HUT63627A - Process for producing benzodiazepine derivatives and pharmaceutical compositions comprising same - Google Patents

Description

The present invention relates to novel benzodiazepine derivatives for use as a medicament, and pharmaceutically acceptable salts thereof.

Certain benzodiazepine derivatives are known, for example, from European Patent Application Publication No. 349949 and U.S. Patent No. 4,820,834.

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

More particularly, the present invention relates to novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are antagonists (agents) of cholecystokinin (CCK), such as vomiting, inflammation of the pancreas, disorders of the appetite control system, pain, pancreas. cancers of the islands, gastric obstruction, pancreatic diseases, gallbladder diseases (such as acute inflammation of the gallbladder, gallstones and the like), disorders associated with hyperactivity of the intestinal smooth muscle (e.g., gastrointestinal hypersensitivity syndrome, , for the therapeutic and / or prophylactic treatment of increased insulin production, indigestion, nausea and the like.

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

R · * · is a heterocyclic group or a cyano group optionally substituted with one or more suitable groups;

R ²

R ³

R ⁴ is hydrogen or halogen, aryl optionally substituted with one or more suitable groups, aryl optionally substituted with one or more suitable groups, lower alkenyl optionally substituted with one or more suitable groups, optionally with one or more suitable groups substituted arylamino-substituted, optionally substituted with one or more suitable groups, monocyclic (monocyclic) heterocyclic, quinolyl, isoquinolyl, cinnolinyl, indolyl or quinoxalinyl, and with the proviso that when R ⁴ is , then

the)

represents a tetrazolyl group optionally substituted with one or more suitable groups and at the same time represents a halogenated phenyl group or an imidazolyl group optionally substituted with one or more suitable groups, represents a halogenated phenyl group and represents an ethylene group.

• · · ·

According to the present invention, the benzodiazepine derivatives of formula (I) may be prepared according to process variant (a) to (e) as illustrated in Schemes A to E.

In the general formulas of the above Schemes

R ^1, R ^2, R ^3, R ⁴ and A are as defined above,

R _¹ is optionally substituted with one or more suitable substituents heterocyclyl radical in which R6 is imino-protective group, a protected imino group of the heterocyclic ring contains a formula (a),

R ¹ -) is a heterocyclic group optionally substituted with one or more suitable groups and containing an imino group of formula (b) in the heterogene ring,

R ⁴ is substituted with _the nitro group, to groups bearing a lower alkenyl group,

R ^{4 'represents} a substituted amino group, a lower alkenyl group bearing chapter, and

X is an acid residue.

The starting compounds of formula (II) and (IV) may be prepared according to process variants (f) and (g) as illustrated in Schemes F and G.

In the general formulas in the latter two schemes, · · · ·

R 5, R ² , R ³ , R ⁴ and A are as defined above, and

R ⁷ is a protected amino group.

Compounds of formula (VII) used as starting material in process variant (f) and salts thereof may be prepared by the methods described in Examples 1-3, 6 and 7 below or in a similar manner.

When a compound of formula I contains a 4-imidazolyl group of formula R ^{1 in} R ¹ , this group may exist in two tautomeric forms and the equilibrium of the two tautomeric forms can be illustrated by the Scheme H.

The present invention encompasses both isomers which can be prescribed by tautomerism. For the sake of simplicity, compounds containing such tautomeric groups in the present specification and claims are characterized by the tautomer of formula (A).

Further, when a compound of formula (I) contains an 1H-tetrazol-5-yl group of formula (R ¹ ) in the R ¹ group, this group may exist in two tautomeric forms and the equilibrium of the tautomers may be represented by the following scheme. .

Both isomers formed by tautomerism are within the scope of the present invention. In the present specification and claims, compounds containing such tautomeric groups are represented by formula (C) for simplicity.

«· · · ·

Suitable pharmaceutically acceptable salts of the compounds of formula (I) of the present invention include the conventional non-toxic salts. These include, for example, metal salts such as alkali metal salts (e.g., sodium salt, potassium salt and the like), alkaline earth metal salts (e.g., calcium salt, magnesium salt and the like), ammonium salts, salts with organic bases (e.g., trimethylamine, with triethylamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like, salts with organic acids (e.g., acetate, maleate, tartrate, methanesulfonate, benzene). sulfonate, formate, toluene sulfonate, trifluoroacetate and the like), salts with organic acids (e.g. hydrochloride, hydrobromide, sulfate, phosphate and the like), salts with amino acids (e.g. arginine, aspartic acid, glutamic acid) and the like, and the like).

Examples which may be used in connection with each of the definitions hereinabove and hereinbelow are illustrative of the scope of the present invention and are explained in detail below.

Unless otherwise stated, the term "lower carbon" refers to a group containing 1 to 6 carbon atoms.

A suitable heterocyclic group may be, for example, a saturated or unsaturated, monocyclic (monocyclic) or polycyclic (multicyclic) heterocyclic group containing at least one heteroatom such as oxygen, sulfur,

containing nitrogen or the like. Particularly preferred heterocyclic groups include an unsaturated 3-8 membered monocyclic heterocyclic group containing 1-4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydro , tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, and the like), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, and the like), dihydro-triazinyl (e.g.

4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl and the like), and the like;

a saturated 3- to 8-membered monocyclic heterocyclic group containing from 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and the like;

unsaturated condensed heterocyclic groups containing from 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolepyridyl, 5-b-pyridazinyl and the like), dihydro-triazolo-pyridazinyl and the like;

··· ♦ «♦«

an unsaturated 3 to 8 membered monocyclic heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g., oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3); , 4-oxadiazolyl, 1,2,5-oxadiazolyl and the like), and the like;

a saturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl and the like;

unsaturated, fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl and the like;

unsaturated 3-8 membered monocyclic heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g.

1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl) , 1,2,3-thiadiazolyl and the like;

a saturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl and the like;

an unsaturated 3- to 8-membered monocyclic heterocyclic group containing one oxygen atom, such as furyl and the like;

an unsaturated 3- to 8-membered monocyclic heterocyclic group containing a sulfur atom, such as thienyl and the like;

"· · ·

- 9 unsaturated, fused, heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl and the like.

An optionally substituted heterocyclic group and one or more suitable monocyclic heterocyclic group optionally substituted group include, for example, an amino group, a protected amino group, exemplified below, an oxo group, a hydroxy group, Examples include the imine protecting group, lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like, and others like that.

A suitable protected amino group may be, for example, an acylamino group and the like.

A suitable imine protecting group may be, for example, an acyl group, a lower alkyl group substituted by one, two or three phenyl groups (such as trityl and the like), tetrahydropyranyl and the like.

Suitable acyl groups on an acylamino group include, for example, an aliphatic acyl group or an acyl group containing an aromatic or heterocyclic group.

A suitable, said acyl group is, for example, a lower alkanoyl group (e.g., formyl group, acetyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, oxalyl group). , succinyl, pivaloyl and the like);

lower alkoxycarbonyl group (e.g. methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, 1-cyclopropylethoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like);

lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, and the like); arylsulfonyl group (e.g. benzenesulfonyl group, tosyl group and the like);

aroyl (e.g., benzoyl, toluyl, xyloyl, naphthoyl, phthaloyl, indanecarbonyl and the like);

lower alkanoyl (such as phenylacetyl, phenylpropionyl and the like); lower alkoxycarbonyl (e.g., benzyloxycarbonyl, phenylethoxycarbonyl, and the like) and the like.

As mentioned above, the acyl group may be linked to at least one suitable substituent group such as a halogen atom (e.g., chlorine, bromine, fluorine).

V ··· or iodine), an amino group, a protected amino group (e.g., a lower alkanoylamino group, a phenylthioureido group, and the like), and the like.

A suitable acid residue group may be, for example, halogen and the like.

A suitable halogen atom is, for example, a chlorine atom, a bromine atom, a fluorine atom or an iodine atom.

Suitable aryl groups on a lower alkenyl group or on an arylamino group include, for example, phenyl, naphthyl and the like.

A suitable substituent on an aryl group optionally substituted by one or more suitable groups, a lower alkenyl group optionally substituted by one or more suitable groups, or an arylamino group optionally substituted by one or more suitable groups examples include hydroxy groups, protected hydroxy groups exemplified below, nitro groups, lower alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tertiary-pentyloxy), amino group exemplified above, protected amino, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl «·« «4« * «· ·· • * _Α · · · *? · 4 · group, secondary butyl, ter cert-butyl, pentyl, tertiary-pentyl, hexyl and the like), the halogen atom exemplified above, and the like.

Suitable lower alkenyl groups for lower alkenyl include, for example, vinyl, allyl, 1-propenyl, 1-, 2-, or 3-butenyl, 1-, 2-, 3- or 4-pentenyl. , 1-, 2-, 3-, 4- or 5-hexenyl and the like.

A suitable monocyclic heterocyclic group may be, for example, a saturated or unsaturated monocyclic heterocyclic group containing at least one heteroatom such as oxygen, sulfur, nitrogen or the like. Particularly preferably, the monocyclic heterocyclic group may be, for example, an unsaturated 3-8-membered monocyclic heterocyclic group containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, pyridazinyl, , tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, and the like). , tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl and the like), dihydro-triazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro- 1,2,4-triazinyl and the like) and the like;

13 saturated, 3 to 8 membered, monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and the like;

unsaturated 3-8 membered monocyclic heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3) , 4-oxadiazolyl, 1,2,5-oxadiazolyl and the like), and the like;

a saturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl and the like;

unsaturated 3-8 membered monocyclic heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g.

1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl) , 1,2,3-thiadiazolyl and the like); a saturated 3- to 8-membered monocyclic heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl and the like;

an unsaturated 3- to 8-membered monocyclic heterocyclic group containing one oxygen atom, such as furyl and the like;

· ♦ ♦ * * * * * * * ♦ ♦ ♦ · · · · ·

14 unsaturated 3 to 8 membered monocyclic heterocyclic groups containing one sulfur atom, such as thienyl and the like; and the like.

