PT98370A - METHOD FOR PREPARING BENZODIAZEPINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

t

Description of the Japanese / industrial and commercial FUJISAWA PHARMA.CEUPIOAL CO., LTD. Patent, headquartered at 4-7, Doshomachi 3-come, Chuo-ku, Osaka-shi, OSAKA 541, Japan, (inventoress Yoshinari Sato, Takatomo Ogahara and Hiromichi Itani, residing in Japan) for " PROCEDURE FOR THE PREPARATION OF BENZODIA-2EPINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAINS THEM "

The present invention relates to novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof.

GSP

More particularly, it relates to novel benzodiazepine derivatives and their pharmaceutically acceptable salts which are cholecystokinin (CCK) antagonists and are therefore useful as therapeutic and / or preventive agents for emesis, pancreatitis, diseases of the system of regulation of appetite, pain, insulinoma, gastroparesis, pancreatic carcinoma, bladder diseases (eg acute cholecystitis, calculi, etc.), problems associated with the hyperactivity of the intestinal soft muscle (eg irritable spleen syndrome, spasm sphincter, etc.), hyperinsulinemia, dyspepsia, nausea, etc.

The benzodiazepine derivatives of the present invention may be represented by the following formula (I):

in which B 1 is a heterocyclic group which may have one or more suitable substituents, or cyano, < R e is an aryl group which may have one or more suitable substituents, lower aralkenyl which may have one or more suitable substituents, arylamino which may have one or more substituents, more suitable substituents, heteromonocyclic which may have one or more suitable substituents, quinolyl, iso-quinolyl, cinnolyl, indolyl, or quinoxalinyl, and A and lower alkylene, with the proviso that when R is indolyl,

* | (i) R1 is tetrazolyl which may have one or more suitable substituents, and R1 is halophenyl or (ii) R1 is imidazolyl which may have one or more suitable substituents, and is halophenyl and A is ethylene,

According to the present invention, the novel benzodiazepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme.

Pr-process 1

or its reactive derivative at the amino group, or a salt or reactive derivative thereof, or a salt thereof

Process 2 A-R1

NHCO-R4 or a salt thereof

NHCO-R 4 elimination reaction of

sP

imino-protecting group (Ib) or a salt thereof

5 5 * 7 > Process 5

AIR

R

(I) or a salt thereof

A-CN

4 NHCO-R + HN- (VI)

or a salt thereof H

N-NR '

R (If) pu of a salt thereof 6 Φ Ί >

wherein R 1, R 2, R 3, R 4 and A are as defined above, R 13 is a heterocyclic group having an imino group of formula

M

R (where it is an imino-protecting group) on its hetero ring, which may have one or more suitable substituents, R b is a heterocyclic group having an imino group of formula

N

H on its hetero ring, which may have one or more suitable substituents, R 2 is ar-lower alkenyl having a nitro group. is ar-lower alkenyl which is an amino group and is an acid residue.

The starting compounds (II) and (IV) may be prepared by the following processes. 7

(VII) or a salt thereof

Reaction of elimination of the protecting group of. amino

R 3 (II) or a salt thereof

Process B

(VIII) 0

Or its reactive derivative at the amino group, or a salt thereof (III) or its reactive derivative at the amino group or a salt thereof

NHGO-R4 > Wherein R, R, R, R and A are each as defined above, and R 7 is amino protected. The starting compound (VII) or a salt thereof can be prepared by the processes recited in Preparations 1 to 3, 6 and 7 described below or similar processes thereto. 9 ΐ ·

With respect to the desired compound (I), in case the compound (I) has the group of formula

wherein said group may also exist in the tau-tomeric form, said tautomeric balance may be represented by the following scheme.

Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and appended claims, the compounds including the group of such tautomeric isomers are represented by agreement with an expression of the group of formula (A).

In addition, in the case of compound (i) having the group having the formula

H _/\ \\ //

N-N 10

1 t wherein R 2, said group may also exist in tautomeric form and such tautomeric balance may be represented by the following scheme.

W

N-NH (D)

(O

Both of the aforementioned tautomeric isomers are included within the scope of the present invention. In the present invention and the appended claims, the compounds including the group of such tautomeric isomers are represented for convenience by an expression of the group of formula (C).

Suitable pharmaceutically acceptable salts of the desired compound (1) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (for example a sodium salt, potassium salt, etc.) and an alkali metal salt (for example a calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (for example a trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, a salt of an organic acid (for example an acetate, maleate, tert-arate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), a salt of a dicarboxylic acid, salt of an inorganic acid (for example a hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt of an amino acid (for example arginine, aspartic acid, glutamic acid, etc.) and the like. 11

In the foregoing and subsequent descriptions of the present specification the examples and appropriate illustrations of the various definitions which are included in the present invention within its scope are explained as the following. The term " bottom " refers to 1 to 6 carbon atoms, unless otherwise noted. " Heterocyclic group " may include an unsaturated, thiocyclic or polycyclic heterocyclic group containing at least one heteroatomotal as an oxygen, sulfur, nitrogen atom and the like.

An especially preferred heterocyclic group may be; a 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, dihydro-pyridazinyl, tetrahydropyridazinyl, triazolyl (for example, 1,2,4-triazolyl, 1X-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H-tetrazolyl, 2H- tetrazolyl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc. a 3- to 8-membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .; a condensed unsaturated heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, guinolyl, isoquinolyl, indazozolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (for example tetrazol- Pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc .; 12

a 3 to 8 membered unsaturated heteromonocyanic group containing 1 to 2 oxygen atoms, and 1 to 3 nitrogen atoms for example oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, (for example 1,2,4-oxadiazolyl, 3,4-oxa-diazolyl, 1,2,5-oxadiazolyl, etc.) etc .; a 3 to 8 membered saturated heteromonocyclic group containing 1 to 2 oxygen atoms, and 1 to 3 nitrogen atoms, for example morpholinyl, etc .; a condensed unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, cetyl; a 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms, and 1 to 3 nitrogen atoms, for example 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. Thiadiazolyl, 1,2,3-thiadiazolyl, etc., a 3- to 8-membered saturated heteromonocyclic group containing 1 to 2 sulfur atoms, and 1 to 3 nitrogen atoms, for example thiazolidinyl, etc., a 3 to 8 membered unsaturated heteromonocyclic group containing 1 oxygen atom, for example furyl, etc., a 3- to 8-membered unsaturated heteromonocyclic group containing 1 sulfur atom, for example thienyl, etc., a condensed unsaturated heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl, etc., and the like.

" Substitute " suitable were terms of " heterocyclic group which may have one or more suitable substituents " and " heteromonocyclic group which may have one or more suitable substituents " may include amino, protected amino as exemplified below, oxohydroxy, imino protecting groups as exemplified below, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t butyl, pentyl, t-pentyl, hexyl, etc.) and the like. " Amino protected " may include acylamino and the like groups. " Protective amino group " may include acyl, mono (or di or tri) phenyl lower alkyl (e.g. trityl, etc.) tetrahydropyranyl and the like groups. " Acyl " and " acyl radical " suitable in the " acylamino " may include an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of said acyl may be lower alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulphonyl (for example mesyl, ethanesulphonyl, propanesulphonyl, isopropanesulphonyl, butanesulphonyl, etc.); (for example benzoyl, toluoyl / xylyl, naphthoyl, phthaloyl, indancarbonylO / etc) ar-lower alkanoyl (for example benzenesulfonyl, tosyl, etc.)

