 7.00~8.1(28H,m ), 9.05 (IH.

Great treatment (3RS)-1,3-dihydro-3-(2-naphthoylamino)-5-(2-phthoylamino) fluorophenyl)-2H-1,4-benzodiazepin-2-one (1,25g) was added to a solution of N,N-dimethylformamide (31 ml) in a water bath under a nitrogen gas atmosphere. Cool to 0 °C and add sodium hydride (60% suspension in mineral oil, 130 °C) with stirring. mg) was added. After stirring at room temperature for 45 minutes, the mixture was added with chloroacetonitrile. A solution of Ril (270 mg) in N,N-dimethylformamide (5 ml) was stirred. I added while doing so. The resulting mixture was stirred at room temperature overnight, and then acetic acid (0.5 g ) was added. Mix this mixture with ethyl acetate (200 ml) and water (300 ml). Pour into the liquid while stirring, then adjust the pH to 8 with an aqueous sodium hydrogen carbonate solution. Ta. The separated organic phase was washed with water and the solvent was removed under reduced pressure to yield an amorphous residue. This was analyzed using column chromatography packed with silica gel. lum was used as the eluent. When the two parts containing the target substance are combined and evaporated to dryness, it becomes amorphous. A solid mass was obtained, which was dried under reduced pressure to give (3RS)-1,3-dihydro-1- Cyanomethyl-3-(2-naphthoylamino)-5-(2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (1,19 g) was obtained.

NMR (DMSQ-d, δ): 5.08-5.32 (2H, m), 5.7 4 (LH, d, J near 45Hz), 7.25-7.32 (14H, m), 8 ．． 71 (LH, s), 9.95 (LH, d, J = 7.68Hz) Following a method similar to Examples 8 and 9, the following compounds were obtained.

(1)(3R3)-1,3-dihydro-3-(3-quinolylcarbonylamino) -5-(2-fluorophenyl)-1-[(IH-tetrazol-5-yl)methyl Chill]-2H-1,4-benzodiazepine-2-one mp: 284-285°C ( Disassembly) IR (Nujol): 3400.1695.1650.1600.1525 am”NMR (DMSO-ds, δ): 5.4-5.62 (2H, m), 5.76 (IH, d, J = 7.74Hz), 7.23-7.39 (4H, + al, 7.63-7.79 (4H, m), 7.86-7.93 (2H, m) .

8.09-8.32 (2H, m), 9.05 (IH, s), 9.37 (l) (, d, J=2.36)1z).

10.12 (LH, d, J=7.78Hz), 15.2-16.0 (1B, br s) MASS (m/e): 507 (M, 424 (M’″- 83)(2)(3RS)-1,3-dihydro-3-(3,4-dichlorobenzoy Ruamino)-5-(2-fluorophenyl)-1-[(LH-tetrazole-5 -yl)methyl]-2H-1,4-benzodiazepine-2-one mp: 26 0-265℃ (decomposition) IR (Nushor): 3600.3050.　1650. 1600 cm "NMR (DMSO-d, δ): 3.83 (IH, brs), 5.2 ~5.4 (2H, m), 5.63 (LH, d, J = 7.8gz).

7.14-7.33 (5H, m), 7.55-7.67 (4H, m), 7. 77 (IH, d.

J = 8.4Hz), 7.97 (2H, d, 8.4Hz), 8.28 (L H,d.

MASS (m/e): 524 (M, 368 (M"-156) (3) (3R S)-1,3-dihydro-3-(2-indolylcarbonylamicar 5-(2- Fluorophenyl)-1-[(LH-tetrazol-5-yl)methyl]-2H -1.4-Benzodiazepine-2-one mp: 280-290°C (decomposition) IR (Nujol): 3150.1640.1540 cm-1NMR (D MSO-d,, δ): 5.21-5.3 (2H, m), 5.69 (IH, d, J=8.14Hz), 7.02~7.6U (13H, m), 7.97 (LH, d, J: 8.26Hz), 9.52 ( IH, d.