A suitable lower alkylene group may be, for example, a linear or branched C 1 -C 6 group such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like, preferably C 1 -C 4. The heterogene ring of formula (a) wherein

Preferred heterocyclic groups in the groups represented by the terms imino-protecting group, protected imino-containing heterocyclic group and heterocyclic group containing an imino-group of formula (b) in the heterocycle include, for example, an unsaturated 3-8 membered, 1-4 nitrogen atom, a monocyclic heterocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl and the like), dihydro-triazinyl (e.g., 4,5-dihydro- 1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl and the like), and the like;

• · · - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

A saturated 3 to 8 membered monocyclic heterocyclic group containing from 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and the like;

and other, like. Preferred are compounds of formula I wherein R ¹ is a heterocyclic group (more preferably an unsaturated 3-8 membered monocyclic heterocyclic group containing 1-4 nitrogen atoms, most preferably a tetrazolyl group or an imidazolyl group) which may be optionally substituted with one to three (more preferably one) suitable groups. more preferably tetrazolyl or imidazolyl, any of which may have an imine protecting group; most preferably, a tetrazolyl group or an imidazolyl group, any of which may be substituted with a lower alkyl group having one, two or three phenyl groups, or a cyano group; R ² is hydrogen; R ³ is aryl (more preferably phenyl) which may be substituted with one to three (more preferably one) suitable groups (more preferably phenyl or halogenated phenyl);

• · · * · · ·

- 16 R ⁴ is aryl (more preferably phenyl or naphthyl) which optionally may be substituted by one to three (more preferably one or two) suitable substituent / is this group, more preferably phenyl or naphthyl, each of which is one or two groups selected from halogen and / or substituted with amino; most preferably naphthyl, dihalophenyl or phenyl substituted by halogen and amino; lower alkenyl (more preferably lower alkenyl) which may be optionally substituted with one to three (more preferably one); lower alkenyl, phenyl, which may be substituted with amino or nitro; most preferably a lower alkenyl group having a nitrophenyl group or a lower alkenyl group having an aminophenyl group, an arylamino group (more preferably a phenylamino group) which may be substituted with one to three (more preferably one) suitable groups / more preferably, a phenylamino group which may be optionally substituted by a lower alkyl group or a halogen atom; most preferably, lower alkyl phenylamino; ········································································ ·

- 17 or a halophenylamino group, a monocyclic heterocyclic group (more preferably a pyridyl group or a tetrahydropyridazinyl group) which may be optionally substituted with one to three (more preferably one) suitable groups (more preferably a pyridyl group or an oxo group). most preferably a pyridyl group or an oxo substituted tetrahydropyridazinyl group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, an indolyl group or a quinoxalinyl group, and

A is lower alkylene (more preferably C 1-4 alkylene) with the proviso that when R ⁴ is indolyl then

(a) R ¹ is tetrazolyl and

R 1 is halogenated phenyl, or

b) R ¹ is imidazolyl, which may be optionally substituted by one, two or three lower alkyl groups, r 3 is halogenated phenyl, and A is ethylene.

Various variants of the process for the preparation of the compounds of formula (I) of the present invention and starting materials for their preparation are described in detail below.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · „„ end option - •

(a) Flood variant (Scheme A)

The compounds of formula (I) and salts thereof may be prepared by reacting a compound of formula (II), an activated amino derivative or salt thereof, with a compound of formula (III), an activated derivative thereof, or a salt thereof.

Suitable derivatives of a compound of formula II activated at the amino group include, for example, a Schiff-base type imino compound or a tautomer thereof, an enamine type isomer, which is a compound of formula II and a carbonyl compound such as an aldehyde, by reaction of ketone or the like; a silyl derivative prepared by reacting a compound of formula (II) with a silyl compound such as N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; or a derivative prepared by reacting a compound of formula (II) with phosphorus trichloride or phosgene or the like. Suitable salts of the compounds of formula (II) and (III) may be the same as those exemplified as salts of the compounds of formula (I).

The reactive derivative of a compound of formula (III) may be, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, an isocyanate, and the like. A suitable reactive such derivative may be, for example, an acid chloride; an acid azide; an acid such as a substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, a halogenated phosphoric acid, and the like), a dialkylphosphorous acid, sulfuric acid, sulfonic acid, ethane sulfonic acid and the like), sulfuric acid, an alkyl carbonic acid, an aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid and the like), or an aromatic carboxylic acid (e.g. benzoic acid and other mixed anhydrides; a symmetric acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl / (CH 3) 2 N = CH - / - ester, vinyl ester, propargyl ester, p-nitrophenyl ester , 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester and the like) or with an N-hydroxy compound (e.g. N, N-dimethylhydroxylamine) ester with 1-hydroxy-2 (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-ΙΗ-benzotriazole and the like), R ⁵ -N = C = O where: ·

^R5 is an optionally substituted aryl group, isocyanate, and the like, one or more suitable substituents.

Such a reactive derivative may optionally be selected according to the nature of the compound of formula III.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, Ν, Ν-dimethylformamide, pyridine or any other organic solvent. which does not adversely affect the reaction. These customary solvents may also be used in the form of mixtures thereof with water.

When the compound of formula (II) is used in this reaction in the form of the free acid or a salt thereof, the reaction is preferably carried out in the presence of a conventional condensing agent known per se. Examples of such condensing agents are N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholino-ethylcarbodiimide; N-cyclohexyl-N '- (4-diethyl-aminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide; N, N-carbonyl-bis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l

chloro-ethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorV · · · · · · · ··············································•

- 21-trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine;

2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) -isoxazolium hydroxide inner salt; 1- (p-chlorobenzene-sulfonyloxy) -6-chloro-ΙΗ-benzotriazole; the so-called Vilsmeier reagent, which is prepared by reacting?,? -dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride or the like; and the like.

The reaction may be carried out using an inorganic or organic base such as an alkali metal hydrogencarbonate, a tri (lower alkyl) amine, pyridine, an N- (lower alkyl) morpholine, an N, N-di (lower alkyl) benzyl. in the presence of amine and the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or heating.

(b) Process variant (Scheme B)

The compounds of formula (Ib) and their salts may be prepared by deprotection of a compound of formula (Ia) or a salt thereof. This operation is carried out in a conventional manner known per se, for example by hydrolysis, reduction or the like.

1) hydrolysis

Preferably, the hydrolysis is carried out on a base or on a base or a base.

- in the presence of 22 acids, including Lewis acids.

Suitable bases include inorganic and organic bases such as alkali metals (e.g. sodium, potassium and the like), their hydroxides, carbonates and bicarbonates, trialkylamines (e.g. trimethylamine, triethylamine and the like). ), picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and others, like.

A suitable acid may be, for example, an organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, and the like) or an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and the like). Lewis acid such as a trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid and the like) and the like are preferably deprotected with a cation-binding reagent (e.g. anisole, phenol, and the like). and the like). The reaction is generally carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol and the like), N, N-dimethylformamide, dichloromethane, tetrahydrofuran or mixtures thereof, or any other solvent which does not adversely affect the reaction. A liquid base or acid may also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling or heating.

· · · · · · · · · · · ···························································•

- 23 2) reduction

The reduction is carried out in a conventional manner known per se, for example by chemical reduction or catalytic reduction.

Suitable reducing agents for chemical reduction include a metal (e.g., tin, zinc, iron and the like) or a metallic compound (e.g., chromium (II) chloride, chromium (II) acetate, and the like), and an organic or inorganic acid (e.g. combinations of formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid and the like).

Suitable catalysts for catalytic reduction include standard catalysts known per se, such as platinum catalysts (e.g., platinum plate, platinum sponge, platinum carbon black, colloidal platinum, platinum oxide, platinum wire and the like), palladium catalysts (e.g., palladium sponge, palladium palladium oxide, palladium on charcoal, palladium on colloidal, palladium on barium sulphate, palladium on barium carbonate and the like, nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel and the like), cobalt catalysts (e.g., reduced cobalt, Raney-cobalt and the like), iron catalysts (e.g., reduced iron, Raney-iron and the like), copper catalysts (e.g., reduced copper, Raney copper, Ullman copper, and the like). other similar) and other similar. The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction. Examples include water, methanol, ethanol, propanol, N, N-dimethylformamide, tetrahydrofuran and mixtures thereof. Furthermore, if the acids mentioned in the description of the chemical reduction are liquid, they can also be used as a solvent.

The temperature of this reduction is not critical and the reaction is usually carried out under cooling or heating.

c) Flood variant (Scheme C)

Compounds of formula (Id) and salts thereof may be prepared by reducing a compound of formula (Ic) or a salt thereof. The reduction can be carried out in the same way as

b) the reduction described in the process variant.

Process variant d (Scheme D)

The compounds of formula (I) and salts thereof may be prepared by reacting a compound of formula (IV) or a salt thereof with a compound of formula (V) or a salt thereof.

Suitable salts of the compounds of formula (IV) and (V) may be the same as those exemplified as salts of the compounds of formula (I).

«**« «· · <<4 4 4 4 4 4 4 4» »» »4 4 4 4 4 4

The reaction of 25E is generally carried out in the presence of a base.

A suitable base may be, for example, an inorganic base such as an alkali metal hydride (e.g., sodium hydride and the like), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide and the like), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide and the like), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate and the like), an alkaline earth metal carbonate (e.g., magnesium carbonate, calcium carbonate) and the like), an alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, and the like), an alkali metal acetate (e.g., sodium acetate, potassium acetate, and the like), an alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate and the like), an alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like), and the like; s, or the like, or an organic base such as a trialkylamine (e.g., trimethylamine, triethylamine and the like), picoline, N-methylpyrrolidine, N-methylmorpholine and the like.

This reaction is usually carried out in a solvent such as an alcohol (e.g. methanol, ethanol and the like), benzene, N, N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction. .

«« «· · ·« 9 9 • · • 4 · · · · · ··· «4 · * ··« · «« ««

The reaction temperature is not critical and the reaction is usually carried out under cooling or heating.

(e) Process variant (Scheme E)

The compound of formula (If) and salts thereof may be prepared by reacting a compound of formula (le) or a salt thereof with a compound of formula (VI).

Suitable salts of the compounds of the formulas (le) and (If) may be the same as those exemplified as the salts of the compounds of the formula (I).