(e.g. phenylacetyl, phenylpropionyl, etc.) ar-lower alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyl-xycarbonyl, etc.), and the like. The acyl radical as mentioned above may have at least one suitable substituent such as, for example, a halogen (eg chlorine, bromine, fluorine and iodine), amino, protected amino (eg lower alkanoylamino, phenylthioureido etc.) , or similar groups. "Acid residue" Suitable halogen may include halogen and the like. " Halogen " may include chlorine, bromine, fluorine and the like. " Aryl " and " aryl radical " suitable in the terms " ar-lower alkenyl " and " arylamino " may include phenyl, naphthyl, and the like. " Substitute " suitable within " aryl " which may have one or more suitable substituents " ar-lower alkenyl which may have one or more suitable substituents " and " arylamino which may have one or more suitable substituents " (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butyloxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.), halogen as exemplified below, and similar groups. " Radical lower alkenyl " suitable in terms of " ar-lower alkenyl " may include vinyl, allyl, 1-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like groups. 15

"Beterornonocyclic group " may include a saturated or unsaturated heteromonocyclic group containing at least one heterocyclic such as an oxygen, sulfur, nitrogen and the like atoms. E, the especially preferred heteromonocyclic group may be a heteromonocyclic group such as a 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide , pyridazinyl, dihydro-pyridinyl, tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl ( for example, ΙΗ-4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, , etc.); a 3 to 8 membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc. a 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms, and 1 to 3 nitrogen atoms, for example oxazolyl, isoxasolyl, dihydroisoisoxazolyl, oxadiazolyl, (for example 1,2,4-oxadiazolium, 1,3 , 4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc .; a 3 to 8 membered saturated heteromonocyclic group containing 1 to 2 oxygen atoms, and 1 to 3 nitrogen atoms, for example morpholinyl, etc .; a 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms, it 3 nitrogen atoms, for example 1,3-thiazolyl, 1,2-thiazolyl, 16-

thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazoylyl, 1,2,3-thiadiazolyl, etc., a 3- to 8-membered saturated heteromonocyclic group containing 1 to 2 sulfur atoms, and 1 to 3 nitrogen atoms, for example thiazolidinyl, etc., a 3 to 8 membered unsaturated heteromonocyclic group containing 1 oxygen atom, for example furyl, etc., an unsaturated heteromonocyclic group with 3 to 8 members containing 1 sulfur atom, for example thienyl, etc., and the like. &Quot; Lower alkylene " may include a straight or branched chain of 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene , " Heterocyclic group " preferred in the terms " heterocyclic group " having a protected imino group of the formula "

N

I 6

R (wherein R6 is an imino-protecting group) on its hetero ring " and " heterocyclic groups " having an imino group of the formula

N

H in its hetero ring " may include a 3- to 8-membered unsaturated heterocyclic group containing 1 to 4 nitrogen sites, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (for example 1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-thetaazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro- -1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc .; a 3 to 8 membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc. and similar groups.

Preferred embodiments of the desired compound (I) are as follows. 1 / r is a heterocyclic group (more preferably 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, more preferably tetrazolyl or imidazolyl which may have one to three (most preferably one) suitable substituents (more preferably tetrazolyl or imidazolyl, each of which may have an imino-protecting group, more preferably tetrazolyl or imidazolyl, each of which may have mono (or di or tri) phenyl lower alkyl, or cyano; more preferably phenyl) which may have one to three (most preferably one) suitable substituents (more preferably phenyl or halophenyl) 4> and aryl (more preferably phenyl or naphthyl) which may have one to three (most preferably one or two) suitable substituents (more preferably phenyl or naphthyl, each of which may have one or two substituents);

which are selected from the group consisting of halogen and amino; more preferably naphthyl, dihalophenyl or phenyl having halogen and amino), ar-lower alkenyl (more preferably phenyl) lower alkenyl which may have one to three (more preferably a suitable substituent (more preferably phenyl-lower alkenyl which may have amino or nitro) more (more preferably phenylamino) which may have one to three (most preferably one) suitable substituents (more preferably phenylamino which may have a lower alkyl or halogen group, more preferably a lower alkyl, phenylamino or (more preferably pyridyl or tetrahydropyridazinyl) which may have one to three (most preferably one) suitable substituents (more preferably pyridyl, or tetrahydropyridazinyl which may have an oxo group, more preferably pyridyl, or tetrahydropyridazinyl which may have a oxo, quinoline isopropyl, isoquinolyl, cinnolinyl, indolyl or quinoxalinyl, and A is lower alkylene (more preferably (1-4C) alkenylene, with the proviso that when R is indolyl, then (1) is tetrazolyl and is halophenyl or (11) R1 is imidazolyl may have a mono (or di or tri) phenyl lower alkyl group, R is halophenyl and A is ethylene.

The processes for the preparation of the desired compound (1) and the starting compounds of the present invention are explained below.

19

Process 1;

The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof. The reactive acid derivative of the amino group of the compound (II) may include an imino-type Schiff base or its enamine-type tautomeric isomer formed by the reaction of the compound (II) with an alkoxy group such as an aldehyde, ketone or the like ; a silyl derivative formed by the reaction of the compound (II) with a silane compound such as α, β-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloro or phosgene and the like.

Suitable salts of the compounds (II) and (III) may be referred to as those exemplified for the compound (I). Suitable reagent of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, an isocyanate, and the like. The suitable example may be an acid chloride, an acid azide (for example dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, diphenylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, thiosulfuric acid, (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or an aromatic carboxylic acid (for example benzoic acid, etc.);

an imidazole activated amide, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (for example a cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester Γ (CH 2) 3, vinyl ester, propargyl ester, p-nitrophenyl ether, 2, 4-dinitrophenyl, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl, piperidyl ester, 8-quinolyl thioester, etc.), or an ester formed with a N-hydroxy compound (e.g. N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide , N-hydroxy-benzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.), an isocyanate of the formula: wherein R is and aryl which may have a (III) may be selected from the group consisting of: (i) reacting the compounds of the present invention; The reaction is usually conducted in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvents which do not influence the reaction. These conventional solvents may also be used in admixture with water.

When the compound (II) is used in the free acid form or in the form of its salt in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N -dicyclohexylcarbodiimide; N-cyclohexyl-N-morpholinoethylcarbodiimide; N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; 21

N-ethyl-N1- (3-dimethylaminopropyl) carbodiimide; Ν, Ν-carbonylbis- (2-methylimidazole); N-cyclohexylamine? diethylenetone-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphate? polyphosphate; isopropyl polyphosphate; phosphorous oxychloride phosphorous chloride? phosphorus tri-chloride $ -tionyl chloride; oxalyl chloride? triphenylphosphine? 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide; intra-molecular salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, the so-called Vilsmeier reagent prepared by reaction of N, N-dimethylformamide with thionyl chloride, phosgene, oxychloride, phosphorus, etc. or similar products. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower alkyl) amine, pyridine, N-lower alkyl morpholine, N, N- benzylamine, or the like. The reaction temperature is not critical, and the reaction is usually effected by cooling and heating.

Process 2: The compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to a deletion reaction in the imino protecting group. The process suitable for carrying out this reaction may include a conventional process such as hydrolysis, reduction and the like. (I) For hydrolysis. The hydrolysis is preferably effected in the presence of a base or an acid including a Lewis acid. The appropriate base may include an inorganic base and an organic base such as an alkali metal (e.g. sodium, potassium, etc.), a trialkylamine hydroxide or carbonate or bicarbonate thereof (for example trimethylamine, triethylamine, etc.), picoline, 1.5 5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [4.8.0] undec-7-7-ene, or the like. The suitable acid may include an organic acid (for example formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and an inorganic acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.). The elimination using a Lewis acid such as trihydroacetic acid (for example trichloroacetic acid, trifluoroacetic acid, etc.) or the like is preferably effected in the presence of cation-absorbing agents (for example anisole, phenol, etc). The reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, etc.), Ν, Ν-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any solvent which does not adversely affect the reaction. A liquid base or acid may also be used as the solvent. The reaction temperature is not critical and the reaction is usually effected by cooling and heating. (Ii) For reduction s The reduction is carried out in a conventional manner / including chemical reduction and catalytic reduction.

Suitable reducers to be used in chemical reduction are the combination of a metal (for example tin, zinc, iron, etc.) or a metal compound (for example chromium chloride, chromium acetate, etc.) and an organic or inorganic acid for example formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts to be used in the catalytic reduction are conventional ones such as platinum catalysts (for example platinum plates, sponge platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (for example nickel reduced, nickel oxide, nickel etc.), cobalt catalysts (for example reduced cobalt, Raney cobalt, etc. iron catalysts (for example reduced iron, Raney iron, etc.), copper catalysts (eg reduced copper, Raney copper, copper The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction such as water, methanol, ethanol, propanol, N, N-dimethyl tetrahydrofuran, or a mixture thereof. Additionally, in case the above-mentioned acids to be used in the chemical reaction are in liquid form they can also be used as the solvent. The reaction temperature of this reduction is not critical and the reaction is usually effected by cooling and heating.

Process 3s The compound (id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to a reduction reaction. This reduction reaction may be as recited in process 2 mentioned above.

Process 4: Compound (I) or a salt thereof can be prepared by reacting the compound (iv) or a salt thereof with the compound (V) or a salt thereof.

Suitable salts of compounds (IV) and (V) may be referred to as those exemplified for compound (I). The reaction is usually carried out in the presence of a base. The appropriate base may include an inorganic base such as an alkali metal hydride (for example sodium hydride, etc.), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydroxide- (for example magnesium hydroxide, calcium hydroxide, etc.), an alkali metal carbonate (for example sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (for example magnesium carbonate, carbonate etc.), an alkali metal bicarbonate (for example sodium bicarbonate, potassium bicarbonate, etc.), an alkali metal acetate (for example sodium acetate, potassium acetate, etc.), an alkali metal phosphate (eg magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (for example disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like. like products, and an organic base such as a trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine or the like.