J=8.18Hz), 11.67 (IH, s) MASS (m/e): 351 (M”-144), 332 (M”-162) (4) (3RS)-1,3-dihyde Rho-1-[2-(4-imidazolyl)ethyl]-3-(3-quinolylcarbonyl Ruami/)-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-one mp: 165-175℃ (decomposition) IR (Nujor): 3600-3000.1650.1600 am” ( 5) (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro- 5-(2-fluorophenyl)-1-[(IH-tetrazol-5-yl)methy ]-2H-1,4-benzodiazepine-2-one NMR (DMSO-da, δ ): 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5 ．． 73 (1N, d.

J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (LH, d, J=8.0Hz).

11, 65 (LH, s) Medical treatment upstream 1 (3RS)-1,3-dihydro-1-[2-(1-tritylimidazole-4- yl)ethyl]-3-(3-quinolylcarbonylamino)-5-(2-fluoro phenyl)-2H-1,4-benzodiazepin-2-one (740mg) - Stir in a solution of N,N-dimethylformamide (7.4ml) while cooling in a water bath. While stirring, 6N-hydrochloric acid (5.18 ml) was added. Heat this mixture to 60-70℃. The mixture was warmed and stirred for 1 hour. After cooling to room temperature, stir the reaction mixture with sewage water and vinegar. After adding ethyl acid, the pH was adjusted to 8 with an aqueous sodium hydrogen carbonate solution.

The separated organic phase was washed with water and dried. Removing the solvent under reduced pressure leaves an amorphous residue. This was chromatographed using column chromatography packed with silica gel. lum was used as the eluent. When the fractions containing the target compound are combined and evaporated to dryness, an amorphous A lump was obtained which was crushed and stirred in diisopropyl ether for several hours. . The precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give (3 R8)-1,3-dihydro-1-[2-(4-imidazolyl)ethyl]-3-( 3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1 , 4-benzodiazepin-2-one (0.25 g) was obtained.

mp: 165-175℃ (decomposition) IR (Nujol): 3600-3000.1650.1600 cm”N MR (DMSO-d,, δ): 2.52-2.66 (2H, m), 4.0 9-4.63 (2H, m), 5.65 (IH, d.

J=7.6Hz), 6.77 (IH, s), 7.24-8.32 (138, m), 9.07 (LH, d.

J=1.92Hz), 9.39 (IH, d, J=2.2Hz), 1O-1 1 (IH, d.

J Near, 6Hz), 11.82 (LH, br　s) MASS (m/e): 5 18 (M”) 11 (3R3)-1,3-dihydro-3-(3,4-dichlorobenzoyl aminocar 5 -(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one ( 500mg) and 1-trityl-4-(2-chloroethyl)imidazole hydrochloride (295 mg) and N,N-dimethylformamide (7.5 ml) was added nitrogen. Sodium hydride (mineral ore 60% suspension in oil, 99.5 mg) and sodium iodide (2.25 g) were added. . This mixture was stirred at room temperature for 1.5 hours and then at 60-65°C for 6 hours, and then acetic acid (1.1 ml) and 6N-hydrochloric acid (5 ml) were added and stirred at 60-70°C for 1 hour. . The resulting mixture was dissolved in ethyl acetate (100ml) and water (100ml). The mixture was poured while stirring, and then the pH was adjusted to 8 with an aqueous sodium hydrogen carbonate solution.

The separated organic phase was washed with water and then dried. The solution is removed under reduced pressure to remove the amorphous residue. A distillate was obtained, which was subjected to column chromatography packed with silica gel. The product was purified using chloroform as an eluent. Combine fractions containing the target substance and evaporate to dryness An amorphous mass was obtained, which was crushed and dissolved in diisopropyl ether. Stir for several hours. Then collected by filtration, washed with diisopropyl ether and reduced. When dried under pressure, (3R3)-1,3-dihydro-1-[2-(4-imidazolyl) )ethyl]-3-(3,4-dichlorobenzoylamino)-5-(2-fluoro Lophenyl)-28-1,4-benzodiazepin-2-one (0.18 g) was obtained. It was done.

mp: 149-159℃ (decomposition) IR (, iZ shawl): 3600-3100.1650.1600 cm -'NMR (DMSO-da, δ): 2.5-2.59 (2H, a+), 3.95-4.62 (28, m), 5.5 (LH, d.