Suitable salts of the compounds of formula (VI) include, for example, alkali metal salts (e.g., sodium salt, potassium salt and the like) and the like.

The reaction is usually carried out in a conventional solvent such as 1-methyl-2-pyrrolidinone, Ν, Ν-dimethylformamide, dichloromethane, dichloroethane or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under heating or heating.

(f) Process variant (Scheme F)

The compounds of the general formula (II) and their salts may be used in the following manner: · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

27 may be prepared by deprotection of a compound of formula VII or a salt thereof.

Suitable salts of compounds of formula (VII) may be the same as those exemplified as salts of compounds of formula (I).

The protecting group may be cleaved by any conventional method known per se; such methods include hydrolysis, reduction, the Edman method (phenylisothiocyanate method) and the like. The hydrolysis may be carried out using an acid, a base, hydrazine or the like. The method may be selected according to the nature of the protecting group to be cleaved.

Of these methods, acid hydrolysis is the most commonly used and preferred method for the removal of protecting groups such as a substituted or unsubstituted alkoxycarbonyl group such as a tertiary pentyloxycarbonyl group, an alkanoyl group (e.g. formyl group, acetyl group and the like). ), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene and the like.

A suitable acid may be, for example, an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The most·"·· " "··· ·· • · · • "· • · · • ··

Rather, acids which are readily removed from the reaction mixture by conventional means known in the art, such as by distillation under reduced pressure, are preferred. For example, formic acid, trifluoroacetic acid, hydrochloric acid and the like. The acid may be selected according to the nature of the protecting group to be cleaved.

The deprotection with trifluoroacetic acid can be carried out in the presence of anisole. The hydrazine method is generally used to cleave amine protecting groups such as phthaloyl and succinyl.

The deprotection using bases is used to remove acyl groups such as trifluoroacetyl. A suitable base may be, for example, an inorganic or organic base.

Reductive protecting groups are generally used to remove protecting groups such as halogenated alkoxycarbonyl groups (e.g. trichloroethoxycarbonyl and the like), substituted or unsubstituted aralkoxycarbonyl groups (e.g. benzyloxycarbonyl). and the like), 2-pyridylmethoxycarbonyl and the like. Methods and reagents for the reduction include, for example, an alkali metal borohydride (e.g., sodium borohydride and the like), a metal (e.g., tin, zinc, iron and the like), or said metal and one • · ♦ ··. · ·.

··· · · ···

Combination of 29 metal-containing salts (e.g., chromium (II) chloride, chromium (II) acetate, and the like) with an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, and the like), and catalytic reduction. Suitable catalysts include, for example, conventional catalysts such as Raney nickel, platinum oxide, palladium on charcoal and the like.

Of the protecting groups, the acyl groups can generally be cleaved by hydrolysis. On the other hand, especially the halogenated alkoxycarbonyl groups and the 8-quinolyloxycarbonyl group are usually removed with the aid of a heavy metal such as copper, zinc or the like.

The reaction is usually carried out in a conventional solvent such as water, chloroform, dichloromethane, an alcohol (e.g. methanol, ethanol or the like), tetrahydrofuran or any other organic solvent which does not adversely affect the reaction.

The reaction temperature is not critical and may be selected according to the nature of the amine protecting group and the cleavage methods mentioned above. The reaction is usually carried out under mild conditions, such as cooling, or at temperatures slightly above room temperature. Among the protecting groups, the acyl groups derived from the α-amino acids can be cleaved by the Edman method.

♦ ··· ♦ · · · • • • * r r • • · ·. · «··· · · ···

(g) Flood variant (Scheme G)

Compounds of formula (IV) and salts thereof may be prepared by reacting a compound of formula (VIII), an amino-activated derivative thereof or a salt thereof, with a compound of formula (III), a reactive derivative thereof, or a salt thereof.

The reaction may be carried out in substantially the same manner as Process variant (a), so that reference is made here only to the description of Process variant (a) in terms of reaction mode and conditions.

The compounds of formula (I) and their pharmaceutically acceptable salts are antagonists of cholecystokinin and are thus useful in the therapeutic treatment of vomiting, inflammation of the pancreas and other similar conditions.

It is further expected that the compounds of formula (I) and their pharmaceutically acceptable salts will also be useful in the treatment of certain gastric disorders and thereby therapeutically and / or prophylactically treat ulcers, excessive gastric acid production, Zollinger-Ellison syndrome and the like. will be applicable.

In order to illustrate the utility of the compounds of formula I, the pharmacological data of a representative compound of formula I are given below.

• · · · ♦

- 31 I. COMPOUND TESTED:

(3S) -1,3-Dihydro-l- (4-imidazolylmethyl) -3 - / (E) -3- (2-aminophenyl) -propenoylamino / -5- (2-fluorophenyl ) -2H-1,4-Benzodiazepin-2-one dihydrochloride (Compound A)

II. THE TEST METHOD:

Investigation of Cholecystokinin Receptor Antagonist Activity in Circular Gastric Muscle Separated from Guinea Pig Stomach

The circular muscle chick, isolated from the stomach of a guinea pig, was bathed in a 25 ml organ bath in Krebs's bicarbonate solution (118 mmol sodium chloride, 4.8 mmol potassium chloride,

1.2 mmol potassium dihydrogen phosphate, 1.2 mmol magnesium sulfate,

2.5 mmol of calcium chloride, 25 mmol of sodium bicarbonate, 11 mmol of glucose and 0.1% bovine serum albumin) are suspended, the solution is kept at 37 ° C and 95% oxygen and 5% carbon dioxide containing a gas mixture.

An initial load of 0.5 g was added to the muscle chick, allowed to equilibrate for 60 minutes, and the bath solution was changed every 15 minutes. Isometric (non-dimensional) contractions are measured with a force sensor. Then the quail • ·

Add 3.2 to the solution in drum 32. 10 ^_7 moles of cholecystokinin-8 and measure the contractile force. Waiting for about 15 minutes after washing the cholecystokinin-8, during which time the contractile force becomes constant. Then 1 was added to the mixture. 10θ mol of Compound A. Five minutes later, cholecystokinin-8 was added to the solution and the contractile force measured again. The cholecystokinin antagonist activity is calculated by comparing the collecystokinin-induced contractile force in the presence and absence of Compound A.

TEST RESULT:

Inhibition: 89.9%.

The compounds of formula (I) and their pharmaceutically acceptable salts may be administered to mammals, including man, generally in the form of conventional pharmaceutical preparations known per se. Such dosage forms include, for example, capsules, microcapsules, tablets, granules, powders, pills, syrups, aerosols, inhalable formulations, solutions, injectables, suspensions, emulsions, suppositories and the like. The most suitable forms are those for injection.

The pharmaceutical compositions of the present invention may contain a variety of organic and inorganic carriers commonly used in the pharmaceutical art, such as:. · Fillers (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate and the like), binders (e.g. cellulose, methylcellulose, hydroxypropyl) cellulose, polypropylpyrrolidone, gelatin, acacia, polyethylene glycol, sucrose, starch and the like), disintegrants (e.g., starch, carboxymethylcellulose, carboxymethylcellulose calcium salt, hydroxypropyl). starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate and the like, lubricants (e.g., magnesium stearate, talc, sodium lauryl sulfate) and the like), flavoring agents (e.g., citric acid, menthol, glycine, orange flavoring and the like), preservatives (e.g., sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben and the like), stabilizers (e.g. citric acid, sodium citrate, acetic acid and the like), suspending agents (e.g. methylcellulose, polyvinylpyrrolidone, aluminum stearate and the like), dispersants, aqueous diluents (e.g. water), base waxes (e.g. cocoa butter) polyethylene glycol, white petrolatum and the like).

Generally, the active ingredient may be administered in a unit dose of 0.01 mg / kg to 50 mg / kg, 1 to 4 times daily. However, the above dosage may be increased or decreased according to the age, weight, condition and route of administration of the patient to be treated.

··· ♦ * • · • · • ·

The invention is further illustrated by the following non-limiting Examples.

Example 1

To a solution of (3RS) -3-phthalimido-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one (21.17 g) in 400 ml N, N-dimethylformamide In an ice bath under nitrogen, 2.0 g of sodium hydride (60% suspension in mineral oil) was added in portions. The reaction mixture was stirred for half an hour under the same conditions and then for another hour at room temperature. The mixture was then cooled in an ice bath and a solution of 3.48 ml of chloroacetonitrile in 5 ml of N, N-dimethylformamide was added dropwise. The mixture was then stirred for 1 hour at the same temperature and then overnight at room temperature. The next day, 3.5 g of acetic acid was added with cooling, and the resulting mixture was poured into a mixture of ethyl acetate and water, with stirring. The pH of the mixture was adjusted with aqueous sodium bicarbonate solution

After adjustment to 7.5, the precipitated crystals were filtered off and washed with cooled ethyl acetate. 20.9 g of (3RS) -3-phthalimido-1-cyanomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one are obtained, m.p. 260 ° C (dec.).

IR (Nujol): 2160, 1776, 1725, 1700,

1604 cm ¹ .

¹ H NMR (DMSO-d 6) delta:

5.15 (2H, ABq, J = 24.6Hz, 17.8Hz), 5.83 (1H, s), 7.2-8.1 (12H, m).

··· «·· · ·

Example 2

20.0 g of (3RS) -3-phthalimido-1-cyanomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one, 8.43 g sodium azide,

A mixture of 8.92 g of triethylamine hydrochloride and 350 ml of N-methyl-2-pyrrolidone was stirred at 145 ° C for 3.5 hours. After cooling to room temperature, the reaction mixture was poured into 500 ml of a mixture of 5% hydrochloric acid and ice. The resulting precipitate was filtered off, washed several times with cold water and dried under reduced pressure over phosphorus pentoxide. 18.07 g of (3RS) -3-phthalimido-1,3-dihydro-5- (2-

- fluorophenyl) -1 - ((1H-tetrazol-5-yl) methyl) -2H-1,4-benzodiazepin-2-one.

IR (Nujol): 1778, 1720, 1693,

1610 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.46 (2H, s), 5.85 (1H, s), 7.2-8.0 (13H, m).