This reaction is usually carried out in a solvent such as an alcohol (methanol, ethanol, etc.), benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction. The reaction temperatures are not critical and the reaction is usually effected with cooling and heating.

Process 5i The compound (i) or a salt thereof can be prepared by reacting the compound (Ie) or a salt thereof with the compound (VI) or a salt thereof.

Suitable salts of the compounds (Ie) and (s) may be referred to as those exemplified for the compound (I).

Suitable salts of the compound (VI) may include an alkali metal salt (for example sodium salt, potassium salt, etc.), and the like. The reaction is usually carried out in a conventional solvent such as 1-methyl-2-pyrrolidinone, N, N-dimethylformamide, dichloromethane, ethylene chloride and any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually effected with heating. 26

Process A The compound (II) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to a removal reaction of the imino protecting group.

Suitable salts of the compound (VII) may be referred to as those exemplified for the compound (I). The elimination reaction is carried out according to a conventional procedure such as hydrolysis; reduction; Edman process (phenyl isothiocyanate process); or similar techniques. The hydrolysis may include a process using an acid or base or hydrazine and the like. These processes may be chosen depending on the type of protecting groups to be removed.

Among these processes, the hydrolysis of an acid is most commonly used and is also the preferred method for eliminating protecting groups such as substituted or unsubstituted alkoxycarbonyl, for example tert-pentyloxycarbonyl, lower alkanol (e.g. formib, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g., triethyl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene, or the like.

Suitable acids include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can be easily removed from the reaction mixture by a conventional procedure such as. for example, distillation under reduced pressure, with for example formic acid, trifluoroacetic acid,

drico, etc. The acids may be chosen according to the type of protecting group to be eliminated. The elimination reaction using trifluoroacetic acid can be effected in the presence of anisol. Hydrolysis using hydrazine is commonly applied to eliminate a phthaloyl, succinyl amino protecting group. The elimination using a base is used to eliminate an acyl group such as trifluoroacetyl. A suitable base may include an inorganic base and an organic base. The reductive elimination is generally applied to remove the protecting group, for example, haloalkylcarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, and the like. Suitable reduction may include, for example, reduction with an alkali metal (e.g. sodium borohydride, etc.). reduction with a combination of metal (for example tin, zinc, iron, etc.) or said metal together with a metal salt compound (for example chromium chloride, chromous acetate, etc.) and an organic or inorganic acid acetic acid, propionic acid, hydrochloric acid, etc.) and catalytic reduction. Suitable catalysts include conventional ones, for example Raney nickel, platinum oxide, palladium on charcoal and the like.

Among the protecting groups, the acyl group can generally be removed by hydrolysis. Especially, halogen-substituted and 8-quinolyloxycarbonyl-substituted alkoxycarbonyl groups are usually removed by treating with a heavy metal such as copper, zinc, or methacrylic acid. ducts. 28

The reaction is usually conducted in a conventional solvent such as water / chloroform / methylene chloride / alcohol (for example methanol / ethanol / etc.) / Tetrahydrofuran or any other organic solvent which does not adversely affect the reaction. The reaction temperature is not critical and may suitably be chosen according to the type of amino protecting group and the elimination process as mentioned above and the reaction is usually conducted under mild conditions such as with cooling or at a temperature slightly raised. Of the protecting groups the acyl group derived from an is-amino acid can be eliminated by the Edman process.

The compound (IV) or a salt thereof can be prepared by reacting the compound - (VIII) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereof. The reaction is carried out essentially in the same manner as in process 1, and thus the process and reaction conditions should be those for Process 1. The intended compound (I) and the pharmaceutically acceptable salts thereof are not CCK antagonists and therefore are useful as therapeutic agents for emesis, pancreatitis, etc.

In addition, the desired compound (i) and its pharmaceutically acceptable salts are expected to have gastric antagonism and are useful as therapeutic and / or preferential agents for ulcers / excessive gastric secretion / Zollinger-Ellison Syndrome / etc. 29 -

In order to show utility in the desired compound (i), the pharmacological activity of its representative compound is shown below. (i) Test Compound:

(3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- [3- (2-aminophenyl) propenoylamino] -5- (2-fluorophenyl) -2H-1 , 4-benzodiazepine-2-one (hereinafter referred to as Test compound A) (ii) Assay

CCK receptor antagonism in isolated fundic circular muscle of the guinea pig's stomach

Testing Process

A strip of guinea-pig stomach muscle was suspended in 25 ml of an organic bath containing Krebs' bicarbonate lotion (118 mM NaCl, 4.8 mM KCl, KH PO,

Ck TI 1.21τμ, MgSO 1.2 1.2 μM, CaCl₂ 2.5mM. 25 mM NaHCO 3, 0.1 mM glucose and 0.1% bovine serum albumin maintained at 37 ° C and cleaved with 95% 0% and 5% CO 2. The strip was placed in an initial strain of 0.5 g and alkylated for 60 minutes, during which time the bath volume was replaced every 15 minutes. The isometric contraction was measured using a force probe. CCK-8 (3.2 x 10 M) was added to the bath solution and the contractile force was measured. After washing the CCK-8, it was allowed to stand for 15 minutes until the contractile force became constant. Thereafter, a Test composition A (1 x 10 M) was added. After 5 minutes, CCK-8 was added and the contractile force was recorded. CCK antagonism was calculated by comparing the inducible contractile force.

by CGK in the absence or presence of the enantiomeric compound A,

The test compound (I) or the pharmaceutically acceptable salts thereof can usually be administered to mammals including man in the form of a conventional pharmaceutical composition such as capsule, microcapule, tablet, granulate, powder, wafer, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository or the like, and the most suitable dosage form is injection. The pharmaceutical composition of this invention may contain various organic or inorganic carrier materials which are conventionally used for pharmaceutical purposes, such as excipients (for example sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium carbonate, etc.), a binder (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), a disintegrant (e.g. starch, carboxymethylcellulose, carboxymethyl cellulose, hydroxypropyl starch, sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium nitrate, etc.), lubricant (for example magnesium stearate, talc, sodium lauryl sulfate, etc.), a flavoring agent (e.g., citric acid, menthol, glycine, orange powders, etc.), a preservative (for example sodium benzoate, sodium bisulfite, methyl paraben, propylparaben, etc.), a stabilizer (for example citric acid, sodium citrate, acetic acid, etc.), a suspending agent (for example methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc.), a dispersing agent, an aqueous diluent (eg water), a base wax (for example cocoa butter, polyethylene glycol, white petrolatum, etc.). The effective ingredient can usually be administered at a unit dose of 0, 01 mg / kg to 50 mg / kg, 1 to 4 times daily. However, the above dosage can be increased or decreased. according to the age, weight, conditions of the patient or process of administration.

The following Preparations and Examples are presented for the sole purpose of illustration of the present invention in greater detail.

Pyeparation 1 n

To a solution of (3RS) -3-phthalimido-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (21.17 g) in N, N-dimethylformamide (400 ml), sodium hydride (2.0 g, suspension in 60% mineral oil under cooling in an ice bath under a nitrogen atmosphere. The mixture was cooled in an ice bath and a solution of chloroacetonitrile (3.48 ml) in N, N-dimethylformamide (5 ml) was added dropwise. the mixture was stirred for 1 hour at the same temperature and overnight at ambient temperature. Acetic acid (3.5 g) was added to the reaction mixture with cooling and the resulting mixture was poured into a mixture of ethyl acetate and water The crystals were collected by filtration and washed with cold ethyl acetate to give (3RS) -3-phthalimido-2-methyl- l-ci anomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (20.9 g). mp: 260øC (dec.) IR (Nujol) 2160, 1776, 1725, 1700, 1604 cm -1 NMR (DMSO-d6, Î'): 5.15 (2H, ABq, J = 24.6 Hz, 17.8 Hz ), 5.83 (1H, s), 7.2-8.1 (12H, m)

Preparation 2

A mixture of (3RS) -3-phthalimido-1-cyanomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4- benzodiazepin-2-one (20.0 g), sodium azide (8.43 g) and triethylamine hydrochloride (8.92 g) in N-methyl-2-pyrrolidone (350 ml). After cooling to room temperature, the mixture was poured into 5% hydrochloric acid (500 ml) and ice. The resulting precipitates were collected by filtration, washed with cold water several times and dried over phosphorus pentoxide under reduced pressure to give (3RS) -3-phthalimido-1,3-dihydro-5- ( 2-fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (18.07 g). IR (Nujol): 1778, 1720, 1693, 1610 cm-1 NMR (DMSO-d6, δ): 5.46 (2H, s), 5.85 (1H, s), 7.2-8.0 (13H, m).