J=7.52Hz), 6.77(IH,brs), 7.23~8.32( 12H, m).

9.99 (IH, br s), 11.8 (IH, br s) 1i1ASS (m /e): 386 (M”-150) lining and transparent work Following a method similar to Example 12, the following compound was obtained.

(1)(3R3)-1,3-dihydro-1-[2-(4-imidazolyl)ethyl ]-3-(2-naphthoylami/)-5-(2-fluorophenyl)-2H- 1,4-benzodiazepine-2-one mp: 198-205°C (decomposition) IR (Nujol): 3275.1680.1630.1530 cm-1 NMR (DMSO-d, δ): 2.5-2.8 (2H, ml, 4.0-4 ．． 6 (2H, m), 5.65 (LH, d.

J = 7.67Hz), 6.81 (LH, br s), 7.24-8.09 ( 15H, a+).

8.71 (1N, s), 9.78 (IH, d, J=7.71Hz), 11 ．． 8 (IH, br　s)! +lASS (m/e): 51g (M (2) (3R S)-1,3-dihydro-1-(2-(4-imidazolyl)ethyl)-3-( 2-indolylcarbonylamino)-5-(2-fluorophenyl)-2H-1 ,4-benzodiazepine-2-one mp: 1g 8-205℃ (decomposed) IR (Nujol): 3550-3100.1640.1540 cm-' NMR (DMS (1-d,, δ): 2.51-2.65 (2H, m), 4. OJ ~ 4.08 (IH, m), 4.50 ~ 4.57 (IHB ml, 5.63 (IH, d, J = 7.9Hz), 6.56 (lH, s), 6.76-7J1 (14H, m), 9.60 (IH, d, J=7.9Hz L Ll, 64 (IH, s).

11.81 (LH, br sl Medical technician (1)(3R3)-1,3-dihydro-1-cyanomethyl-3-(2-naphthoyl Ruamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-one (1,15g), sodium azide (480mg) and triethyl Amine-hydrochloride (510mg) of 1-methyl-2-pyrrolidinone (20ml) ) The mixture was stirred at 145°C for 3.5 hours. This reaction mixture was mixed with hydrochloric acid at 5°C while stirring. (100 ml), collect the formed precipitate by filtration, wash it with water, and then Purify by column chromatography using chloroform as eluent. Ta. When the fractions containing the target substance were combined and evaporated to dryness, an amorphous mass was obtained. This was ground and stirred in diisopropyl ether for several hours. Then filter collection, di After washing with isopropyl ether and drying under reduced pressure, (3RS)-1 ゜3-dihydro-3-(2-naphthoylamino)-5-(2-fluorophenyl )-1-((LH-tetrazol-5-yl)methyl]-2H-1,4-benzo Diazepin-2-one (540 mg) was obtained.

mp: 265-275℃ (decomposition) IR (Nujol): 3570-3100.1650.1490 cm-' NMR (DMSO-d, δ): 5.33 (2H, s), 5.73 (IH, d, J=7.98)1z), 7.18~8.09(15HB ml, 8.69 (IH, s), 9.72 (LH, d, J: 8Hz) MAS S (IIl/e): 505 (M) Follow the same method as Example 14 (1) The following compound was obtained.

(2) (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro -5-(2-fluorophenyl)-1-[(IH-tetrazol-5-yl)methyl Chil]-28-1,4-benzodiazepin-2-one NMR (DMSO-d, , δ): 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (IH, d.

J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (IH, d, J=8Hz).

11, 65 (LH, s) East Shigo 1 each other (3RS)-3-amino-1,3-dihydro-5-phenyl-1-[(1-tri methyl-IH-tetrazol-5-yl)-2H-1,4-benzodiaze A solution of pin-2-one (0.50 g) in dry tetrahydrofuran (LOML) 4-chlorophenylisocyanate (0.14 g) was added at room temperature. This mixture After stirring for 3 hours, 8.4N-ethanolic hydrochloric acid (1.5ml) was added at room temperature. and stirred for 3 hours. Solvent was removed under reduced pressure. Etch the residue with ethanol and vinegar (3RS)-1゜3-di Hydro-3-[3-(4-chlorophenyl)ureido]-5-phenyl-1-( (IH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepine -2-one-hydrochloride (0.40 g) was obtained.

mp: 205-208℃ (decomposition) IR (Nujol) + 3325.3250.3190.2725.1690 ．． 1600.1545 cm-'NMR (DMSO-d,, δ): 5.3 ( 1-5,50 (LH, m), 5.46 (2H, ABq, J:17Hz, 2 4Hz).

7.20-7.85 (15H, m), 9.0-11.0 (IH, 70-do), 9 ．． 42 (LH, s) Daishiden Jodan Following the same method as Example 15, the following compound was obtained.

(1) (3R3)-1,3-dihydro-3-(3-(4-chlorophenyl)ure) ]-5-(2-fluorophenyl)-1-[(LH-tetrazole-5- yl)methyl]-2H-1,4-benzodiazepin-2-one-hydrochloride mp: 203-205℃ (decomposition) IR (Nujol): 3320.3250.3190.2720.1695 ．． 1605.1525 crn-'NMR (DMSO-d,, δ): 5. 30-5.40 (LH, m), 5.48 (2H, ABq, J: 17 [(z, 21Hz), @7.20 ~7.80 (13H, m), 8.0 ~ 10.5 (2H, broad), 9.3 7(LH,5)(2)(3R3)-1,3-dihydro-3-[3-(3-methyl phenyl)ureido]-5-phenyl-1-[(IH-tetrazol-5-yl ) methyl], 2H-1,4-benzodiazepine-2-one-hydrochloride mp: 188-194℃ (decomposition) IR (Nujol): 3290.2720.2605.1685.1610 ．． 1595.1540 cm-'NMR (DMSO-d,, δ): 2.24 (3H, s), 5.30-5.48 (LH, m), 5.46 (2H, ABq , J=17gz.

25Hz), 6.70-6.80 (IH, m), 7.00-7.54 (12H , m), 7.70-7.80 (2H, m), 8.0-10.20 (2i (, Bro. 9.12(18,5)(3)(3R3)-1,3-dihydro-5-( 2-fluorophenyl)-3-[3-(3-methylphenyl)ureido]-1 -[(IH-tetrazol-5-yl)methyl]-2H-1,4-benzodiaze Pin-2-one-hydrochloride mp: 181-191℃ (decomposition) IR (Nujol): 3300.2710.2610.1690.1595 ．． 1550 cm-'NMR (DMSO-d,, δ): 2.24 (3H, s) , 5.35-5.45 (IH, m), 5.48 (2H, ABq, J=11 H 噤B 22Hz), 6.70-6.78 (IH, m), 7.05-7.38 (7H, ++), 7.50-7.81 (6H, m), 8.0-10.4 (2H, blow ), 9.11 (IH, s) (3S)-1,3-dihydro-1-[(1-tritylimidazol-4-yl ) methyl]-3-(3,4-dichlorobenzoylamino)-5-(2-fluoro phenyl)-28-1,4-benzodiazepin-2-one (20,34g) A solution of N,N-dimethylformamide (204 ml) was stirred while cooling in a water bath. 6N-hydrochloric acid (157 ml) was added. Heat this mixture to 70-80℃ and Stir for hours. After cooling to room temperature, the reaction mixture was poured with ice water and acetic acid with stirring. Added ethyl. The mixed solution was adjusted to pH 8.0 with an aqueous sodium hydrogen carbonate solution.

The separated organic phase is washed with water, dried, and the solvent is removed under reduced pressure to obtain an amorphous residue. This was analyzed using column chromatography packed with silica gel. Purification was carried out using form as the eluent. The fractions containing the target substance are combined and evaporated to dryness. A solid mass was obtained and dried under reduced pressure to obtain (3S)-1,3-dihydro-1-(4- imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-(2 -fluorophenyl)-2H-1,4-benzodiazepin-2-one was obtained. . Dissolve this in chloroform (200 ml) and add 20% to the resulting solution under cooling. A solution of hydrochloric acid in ethanol (50 ml) was added. The resulting yellow transparent solution was placed under reduced pressure. Evaporation drying yields an amorphous mass, which is freeze-dried to yield (3S)-1゜3- Dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobenzo ylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepi Neon-2-one hydrochloride was obtained as a yellow powder (12.97 g).

IR (Nujol): 3000.2900-2200.1660.1600 ．． 1500 cm-NMR (DMSO-d, δ): 5.19 (LH, d , J: 16Hz), 5.43 (IH, d, J=16Hz), 5.61 ( Ig.

d, J=7.3 Hz), 7.19~7.39 (5H, ml, 7.56~ 7.82 (5H, m).

7.95-8.00 (IH, m), 8.30 (LH, d, J4.9Hz), 9.01 (LH, s).

9.99 (LH, d, J near, 3Hz), 14.6 (LH, br s) MA SS (m/e): 521 (M"-37) [α] 30° = -24,75" (C=0.832.CH,OH) Example 1 2-indolecarboxylic acid (161,2 mg) in methylene chloride (3,25 ml) To the suspension was added thionyl chloride (119,0 mg) and 1 drop of N,N with stirring at room temperature. -Dimethylformamide was added. This mixture was refluxed for 1 hour while stirring. ( 3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1- [(11-I-tetrazol-5-yl)methyl]-2H-1,4-benzodia Zepin-2-one hydrochloride (387.8 mg) and triethylamine (506.0 m g) in methylene chloride (8 ml), add the 2-indolylcarbonyl obtained above. A methylene chloride solution of chloride was added dropwise while stirring under water cooling. This mixture The mixture was stirred under the same conditions for 3 hours. Add chloroform to this reaction mixture, dilute hydrochloric acid and After successively washing with water, it was dried over magnesium sulfate. After removing the solvent under reduced pressure, Stir to suspend in isopropyl ether. The resulting powder was collected by filtration and diluted. After washing with isopropyl ether and drying under reduced pressure, (3S)-3-(2- indolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenylate) )-1-[(LH-tetrazol-5-yl)methyl]-2H-1,4-ben Zodiazepin-2-one was obtained.

mp: 270-271℃ (decomposition) [a]"8'o = -18,87° (C = 0.62. Tetrahydrofuran) NM R (DMSO-d,, δ): 5.49 (2H, ABq, J46.4Hz, 24.8Hz), 5.73(LH, d.

J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (LH, d, J=8.0Hz).

11.65 (LH, S) MASS (m/e): 494 (M”) 1 unit Following a method similar to Example 18, the following compound was obtained.

(3R)-3-(2-indolylcarbonylamino)-1,3-dihydro-5- (2-fluorophenyl)-1-[(LH-tetrazol-5-yl)methyl] -2H-1.4-benzodiazepine-2-one mp: 270-271°C (decomposition ) [α] zaS, = +18.72 @ (C = 0.625. Tetrahydrofuran) NMR (DMSO-d, δ): 5.49 (2H, ABq, J=16.3 Hz, 24.7Hz), 5.73 (IH, d.

J=8.0Hz1. 7.0-7.91 (14H, m), 9.60 (IH, d , J=8.0Hz).

11, 65 (IH, s) MASS (m/e): 494 (M”) Following a method similar to Example 1, the following compound was obtained.

(1) (3S)-1,3-dihydro-1-[(1-tritylimidazole-4 -yl)methyl] -3-(3,4-dichlorobenzoylamino) -5-(2 -fluorophenyl)-28-1,4-benzodiazepin-2-one NMR (C DC1, δ): 5.02 (IH, d, J=15f(z), 5.11(L H, d, J: 15Hz), 5.67 (IH, пB J=7.8Hz), 6.84-8.04 (29H, m) (2) (3RS)-1 ,3-dihydro-1-(2-(4-imidazolyl)ethyl)-3-(3-quino lylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-ben Zodiazepine-2-Oaf Lnp: 165-175°C (decomposed) IR (Nujol): 3600-3000.1650.1600 cm-' Bench example 1 Following a method similar to Example 11, the following compound was obtained.

(3S)-3-(2-indolylcarbonylamino)-1,3-dihydro-5 -(2-fluorophenyl)-1-[(IH-tetrazol-5-yl)methyl ]-2H-1,4-benzodiazepine-2-one NMR (DMSO-da, δ) :5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5. 73 (IH, d.

J=8.0Hz), 7. (]-7,91 (14H, m), 9.60 (IH, d , J=8.0)lz).

11, 65 (LH, s) international search report 1+mmmm Pass ■＾-1+11＾H・ρCT/JP 91100952S＾〾4 9394 Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number C07D403106 243 8829-4C403/14 233 8829-4CI

Claims (1)