Example 3

18.07 g of (3RS) -3-phthalimido-1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl / -2 H -1,4- benzodiazepin-2-one and 10.99 g of trityl chloride in 330 ml of Ν, Ν-dimethylformamide are added dropwise with stirring in an ice bath, 4.6 g of triethylamine in 10 ml of Ν, Ν-dimethylformamide. The mixture was then stirred for 20 minutes under the same conditions and then overnight at room temperature. The next day, the reaction mixture was poured into 500 mL of ice water and the precipitate was filtered off with water.

Wash and dry under reduced pressure over phosphorus pentoxide. In this way, 33.41 g of (3RS) -3-phthalimido-1,3-dihydro-5- (2-fluorophenyl) -1 H- (1-trityl-1H-tetrazol-5-yl) as a white powder are obtained. ) methyl-2H-1,4-benzodiazepin-2-one is obtained.

IR (Nujol): 1778, 1723, 1695,

1610 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.56 (2H, ABq, J = 16.0Hz, 52.6Hz), 5.80 (1H, s), 6.8-8.1 (27H, m).

Example 4

33.4 g of (3RS) -3-phthalimido-1 ((1-trityl-1H-tetrazol-5-yl) methyl] -5- (2-fluorophenyl) -1,3-dihydro-2H-1 To a suspension of 4-benzodiazepin-2-one in 500 ml of tetrahydrofuran is added 1.90 g of hydrazine hydrate with stirring at room temperature. The mixture was stirred at the same temperature for 2 hours and then boiled for 2 hours. The reaction mixture was cooled in an ice bath and the precipitate was filtered off. The filtrate and washings were combined and the solvent was distilled off. The residue was stirred with ethyl acetate and the insolubles were filtered off. The filtrate and washings were combined and the solvent was distilled off. In this way, 14.43 g of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -1- (1-trityl-1H-tetrazol-5-yl) are obtained as a white powder. ) methyl-2H-1,4-benzodiazepin-2-one is obtained.

IR (Nujol) 3350, 1686, 1597, 760,

700 cm ^-1 .

¹ H NMR (CDCl 3) 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).

Example 5

The following compound was prepared in a similar manner to that described in Example 4.

(3RS) -3-amino-l, 3-dihydro-5-phenyl-l - / (l-trityl-lH-tetrazol-5-yl) methyl / -2H-1,4-benzodiazepin-2-one

132-135 ° C.

IR (nujol) 3375, 1680, 1595, 1575,

1560 cm ^-1 .

¹ H NMR (CDCl 3) delta:

2.72 (2H, s), 4.55 (1H, s), 5.46 (2H, ABq, J = 16Hz, 51Hz), 6.90-6.70 (6H, m), 7.15-7.50 (18H, m).

Example 6

11.54 g of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -1- (1-trityl-1H-tetrazol-5-yl) methyl / -2H- To a solution of 1,4-benzodiazepin-2-one and 5.42 g of N-tert-butoxycarbonyl-L-phenylalanine in 200 ml of N, N-dimethylformamide, 2.76 g of 1- hydroxybenzotriazole followed by 3.91 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and finally 2.36 g of triethylamine. The mixture is stirred for 4.5 hours under the same conditions and then 1.5 L ·· ·

- Pour into 38 water. The aqueous mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, the precipitate was filtered off, washed with water and dried under reduced pressure over phosphorus pentoxide. Thus, (3R) -3 - [((2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1 - ((1-trityl-1H-tetrazol-5-yl) methyl) -2H-1,4-benzodiazepin-2-one and (3S) -3 - [(2S) -2-tertiary butoxycarbonyl-amino-3-phenylpropyl) amino / -l, 3-dihydro-5- (2-fluorophenyl) -1 - / (1-trityl-lH-tetrazol-5-yl) methyl A mixture of 2H-1,4-benzodiazepin-2-one weighed 16.29 g, mp 108-114 ° C.

IR (nujol): 3330, 1700, 1690, 1675, 1610 cm ^-1 .

1 H NMR (DMSO-d6), delta:

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, both d, J = 8Hz), 5.58 (2H, ABq, J = 16.8Hz, 82.2Hz), 6.8-7.95 (14H, m), 9.25, 9.37 (1H, both d, J = 8Hz).

Example 7

(3R) -3 - [((2S) -2-tert-Butoxycarbonylamino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1 - ((1-Trityl-1H-tetrazol-5-yl) methyl) -2H-1,4-benzodiazepin-2-one and (3S) -3 - ((2S) -2-tert-butoxy) butoxycarbonylamino-3-phenyl-propanoyl) amino / -1,3-dihydro-5- (2-fluorophenyl) -1 - / (1-trityl-lH-tetrazol-5-yl) methyl / ~ 2H-1,4-benzodiazepin-2-one

- 39 (16.2 g) was stirred with 200 ml of 4N hydrochloric acid in ethyl acetate for 5 hours at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in 100 ml of methanol. The solution was neutralized with ethanolic ammonia solution and the solvent was distilled off under reduced pressure. The resulting residue was chromatographed on a silica gel column using chloroform / methanol 10: 1 as eluent. The fractions containing one product were combined and the solvent was distilled off. The resulting amorphous material was triturated with diisopropyl ether and the solid was filtered off. 4.57 g of (3S) -3 - [((2S) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1- (1H-Tetrazol-5-yl) methyl-2H-1,4-benzodiazepin-2-one is obtained.

1 H-NMR (DMSO-d 6) delta:

2.91 (1H, dd, J = 14.0Hz, 8.4Hz),

3.20 (1H, dd, J = 4Hz, 14.0Hz), 4.13 (1H, dd,

J = 4Hz, 8.4Hz), 5.26 (2H, ABq, J = 15.4Hz, 31.6Hz),

5.39 (1H, d, J = 8.0Hz), 7.1-7.35 (10H, m),

7.52-7.66 (4H, m), 7.96 (1H, d, J = 8.4Hz), 9.77 (1H, d, J = 8.0Hz).

The fractions containing the other product were combined and the solvent was distilled off. The resulting amorphous material was triturated with diisopropyl ether and the solid product was filtered off. In this way, 4.76 g of (3R) -3 - [((2S) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1- (1 H -tetrazol-5-yl) methyl-2 H -1,4-benzodiazepin-2-one is obtained.

··· »·

- 40 ^1H-NMR (DMSO-d₆) delta,

3.0-3.17 (1H, m), 3.57-3.64 (1H,

m), 3.0-4.1 (2H, br} _? 4.21 (1H, t, J = 4.2Hz),

5.19 (2H, ABq, J = 15.6Hz, 70.1Hz), 5.38 (1H, d,

J = 8.3Hz), 7.16-7.4 (10H, m), 7.51-7.67 (4H, m),

7.97 (1H, d, J = 8.2Hz), 9.78 (1H, d, J = 8.3Hz).

Example 8

4.57 g of (3 S) -3 - [((2 S) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro-5- (2-fluorophenyl) -1 H- ( To a solution of 1H-tetrazol-5-yl) methyl / -2H-1,4-benzodiazepin-2-one and 0.974 g of triethylamine in 45 ml of anhydrous tetrahydrofuran was added 2.54 g of phenyl isothiocyanate with stirring at room temperature. The mixture was stirred for 2 hours at room temperature and then for 1 hour at 50 ° C. 9.64 ml of 1N hydrochloric acid are then added under ice-cooling, and the solvent is distilled off under reduced pressure. The residue was extracted with ethyl acetate, the ethyl acetate portion was washed twice with water, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the resulting amorphous material (7.23 g) was stirred with diisopropyl ether for 3 hours. The powder thus obtained is filtered off and washed with diisopropyl ether. Thus, 5.63 g of (3 S) -3 - [((2 S) -2- (N'-phenylthioureido) -3-phenylpropanoyl) amino] -1,3-dihydro-5- (2 - fluorophenyl) -1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one is obtained. The product obtained as above was suspended in 35 ml of tetrahydrofuran and cooled with ice-cooling »4 4 4 4 4 4» »» «

- We'll drop it next to 41. 33.5 ml of 4N hydrochloric acid in ethyl acetate. The resulting mixture was stirred for 5 hours and then the solvent was distilled off under reduced pressure. The resulting viscous oil was stirred with ethyl acetate for 3 hours. The powder thus obtained is filtered off and dried under reduced pressure. There were thus obtained 2.91 g of (3S) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl / -2 H -1. 4-Benzodiazepin-2-one hydrochloride is obtained.

/ α / β ^ ⁰ = -36.36 ° (c = 0.495, methanol).

Example 9

The following compound was prepared in a similar manner to that described in Example 8.

(3R) -3-Amino-1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H-tetrazol-5-yl) methyl 2 H -1,4-benzodiazepine-2 one hydrochloride / α / ₀ → θ = + 33.46 ° (c = 0.505, methanol).

Example 10

A suspension of 2.0 g of (3RS) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 30 ml of dichloromethane is stirred under ice-cooling. 1.61 g of triethylamine are added dropwise in a bath. Then, 1.52 g of 2-naphthoyl chloride are added under the same conditions and the mixture is stirred at the same temperature for 2 hours. The precipitate was filtered off, washed with dichloromethane and water, and dried under reduced pressure over phosphorus pentoxide. There were thus obtained 2.33 g of (3RS) -3- (2-naphtho-1-amino) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one.

1 H NMR (DMSO-d 6) delta:

5.6U (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 Spectrum (m / e): 423 (M ⁺ ).

Example 11

The following compounds were prepared in a similar manner to that described in Example 10.

1) (3RS) -3- (3-Quinolylcarbonylamino) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one

IR (Nujol): 3600, 1695, 1670, 1610, 1590, 1515 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.59 (1H, d, J = 7.6Hz), 7.23-7.40 (5H, m), 7.61-7.76 (4H, m), 7.67-7.94 (1H, m),

8.1-8.16 (2H, m), 9.09 (1H, s), 9.40 (1H, d, J = 2.1Hz), 10.1 (1H, d, J = 7.6Hz), 11.08 (1H, s).

2) (3RS) -3- (3,4-Dichlorobenzoylamino) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one »· «« • ♦ · · ··· · · ···

- 43 1 H-NMR (DMSO-d 6) delta:

5.49 (1H, d, J = 7.6Hz), 7.2-8.02 (11H, m), 8.21 (1H, s), 9.93 (1H, d, J = 7.6Hz), 11.03 (1H, s).