Preparation 3

To a solution of (3RS) -3-phthalimido-1,3-dihydro-5- (2-fluorophenyl) -1H-tetrazol-5-yl) methyl 2β-1,4- 2-one (18.07 g) and trityl chloride (10.99 g) in N, N-dimethylformamide (330 ml) was added a solution of triethylamine (4.6 g) in N, N- dimethylformamide (10 ml) under stirring and cooling in an ice bath. The mixture was stirred for 20 minutes under the same conditions and at room temperature overnight. The reaction mixture was poured into ice-water (500 mL), and the resulting precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give (3RS) -3- (2-fluorophenyl) -1- (1-trityl-1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (33) , 41 g) as a white powder. 33

NMR (DMSO-d6) δ 5.56 (2H, ABq, J = 16.0 Hz, 52.6 Hz), 5.80 (1H, s), 6.8-8.08 (1H, 1 (27H, m)

Preparation 4

To a suspension of (3RS) -3-phthalamido-1 - [(1-trityl-1H-tetrazol-5-yl) methyl] -5- (2-fluorophenyl) -1,3-diboron-2H-1,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran (500 ml). The mixture was stirred for 2 hours at the same temperature and refluxed under stirring for 2 hours. The reaction mixture was cooled in an ice bath and the resulting precipitates were collected by filtration. The filtrate was combined and washed and evaporated to give a residue which was stirred in ethyl acetate and filtered. The filtrate and washings were combined and evaporated to give a white powder (14.43 g) of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) (1-trityl-1H-tetrazol-5-yl) methyl] -2- (1,4-benzodiazepin-2-one. IR (Nujol): 3350, 1686, 1597, 760, 700 cm-1 NMR (CDCl3, .delta.) 2.95 (2H, br s), 4.62 (1H, s), 5.42 (2H, ABq , J = 19.6Hz, 15.8Hz), 6.8-7.6 (23H, m).

Preparation 5

The following compounds were obtained according to a similar procedure to that of Preparation 4. (3RS) -3-Amino-1,3-dihydro-5-phenyl-1- (1-trityl-1H-tetrazol-5- yl) methyl] -2H-1,4-benzodiazepin-2-one.

mp: 132-135 ° C IR (Nujol): 3375, 1680, 1595, 1575, 1560 cm @ -1 NMR (CDCl3, δ): 2.72 (2H, s), 4.55 (1H, s), 5 (2H, ABq, J = 16Hz, 51Hz), 6.90-6.70 (6H, m), 7.15-7.50 (18H, m)

Preparation 6

To a solution of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -1- (1-trityl-1H-tetrazol-5-yl) methyl] (11.54 g) and Rt-butoxycarbonyl-1-phenylalanine (5.42 g) in N, α-dimethylformamide (200 ml), 1-hydroxy benzotriazole (2.76 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.91 g) and triethylamine (2.36 g) under stirring at room temperature. The mixture was stirred under the same conditions for 4.5 hours and then poured into water (1.5 L) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The resulting precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give a mixture (16.29 g) of (3R) -3 - [(2S) - 2-t-butoxycarbonylamino-3-phenylpropanoyl) amino] -1,3-dihydro- 5 - (2-fluorophenyl) -1 - [(1-trityl-1H-tetrazol-5- yl) methyl) -1H-1,2,4-benzodiazepine-2-one and (3S) -3 - [(2S-) - 2-t-butoxycarbonylamino-3-phenylpropanol) (2-fluorophenyl) -1- (1-trityl-1H-tetrazol-5-yl) methyl] -7'-2H-1,4-benzodiazepi a-2-one .

mp: 108-114 ° C IR (Fujol) 3330, 1700, 1690, 1675, 1610 cm -1 1 M (DMSO-d 6, δ-): 1.28 (9H, s), 2.65-2.9 (1H, m). 3.0-3.2 (1H, m), 4.40 (1H, m), 5.33-5.41 (2H, m), 5.39, 5.40 (1H, each d, J = 8Hz ), 5.58 (2H, ABq, J = 16.8Hz, 82.2Hz), 6.8-7.95 (14H, m), 9.25, 9.37 (1H, each d, J-

Preparation 7

A mixture (16.2 g) of (3R) -3 - [(2S) -2-

-2-t-butoxycarbonylamino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1-7- (1-trityl-1H-tetrazol-5-yl) methyl] -2K (3S) -3 - [(2S) -2-t-butoxycarbonylamino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluoro- 1-yl) methyl] -2H-1,4-benzo-diazepin-2-one and 4N hydrogen chloride solution in ethyl acetate (200ml) ml). The mixture was concentrated in vacuo to give a residue which was dissolved in methanol (100 ml) and neutralized with ethanolic ammonia. The mixture was concentrated in vacuo for drying. The residue was subjected to silica gel column chromatography with an eluent (CHCl3) (CH3 OH = 10: 1). Fractions containing the desired compound were evaporated and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3S) -3 - [(2S) -2- amino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] -2 H -1,4-benzodiazepin-2- (4.57 g). NMR (DMSO-d6,%): 2.91 (1H, dd, J = 14.0Hz, 8.4Hz),

Dd, J = 4Hz, 8.4Hz), 5.26 (2H, ABq, J = 15.4Hz, 31.6Hz), 5.39 (1H, (1H, d, J = 8.4Hz), 7.1-7.35 (1H, m), 7.52-7.66 (4H, m), 7.96 (1H, d, J = 8.0Hz)

The fractions containing the other desired compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3R) -3 - ((2S) -2- 3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2 H -1,4-benzodiazepin- 2-one (4.76 g)

NMR (DMSO-d6 / Î'): 3.0-3.17 (1H, m), 3.57-3.64 (1H, m), 3.0-4.1 (2H, broad), 4.21 (1H, t, J~4.2Hz), 5.19 (1H, d, J = 8.3 Hz), 7.16-7.4 (10H, m), 7.51-7.67 (4H, m), 7.97 (1H, d, J8.2Hz), 9.78 (1H, d, J = 8.3Hz)

Production, 8

To a solution of (33) -3 - [(2S) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro- (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (4.57 g), and triethylamine ( 0.974 g) in tetrahydrofuran (45 ml). The mixture was stirred for 2 hours at ambient temperature and for 1 hour at 50 ° C. To the reaction mixture was added 1N hydrochloric acid (9.64 ml) under ice-cooling. The mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate. The extract was washed twice with water and dried over magnesium sulfate. Reaction of the solvent in vacuo afforded an amorphous mass (7.23 g) which was converted into dichloromethane in diisopropyl ether for 3 hours. The resulting powder was collected by filtration and washed with diisopropyl ether to give (3S) -3- [ ((2S) -2- (N1- (phenyl) thioureido) -3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] -2,4-benzodiazepin-2-one (5.63 g). The above product was suspended in tetrahydrofuran (35 ml) and 4N hydrogen chloride in ethyl acetate (33.5 ml) was added dropwise under ice-cooling. The mixture was stirred for 5 hours and then evaporated in vacuo to give a viscous oil, which was washed with ethyl acetate with stirring for 3 hours. The resulting powder was collected by filtration, and dried under reduced pressure to give (3S) -3-amino-7- [1,3-dihydro-5- (2-fluorophenyl) (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (2.91 g). - 37 -

Preparation 9 The following compound was obtained according to a similar procedure to that of Preparation 8.

(3 R) -3-Amino-1,3-dihydro-5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one [α] D = 33.46 (C = 0.550, CHOH)

Preparation 10

Triethylamine (1.61 g) was added dropwise to a suspension of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2- (2.0 g) in methylene chloride (30 ml) under stirring and cooling in an ice bath. The mixture was added under the same conditions as 2-naphthoyl chloride (1.52 g). The resulting precipitate was collected by filtration and washed successively with methylene chloride and water. The crystals collected were dried over phosphorus pentoxide under reduced pressure to give (3RS) -3- (2-naphylamino) -5- (2-fluorophenyl) -1,3-dihydro-2H- benzodiazepin-2-one (2.33 g) NMR (DMSO-d6, δ): 5.60 (1H, d, J = 7.7Hz), 7.22-7.39 (5H, m), 7.54-7.66 (5H, m), 7.99-8.11 (4H, m), 8.72 (1H, s), 9.74 (1H, d, J = 7.7Hz), 11.05 (1H, m). MASS (m / e): 423 (M +)

Preparation 11

The following compounds were obtained by a similar procedure to that of Preparation 10. 38 -

(3RS) -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one IR (Nujol): 3600, 1695, NMR (DMSO-d6, δ): 5.59 (1H, d, J = 7.6Hz), 7.23-7.40 (5H, m), 7.61-7.76 (4H, m) , 9.09 (1H, s), 9.40 (1H, d, J = 2.1Hz), 10.1 (1H, d, J1.6Hz), 8.16-8.16 (1H, m). 11.08 (1H, s) (2) (3RS) -3- (3,4-Dichlorobenzoylamino) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, Î'): 5.49 (1H, d, J = 7.6Hz), 7.2-8.02

MASS (m / e): 442 (M +), 11.03 (1H, s), 8.21 (1H,

Example 1

To a solution of (3S) -3-1,3-dihydro-5- (2-fluorophenyl) -1 - [(triethylamidazol-4-yl) methyl] -2- 4-benzodiazepin-2-one (1.0 g) in N, N-dimethylformamide (10 ml), (E) -3- (2-nitrophenyl) propanoic acid (330 mg), 1-hydroxybenzotriazole , N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride (320 mg) and triethylamine (170 mg) under stirring at room temperature. The mixture was stirred for 3 hours and then allowed to stand overnight. The reaction mixture was poured into a mixture of ethyl acetate and water under stirring. The separated organic phase was washed twice with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were pooled and evaporated to give an amorphous mass, which was pulverized and stirred for 3 hours.

several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure afforded (3S) -1,3-dihydro-1 - [(1-tritylamidazol-4-yl) methyl] -3- (E) -3- (2-nitrophenyl) propenoylamino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (1.16 g). NMR (CDCl 3, δ): 5.07 (2H, br s), 5.66-5.7 (1H, m), 6.49-3.84 (32H, m)

Example 2

The following compounds were obtained according to a similar procedure to Example 1. (1) (3S) -1,3-Dihydro-1 - [[ (2-amino-4-chlorobenzoyl) amino] -5- (2-fluoro-phenyl) -2H-1,4-benzodiazepin-2-one NMR (CDCl3, δ): 5.06 (2H, d, J = 3.7Hz), 5.62-5.68 (3H, m), 6.63-8.04 (29H, m) MASSA (m / e): 502 (3RS) -1,3-Dihydro-1 - [(1-tritylimidazol-4-yl) methyl] -3 - [(2,3,4,5-tetrahydro-3- oxopyridazin-6-yl) carbonylamino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

(3RS) -1,3-Dihydro-1- (1-tritylamidazol-4-yl) methyl] -3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H- , 4-benzodiazepin-2-one NMR (CDCl3, δ): 5.02 (1H, d, J = (3RS) -1,3-Dihydro-1 - [(1-tritylamidazol-4-yl) methyl] -3- (3-guinolylcarboniamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one 40 (5) (6) (7)

NMR (DMSO-d6): 5.01-5.18 (2H, m), 5.78 (1H, d, J = 7.8Hz), 6.87-8.26 (30H, m), 8.72 (1H, d, J = 1.9 MASS (m / z): 504 (M + -243), 424 (RS) -1,3-Dihydro-1 - [(1-tritylimadiazol-4- yl) methyl] -3- (2-quinoxalinylcarbonylamino) -5- (2-fluoro-phenyl) -2 H -1,4-benzodiazepin-2-one (3RS) -1,3-Dihydro- 4-yl) methyl] -3- (4-cinnolinylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one NMR (CDCl3, δ) J = 7.8Hz), 6.86-8.09 (2H, m), 8.49-8.66 (2H, m), 9.54 (2H, 1H-s) (3RS) -1,3-Dihydro-1-7- (1-tritylimidazol-4-yl) methyl] -3- (1-isoquinolylcarbonithamino) -5- (2-fluorophenyl) -2H-1 NMR (CDCl 3): 5.11 (2H, s), 5.78 (1H, d, J = 8.3Hz), 6.89-7.89 (28H, m), 8.05 (1H, , 8.59 (1H, d, J = 5.5Hz), 9.52-9.56 (1H, m), 9.93 (1H, d, J = 8.2Hz). (RS) -1,3-Dihydro-1 - [(1-tritylimidazol-4-yl) methyl] -3-nicotinoylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepine-3-one NMR (CDCl 3, δ) δ 4.99-5.16 (4H, m), 5.71 (1H, d, J = 7.7Hz), 6.85-9.18 (28H, m)

Example 3

Triethylamine (340 mg) and 2-naphthoyl chloride (320 mg) were added successively to a solution of (3RS) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl] Amino-5- (2-fluoro-phenyl) -2H-1,4-benzodiazepin-2-one (1.0 g) in methylene chloride (10 ml). The mixture was stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to an oil, which was dried under reduced pressure to give (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). NMR (CDCl 3, δ): 5.03 (2H, d, J = 15Hz), 5.15 (2H, d, J = 15Hz), 5.79 (1H, d, J = 8Hz), 6.89-8.07 (29H, m) , 8.22 (1H, d, J = 8Hz), 8.47 (1H, s)

Example 4

To a solution of (3RS) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl] -3-amino-5- (2-fluorophenyl) -2H- 4-benzodiazepin-2-one (1.5 g) in tetrahydrofuran (23 ml), m-tolyl isocyanate (0.35 g) under stirring at room temperature. The mixture was stirred for 2 hours under the same conditions. The solvent was removed from the reaction mixture in vacuo to give a crude product, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give (3RS) -1,3-dihydro-1- (1-tritylimidazol-4- -yl) methyl] -3- (3-methylphenyl) ureido-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (1.47 g). NMR (DMSO-d6, δ): 2.24 (3H, s), 4.85 (1H, d, J = 14.8Hz), 5.24-5.33 (2H, m). 6.67-7.68 (29H, m), 7.91 (1H, d, J = 8.2Hz), 8.97 (1H, s). - 42 -

Example 5

It was added portionwise to a slurry mixture of iron (1.1 g) and ammonium chloride (0.13 g) in a mixture of water (2.5 ml) and ethanol (7.5 ml) (3S) -1,3-dihydro-1 - [(1-tritylimidazol-4-yl) methyl] -3- (E) -3- (2-nitrophenyl) propenoylamino] -5- (2-fluorophenyl) ) -Hydro-1,4-benzodiazepin-2-one (1.1 g) under reflux and with stirring. Ethanol (7.5 ml) and water (2.5 ml) were then added, and the resulting mixture was refluxed under stirring for 1.5 hours. The reaction mixture was filtered through celite and the filter cake was washed several times with hot ethanol. The ethanol from the filtrate and washings were removed under reduced pressure. To the residual mixture was added a saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml). After washing with water and drying over magnesium sulfate, the extract was evaporated to give an amorphous residue which was pulverized with diisopropyl ether and collected by filtration to give (3S) -1,3-dihydro- 4-yl) methyl] -3 - [(E) -3- (2-aminophenyl) propenoylamino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepine NMR (CDCl3, δ): 3.71-4.07 (2H, br d), 5.06 (2H, s), 5.68 (1H, d, J = 8Hz), 6.47- 7.99 (32H, m) MASS (m / e): 476 (M + -260)

Example 6

To a solution of (3S) -1,3-dihydro-1 - [(1-tritylamino4-yl) methyl] -3 - ((S) -3- (2-aminophenyl) ) propenoylamino] -S- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (0.49 g) in N, N-dimethylformamide (4.9 mL), 6N hydrochloric acid (3.4 mL ) under stirring and cooling in an ice bath. The mixture was warmed to 50 ° C and stirred for 1 hour. After cooling to the temperature

After stirring to the reaction mixture, water and ethyl acetate were added. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic phase was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with disopropyl ether and drying under reduced pressure gave (3S) -1,3-dihydro-1- (4-imidazol-3-yl) -3- (2-aminophenyl) ) propenylamino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride (350 mg) was added 20% hydrogen chloride in ethanol (5 ml) under cooling.

The pale yellow solution was evaporated to dryness under reduced pressure. The residue was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure afforded a yellow powder (234mg) of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (E ) -3- (2-aminophenyl) propenoylamino] > 7-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. NMR (CDCl3, δ): 3.8-4.8 (2H, b), 5.15-5.56 (3H, m), 7.04-7.81 (18H, m), 9.03 (1H, s), 9.43 (1H, d, J-8Hz) MASS (m / e): 494 (M + -73), 476

The following compounds were obtained according to a similar procedure to Example 6. (1) (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3 - [(2-amino-4- chloro-benzoyl) amino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-

NMR (CDCl3) δ 4.93 (1H / d, J = 15Hz), 5.20 (1H, d, J = 15Hz) (2H, m), 6.98-7.26 (6H, m), 7.40-7.69 (5H, m), 7.89-7.91 (2H, m) MASS (m / e): 502 (M +) (2) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- [ tetrahydro-3-oxopyridizin-6-yl) carbonyl] -5- (2-fluorophenyl) -2H-1,4-benzo-diazepin-2-one mp 230-240 ° C (dec.) IR (1H, d, J = 16Hz), 5.42 (1H, m) (1H, d, J = 16Hz), 5.43 (1H, d, J = 7.8Hz), 7.15-7.78 (9H, m), 8.58 (1H, d, s), 11.31 (1H, s), 14.67 (1H, br s) MASS (m / e) s 393 (M + -153) (3) (3RS) -1,3-Dihydro- (4-imidazolylmethyl) -3 - [(3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp 212-230 ° C (dec.) IR (Nujol): 3650, 3150, 2650-2000, 1650, 1600, 1510 cm @ -1 NMR (DMSO-d6, δ): 5.20 (1H, d, J = 16Hz), (1H, d, J = 7.3Hz), 7.19-7.82 (10H, m), 7.98 (1H, dd, J = 2Hz, 8Hz), 8.30 (1H, d, J = = 2Hz), 9.02 (1H, m), 4. V (4) (5)

MASS (m / e): 521 (M + -37), 441 (3RS) -1,3-Dihydro- Dihydro-1- (4-imidazolylmethyl) -3 - [(3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride (230-233 ° C dec.) IR (Nujol) 3600-3100, 2700-2100, 1670, 1610, 1510 cm -1 NMR (DMSO-d6, Î') Î'5.24 (1H, d, J = 16Hz), 5.47 (1H, d , J = 16.1Hz), 5.71 (1H, d, J = 7.2Hz), 7.2-8.39 (13H, m), 9.05 (1H, d, J = 1.1Hz), 9.48 (1H, d, J (1H, d, J = 7.2Hz), 14.72 (1H, br.s) MASS (m / e): 504 (M + -73) (4RS) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-quinoxanylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride NMR (DMSO-d6, δ): δ 5.25 (1H, d, J = 16.1Hz), 4.95 (1H, d, J = (1H, d, J = 7.8Hz), 7.18-8.35 (13H, m), 9.04 (1H, s), 9.53 - 9.61 (2H, m) ), 14.63 (1H, m) MASS (m / e) t 505 (M + -36), 425-146 (6)

(3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (4-imidazolylmethyl) -3- (4-cinnolinylcarbonylamino) -5- (2-fluoro-phenyl) -2H-1,4-benzodiazepin-2-one mp 215-230 ° C (dec.) -1 IR (Nujol): 3600-3100, 2700-2100, 1660, 1610 cm -1 NMR (DMSO- (1H, m), 9.01 (1H, s), 9.48 (1H, s), 10.46 (1H, d, J = 7.1Hz), 5.21-5.72 (3H, m), 7.18-8.61 (13H, 14.61 (1H, br s) MASS (m / e). 505 (M + -73), 448 (7) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3 - [(1-isoquinolylcarbonylamino) -5- (2-fluoro- phenyl) -2H-1,4-benzodiazepin-2-one mp 209-220 ° C (dec.) IR (Nujol) 3600-3200, 2700-2100, 1670-1610 cm- 1 NMR (DMSO) (1H, d, tf = 5.6Hz), 9.03 (1H, d, J = 7.7Hz), 7.23-8.19 (13H, m) (1H, d, J = 7.7 Hz), 14.62 (1H, br s) MASS (m / e): 504 (M + -73), 424 (8) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3-nicotinoylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one dihydrochloride NMR (DMSO-d6, δ): 5.21 (1H, d, J = 16.1Hz), 5.45 (1H, d, J = 10.1Hz), 5.64 (1H, d, J J = 7.2Hz), 7.2-8.0 (1H, m), 8.76-9.04 (2H, m), 9.32 (1H, s), 10.32 (1H, d, J = 7.2Hz), 14.67 (1H, br s) MASS (m / e): 454 (M + -73) -47 (9)

(3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-naphthoylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride NMR (DMSO-d6, Î'): 5.22 (1H, d, J = 16Hz), 5.22 (1H, d, J = 16Hz) D, J = 7.4Hz), 7.19-8.1 (15H, m), 8.70 (1H, s), 9.03 (1H, s), 9.78 (1H, MASS (m / e): 503 (M + -37), 427 (10) (3RS) -1,3-Dihydro-1- (4-chlorophenyl) imidazolylmethyl) -3- [3- (3-methylphenyl) ureido-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp: 217-225 ° C (dec.) NMR (DMSO-d6, δ): 2.24 (3H, s), 5.06 (2H, s), 5.26 (1H, d, J = 8.4Hz) ), 6.74 (1H, d, J = 6.6Hz), 6.87 (1H, s), 7.07-7.71 (13H, m), 8.02 (1H, d, J = 8,0Hz), 8.99 (1H, s) )

Ixemolo 8

To a mixture of (3RS) -1,3-dibhydro-3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one ( 850 mg) and 1-trityl-4- (2-chloroethyl) imidazole monohydrochloride (900 mg) in N, N-dimethylformamide, sodium hydride (60% suspension in mineral oil, 180 mg) and iodide (3.98 g) was added dropwise under stirring and recooled at 0øC in an ice bath in a stream of nitrogen. The mixture was stirred at room temperature for 1.5 -

hours and at 60-65 ° C for 6 hours. Acetic acid (2 ml) was added to the reaction mixture. The reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic phase was washed with water. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were evaporated and evaporated to give an amorphous mass, which was dried under reduced pressure to give (3RS) -1,3-dihydro-1- [2- (1- 4-yl) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (750 mg). NMR (DMSO-d6, δ): 2.49-2.65 (2H, m), 3.8-4.6 (2H, m), 5.62 (1H, d, J = 7.48Hz), 6.70 (1H, s) 8.1 (28Hz, m), 9.05 (1H, s), 9.35 (1H, d, J = 2.2Hz), 10.0 (1H, d, J = 7.64Hz).

Example 9

To a solution of (3RS) -1,3-dihydro-3- (2-phthyoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2- , 25 g) in N, N-dimethylformamide (31 ml), sodium hydride (60% suspension in mineral oil, 130 mg) under stirring and cooling to 0øC in a nitrogen salt bath. After stirring the mixture at room temperature for 45 minutes, a solution of chloroacetonitrile (270 mg) in N, N-dimethylformamide (5 ml) was added to the mixture at 0 ° C under stirring. The resulting mixture was stirred overnight at ambient temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resulting mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. Washed; the organic phase separated with water. The solvent was removed under reduced pressure.

reduced pressure to give an amorphous residue, which was purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to an amorphous mass, which was dried under reduced pressure to provide (3RS) -1,3-dihydro-1-cyanomethyl-3- (2-naphthoylamino) ) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (1.19 g), NMR (DMSO-d6, δ): 5.08-5.32 (23.0), 5.74 ( 1H, d, J 7.65Hz), 7.25-7.82 (14H, m), 8.71 (1H, s), 9.95 (1H, d, J = 7.6Hz).

Exemolo 10

The following compounds were obtained by procedures similar to those reported in Examples 8 and 9 (1). (3RS) -1,3-Dihydro-3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) (1H-tetrazol-5-yl) methyl] -2 H -1,4-benzodiazepin-2-one

NMR (DMSO-d6, δ): 5.4-5.62 (2H, m), 5.76 (1H, d, J = 7.4Hz) (1H, m), 7.86-7.93 (2H, m), 8.09-8.32 (2H, m), 9.05 (1H, s) (M / e): 507 (M +), 424 (M + H) +. 1H NMR (400 MHz, CDCl3) (3RS) -Dihydro-3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2H- Benzodiazepin-2-one 50-

NMR (DMSO-d6): 3.83 (1H, br s), 5.2-5.46 (2H, m), 4.60 (1H, , 5.63 (1H, d, J = 7.8Hz), 7.14-7.33 (5H, m), 7.55-7.67 (4H, m), 7.77 (1H, d, J = 8.4Hz), 7.97 (2H, d, J MS (m / e): 524 (M +), 368 (M + -156), 8.48 (1H, d, J = (3) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -1- [ (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one mp 280-290 ° C (dec.) IR (Nujol)% 3150, 1640, 1540 cm -1 NMR (DMSO- (1H, d, J = 8.1Hz), 7.02-7.66 (13H, m), 7.97 (1H, d, J = 8.2Hz), 9.52 (1H, 1H NMR (d6-DMSO-d6): δ (1H, d, J = 8.18Hz), 11.67 (1H, s) 2- (4-imidazolyl) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp 165 DEG- (3S) -3- (2-indolylcarbonylamino) -1,3-dihydro-3- (3,4-dichlorophenyl) -1,3-dihydro- , 5- (2-fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-

(DMSO-d 6, δ): 5.49 (2H, ABq, J = 16.4Hz, 24.8Hz), 5.73 (1H, d, J = 8.0Hz), 7.0-7.91 (14H, m), 9.60 (1H, d , J = 8.0Hz), 11.65 (1H, s)

Example 11

To a solution of (3RS) -1,3-dihydro-11- [2- (2- (1-tritylimidazol-4-yl) ethyl] -3- (3-quinolinylcarbonylamino) -5- (740 mg) in N, N-dimethylformamide (7.4 ml), 6N hydrochloric acid (5.18 ml) under argon was added The mixture was warmed to 60-70 ° C and stirred for one hour. After cooling to room temperature, water was added to the reaction mixture with ice-water and ethyl acetate under stirring The organic phase was washed with water and dried, and the solvent was removed under reduced pressure to give an amorphous residue which was evaporated to dryness. was purified by column chromatography on silica gel with an eluent of chloroform The fractions containing the desired product were combined and evaporated to give an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether The filtrate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give (3RS) -1,3-dihydro-1- [2- (2- (4- imidazole) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiaperpin-2-one (0.25 g), mp 165-175 ° C (dec. ) IR (Nujol) 3600-3000, 1650, 1600 cm -1 NMR (DMSO-d6, δ): 2.52-2.62 (2H, m), 4.09-4.63 (2H, m), 5.65 ( (1H, d, J = 7.6Hz), 6.77 (1H, s), 7. 24-8.3 (13H, m), 9.07 (1H, d, J = 1.92Hz), 9.39 (1H, d, J = 2.2 J = 7.6 Hz), 11.82 (1H, br s) MASS (m / e): 518 (M +): 52

Example 12

To a mixture of (3RS) -1,3-dihydro-3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one ( 500 mg) and 1-trityl-4- (2-chloroethyl) imidazole monohydrochloride (295 mg) in N, N -dimethylformamide (7.5 ml), sodium hydride (60% suspension in mineral oil, , 5 mg) and sodium iodide (2.25 g) under stirring and cooling to 0Â ° C in a salt bath is ice under nitrogen stream. The mixture was then stirred at room temperature for 1.5 hours and at 60-65 ° C for 6 hours. Acetic acid (1.1 ml) and 6N hydrochloric acid (5 ml) were added to the reaction mixture and the mixture was stirred at 60-70 ° C for one hour. The mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml) under stirring. The mixture was stirred at pH 8 with aqueous sodium bicarbonate solution. The separated organic phase was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were cotrified and evaporated to give an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure afforded (3RS) -1,3-dihydro-1-2- (4-imidazolyl) ethyl] -3- (3,4-dichlorobenzoylamino) -5- (2-fluoro-phenyl) -2H-1,4-benzodiazepin-2-one (0.18 g).

mp: 149-159 ° C IR (Nujol) 3600-3100, 1650, 1600 cm -1 NMR (DMSO-d6 / δ): 2.5-2.59 (2H, m), 3.95-4.62 (2H, m), 5.5 (1H, br s), 11.8 (1H, br s), MASS (m / z) e) i 386 (M + -150) 53

Example 13

The following compounds were obtained according to a similar procedure to Example 12. (1) (3RS) -1,3-Dihydro-1- [2- (4-imidazolyl) ethyl] -3- (2-naphthoylamino ) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2-one mp 198-205 ° C (dec.) IR (Nujol) s 3275, 1580, 1630, 1530 cm -1 NMR (DMSO-d6, Î'): 2.5-2.8 (2H, m), 4.0-4.6 (2H, m), 5.65 (1H, d, J = 7.67Hz), 6.81 (1H, br s), 7.24 MS (m / e): 518 (M +) (2) (3RS), 8.89 (1H, ) -1,3-Dihydro-1- [2- (4-imidazolyl) ethyl] -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2 -one mp 188-205 ° C (dec.) IR (Nujol) s 3550-3100, 1640, 1540 cm-1 NMR (DMSO-d6, δ): 2.51-2.65 (ZH, m), 4.01-4.08 (1H, m), 4.50-4.57 (1H, m), 5.63 (1H, d, J = 7.9Hz), 6.56 (1H, s), 6.76-7.81 (14H, m), 9.60 (1H, d, J = 7.9Hz), 11.64 (1H, s), 11.81 (1H, br s)

Example 14

A mixture of (3RS) -1,3-dihydro-1-cyanomethyl-3- (2-naphthoylamino) - (1)

(1.15 g), sodium azide (480 mg) and triethylamine monohydrochloride (510 mg) in 1-methyl-2-pyrrolidone (20 ml). The reaction mixture was poured into 5 g hydrochloric acid (100 ml) under stirring. The resulting precipitates were collected by filtration, washed with water and purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were partitioned and evaporated to give an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure afforded (3RS) -1,3-dihydro-3- (2-naphthoylamino) -5- (2-fluorophenyl) -1- [ 1H-tetrazol-5-yl) metsl-5-yl) methyl] -2 H -1,4-benzodiazepin-2-one (540 mg). (DMSO-d 6, δ): 5.33 (2H, s), 5.73 (1H, d, J = 7.6Hz) = 7.98Hz), 7.18-8.0 9 (15H, m), 8.69 (1H, s), 9.72 (1H, d, J = 8Hz) MASS (m / e): 505 (M +) The following compound was obtained (3S) -3- (2-indolylcarbonylamino) -1,3-dibromo-5- (2-fluorophenyl) -1- (1H, tetrazole NMR (DMSO-d6, δ): 5.49 (2H, ABq, J = 16.4Hz, 24.8Hz), 5.73 (δ, d, J = = 8.0Hz), 7.0~7.91 (14H, m), 9.60 (1H, d, J = 8Hz), 11.65 (1H, s).

Example 15

4-Chloro-phenyl isocyanate (0.14 g) was added to a solution of (3RS) -3-amino-1,3-dihydro-5- (4-chlorophenyl) 1H-tetrazol-5-yl) methyl 2 H -1,4-benzo-diazepin-2-one (0.50 g) in anhydrous tetrahydrofuran (10 ml) at room temperature. The mixture was then stirred for 3 hours, 8.4N hydrogen chloride in ethanol (1.5 ml) was added to the mixture at room temperature and then the mixture was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was suspended with a mixture of ethanol and ethyl acetate and the resulting precipitate was collected by filtration to give (3RS) -1,3-dihydro-3- [3- (4-chlorophenyl) 5-phenyl-1- (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (0.40 g).

1 H-NMR (DMSO-d 6, δ) 5.30-5.50 (1H, m), 5.46 (2H, d, ABg, J = 17Hz, 24Hz), 7. 20-7.85 (15H, m), 9.0-11.0 (1H, broad), 9.42 (1H, s)

Example 16

The following compounds were obtained according to a similar procedure to Example 15. 56 - 1

(3RS) -1,3-Dihydro-3- [3- (4-chlorophenyl) ureido] -5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] -2H-1 , 4-benzodiazepin-2-one

mp: 203-205 ° C IR (Nujol) 3320, 3250, 3190, 2720, 1695, 1605, 1525 cm @ -1 NMR (DMSO- d6, δ): 5.30-5.40 (1H, m), 5.48 (2H, ABq , J = 17 Hz, 21 Hz), 7. 20- 7.80 (13H, m), 8.0-10.5 (2H, br), 9.37 (1H, s)

(3RS) -1,3-Dihydro-3- (3-methylphenyl) ureido] -5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] benzoic acid monohydrochloride (Nujol): 3290, 2720, 2605, 1685, 1610, 1595, 1540 cm -1 NMR (DMSO-d 6, (1H, m), 7.00-7.54 (12H, m), 5.00 (1H, s), 5.46 (2H, (3RS) -1,3-Dihydro-5- (2-fluorophenyl) -3- (3-methylphenyl) -1H-benzoimidazole monohydrochloride (1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one mp 181-191 ° C NMR (DMSO-d6, δ): 2.24 (3H, s), 5.35-5.45 (1H, m), 5.48 (1H, 2H), 7.50-7.38 (7H, m), 7.50-7.81 (6H, m), 8.0-10.4 (2H, broad), 9.11 (1H, , s).

Example 17 To a solution of (3S) -1,3-dihydro-1 - (1-tritylimidazol-4-yl) methyl] -3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (20.34 g) in N, N-dimethylformamide · (204 ml), 6N hydrochloric acid (157 ml) under stirring and cooling in an ice bath . The mixture was heated to 70-80 ° C and stirred for 1 hour. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture.

under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic phase was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous residue, which was purified by silica gel column chromatography with an eluent of chloroform. The fractions containing the desired product were combined and evaporated to give an amorphous mass, which was dried under reduced pressure to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -4-yl) -3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1,4-benzo-diazepin-2-one. This compound was dissolved in chloroform (200 mL) and 20% hydrogen chloride in ethanol (50 mL) was added under cooling to the resulting solution. The yellow solution was evaporated to dryness under reduced pressure to give an amorphous mass, which was lyophilized to give (3S) -1,3-dihydro-1 - [(4-imidazolyl) (3,4-dichlorobenzoylamino) -5- (2-fluoro-phenyl) -2H-1,4-benzodiazepin-2-one as a yellow powder (12.97%). NMR (DMSO-d6 / S) δ 5.19 (1H, d, J = 10Hz), 5.43 (1H, d, J = 16Hz) , 5.61 (1H, d, J = 7.3Hz), 7.19-7.39 (5H, m), 7.56-7.82 (5H, m), 7.95-8.00 (1H, m), 8.30 (1H, d, J = 1.9 MASS (m / e): 521 (M + -37) Î'-24.75Â ° (DMSO-d6): Î'= 0.6 (1H, 0.83 (br, 2H)

Example 18

To a suspension of 2-indolecarboxylic acid (161.2 mg) in methylene chloride (3.25 ml), thionyl chloride (119.0 mg) and one drop of N, N-dimethylformamide under stirring at room temperature. The mixture was re-fluxed for 1 hour with stirring. 58-

was added dropwise to a solution of (3S) -amino-1,3-dihydro-5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] -2H-1 , 4-benzodiazepin-2-one (387/8 mg) and triethylamine (506/0 mg) in methylene chloride (8 ml) were added dropwise the above solution of 2-indolylcarbonyl chloride in methylene chloride under ice-cooling and stirring . The mixture was stirred under the same conditions as above for 3 hours. Chloroform was added to the reaction mixture. The mixture was washed successively with dilute hydrochloric acid and water and dried over magnesium sulfate. Removal of the solvent in vacuo afforded an amorphous mass, which was slurried with stirring in diisopropyl ether. The resulting powder was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to afford (3S) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1- [1 (t-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one. mp 270-271 ° C (dec.) / -quot; -18.87 ° (C = 0.62, tetrahydrofuran)

NMR (DMSO-d6, δ): 5.49 (2H, ABq, J = 16.4Hz, 24.8Hz), 5.73 (1H, d, J = 8.0Hz), 7.0-7.91 (14H, m), 9.60 (1H, d , J = 8.0Hz), 11.65 (1H, s) MASS (m / e) 494 (M +).

Example 19 The following compound was obtained according to a similar procedure to Example 18. (3R) -3- (2-Indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) (1H -tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one NMR: (DMSO-d6) (1H, d, J = 8.0Hz), 7.0-7.91 (14H, m), 9.60 (1H, d, J = J = 8.0Hz), 11.65 (1H, s) MASS (m / e) 494 (M +)

Example 20

The following compounds were obtained according to a similar procedure to that of Example 1 (1) (3S) -1,3-dihydro-1 - [(1-tritylimidazol-4-yl) methyl] -3- (3- (1H, d, J = 15Hz), 5.11 (1H, d, J = 15Hz) (1H, d, J = 15Hz), 5.67 (1H, d, J = 7.8Hz), 6.84-8.04 (29H, m) (2RS) -1,3-dihydro- 4-imidazolyl) ethyl] -3- (3-quinolinecarboxylic acid) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp 165-175Â ° C (dec.) IR (Netirol) 3600-3000, 1650, 1600 cm -1 Example 21 The following compound was obtained according to a similar procedure to Example 11. (3S) - 3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2- one 60

Claims (1)

NMR (DMSO-d 6) δ 5.49 (2H, ABq, J = 16.4Hz, 24.8Hz), δ 5.73 (1H, d, J = 8.0Hz), 7.0-7.91 (14H, m), 9.60 (1H, d , J = 8.0Hz), 11.65 (1H, s) A process for the preparation of a compound of formula AR 1 NHCO-R wherein R 1 is a heterocyclic group which may have one or more suitable substituents, or cyano, R 2 is hydrogen or halogen, R 2 is aryl which may have one or more suitable substituents, R 2 is an aryl group which may have one or more suitable substituents, aralkenyl (lower) which may have one or more suitable substituents, arylamino which may have one or more suitable substituents, heteromonocyclic which may have one or more suitable substituents, quinolyl, isoquinolyl, cinnolyl, indolyl, or quinoxalyl, and A is lower alkylene, (I) R '*' is tetrazolyl which may have one or more suitable substituents, and R is halophenyl or (ii) R 'and imidazolyl which may be one or more suitable substituents, and R is halophenyl and A is ethylene, or a salt thereof, characterized in that (1) reacting a compound of formula 1 AR In which R 1, R 2 and R 3 are as defined above, or a reactive derivative thereof on the amino group, or a salt thereof with a compound of the formula wherein R 2 and as defined above, or a reactive derivative thereof or a salt thereof to provide a compound of formula R AIR (2) wherein R, R 2, R 3, R 4 and A are as defined above or a salt thereof or a compound of formula Wherein R, R / R " and A are as defined above, and is a heterocyclic group with an imino group of the formula XI / 6,6 *. wherein R 1 is an imino protecting group in its hetero ring which may have one or more suitable substituents or a salt thereof for the imino-protective group elimination reaction to give a compound of formula 63- * > NHCO-R '4 2 3 4 in which R 1, R 2, R 3 and A are as defined above, and R' * ' is a heterocyclic group having an imino group of the formula in its hetero ring, which may have one or more suitable substituents, or a salt thereof, or In which R 1, R 2, R 3 and A are as defined above, and R 4 and (lower) aralkenyl having a nitro group, or a salt thereof to give a compound of the formula In which R 1, R 2, R 3 and A are as defined above, and R 4 and (lower) aralkenyl having an amino group, or a salt thereof, or reacting a compound with the formula Wherein R1, R2 and R3 are as defined above, or a salt thereof with a compound of formula X-A-R1 in which R1 and A are as defined above, and X is an acid residue, or a salt thereof to provide a compound of formula A-R 1, NPICO-R to R " in which R 1, R 2, R 3, R 4 and A are as defined above or a salt thereof or reacting a compound of the formula U A-CN a salt thereof with a compound of formula m 3 or a salt thereof to provide a compound of formula in which R 1, R 2, R 3 and A are as defined above or a salt thereof. A process for the preparation of a compound of formula 66 - In which is tetrazolyl which may have one or more suitable substituents, R is hydrogen or halogen, R is aryl which may have one or more suitable substituents, and A is lower alkylene, or a salt thereof, characterized in that there is provided a compound of formula A-R1 In which R 1, R 2, R 3 and A are as defined above, and ???????? R is protected amino, or a salt thereof for the amino-protecting group elimination reaction. 3. A compound according to claim 1, wherein R 1 is tetrazolyl which may have an imino-protecting, imidazolyl group which may have an imino-protecting group, or cyano. 67 - R " is phenyl or halophenyl, is phenyl or naphthyl, each of which may have one or two substituents selected from the group consisting of halogen and amino, phenyl (lower) alkenyl which may contain amino or nitro, phenylamino which may contain alkyl or halogen, pyridyl, tetrahydropyridazinyl group which may contain an oxo, quinolinyl, isoquinolinyl, cinnolinyl, indolyl, or quinoxalyl group. 4. A compound according to claim 3, wherein R 1 is tetrazolyl which may have mono (or di or tri) phenylalkyl (lower), imidazolyl which may have mono (oudi or tri) phenylalkyl ( (lower) alkylaminophenyl (lower) alkenyl, lower alkylphenylamino, halophenylamino, pyridyl, tetrahydropyridazinyl having an oxo, quinolinyl, isoquinolinyl, , cinnolinyl, indolyl, or quinoxalinyl. A compound according to claim 4, wherein R 1 is tetrazolyl, R 2 is hydrogen, 3, R 4 and halo phenyl, R 4 is indolyl and A is (1-4C) alkylene, . A process according to claim 5, in which the compound A process for the preparation of a pharmaceutical composition comprising incorporating as the active ingredient a compound as prepared according to claim 1 in association with a pharmaceutically acceptable carrier. The applicant claims the priority of the British patent application filed on July 19, 1990, under Nos. 9015879.1. Lisbon, 18 July 1991. 0 AffiSIIE OElCIAt ®Λ ΕΕΘΓΜΞϋΑΜ MBIJSTJEIAJL 69 -