[Claims] 1. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 represents a heterocyclic group or a cyano group which may have one or more suitable substituents. , R2 is a hydrogen atom or a halogen, R3 is an aryl group which may have one or more suitable substituents, and R4 is a suitable substituent. An aryl group which may have one or more groups, an aryl group which may have one or more suitable substituents. (lower)alkenyl group, aryl which may have one or more suitable substituents Amino group, heteromonocyclic group which may have one or more suitable substituents, quinolyl group, i Soquinolyl group, cinnolinyl group, indolyl group, or quinoxalinyl group, and A represents a lower alkylene group. However, when R4 is an indolyl group, (i) R1 has one or more suitable substituents. R3 represents a halophenyl group, or (ii) R1 is an imidazolyl group which may have one or more suitable substituents, R3 represents a halophenyl group, and A represents ethylene. and pharmaceutically acceptable salts thereof. 2. During the ceremony, R1 is a tetrazolyl group optionally having one protected imino group, one protected An imidazolyl group, which may have a protected imino group, or a cyano group, R3 is a phenyl group or a halophenyl group, R4 is a halogen and an amino group, respectively. a phenyl group which may have one or two substituents selected from the group consisting of or naphthyl group; phenyl (lower) which may have an amino group or a nitro group Alkenyl group; phenylamine which may have a lower alkyl group or halogen pyridyl group; tetrahydropyridazine which may have one oxo group quinolyl group; isoquinolyl group; cinnolinyl group; indolyl group; Noxalinyl group, The compound according to claim 1, which is 3. During the ceremony, R1 is a group which may have a mono(di- or trip)phenyl(lower) alkyl group; Contains a torazolyl group, a mono (di or tri) phenyl (lower) alkyl group may be an imidazolyl group or a cyano group, R4 is a naphthyl group; dihalophenyl group; phenyl group with halogen and amino group; nitrophenyl (lower) alkenyl Aminophenyl (lower) alkenyl group; Lower alkylphenylamino group; Halophenylamino group; Biridyl group; Tetrahydropyrin with one oxo group dazinyl group; quinolyl group; isoquinolyl group; cinnolinyl group; indolyl group; or quinoxalinyl group, The compound according to claim 2, which is a compound as shown in claim 2. 4. During the ceremony, R1 is a tetrazolyl group, R2 is a hydrogen atom, R3 is a halophenyl group, R4 is an indolyl group, and A is a C1-C4 alkylene group 4. The compound according to claim 3, which is 5. (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro- 5-(2-fluorophenyl)-1-[(1H-tetrazol-5-yl)methy The compound according to claim 4, which is -2H-1,4-benzodiazepin-2-one Compound. 6. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 represents a heterocyclic group or a cyano group which may have one or more suitable substituents. , R2 is a hydrogen atom or a halogen, R3 is an aryl group which may have one or more suitable substituents, and R4 is a suitable substituent. An aryl group which may have one or more groups, an aryl group which may have one or more suitable substituents. (lower)alkenyl group, aryl which may have one or more suitable substituents Amino group, heteromonocyclic group which may have one or more suitable substituents, quinolyl group, i Soquinolyl group, cinnolinyl group, indolyl group, or quinoxalinyl group, and A represents a lower alkylene group. However, when R4 is an indolyl group, (i) R1 has one or more suitable substituents. R3 represents a halophenyl group, or (ii) R1 is an imidazolyl group which may have one or more suitable substituents, R3 represents a halophenyl group, and A represents ethylene. A compound represented by or a salt thereof, (1) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R3 and A are each the same as above, or a compound represented by a reactive derivative or a salt thereof at the amino group of the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R4 is the same as above, A compound represented by the formula or a reactive derivative thereof or a salt thereof is reacted to form the formula : ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R3, R4 and A are each the same as above, or a compound represented by is the method to obtain the salt, or formula (2): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R2, R3, R4 and A are each the same as above, and R1a is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R6 represents a protected imino group. ) represents a heterocyclic group having a protected imino group, and this heterocyclic group is may have one or more appropriate substituents, By the elimination reaction of the imino protecting group in the compound represented by the formula or its salt, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R2, R3, R4 and A are each the same as above, and R1b is ▲There are mathematical formulas, chemical formulas, tables, etc.▼Represents a heterocyclic group having an imino group. and the heterocycle may have one or more suitable substituents. A method for obtaining a compound or a salt thereof, or formula (3): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R3 and A are each the same as above, and R4a has a nitro group. represents an al(lower) alkenyl group, From the compound shown or its salt, formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R3 and A are each the same as above, and R4b has an amino group. represents an al(lower) alkenyl group, A method for obtaining a compound represented by or a salt thereof, or formula (4): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R2, R3, R4 and A are each the same as above, or a compound represented by salt of Formula: X-A-R1 In the formula, R1 and A are each the same as above, and X represents an acid residue. By reacting with a compound or a salt thereof, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R3, R4 and A are each the same as above, or a compound represented by or a method for obtaining its salt, or formula (5): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R2, R3, R4 and A are each the same as above, or a compound represented by salt, Formula: HN3 By reacting with the compound shown or its salt, there are ▲mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R2, R3, R4 and A are each the same as above, or a compound represented by A method for obtaining salt. 7. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1c is a tetrazolyl group which may have one or more suitable substituents, and R2 is a hydrogen atom or a halogen, R3 is an aryl group which may have one or more suitable substituents, and A is a lower aryl group. represents a lekylene group, A compound represented by or a salt thereof. 8. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1c is a tetrazolyl group which may have one or more suitable substituents, and R2 is a hydrogen atom or a halogen, R3 is an aryl group which may have one or more suitable substituents, and A is a lower aryl group. represents a lekylene group, A compound represented by or a salt thereof, formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1c, R2, R3 and A are each the same as above, and R7 is a protected atom. represents a mino group, By an elimination reaction at the protected amino group of the compound shown or its salt How to get it. 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. 10. The compound according to claim 1 used as a cholecystokinin antagonist or Pharmaceutically acceptable uses of its salts. 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered to humans or Treatment or prevention of cholecystokinin-mediated diseases, which involves administering the disease to animals or animals. Law. 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is used as a pharmaceutical agent. 1. A method for making a pharmaceutical composition comprising admixing it with a carrier that is acceptable as a pharmaceutical composition.