Mass Spectrum (m / e): 442 (M ⁺ ).

Example 12

1.0 g of (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-tritylimidazol-4-yl) methyl / -2H-1, To a solution of 4-benzodiazepin-2-one in 10 ml of N, N-dimethylformamide was added at room temperature, under stirring, 330 mg of (E) -3- (2-nitrophenyl) propenoic acid, followed by 230 mg of 1-hydroxybenzotriazole. followed by 320 mg of N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride and finally 170 mg of triethylamine. The reaction mixture was stirred for 3 hours and then allowed to stand overnight. The next day, the mixture was poured into a biphasic mixture of ethyl acetate and water with stirring. The organic layer was separated, washed twice with water and dried. The solvent was distilled off under reduced pressure and the amorphous residue was purified by chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The resulting amorphous material was triturated with diisopropyl ether for several hours. The solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure. There was thus obtained 1.16 g of (3S) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl-3 (E) -3- (2-nitrophenyl) -. 44-Propenoylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one is obtained.

@ 1 H-NMR (CDCl3) delta:

5.07 (2H, br s), 5.66-5.7 (1H, m), 6.49-8.14 (32H, m).

Example 13

The following compounds were prepared in a similar manner to that described in Example 12.

1) (3S) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl-3 - [(2-amino-4-chlorobenzoyl) amino] -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one ^X H-NMR (CDCl3) delta

5.06 (2H, d, J = 3.7Hz), 5.62-5.68 (3H, m), 6.63-8.04 (29H, m).

Mass Spectrum (m / e): 502 (M ⁺ -243).

2) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl] -3- (2,3,4,5-tetrahydro-3-oxopyridazine) 6-yl) carbonylamino / -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

3) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl--3- (3,4-dichlorobenzoylamino) -5- (2-fluoro) phenyl) -2H-1,4-benzodiazepine

-2-one 1 H-NMR (CDCl 3) delta:

5.02 (1H, d, J = 15Hz), 5.12 (1H, d, J = 15Hz), 5.67 (1H, d,

J = 7.8Hz), 6.85-8.04 (29H, m).

4) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) -methyl- -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) ¹ H-Nuclear Magnetic Resonance Spectrum (CDCl 3), -2H-1,4-benzodiazepin-2-one:

5.01-5.18 (2 H, m),

5.78 (1H, d, J = 7.8Hz), 6.87-8.26 (30H, m),

8.72 (1H, d, J = 1.9Hz), 9.44 (1H, d, J = 2.2Hz).

Mass Spectrum (m / e): 504 (M ⁺ -243), 424.

5) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl- -3- (2-quinoxalinylcarbonylamino) -5- (2-fluorophenyl) ) -2H-1,4-benzodiazepin-2-one

6) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl--3- (4-cinnolinylcarbonylamino) -5- (2-fluorophenyl) ¹ H-Nuclear Magnetic Resonance Spectrum (CDCl 3), -2H-1,4-benzodiazepin-2-one:

5.09 (2H, s), 5.80 (1H, d, J = 7.8Hz),

6.86-8.09 (28H, m), 8.49-8.66 (2H, m), 9.54 (1H

s).

.:

• «··· ♦ J * ·« • · · 9 • * ·· 99 • 99

7) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl] -3- (1-isoquinolylcarbonylamino) -5- (2-fluorophenyl) ) -2H-1,4-benzodiazepin-2-one

@ 1 H-NMR (CDCl3) delta:

5.11 (2H, s), 5.78 (1H, d,

J = 8.3Hz), 6.89-7.89 (28H, m), 8.05 (1H, d,

J = 8.2Hz), 8.59 (1H, d, J = 5.5Hz), 9.52-9.56 (1H,

m), 9.93 (1H, d, J = 8.2Hz).

8) (3RS) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl-3-nicotinone carbonylamino-5- (2-fluorophenyl) -2H -1,4-benzodiazepin-2-one ^1H-NMR (CDCl3) delta

⁴ · 99-5.16 (4H, m),

5-71 (1h, d, J = 7.7Hz), 6.85-9.18 (28H, m).

Example 14

1.0 g of (3RS) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl] -3-amino-5- (2-fluorophenyl) -2H-1, To a solution of 4-benzodiazepin-2-one in 10 ml of dichloromethane is added 340 mg of triethylamine, followed by 320 mg of 2-naphthoyl chloride. After stirring for 1.5 hours, the mixture was washed with water and dried. The solvent was distilled off under reduced pressure and the amorphous residue was purified by chromatography on a silica gel column using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off.

The oily residue was dried under reduced pressure to give 1.21 g of (3RS) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl] -3-

- (2-Naphthoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one is obtained.

¹ H NMR (CDCl ₃ ) delta:

5:03 (2H, d, J = 15Hz), 5th 15 (2H, d, J = 15Hz), 5.79 (1H, d, J = 8Hz), 6.89- • 8th 07 (29H, m), 8.22 (1H, d, J = 8Hz), 8.47 (1H, s) Example 15 1 . 5g (3RS) -1,3-dihydro-1 / (1- -trityl-imidazol-4-yl) -

To a solution of methyl 3-amino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in tetrahydrofuran (1 mL) was added m-tolyl isocyanate (0.35 g) at room temperature. The mixture was then stirred for 2 hours under the same conditions and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethyl acetate-tetrahydrofuran to give 1.47 g of pure (3RS) -1,3-dihydro-1 - [(1-tritylimidazol-4-yl) methyl] -3- [3- yielding methyl-phenyl) -ureido / -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

¹ H NMR (DMSO-d 6) delta:

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).

Example 16

1.1 g of iron powder and 0.13 g of ammonium chloride in 2.5 ml of water and

To a suspension of 7.5 ml of ethanol is added 1.1 g of (3S) -1,3-dihydro-1- (1-trityl-imidazol-4-yl) methyl (-3-) under stirring and reflux. (E) -3- (2-nitrophenyl) -propenoylamino / -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one. A further 7.5 ml of ethanol and 2.5 ml of water were added and the reaction mixture was stirred for 1.5 hours. The mixture was then filtered through a pad of celite and the filter pad washed several times with hot ethanol. From the filtrate and washings, ethanol was distilled off under reduced pressure and 100 ml of a saturated aqueous solution of sodium bicarbonate were added to the residue. The mixture was partitioned between ethyl acetate (100 mL), the organic layer was washed with water, dried over magnesium sulfate and the solvent was distilled off. The amorphous residue was triturated with diisopropyl ether and the solid product was filtered off. 0.98 g of (3S) -1,3-dihydro-1- (1-trityl-imidazol-4-yl) methyl] -3- (E) -3- (2-aminophenyl) is thus obtained. There is thus obtained -propenoylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

1 H-NMR (CDCl 3) delta:

3.71-4.07 (2H, br d), 5.06 (2H, s), 5.68 (1H, d, J = 8Hz), 6.47-7.99 (32H, m).

Mass Spectrum (m / e): 476 (M ⁺ -260).

···· ··· · ·

Example 17

0.49 g of (3S) -1,3-dihydro-1 H- (1-tritylimidazol-4-yl) methyl] -3- (E) -3- (2-aminophenyl) propenoyl -amino- -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 4.9 ml of N, N-dimethylformamide was added with stirring in an ice bath.

3.4 ml of 6N hydrochloric acid. The mixture was heated to 50 ° C and stirred for 1 hour. After cooling to room temperature, water and ethyl acetate were added with stirring. The pH of the mixture was adjusted to 8 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and dried. The solvent was distilled off under reduced pressure and the amorphous residue was triturated with diisopropyl ether for several hours. The solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure. 350 mg of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (E) -3- (2-aminophenyl) -propenoylamino-5- (2 -fluorophenyl) -2H-1,4-benzodiazepin-2-one is obtained. To a solution of the above product in 10 ml of chloroform was added 5 ml of 20% hydrochloric acid in ethanol while cooling. From the resulting clear yellow solution, the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether for several hours. The solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure. There was thus obtained (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (E) -3- (2-aminophenyl) propenoylamino (234 mg) as a yellow powder. Obtained -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one dihydrochloride.

• ·

* ·· χ:

• · · ···· · ·

IR (Nujol): 3650-3050, 2700-2150, 1660, 1605 cm @ ^-1 . ¹ H NMR (CDCl 3) delta 3.8-4.8 (2H, b), 5.15-5.56 (3H, m), 7.04-7.81 • J = 8Hz). (18H, m), 9.03 (1H, s), 9.43 (1H, d,).

MS (m / e): 494 (M ⁺ -73), 476.

Example 18

The following compounds were prepared in a similar manner to that described in Example 17.

1) (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-amino-4-chlorobenzoyl) amino-5- (2-fluorophenyl) - 2H-1,4-benzodiazepin-2-one m.p. 180-220 ° C (dec.).

IR (Nujol): 3500-3000, 1675, 1640 ^cm-first

¹ H NMR (CDCl 3) delta:

4.93 (1H, d, J = 15Hz), 5.20 (1H, d, J = 15Hz), 5.25-5.69 (3H, m), 6.62-6.67 (2H, m),

6.98-7.26 (6H, m), 7.40-7.69 (5H, m), 7.89-7.91 (2H, m).

Mass Spectrum (m / e): 502 (M ⁺ ).

···· · • ♦ • · · · · · · · · · · · · ···

- 51 2) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2,3,4,5-tetrahydro-3-oxopyridazin-6-yl) carbonyl -amino--5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one dihydrochloride m.p. 230-240 ° C (dec.).

IR (Nujol): 3650-3050, 2650, 2200, 1670, 1610,

1500 cm ^-1 .

1 H-NMR (DMSO-d 6) delta:

2.41-2.88 (4H, m), 5:20 (1H, d, J = 16Hz), 5.42 (1H, d, J = 16Hz), 5:43 (1H, d, J = 7.8Hz), 7.15-7.78 (9H, m), 8:58 (1H, d. J = 7.8Hz), 9.02 (1H, s), 11:31 (1H, s), 14.67

(1H, br s).

Mass Spectrum (m / e): 393 (M ⁺ -153).

3) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1 , 4-Benzodiazepin-2-one dihydrochloride m.p. 212-230 ° C (dec.).

IR (Nujol): 3650, 3150, 2650-2000, 1650, 1600,

1510 cm ^-1 .

@ 1 H NMR (DMSO-d6) delta:

5.20 (1H, d, J = 16Hz),

5.43 (1H, d, J = 16Hz), 5.61 (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, d, J = 1.2Hz), 10.0 (1H, d, J = 9.4Hz), 14.64 (1H, br s).

···· V • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Mass spectrum (m / e): 521 (M ⁺ -37), 441.

4) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4 benzodiazepin-2-one dihydrochloride m.p. 230-233 ° C (dec.).

IR (nujol): 3600-3100, 2700-2100, 1670, 1610,

1510 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

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 = 1.8Hz), 9.60 (1H, d, J = 2Hz),

10.36 (1H, d, J = 7.2Hz), 14.72 (1H, br s).

Mass Spectrum (m / e): 504 (M ⁺ -73), 424.

5) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-quinoxalinylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4 benzodiazepin-2-one hydrochloride m.p. 205-220 ° C (dec.).

IR (Nujol): 3600-3050, 2700-2000, 1670, 1600 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.25 (1H, d, J = 16.1Hz),

5.48 (1H, d, J = 16.1Hz), 5.68 (1H, d, J = 7.8Hz),

7.18-8.35 (13H, m), 9.04 (1H, s),

9.53-9.61 (2 H, m), 14.63 (1H, m).

Mass Spectrum (m / e): 505 (M ⁺ -36), 425.

6) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (4-cinnolinylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4 benzodiazepin-2-one dihydrochloride m.p. 215-230 ° C (dec.).

IR (Nujol): 3600-3100, 2700-2100, 1660, 1610 cm ^-1 .

1 H-NMR (DMSO-d 6) delta:

5.21-5.72 (3 H, m),

7.18-8.61 (13H, m), 9.01 (1H, s), 9.48 (1H, s),

10.46 (1H, d _z J = 7.1Hz), 14.61 (1H, br s).

Mass Spectrum (m / e): 505 (M ⁺ -73), 448.

7) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (1-isoquinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4 benzodiazepin-2-one dihydrochloride m.p. 209-220 ° C (dec.).

IR (nujol): 3600-3200, 2700-2100, 1670, 1610 cm ^-1 .

1 H-NMR (DMSO-d 6) delta:

5.2-5.55 (2 H, m),

5.67 (1H, d. J = 7.7 Hz); 7.23-8.19 (13H, m), 8. 67 (1H, d. J = 5.6Hz), 9.03 (1H, s), 9:19 (1H, d. J = 8.4 Hz); 9.9 (1H, d, J = 7 .7Hz) 14.62 (1H , br 's).

• · ·

54 Mass Spec (m / e): 504 (M ⁺ -73), 424.

8) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3-nicotinolylamino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one; dihydrochloride m.p. 220-235 ° C (dec.).

1 H NMR (DMSO-d 6) delta:

5.21 (1H, d, J = 16.1Hz)

5.45 (1H, d, J = 16.1Hz), 5.64 (1H, d, 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 Spectrum (m / e): 454 (M ⁺ -73).

9) (3RS) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-naphthoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one hydrochloride m.p. 220-230 ° C (dec.).

IR (nujol): 3600-3050, 2800-2000, 1690, 1660, 1610 cm ^-1 .

@ 1 H-NMR (DMSO-d6) delta:

5.22 (1H, d, J = 16Hz),

5.45 (1H, d, J = 16Hz), 5.70 (1H, d, J = 7.4Hz),

7.19-8.1 (15H, m), 8.70 (1H, s), 9.03 (1H, s),

9.78 (1H, d, J = 7.4Hz), 14.61 (1H, br s).

Mass Spectrum (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-Benzodiazepin-2-one hydrochloride, m.p. 210-225 ° C (dec.).

IR (Nujol): 3600-3050, 1680;

1610, 1555 cm ^1st

@ 1 H NMR (DMSO-d6) delta:

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,

Example 19 J = 8.0Hz), 8.99 (1H, s) _v

850 mg of (3RS) -1,3-dihydro-3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one and 900 mg of 1- To a mixture of trityl 4- (2-chloroethyl) imidazole monohydrochloride in N, N-dimethylformamide was added 180 mg of sodium hydride (60%, mineral) in an ice bath at 0 ° C under nitrogen. oil slurry) and 3.98 g of sodium iodide. The mixture was stirred for 1.5 hours at room temperature and for 6 hours at 60-65 ° C. Acetic acid (2 ml) was added and the mixture was poured into a biphasic mixture of ethyl acetate (200 ml) and water (200 ml) with stirring. The mixture was then adjusted to pH 8 with aqueous sodium bicarbonate.

The organic layer was separated, washed with water and the solvent was distilled off under reduced pressure. The amorphous residue was purified by column chromatography on silica gel using chloroform as eluent. Contains the desired product

fractions were combined and the solvent was distilled off. The amorphous residue was dried under reduced pressure to give 750 mg of (3RS) -1,3-dihydro-1- [2- (1-tritylimidazol-4-yl) ethyl] -3 (3-quinolylcarbonylamino) -5. - (2-Fluorophenyl) -2H-1,4-benzodiazepin-2-one is obtained.

1 H-NMR (DMSO-d 6) delta:

2.49-2.65 (2H, m), 3.8-4.6 (2H, m), 5.62 (1H, d, J = 7.48Hz), 6.70 (1H, s),

7.00-8.1 (28H, m), 9.05 (1H, s), 9.35 (1H, d, J = 2.2Hz), 10.0. (1H, d, J = 7.64Hz).

Example 20

1.25 g of (3RS) -1,3-dihydro-3- (2-naphthoylamino) -5- (2-

- To a solution of fluorophenyl) -2H-1,4-benzodiazepin-2-one in N, N-dimethylformamide (31 mL) was added 130 mg of sodium hydride (60%) under stirring at 0 ° C in an ice bath. mineral oil slurry). After stirring for 45 minutes at room temperature, a solution of 270 mg of chloroacetonitrile in 5 ml of Ν, Ν-dimethylformamide was added with stirring at 0 ° C. The resulting mixture was stirred overnight at room temperature, then 0.5 g of acetic acid was added and the mixture was added with stirring to a biphasic mixture of 200 mL of ethyl acetate and 300 mL of water. The pH of the mixture was adjusted to 8 with aqueous sodium bicarbonate solution, the organic layer was separated, washed with water and the solvent was removed under reduced pressure.

- Distill 57. The amorphous residue was purified by column chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The amorphous residue was dried under reduced pressure to give 1.19 g of (3RS) -1,3-dihydro-1-cyanomethyl-3- (2-naphthoylamino) -5- (2-fluorophenyl) -2H-1, 4-Benzodiazepin-2-one is obtained.

¹ H NMR (DMSO-d 6) delta:

5.08-5.32 (2H, m), 5.74 (1H, d, J = 7.65Hz), 7.25-7.82 (14H, m),

8.71 (1H, s), 9.95 (1H, d, J = 7.68Hz).

Example 21

The following compounds were prepared in a manner similar to that described in Examples 19 and 20.

1) (3RS) -1,3-Dihydro-3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl 2H-1,4-benzodiazepin-2-one m.p. 284-285 ° C.

IR (Nujol) 3400, 1695, 1650,

1600, 1525 cm ^-1 .

@ 1 H-NMR (DMSO-d6) delta:

5.4-5.62 (2H, m), 5.76 (1H, d, J = 7.74Hz), 7.23-7.39 (4H, m), 7.63-7.79 (4H,

m), 7.86-7.93 (2H, m), 8.09-8.32 (2H, m), 9.05 (1H, s), 9.37 (1H, d, J = 2.36Hz), 10.12 (1H, d,

J = 7.78Hz), 15.2-16.0 (1H, br s).

58 Mass Spec (m / e): 507 (M ⁺ ), 424 (M ⁺ -83).

2) (3RS) -1,3-Dihydro-3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -1 H- (1 H-tetrazol-5-yl) methyl 260 DEG-265 DEG C. (decomposition): -2H-1,4-benzodiazepin-2-one.

IR (Nujol): 3600, 3050, 1650,

^X 1600 ^cm H-NMR (DMSO-d₆) delta,

7.77

8.28 / z (1H, (1H,

5.2-5.4

7.14-7.33 (5H, d, J = 8.4Hz), d _z J = 1.9Hz),

Mass Spectrum (m / e): 524 (M ⁺ ) (M ⁺ -156).

3) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl 2H-1,4-benzodiazepin-2-one m.p. 280-290 ° C (dec.).

IR (Nujol): 3150, 1640, 1540 cm -1 ¹ H NMR (DMSO-d 6), delta:

5.21-5.3 (2H, m), 5.69 (1H, d, J = 8.14Hz), 7.02-7.66 (13H, m), 7.97 (1H, d,

J = 8.26Hz), 9.52 (1H, d, J = 8.18Hz), 11.67 (1H, s).

Mass Spectrum (m / e): 351 (M ⁺ -144), 332 (M ⁺ -162).

····· ···· ·· • · · • · «♦ · · · · · · · • '• · · · · ··

4) (3RS) -1,3-Dihydro-1- [2- (4-imidazolyl) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H- 1,4-Benzodiazepin-2-one, m.p. 165-175 ° C (dec.).

IR (Nujol): 3600-3000, 1650;

1600 cm ^-1 .

5) (3 S) -3- (2-Indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl -2H-1,4-benzodiazepin-2-one ^1H-NMR (DMSO-d₆) delta,

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 22

740 mg of (3RS) -1,3-dihydro-1- [2- (1-tritylimidazol-4-yl) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluoro) -phenyl) -2H-1,4-benzodiazepin-2-one in N, N-dimethylformamide (7.4 ml) was added 5.18 ml of normal hydrochloric acid with stirring in an ice bath. The mixture was then heated to 60-70 ° C and stirred for 1 hour. The mixture was cooled to room temperature and ice water and ethyl acetate were added with stirring. The pH of the mixture was adjusted to 8 with aqueous sodium bicarbonate solution, and the organic layer was separated with water, · · · · · · · · · · · · · · · · · · · · · · · · · Wash, dry, and evaporate the solvent under reduced pressure. The amorphous residue was purified by column chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The amorphous residue is triturated with diisopropyl ether for several hours, the solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure.

0.25 g of (3RS) -1,3-dihydro-1- [2- (4-imidazolyl) ethyl] -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) are thus obtained. ) -2H-1,4-benzodiazepin-2-one, m.p. 165-175 ° C (dec.).

IR (Nujol): 3600-3000, 1650, 1600 cm @ ^-1 .

¹ H NMR (DMSO-d 6) delta:

2.52-2.66 (2H, m), 4.09-4.63 (2H, m), 5.65 (1H, d, J = 7.5Hz), 6.77 (1H, s),

7.24-8.32 (13H, m), 9.07 (1H, d, J = 1.92Hz), 9.39 '(1H, d, J = 2.2Hz), 10.11 (1H, d, J = 7.6Hz), 11.82 (1H, br s) Mass spectrum (m / e): 518 (M ⁺ ).

Example 23

500 mg of (3RS) -1,3-dihydro-3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one and 295 mg A mixture of 1-trityl-4- (2-chloroethyl) imidazole monohydrochloride in 7.5 ml of N, N-dimethylformamide was stirred at 0 ° C.

99.5 mg of sodium hydride (60% slurry in mineral oil) and 2.25 g of sodium iodide are added in 61 ice baths under nitrogen. The reaction mixture was stirred at room temperature for 1.5 hours and then at 60-65 ° C for 6 hours.

Then, 1.1 ml of acetic acid and 5 ml of 6N hydrochloric acid were added and the mixture was stirred at 60-70 ° C for 1 hour. The resulting mixture was poured into a biphasic mixture of ethyl acetate (100 mL) and water (100 mL) with stirring. The pH of the mixture was adjusted to 8 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water, dried and the solvent was distilled off under reduced pressure. The amorphous residue was purified by column chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The amorphous residue is triturated with diisopropyl ether for several hours, the solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure.

Thus, 0.18 g of (3RS) -1,3-dihydro-1- [2- (4-imidazolyl) ethyl] -3- (3,4-dichlorobenzoylamino) -5- (2-fluoro) are obtained. -phenyl) -2H-1,4-benzodiazepin-2-one, m.p. 149-159 ° C.

IR (nujol): 3600-3100, 1650, 1600 cm @ ^-1 .

¹ H NMR (DMSO-d 6) delta:

2.5-2.59 (2H, m), 3.95-4.62 (2H,

m), 5.5 '(1H, d, J = 7.52Hz), 6.77 (1H, br s),

7.23-8.32 (12H, m), 9.99 (1H, br s), 11.8 (1H, br s).

·· · · ·

62 Mass Spec (m / e): 386 (M ⁺ -150).

Example 24

The following compounds were prepared in a similar manner to that described in Example 23.

1) (3RS) -1,3-Dihydro-1- [2- (4-imidazolyl) ethyl] -3- (2-naphthoylamino) -5- (2-fluorophenyl) -2H-1, 4-benzodiazepin-2-one

M.p. 198-205 ° C (dec.).

IR (Nujol): 3275, 1680, 1630, 1530 cm ^{-1 1} H-NMR (DMSO-d 6) delta:

2.5-2.8 (2H, m), 4.0-4.6 (2H, m),

5.65 (1H, d, J = 7.67Hz), 6.81 (1H, br s),

7.24-8.09 (15H, m), 8.71 (1H, s), 9.78 (1H, d, J = 7.71Hz), 11.8 (1H, br s).

Mass Spectrum (m / e): 518 (M ⁺ ).

2) (3RS) -1,3-Dihydro-1- [2- (4-imidazolyl) ethyl] -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H- 1,4-benzodiazepin-2-one

188 DEG-205 DEG C. (dec.).

IR (Nujol): 3550-3100, 1640, 1540 cm @ ^-1 .

¹ H NMR (DMSO-d 6) delta:

2.51-2.65 (2H, 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 25

1) 1.15 g of (3RS) -1,3-dihydro-1-cyanoethyl-3- (2-naphthoylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine A mixture of 2-one, 480 mg of sodium azide and 510 mg of triethylamine monohydrochloride in 20 ml of 1-methyl-2-pyrrolidinone was stirred at 145 ° C for 3.5 hours. The reaction mixture was then poured into 100 ml of 5 ° C hydrochloric acid with stirring. The resulting precipitate was filtered off, washed with water and purified by column chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The amorphous residue is triturated with diisopropyl ether for several hours, the solid product is filtered off, washed with diisopropyl ether and dried under reduced pressure. There were thus obtained 540 mg of (3RS) -1,3-dihydro-3- (2-naphthoylamino) -5- (2-fluorophenyl) -1- (1H-tetrazol-5-yl) methyl] - 2H-1,4-benzodiazepin-2-one is obtained, m.p. 265-275 ° C (dec.).

IR (Nujol): 3570-3100, 1650, 1490 cm ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.33 (2H, s), 5.73 (1H, d,

J = 7.98Hz), 7.18-8.09 (15H, m), 8.69 (1H, s),

9.72 (1H, d, J = 8Hz).

Mass Spectrum (m / e): 505 (M ⁺ ).

The following compound was prepared in a similar manner to that described in section 1 of this example.

* • 4 Λ

- 64 2) (3 S) -3- (2-Indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl / -2H-l, 4-benzodiazepin-2-one ^1H-NMR (DMSO-d₆) delta,

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 = 8Hz), 11.65 (1H, s),

Example 26

0.50 g of (3RS) -3-amino-1,3-dihydro-5-phenyl-1- (1-trityl-1H-tetrazol-5-yl) methyl / -2H-1,4-benzodiazepine To a solution of 2-10 in anhydrous tetrahydrofuran (10 mL) is added 4-chlorophenyl isocyanate (0.14 g) at room temperature. After stirring for 3 hours, 1.5 ml of 8.4 N hydrochloric acid in ethanol (1.5 ml) was added at room temperature and the mixture was stirred for an additional 3 hours. The solvent was then distilled off under reduced pressure and the residue was suspended in a mixture of ethanol and ethyl acetate. The solid precipitate was filtered off to give (3RS) -1,3-dihydro-3- [3- (4-chlorophenyl) ureido] -5-phenyl-1- (1H-tetrazole) (0.40 g). 5-yl) -methyl / -2H-1,4-benzodiazepin-2-one monohydrochloride is obtained, m.p. 205-208 ° C.

IR (Nujol): 3325, 3250, 3190, 2725, 1690, 1600, 1545 cm ^-1 .

1 H NMR (DMSO-d 6) delta:

5.30-5.50 (1H, m), 5.46 (2H, ABq,

J = 17Hz, 24Hz), 7.20-7.85 (15H, m), 9.0-11.0 (1H, br) _} 9.42 (1H, s).

Example 27

The following compounds were prepared in a similar manner to that described in Example 26.

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 monohydrochloride

M.p. 203-205 ° C.

IR (Nujol): 3320, 3250, 3190, 2720, 1695, 1605, 1525 ^cm-first

¹ H NMR (DMSO-d 6) delta:

5.30-5.40 (1H, m), 5.48 (2H, ABq,

J = 17Hz, 21Hz), 7.20-7.80 (13H, m), 8.0-10.5 (2H, br)> 9.37 (1H, s).

2) (3RS) -1,3-Dihydro-3- (3- (3-methyl-phenyl) -ureido) -5-phenyl-1- (1H-tetrazol-5-yl) -methyl / -2H- 1,4-benzodiazepin-2-one monohydrochloride

Mp 188-194 ° C.

IR (Nujol): 3290, 2720, 2605, 1685, 1610, 1595, 1540 ^cm-first

1 H NMR (DMSO-d ₆ ), delta:

2.24 ·· (3Η, s), 5.30-5.48 (1H, m),

5.46 (2H, ABq, J = 17Hz, 25Hz), 6.70-6.80 (1H, m),

7.00 ⁷ · 54 (12H, m), 7.70-7.80 (2H, m), 8.0-10.20 (2H, br) _t 9.12 (1H, s).

* ··· ·· · ·

- 66 3) (3RS) -1,3-Dihydro-5- (2-fluoro-phenyl) -3- [3- (3-methyl-phenyl) -ureido] -1- (1H-tetrazole-5) yl) methyl / -2H-1,4-benzodiazepin-2-one monohydrochloride

181-191 ° C (dec.).

IR (Nujol): 3300, 2710, 2610,

1690, 1595, 1550 cm ^-1 .

1 H-NMR (DMSO-d 6) delta:

2.24 (3H, s), 5.35-5.45 (1H, m),

5.48 (2H, ABq, J = 11Hz, 22Hz), 6.70-6.78 (1H, m),

7:05 to 7:38 (7H, m), 7.50-7.81 (6H, m), 8.0-10.4 (2H, br) _f 09.11 (1H, s);

Example 28

20.34 g of (3S) -1,3-dihydro-1- (1-tritylimidazol-4-yl) methyl] -3- (3,4-dichlorobenzoylamino) -5- (2) -Fluorophenyl) -2H-1,4-benzodiazepin-2-one in 204 ml of Ν, Ν-dimethylformamide was added 157 ml of 6N hydrochloric acid under stirring in an ice bath. The mixture was heated to 70-80 ° C and stirred for 1 hour. After cooling to room temperature, ice water and ethyl acetate were added with stirring. The resulting mixture was adjusted to pH 8.0 with aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried, and the solvent was distilled off under reduced pressure. The amorphous residue was purified by column chromatography on silica gel using chloroform as eluent. The fractions containing the desired product were combined and the solvent was distilled off. The amorphous residue was dried under reduced pressure to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (3,4-dichlorobenzoylamino) -5- (2-fluorophenyl) - 1,4-Benzodiazepin-2-one is obtained. This product was dissolved in chloroform (200 mL) and 50 mL of 20% hydrochloric acid in ethanol was added under cooling. From the resulting clear yellow solution, the solvent was distilled off under reduced pressure and the resulting amorphous material was freeze-dried. In this way, 12.97 g of (3S) -1,3-dihydro-1- (4-imidazolyl) methyl) -3- (3,4-dichlorobenzene-1-amino) -5- (2) as a yellow powder are obtained. - fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride is obtained.

IR (CHCl3) 3000, 2920-2200, 1660, 1600, 1500 cm @ ^-1 .

¹ H NMR (DMSO-d 6) delta:

5.19 (1H, d, J = 16Hz), 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 = 1.9Hz), 9.01 (1H, s), 9.99 (1H, d, J = 7.3Hz), 14.6 (1H, br s).

Mass Spectrum (m / e): 521 (M ⁺ -37).

[α] _D ³⁰ = -24.75 ° (c = 0.832, methanol).

• * · «· · · · · · · · ···············································•

Example 29

To a suspension of 161.2 mg of 2-indole carboxylic acid in 3.25 ml of dichloromethane was added 119.0 mg of thionyl chloride and 1 drop of N, N-dimethylformamide with stirring at room temperature. After stirring for 1 hour, the resulting solution of 2-indolylcarbonyl chloride in dichloromethane was added dropwise to 387.8 mg of (3S) -3-amino-1,3-dihydro-5- (2-fluoro- phenyl) -1 - ((1H-tetrazol-5-yl) methyl) -2H-1,4-benzodiazepin-2-one hydrochloride and 506.0 mg of triethylamine in 8 ml of dichloromethane stirred in an ice bath added. The resulting mixture was stirred for 3 hours under the same conditions. Chloroform was added and the mixture was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The amorphous residue is triturated with diisopropyl ether, the resulting powder is filtered off, washed with diisopropyl ether and dried under reduced pressure. In this way, (3 S) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1 H- (1 H -tetrazol-5-yl) methyl / -2 H -1,4-benzodiazepin-2-one, m.p. 270-271 ° C (dec.).

[α] _D ^28.5 = -18.87 ° (c = 0.62, tetrahydrofuran).

@ 1 H-NMR (DMSO-d6) delta:

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 Spectrum (m / e): 494 (M ⁺ ).

• · · · · · ·················

Example 30

The following compound was prepared in a similar manner to that described in Example 29.

(3R) -3- (2-Indol-carbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -1 - / (lH-tetrazol-5-yl) methyl / -2 H 1,4-Benzodiazepin-2-one m.p. 270-271 ° C (dec.).

/ a / ²⁸ _D ^'5 = + 18.72 ° (c = 0.625, tetrahydrofuran).

¹ H NMR (DMSO-d 6) delta:

5.49 (2H, ABq, J = 16.3Hz, 24.7Hz),

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 Spectrum (m / e): 494 (M ⁺ ).

Example 31

The following compounds were prepared in a similar manner to that described in Example 12.

1) (3S) -1,3-Dihydro-1- (1-trityl-imidazol-4-yl) methyl] -3- (3,4-dichlorobenzoylamino) -5- (2-fluoro) -phenyl) -2H-1,4-benzodiazepin-2-one 1 H-NMR (CDCl 3) delta:

5-02 (1H, d, J = 15Hz),

5-11 UH, d, J = 15Hz), ₅ . _{67 (1H} , _d , _{J = 7.8Hz) z}

6.84-8.04 (29 H, m).

• ·· · • · · ·

- 70 (3RS) -1,3-Dihydro-1- (2- (4-imidazolyl) ethyl) -3- (3-quinolylcarbonylamino) -5- (2-fluorophenyl) -2H- 1,4-benzodiazepin-2-one

165-175 ° C (dec.).

IR (Nujol): 3600-3000, 1650, 1600 cm @ ^-1 .

Example 32

The following compound was prepared in a similar manner to that described in Example 22.

Claims (10)

A compound of formula (I) wherein R 1 is a heterocyclic group or a cyano group optionally substituted with one or more suitable groups, R ² is hydrogen or halogen, R ³ is an aryl group optionally substituted with one or more suitable groups, R ⁴ represents optionally substituted aryl with one or more suitable groups, optionally substituted with one or more suitable substituent bearing an aryl lower alkenyl, optionally substituted with one or more suitable groups arylamino group optionally substituted by one or more suitable groups, a monocyclic (monocyclic) heterocyclic group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, an indolyl group or a quinoxalinyl group, and A is lower alkylene, provided that when R ⁴ is indolyl then the) R 1 is tetrazolyl optionally substituted with one or more suitable groups, and at the same time R ³ is halogenated phenyl, or b) • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 72 ^R1 is imidazolyl optionally substituted by one or more suitable groups, R ³ is halogenated phenyl, and A is ethylene, compounds and pharmaceutically acceptable salts thereof. Compounds of formula (I) according to claim 1, wherein r 1 represents a tetrazolyl group optionally having an imine protecting group, an imidazolyl group optionally having an imine protecting group or a cyano group, R ³ is phenyl or halogenated phenyl, R ⁴ is phenyl or naphthyl, any of which may be optionally substituted with one or two groups such as halogen and / or amino; lower alkenyl, optionally substituted with amino or nitro, substituted with phenyl; phenylamino optionally substituted with lower alkyl or halogen; pyridyl; tetrahydropyridazinyl optionally substituted with oxo; yl; isoquinolyl; cinnolinyl; an indolyl group or a quinoxalinyl group. Compounds of formula (I) according to claim 2, wherein R ¹ is tetrazolyl optionally substituted by one, two or three phenyl groups, lower imidazolyl or cyano optionally substituted by one, two or three phenyl groups, and R ⁴ is naphthyl; dihalo-phenyl; phenyl substituted with halogen and / or amino; lower alkenyl having a nitrophenyl group; lower alkenyl having aminophenyl; lower alkylphenylamino; halo-phenyl-amino; pyridyl; oxo substituted tetrahydropyridazinyl; yl; isoquinolyl; cinnolinyl; an indolyl group or a quinoxalinyl group. Compounds of formula (I) according to claim 3, wherein is tetrazolyl, is hydrogen, A is halogenated phenyl, is indolyl, and is C 1 -C 4 alkylene. • ··· «· ·············································································· · The compound of formula I according to claim 4, which is (3S) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) - 1 - / (lH-tetrazol-5-yl) methyl / -2H-1,4-benzodiazepin-2-one. 6. A process of the formula I wherein r! is a heterocyclic group or a cyano group optionally substituted with one or more suitable groups, R ² is hydrogen or halogen, aryl optionally substituted with one or more suitable groups, R ⁴ represents optionally substituted aryl with one or more suitable groups, optionally substituted by one or more suitable substituent bearing Chapter lower alkenyl, optionally substituted with one or more suitable groups arylamino group optionally substituted by one or more suitable groups, a monocyclic (monocyclic) heterocyclic group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, an indolyl group or a quinoxalinyl group, and A is a lower alkylene group, with the proviso that if it is an indolyl group, then it is a lower alkylene group. the) R ¹ is tetrazolyl optionally substituted with one or more suitable groups, and at the same time R ³ is halogenated phenyl, or b) R ¹ is imidazolyl optionally substituted with one or more suitable groups, R ³ is halogenated phenyl, and A is ethylene for the preparation of compounds, and salts thereof, characterized in that (a) a compound of formula (II) wherein: R ¹ , R ² , R ³ and A are the above compounds, the amino derivatives thereof or the activated salt thereof, of the formula R ⁴ is reacted with the above compound, a reactive derivative or a salt thereof, to form a compound of formula (I) or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above, or (b) a compound of formula (Ia) wherein: R ² , R ³ , R ⁴ and are as defined above, and R _¹ is optionally substituted with one or more suitable substituents, and the heterocycle of formula (a), wherein 76 <· · * · t ·· »· ··· · · · · · · · · · · · · · · · · · · · · · · ·„ · · · · ^R6 is imino-protective group, a protected imino group bearing a heterocyclic group, the compound or salts thereof are to elimination reaction of the imino-protective group, to form a compound (Ib) or a salt thereof, wherein R ² , R ^3, and R ⁴ are as defined above and are optionally substituted with one or more suitable groups and containing an imino group of formula (b) in the heterogene ring, or (c) a compound of formula (Ic) wherein: R ¹ , R ² , R ³ and A are as defined above, and R ⁴ is substituted with _the nitro group bearing an aryl lower alkenyl group, the compound or a salt thereof is reduced to form (Id) compound or a salt thereof, wherein R ¹ , R ² , R ³ and A are as defined above, and R ^{4 'represents} a substituted amino group, a lower alkenyl group bearing an aryl group, or d) a compound of formula IV wherein: R ² , R ³ and R ⁴ and A are as defined above, a compound or salt thereof having the formula: R ¹ and A are as defined above and are an acid moiety, reacted with a compound or a salt thereof to form a compound of formula (I). formula or a salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above, obsession e) of the general formula (le) in which R ² , R ³ , R ⁴ and A are as defined above, reacting a compound of formula VI or a salt thereof with a compound of formula VI or a salt thereof, to form a compound of formula VI or a salt thereof, wherein R ² , R ³ , R ⁴ and A are as defined above. 7. The formula (Ha) wherein ^r1 c optionally one or more suitable group- a tetrazolyl group substituted with it, R ² is hydrogen or halogen, R ³ optionally one or more suitable group- an aryl group substituted with thal, and THE is lower alkylene, and their salts. ^r1 c 8. A process of formula (IIa) wherein optionally one or more suitable group- R ² Tetrazolyl substituted with thal is hydrogen or halogen, R ³ optionally one or more suitable group- an aryl group substituted with thal, and ♦ ··· * « 4 4 ··· · • * * · «*« • * · * · · «• · ♦ ·» · · 4 • ·· · · · - 78A is a lower alkylene group, for the preparation of compounds and salts thereof, having the formula: wherein: R ¹ _C , k ² , R ³ and A are as defined above, and ^R7 is a protected amino group, to elimination reaction of amino protective group, or salts thereof are the compound. 9. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, together with pharmaceutically acceptable carriers. 10. A process for the use of the compounds of formula I and their pharmaceutically acceptable salts as antagonists of cholecystokinin. 11. A method of treating or preventing cholecystokinin-mediated diseases comprising administering to a human or animal a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 12. A process for the preparation of a pharmaceutical composition comprising the steps of: