HU211324A9 - Benzodiazepine derivatives - Google Patents

Description

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

Specifically, novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof, which are said compounds are cholecystokinin (CCK) antagonists and are thus useful for the treatment of emesis, pancreatitis, insuloma, gastric paresis, gastric ulcer, gastric ulcer, and affecting satiety, etc.

The benzodiazepine derivatives of the invention have the structure represented by the general formula (I), wherein

R ¹ is halogen, substituted with one or more suitable substituents, heterocyclyl, aryl substituted with one or more suitable substituents,

-NH-R ⁵ wherein R ⁵ is hydrogen, lower alkanoyl or lower hydroxyalkyl;

-SR ⁶ , wherein R ⁶ is lower alkyl, lower alkyl substituted with carboxyl and amino, protected lower alkyl or pyridyl substituted with carboxy and protected amino;

-OR ⁷ wherein R ⁷ is hydrogen, hydroxy protecting group, lower alkyl, lower alkenyl, aryl-substituted, lower alkyl, halo-substituted, lower alkyl, substituted-amino, substituted-amino, substituted substituted lower alkyl group, which is a piperazinylalkyl group, may be substituted by another lower alkyl group,

-CONH-R ⁸ , within which

R ⁸ is cyano, carbamoyl-substituted lower alkyl, carboxyl), substituted lower alkyl, protected carboxyl. substituted lower alkyl or lower alkyl substituted with carbamoyl and aryl, or

-ZR ⁹ wherein R ⁹ is hydrogen or lower alkyl and Z is (-C (= O) -, -C (= NR ¹⁰ ) - wherein

R ¹⁰ is hydroxy or amino. and Z is -C (= C (R) (R ¹² )), wherein

R ¹¹ is a carboxyl group or a protected carboxyl group, and

R ¹² is hydrogen or

R ¹¹ and R ¹² are both halogen;

R ² is aryl which may be substituted with one or more suitable substituents;

R ³ is hydrogen or halogen;

R ⁴ is hydrogen, halogen or lower alkoxy; and A is lower alkylene.

The benzodiazepine derivatives of formula (I) according to the present invention are represented by the following compounds. The reaction can be prepared by the reaction processes shown in FIG. In the formulas in the figures, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹² and A have the same definitions as above,

X is halogen,

R 1 is -OR ⁷ within which

R ⁷ is a hydroxyl protecting group - or an aryl group substituted by two protected hydroxyl groups,

Rt is a hydroxy group or an aryl group substituted by two hydroxy groups,

A ¹ is C 1 -C 5 alkylene, R ¹³ is aryl,

R _c represents a protected amino-substituted heterocyclic group or phthalimide group or a -O-R b, in which R ⁷ b is a protected amino group substituted by lower alkyl,

R jj is an amino-substituted heterocyclic group, an amino group, or -OR ⁷ C, within which

Rj. is a lower alkyl group substituted with an amino group,

R 1 is -C (= CH-R ' _a ') -R ⁹ within which

R ⁹ is as defined above, R ¹ , ¹ is a protected carboxyl group, or -CONH-R ⁸ a wherein

R ⁸ represents a protected carboxy substituted lower alkyl;

R ' _f is -C (= CH-COOH) -R ⁹ , within which

R ⁹ is as defined above - or -CONH-R ⁸ b, wherein

R ⁸ is hydroxy-substituted lower alkyl,

R ¹⁴ is hydrogen or lower alkyl,

R ¹⁵ is an imino protecting group,

J is CH or N,

Q is CH or N,

X ^I represents halogen,

R _a is a lower alkyl substituted by a protected carboxyl group and a protected amino group,

R _{b is a} lower alkyl substituted by a carboxyl group or an amino group,

R ⁵ is lower alkanoyl,

Rg is lower alkyl2

GB 211 324 A9 ált piperazinyl or -NH-R ⁵ group of the formula in which

R ⁵ has the same meaning as defined above,

X ² is halogen,

² is lower alkylene and

^R16 is phthalimido, or substituted lower alkyl piperazinyl.

The starting material of formula (IV) is a novel compound prepared according to the reaction scheme shown in Figure 17. In the formulas in Figure 17, R ¹ , R ² , R 1 A and X have the same definitions as above,

Y is an acid residue and

R ¹⁷ is a protected amino group.

The pharmaceutically acceptable non-toxic salts of the compound of formula (I) include, for example, alkali metal salts (e.g., sodium, potassium, etc.), alkaline earth metal salts (e.g., calcium, magnesium, etc.), ammonium salts, salts with organic bases. (e.g. trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine salt, etc.), salts with organic acids (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), salts with inorganic acids (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.).

The terms used in the present invention will be understood in more detail below.

The term "lower" refers to a C 1-6 carbon chain unless otherwise indicated.

The term "lower alkyl substituted with a halogen (halo) group" means a halogen atom or a chlorine, bromine, fluorine or iodine atom.

A suitable "heterocyclic group" may be a saturated or unsaturated, mono- or polycyclic heterocyclic group containing at least one heteroatom, oxygen, sulfur, nitrogen or other. Particularly preferred are unsaturated 3-8 membered monocyclic heterocyclic groups containing from 1 to 4 nitrogen atoms, for example, pyridyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro- 1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.);

saturated 3- to 8-membered saturated monocyclic heterocyclic groups containing from 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .;

unsaturated, fused heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolo-pyridazinyl [e.g. b] pyridazinyl, etc.], dihydro-triazolopyridazinyl, etc .;

3-8 membered monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isooxazolyl, dihydroisooxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl, 1,2 , 5-oxadiazolyl, etc.) and the like;

saturated, 3-8 membered, monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl, etc .;

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

unsaturated, 3-8 membered, monocyclic heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as 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, etc.);

saturated, 3-8 membered, monocyclic heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiadiazolidinyl, etc .;

- unsaturated, 3- to 8-membered, monocyclic heterocyclic groups containing oxygen, such as furyl, etc .;

unsaturated 3-8 membered monocyclic heterocyclic groups containing sulfur, such as thienyl, etc .;

unsaturated, fused, heterocyclic groups containing 1 to 2 carbon atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, etc .;

- or the aforementioned groups, which have one or more suitable substituents such as amino, protected amino, oxo, hydroxy, imino (e.g. tetrahydropyranyl, trityl, etc.), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, etc.) or the like.

In the term "aryl-substituted lower alkyl", suitable "aryl" means phenyl, naphthyl and the like.

^R1 of the "one or more suitable substituents substituted aryl" in the term "substituent" may include hydroxy, protected hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy, etc.) and the like.

Suitable "protected hydroxy" groups include tetrahydropyranyloxy groups, acyloxy groups such as lower alkanoyloxy groups (e.g. formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy). oxy, isovaleryloxy, etc.) and the like.

In the context of R ^2, the term "aryl substituted with one or more suitable substituents" may be taken to mean a halogen atom (e.g., chlorine, bromine, fluorine and iodine) and the like.

Suitable "lower alkanoyl" may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and the like.

"Hydroxy-substituted lower alkyl", "aryl-substituted lower alkyl", "halo-substituted lower alkyl", "amino-substituted lower alkyl", "protected amino-lower alkyl", "protected amino-lower alkyl"

EN 211 324 A9 lower alkynyl substituted with zinyl, "lower alkyl substituted with carbamoyl", "lower alkyl substituted with carboxyl" and "lower alkyl having 6 carbons substituted with protected carboxyl" or "lower alkyl having 6 carbons" such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, etc .; C 1-4 groups are preferred.

As used herein, the term "protected carboxyl substituted lower alkyl" refers to an esterified carboxyl group and the like. The ester group of said esterified carboxyl group may be, for example, a lower alkyl ester group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, 1-cyclopropylethyl), which is a suitable substituent. (s), such as lower alkanoyloxy (lower alkyl) ester (e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyl). oxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl, pivaloyloxyethyl, 2-propionyloxyethyl, hexanoyloxymethyl ester, etc.); lower alkanesulfonyl (lower alkyl) ester (e.g. 2-mesylethyl ester, etc.). or a lower alkyl ester substituted with one, two or three halo groups (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propionyl ester, etc.); substituted with one, two or three phenyl groups. lower alkyl ester which may carry other suitable substituent (s) (e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl, bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); an aryl ester which may carry a suitable substituent (s) (e.g., phenyl, 4-chlorophenyl, tolyl, 4-tert-butylphenyl, xylyl, mesityl, cumenyl ester, etc.) and the like.

The term "protected amino group" as used herein for "lower alkyl substituted with a protected amino group" may be an acylamino group or an amino group substituted with one of the conventional protecting groups. Such a protecting group may be, for example, a lower alkyl group substituted with an aryl group which may carry at least one suitable substituent (e.g., benzyl group, trityl group, etc.) and the like.

In the terms "acylamino group" and "acyloxy group", a suitable acyl group may be an acyl group containing an aliphatic acyl group and an aromatic or heterocyclic ring. Exemplary acyl groups include lower alkanoyl groups (e.g., horn, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl-1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl groups (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl groups (e.g. benzenesulfonyl, tosyl, etc.); aroyl groups (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indanecarbonyl, etc.); aryl-substituted lower alkanoyl groups (e.g., phenylacetyl, phenylpropionyl, etc.); aryl-substituted lower alkoxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like.

The acyl groups listed above may be substituted with at least one suitable substituent selected from the group consisting of halogen (chlorine, bromine, fluorine and iodine), amino, lower alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, etc.) and the like.

Suitable "hydroxy-protecting groups" include tetrahydropyranyl, acyl groups such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, etc.) and the like.

A suitable "lower alkenyl group" may be 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.

Suitable "lower alkoxy" groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like; preferably having from 1 to 4 carbon atoms.

Suitable "lower alkylene groups" may be straight or branched C 1 -C 6, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene. hexamethylene and the like; C 1-4 are preferred.

Suitable "imino protecting groups" include trityl, tetrahydropyranyl and the like.

Suitable "acid residues" include an acyloxy group in which the acyl group is one of the foregoing, halo (fluorine, chlorine, bromine and iodine) and the like.

Preferred are compounds of formula I wherein

R ^! is halogen, thienyl, furyl, lower alkyl substituted piperazinilc swept, imidazolidinyl brushed which may be substituted trityl group, a lower alkyl substituted with aryl, substituted trityl and lower alkyl imidazolyl, substituted trityl pyrazolyl group, a trityl-substituted triazolyl group, amino or protected amino

A9-substituted thiazolyl, especially thiazolyl substituted with amino or acylamino, most preferred thiazolyl substituted with amino or lower alkanoylamino, tetrahydroxy substituted with hydroxy, and isoxazole substituted with hydroxyl. tetrazolyl, two oxo-substituted isoindolyl, phenyl, two-protected hydroxy-substituted phenyl, especially phenyl substituted by two acyloxy groups, most preferably two-lower alkanoyloxy substituted by two lower alkanoyloxy, substituted by two lower alkanoyloxy phenyl, phenyl substituted by two lower alkoxy groups,

-NH-R ⁵ wherein R ⁵ is hydrogen, lower alkanoyl or hydroxy substituted lower alkyl.

-SR ⁶ , wherein R ⁶ is lower alkyl, lower alkyl substituted with carboxyl and amino, lower alkyl substituted with protected carboxyl and protected amino, with lower ester substituted with carboxyl and acyl, and with acyl - lower alkyl substituted with (lower alkoxycarbonyl) and lower alkoxycarbonylamino - or R ^{6 is} further pyridyl,

-O-R ⁷ wherein R ⁷ is hydrogen, hydroxy protecting group, preferably tetrahydropyranyl or lower alkanoyl, lower alkyl, lower alkenyl, lower alkyl substituted with phenyl, lower alkyl, lower alkyl, lower alkyl, lower alkyl, substituted lower alkyl, protected amino-substituted lower alkyl - including lower phthalimido substituted lower alkyl - or lower alkyl substituted piperazinyl (lower alkyl),

^-CONH-R8; where ^R8 is cyano, substituted carbamoyl, lower alkyl, substituted by protected carboxy lower alkyl - preferably including substituted with esterified carboxy, lower alkyl, most preferably a substituted lower alkoxycarbonyl group, a lower lower alkyl substituted with alkyl or carbamoyl and phenyl,

-ZR ⁹ wherein R ⁹ is hydrogen or lower alkyl and Z is -C (= O) -, -C (= NR ¹⁰ ) -, wherein R ¹⁰ is hydroxy, lower alkoxy or amino, or Z is other. is -C [= (R) (R ¹² )] - wherein R 'is a carboxyl group or a protected carboxyl group, more preferably an esterified carboxyl group, most preferably a lower alkoxycarbonyl group, and R ¹² is hydrogen, or R ¹¹ and R ¹² is simultaneously halogen;

R ² is phenyl or halo-substituted phenyl;

R ³ is hydrogen;

R ⁴ is hydrogen, halogen or lower alkoxy, and

A is lower alkylene.

When a compound of formula (I) contains a group of formula (XVIII), it may be in equilibrium with the tautomeric forms shown in Figure 18. The invention encompasses both of these tautomeric isomers. In the description of the invention and in the claims, compounds having a group allowing such tautomeric isomers are described by the structure (XVIUA).

The compound of formula (I) may be prepared by the following reaction procedures:

Process (1) (Figure 1) - A compound of formula (I) or a salt thereof can be prepared by reacting a compound of formula (II) or a salt thereof with a compound of formula (ΠΙ).

The salts of the compounds of the formulas II and UI may be the same as those already mentioned for the compound of the formula I.

The reaction is usually carried out in the presence of a base. Suitable bases include an inorganic base such as an alkali metal hydride (e.g., sodium hydride, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), an alkali metal. carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.). ), alkali metal acetate (e.g., sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate, dipotassium hydrogen) etc.) and the like; or an organic base such as trialkylamine (e.g., trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, Nmethylmorpholine and the like.

The solvents used for the reaction include alcohols, Ν, Ν-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.

The reaction temperature is generally not critical and may be carried out at room temperature under heating or cooling.

Process 2 (Figure 2) - The ve5 of formula (I)

The A9 compound can be prepared by reacting a compound of formula (IV), or an active derivative or amino salt thereof, with a compound of formula (V) or an active derivative or salt thereof, of a carboxyl group.

A suitable derivative formed at the amino group of compound (IV) may be a Schiff-base imino derivative or a tautomeric enamine-type isomer formed by reacting compound (IV) with a carbonyl-containing compound such as an aldehyde, ketone or the like; a silyl derivative prepared by reacting compound (IV) with a silyl compound such as N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide and the like; a derivative of compound (IV) with phosphorus trichloride or phosgene; etc

Suitable salts of the compounds of formula (IV) and (V) are the same as the exemplified salts of compound (I).

The reactive derivative of the compound of formula (V) on a carboxyl group may be an acid halide, acid anhydride, active amide, active ester, and the like. Examples include acid chloride, acid azide, substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphoric acid, e.g. mixed anhydrides with sulfuric acid, alkyl carboxylic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), aromatic carboxylic acid (e.g. benzoic acid), active amides formed with tetrazole, active esters such as cyanomethyl, methoxy, methyl, dimethyliminomethyl [(CH ₃ ) ₂ N ₊ = CH-], vinyl, propargyl, p -nitro-phenyl.

2,4-dinitrophenyl. trichlorophenyl, pentachlorophenyl, mesylphenyl, phenylazo-phenyl, phenylthio, ρ-nitrophenylthio, p-cresylthio, carboxymethylthio, pyranyl; , piperidyl, 8-quinolylthioester, etc., with N-hydroxy compounds (e.g., N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxy) esters with benzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.) and the like. These reactive derivatives are optionally selected according to the structure of the compound of formula (V) to be used.

The reaction is usually carried out in one of the usual solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν, Ν-dimethylformamide, pyridine or other organic solvents. solvent which does not adversely affect the reaction. A suitable mixture of solvents may also be used.

When the compound of formula (V) is used as the free acid or salt for the reaction, it is preferable to carry out the reaction in the presence of one of the conventional condensing agents. Examples of such condensing agents are N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4-dimethylaminocyclohexyl) -carbodiimide, N-ethyl-N'- (3-Dimethylaminopropyl) carbodiimide, N, N-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenyl ketene-N-cyclohexylimine, ethoxyacetylene , 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, trionyl chloride, oxalyl chloride, triphenylphosphine, 2- ethyl 7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, the Ν, Ν- dimethylformamide and thionyl chloride, phosgene, phosphorus oxychloride and the like. skilled so-called Vilsmeier reagent, etc.

The reaction may be carried out on an inorganic or organic base such as an alkali metal bicarbonate, a lower trialkylamine, a pyridine, a lower N-alkylmorpholine, an N, N-di (lower) alkylbenzylamine and the like. presence. The reaction temperature is not critical and may be carried out under cooling or heating.

Process 3 (Figure 3) - The compound of formula (Ib) or a salt thereof can be prepared by removing the hydroxyl protecting group from the compound of formula (Ia) or its salt.

The elimination reaction is carried out according to conventional methods, i.e. hydrolysis, reduction or the like. The hydrolysis may be acidic, alkaline, etc. The choice of procedure depends on the protecting group to be removed.

Hydrolysis is the most common and preferred method for the removal of tetrahydropyranyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl protecting groups.

Suitable acids for this purpose include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The reaction acid is selected according to the protecting group to be removed and other factors.

Alkaline hydrolysis is preferably used to remove the acyl group. Suitable bases include inorganic metals such as alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., magnesium, calcium, etc.), their hydroxides, carbonates, bicarbonates, and the like. and organic such as trialkylamine (e.g., trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine and the like.

The reductive elimination reaction can take place, for example, with a metal (e.g. tin, zinc, iron, etc.) or a metal compound (e.g., chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g., acetic, propionic, hydrochloric, etc.) or the reaction may be carried out using a metal catalyst as the catalytic reduction. Suitable catalysts are conventional metal catalysts such as Raney nickel, platinum oxide, palladium on carbon and the like. The reaction is carried out in one of the conventional solvents, such as water, dioxane, tetrahydrofuran, alcohol, Ν, Ν-dimethylformamide or other solvent which does not adversely affect the reaction.

The reaction temperature is not critical, the temperature being protected by the protecting group and the elimination method6

EN 211 324 A9 winter, cooling or heating can be used.

Process 4 (Figure 4) - The compound (Id) or salt thereof may be prepared by oxidation of the compound (Ic) or salt thereof.

The salts of the compounds of formulas Ic and Id may be those listed above in relation to formula I.

The oxidation may be carried out by conventional methods, for example using oxidizing agents such as the combination of dimethyl sulfoxide with dicyclohexylcarbodiimide or chromium trioxide with pyridine.

The reaction solvent may be, for example, benzene, Ν, Ν-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and cooling and heating may be employed.

Process 5 (Figure 5) - A compound of formula (If) or a salt thereof can be prepared by reacting a compound of formula (Ie) or a salt thereof with a compound of formula (X) or a salt thereof.

Suitable salts of the compounds of the formulas (le) and (If) are those already exemplified for the compound of the formula (I).

The reaction solvent is usually benzene, Ν, Ν-dimethylformamide, tetrahydrofuran, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical, and cooling or heating may be employed.

Process 6 (Figure 6) - A compound of formula (Ig) or a salt thereof can be prepared by reacting a compound of formula (Ic) or a salt thereof with a compound of formula (XI).

Suitable salts of the compound of formula (Ig) include those exemplified for the compound of formula (I).

The solvent commonly used for the reaction is benzene, Ν, Ν-dimethylformamide. tetrahydrofuran, alcohol (e.g. methanol, ethanol, etc.), chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical, and cooling and heating may also be employed.

Process 7 (Figure 7) - The compound of formula (II) or a salt thereof is prepared by removing the amino protecting group from the compound of formula (Ih) or its salt.

This reaction is carried out in substantially the same manner as step (3) of process (17), so the method and reaction conditions are detailed therein.

Process 8 (Figure 8) - The compound (Ik) and its salt are prepared by removing the carboxyl protecting group from the compound (Ij) or its salt.

This reaction is carried out essentially as in (3), and the manner and conditions of the reaction are described therein.

Process 9 (Figure 9) - The compound (IIm) or salt thereof is prepared by removing the imino protecting group from the compound (II) or salt thereof.

The reaction is carried out essentially as in step (3) of process (17), so the method and reaction conditions will be described in detail.

Process 10 (Figure 10) - A compound of formula (In) or a salt thereof is prepared by reacting a compound of formula (ΧΠ) or a carboxylic acid reactive derivative thereof or a salt thereof with a compound of formula (XIII) or an amino acid reactive derivative thereof. or a salt thereof.

The reactive derivatives of the compound of formula (XII) formed on the carboxyl group may be the same as those exemplified for the compound of formula (V).

The reactive derivatives of the compound of formula (XIII) at the amino group may be the same as those exemplified for the compound of formula (IV).

This reaction is essentially carried out in the manner and under the conditions described in Process (2).

Process 11 (Figure 11) - The compound (Ip) or salt thereof may be prepared by reacting the compound (Io) or salt thereof with the compound (XIV) or salt thereof.

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

Suitable bases are listed in Process (1).

The solvent used in the reaction may be an alcohol (e.g. methanol, ethanol, etc.), benzene, Ν, Ν-dimethylformamide, tetrahydrofuran or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical, and the reaction may be carried out at room temperature under heating or cooling.

Process 12 (Figure 12) - The compound (Ireland) or salt thereof is prepared by removing the amino protecting group and the carboxyl protecting group from the compound (Iq) or salt thereof.

The reaction is carried out essentially as described in step (3) of process (17).

Process 13 (Figure 13) - A compound of formula (I) or a salt thereof can be prepared by reacting a compound of formula (I) or a reactive derivative or amino salt thereof with a compound of formula (XV) or a carboxyl group thereof. or a salt thereof.

Suitable reactive derivatives of the compound of formula (Is) at the amino group are the same as those exemplified for the compound of formula (IV).

Suitable reactive derivatives of the compound of formula (XV) on the carboxyl group are the same as those exemplified for the compound of formula (V).

The reaction is carried out essentially as described in Process (2) and under reaction conditions.

Method A9 (14) (Figure 14) - The compound (Iu) or salt thereof is prepared by reacting the compound (Io) or salt thereof with the compound (XVI) or salt thereof.

The reaction solvent is usually Ν, Ν-dimethylformamide, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.

If the compound of formula XVI is liquid, it may also serve as a solvent.

The reaction temperature is not critical, and the reaction may be carried out at room temperature under heating or cooling.

Process 15 (Figure 15) - A compound of Formula Iw or a salt thereof is prepared by reacting a compound of Formula Iu or a salt thereof with a compound of Formula XVII.

The reaction is carried out essentially as described in Process (1) and under reaction conditions.

Process 16 (Figure 16) - The compound (Iy) or salt thereof is prepared by deprotecting the imino group from the compound (Ix) or salt.

The reaction is carried out essentially as described for Process (9) and under reaction conditions.

Process 17 (Figure 17) - The starting material of formula IV is prepared by the following reaction steps.

Step (17-1) - The compound (VIII) or salt thereof can be prepared by reacting the compound (VI) or salt thereof with the compound (VII).

The reaction mode and reaction conditions are described below in Example 1.

Step (17-2) - A compound of formula (IX) or a salt thereof is prepared by reacting a compound of formula (VIII) or a salt thereof with a compound of formula (III). The reaction is carried out essentially as described in Process (1) and under reaction conditions.

Step 17-3 - The compound (IV) or salt thereof is prepared by removing the amino protecting group from the compound (IX) or salt thereof.

Suitable salts of the compound of formula (IX) are the same as those exemplified for the compound of formula (I).

The elimination reaction can be carried out in the usual manner, i.e. by hydrolysis, reduction, Edman's method (phenylisothiocyanate method) and the like. The hydrolysis process may include acidic, alkaline, hydrazine, and the like. method. The appropriate method is selected depending on the protecting group to be removed.

If the protecting group is, for example, tert-pentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, substituted aryl, alkylidene, substituted cycloalkylidene or the like, the most commonly and most preferably used hydrolysis method is the acidic method.

The acid used may be organic or inorganic, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, ptoluenesulfonic acid, hydrochloric acid, and the like. Most preferred are acids which are readily removed from the reaction mixture by any conventional means, such as distillation under reduced pressure. Such acids include, for example, formic acid, trifluoroacetic acid, hydrochloric acid, and the like. The acid may be selected depending on the protecting group to be removed.

Alkaline hydrolysis is used to eliminate an acyl group such as trifluoroacetyl.

Halogen-substituted alkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl and the like. the reductive method is generally used to eliminate protecting groups. It can be reduced, for example, with an alkali metal borohydride (e.g. sodium borohydride, etc.), metal (e.g. tin, zinc, iron, etc.) or the metal and its compound (e.g., chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.) or catalytically. Suitable catalysts include Raney nickel, platinum oxide, palladium on carbon and the like.

Of the protecting groups, the acyl group can generally be removed by hydrolysis. Particularly in the case of halogen substituted alkoxycarbonyl and 8-quinolyloxycarbonyl groups, the elimination is generally carried out with a heavy metal such as copper, zinc and the like. - response.

The reaction is usually carried out in one of the conventional solvents, such as water, chloroform, methylene chloride, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran or other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the choice depends on the protecting group to be removed and the methods mentioned above. The reaction is usually carried out under mild conditions, that is, under cooling or at a slightly elevated temperature.

Among the protecting groups, the acyl group derived from α-amino acids can be removed by the Edman method.

The compound of formula (I) and its pharmaceutically acceptable salts are cholecystokinone (CCK) antagonists and can therefore be used as medicaments for the treatment of vomiting, inflammation of the pancreas, and the like. treatment.

To demonstrate the utility of the compound of formula I, the following assays are described which demonstrate the CCK antagonist activity of the compound.

Detection of CCK receptor antagonism in guinea-pig stomach in isolated circular muscle:

Test compound: (3RS) -1,3-Dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (a) hereinafter Test A).

Test Method: Suspend a section of circular muscle in 25 ml of Kreb's bicarbonate bath. The bath composition was 118 mM sodium chloride, 25 mM sodium bicarbonate, 11 mM glucose and 0.1% bovine serum albumin. The bath was maintained at 37 ° C and aerated with a gas mixture containing 95% oxygen and 5% carbon dioxide.

HU 211 324 A9

The muscle slice was exposed to an initial tension of 0.5 g and equilibrated for 60 minutes while the bath was changed every 15 minutes. Isometric muscle contraction is measured using a force transmission device. Add 3.2 x ^{10 7} M CCK-8 to the bath and measure the contractile force. After washing CCK-8, Ix10 ^-5 M A test compound is added to the bath. After 5 minutes, CCK-8 is added and the force of contraction is measured. To characterize CCK antagonism, CCK-induced contraction in the absence and presence of test compound A is compared.

Test result: 91% inhibition.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to mammals, including man, using conventional pharmaceutical formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, syrups, aerosols, inhalants, solutions, injections, suspensions, emulsions. etc - in shape.

The pharmaceutical composition of the present invention may contain various organic or inorganic additives commonly used, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.). a binder (cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, acacia, polyethylene glycol, sucrose, starch, etc.), a disintegrant (e.g., starch, carboxymethylcellulose, carboxymethylcellulose) , hydroxypropyl starch, sodium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium lauryl sulfate, etc.), flavoring agent (e.g., citric acid, menthol, glycine, orange powder, etc.), preservative (e.g. e.g., sodium benzoate, sodium hydrogen sulfite, methylparaben, propylparaben, etc.), a stabilizer (e.g., citric acid, sodium citrate, acetic acid, etc.), a suspending agent (e.g., methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc.), an aqueous diluent (e.g., water), a base wax (e.g., cocoa butter, polyethylene glycol, white petrolatum, etc.).

An effective amount of the active ingredient is usually 0.01 to 50 mg, administered 1-4 times per kilogram body weight per day. However, this dose may be more or less depending on the age, weight, condition and route of administration of the patient.

The following are examples to illustrate what has been said. The examples are illustrative only and are not intended to limit the scope of the invention.

Starting Example 7

11.75 g of (3RS) -1,3-dihydro-3-acetoxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 11.1 g of potassium phthalimide, 60 g of sodium iodide and 80 ml of Ν, The reaction mixture containing? -Dimethylformamide was stirred at 90-95 ° C for 45 minutes. The reaction mixture was poured into 1 liter of cold water. The precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 8.32 g of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one.

IR (nujol): 3500. 3370, 3230, 1780, 1720, 1695, 1610,

1575 cm ^-1 .

NMR (DMSO-d 6), δ: 5.73 (1H, s), 7.30-7.70 (9H,

m), 7.97 (4H, m), 11.90 (1H, broad s).

Starting Example 2

The reaction mixture (8.2 g) of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H1.4-benzodiazepin-2-one, 1.08 g of hydrazine hydrate and 160 ml of tetrahydrofuran was stirred at room temperature for one hour. and reflux for 1.5 hours. The precipitate is filtered off, the filtrate is concentrated to a small volume and an equal volume of ethyl ether is added. The precipitate was collected by filtration to give 3.64 g of (3RS) -1,3-dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (nujol): 3360, 3290, 2700, 1670, 1600, 1570,

1480 cm ^-1 .

NMR _(DMSO-d6) delta, 4.30 (IH, s), 5.0 (2H, brs), 7.20-7.60 (9H, m).

Starting Example 3

To a solution of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H1.4-benzodiazepin-2-one (1.90 g) in N, N-dimethylformamide (30 mL) was stirred and ice-cooled (<3). In addition to C, sodium hydride (0.20 g, 62% suspension in mineral oil) was added in small portions. The reaction mixture is stirred under cooling for 10 minutes and then 2-[(tetrahydropyran-2-yl) oxy] ethyl bromide (1.60 g) is added in one portion. The mixture was stirred at room temperature for 1 hour, at 45 ° C for 4.5 hours and then allowed to stand overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated to give a pale yellow powder which was washed with ethyl acetate / diethyl ether and collected by filtration to give 1.48 g of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-1- {2 - [(RS) - 2-Tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-1- {2 - [(SR) -2-tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepin-2-one.

IR (nujol): 1770, 1714, 1670, 1600. 1375, 1130, 1014,

710 cm ^-1 .

NMR (CDCl ₃ ) delta 1.3-1.9 (6H, br), 3.4-4.7 (7H, m), 6.00 (1H, s), 7.3-8.1 (13H, m).

Starting Example 4

(3RS) -1,3-Dihydro-5-phenyl-3-phthalimido-1- {2 [(RS) -2-tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepine-2- on and (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-1- {2 - [(SR) -2-tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepine-2 -on, 0.51 g is dissolved in 10 ml of chloroform and 55 g of hydrazine hydrate are added with stirring at room temperature. The reaction mixture was stirred for 1.5 hours at room temperature and then

Reflux for 1.5 hours. After cooling, the precipitate is filtered off and the filtrate is evaporated to dryness. The residue was dissolved in a little ethanol and diethyl ether was added. The white powder is filtered off and the filtrate is evaporated to give 0.43 g of (3RS) -1,3-dihydro-5-phenyl-3-amino-1- {2 - [(RS) -2-tetrahydropyranyloxy] ethyl}. -2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5-phenyl-39

A mixture of A9 amino-1- {2 - [(SR) -2-tetrahydropyranyloxy] ethyl} -2H1,4-benzodiazepin-2-one is obtained.

IR (nujol): 3340.1680, 1660.1600, 780,760,695 cm -1.

Example 1

1.18 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one in 30 ml of N, N-dimethylformamide 0.26 g of sodium hydride (62% suspension in mineral oil) is added while stirring, while maintaining the solution in a salt-ice bath at 0 ° C and purging with nitrogen. After stirring under the same conditions for 40 minutes, 0.39 g of 5-chloromethyl-tetrazole is added to the reaction mixture. The reaction mixture was further stirred at room temperature for 66 hours, then poured into a saturated aqueous solution of sodium bicarbonate and the aqueous solution was washed with ethyl acetate. After filtering out the insoluble material, the separated aqueous phase was acidified with dilute hydrochloric acid.

The acidified aqueous phase was extracted twice with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave 1.27 g of an orange oil which was purified by chromatography on silica gel eluting with chloroform / methanol (10: 1). 0.5 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- (5-tetrazolylmethyl) -2H1,4-benzodiazepin-2-one are obtained.

190-195 ° C (dec.).

IR (nujol): 3350 (shoulder), 3250, 1680, 1635, 1600, 740,

695 cm ^-1 .

NMR _(DMSO-d6) delta: 5.42 (2H, ABq), 5.70 (1H, d,

J = 8.0 Hz), 6.9-8.0 (15H, m). 9.44 (1H, d, J =

8.0 Hz), 11.6 (1H, broad s).

Mass: m / e = 477 (M ⁺ ).

Example 2 To 0.19 g of N-hydroxybenzotriazole in 0.1 ml of chloroform and 0.24 g of N, N-dicyclohexylcarbodiimide are added 0.43 g of (3RS) -1,3-dihydro-5-phenyl-3-amino-1- (2 - [(RS) -2-Tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5-phenyl-3-amino-1- { A mixture of 2 - [(SR) -2-tetrahydropyranyloxy] ethyl} -2H1.4-benzodiazepin-2-one was stirred at room temperature under stirring for another 2 hours and the resulting precipitate was filtered off. The combined filtrate and washings were evaporated under reduced pressure and the resulting oily residue (1.20 g) was chromatographed on a silica gel column using chloroform / ethyl acetate 10: 1 as eluent to give 0.45 g of (3RS) -1,3-dihydro-3- ( 2-indolylcarbonylamino) -5-phenyl-1- (2 - [(RS) -2-tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepin-2-one and (3RS) -1, Consists of 3-dihydro-3- (2-indolylcarbonylamino-5-phenyl-1- {2 - [(SR) 2-tetrahydropyranyloxy] ethyl} -2H-1,4-benzodiazepin2-one kev we get goodies.

IR (nujol): 3340, 3280, 1680, 1630, 1610 (shoulder), 750,

700 cm ^-1 .

Nuclear Magnetic Resonance Spectrum (CDCl,), δ 1.0-2.0 (6H, m), 3.1-4.7 (7H, m), 5.82 (1H, d, J = 8Hz), 7.0-7. 9 (14H, m), 8.13 (1H, d, J = 8Hz), 9.62 (1H, broad).

Example 3

0.42 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- {2 - [(RS) -2-tetrahydropyranyloxy] ethyl } 2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- {2 - [(SR) -2-tetrahydro] Pyranyloxy] ethyl} -2H-1,4-benzodiazepin-2-one was slurried in acetone (10 mL) and 6N hydrochloric acid (0.4 mL) was added with stirring at room temperature. After stirring the yellow clear solution for 45 minutes, additional 4 ml of 6N hydrochloric acid and 1 ml of water were added. The reaction mixture was stirred at room temperature for half an hour. After neutralization with aqueous sodium bicarbonate and removal of the acetone, a yellow precipitate was obtained which was collected by filtration, washed with water and dried. The crude product was chromatographed on a silica gel column using chloroform / ethyl acetate (5: 1) as eluent. 0.28 g of (3RS) -1,3-dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one are obtained. in the form of amorphous material. Trituration with diethyl ether gave a pale yellow powder.

170-175 ° C (dec.).

IR (nujol): 3400 (shoulder), 3260, 1675 (shoulder), 1630, 1595,

740, 690 cm -1.

NMR (CDCl3), delta: 2.32 (1H, broad), 3.65-4.4 (4H, m), 5.74 (1H, d, J = 8Hz), 7.05-7.7 (14H, m), 8.02 (1H, d, J = 8Hz), 9.45 (1H, broad s).

Mass: m / e = 438 (M ⁺ ).

Starting Example 5

a) 1.0 g of (3R) -1,3-dihydro-5-phenyl-3 - {[(2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl] amino) -2H1.4- benzodiazepin-2-one and (3S) -1,3-dihydro-5-phenyl-3 - {[(2S) -2-tert-butoxycarbonylamino-3-phenylpropanol] amino} -2H-1 A mixture of 4-benzodiazepin-2-one was dissolved in 5 ml of Ν, Ν-dimethylformamide and 77.4 mg (62% suspension in mineral oil) of sodium hydride was added with stirring, and the reaction mixture was stirred in an ice bath for approx. Cooled to 3 ° C. Under these conditions, stirring is continued for another 40 minutes. To the reaction mixture was added 0.37 g of 2-acetoxyethyl bromide in one portion with cooling and stirring. The reaction mixture was stirred under ice-cooling for 1.5 hours and then at room temperature for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave 1.29 g of an oily residue which was chromatographed on a silica gel column using chloroform / ethyl acetate 10: 1 as eluent. The fractions containing the desired compound were combined and evaporated to give (3R) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl-3 - ([(2S) -2-tert- butoxycarbonylamino-3-phenylpropanoyl] amino) -2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5 phenyl-3 - {[(2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl] amino) -2H-1,4-benzodiazepin-2-one.

IR (in liquid): 3400 (shoulder), 3300, 1730, 1700 (shoulder),

1690, 1660, 1600, 745. 695 cm ^-1 .

HU 211 324 A9

NMR (CDCl ₃ ), δ: 1.40 (9H, s), 1.62 (3H, s), 3.03.3 (2H, m), 3.9-4.2 (3H, m), 4.4-4.8 (2H, m), 5.06 (1H, broad d), 5.51 and 5.53 (1H, d and d), 7.2-7.85 (14H, m) .

b) The following mixture is also prepared according to the above procedure:

(3R) -1- (2-Acetoxyethyl) -1,3-dihydro-5- (2-fluorophenyl) 3 - {[(2S) -2-tert-butoxycarbonylamino-3-phenyl] propanoyl] amino} -2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5- (2-fluorophenyl) 3 - {[( 2S) -2terc-butoxycarbonyl-amino-3-phenylpropyl] amino} 2H-1,4-benzodiazepin-2-one.

IR (in liquid): 3400 (shoulder), 3320, 1730, 1700 (shoulder),

1690, 1662, 1485, 1440, 1380, 1365, 1230, 1161,

1048,750,695 cm -1.

NMR (CDCl ₃ ), delta: 1.40 (9H, s), 1.79 (3H, s), 3.03.3 (2H, m), 3.8-4.8 (5H, m), 5.07 (1H, broad d, J = 7.4 Hz), 5.53, 5.55 (1H, dd, J = 8 Hz), 6.95-7.9 (14H, m).

Starting Example 6 (3R) -1- (2-Acetoxyethyl) -1,3-dihydro-5-phenyl-3 - {[(2S) 2-tert-butoxycarbonylamino-3-phenylpropanoyl] ] -amino} -2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl-3 - {[(2S) -2-tert- of a mixture of butoxycarbonylamino-3-phenylpropanoyl] amino} -2H-1,4-benzodiazepin-2-one was dissolved in ethyl acetate (20 mL) and hydrogen chloride gas was added to the solution. with cooling and stirring. After the solution was saturated with hydrogen chloride, stirring was continued under cooling for 30 minutes and then at room temperature for 1 hour. The solution was bubbled through with dry nitrogen gas, the hydrochloride removed and the solution evaporated under reduced pressure. Water was added to the residue and neutralized with an aqueous solution of sodium bicarbonate. It was extracted twice with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solvent was evaporated to give 0.57 g of (3R) -1- (2-acetoxyethyl) -3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1,3-dihydro-5 -phenyl 2 H -1,4-benzodiazepin-2-one and (3 S) -1- (2-acetoxyethyl) -3 - {[(2 S) -2-amino-3-phenylpropanoyl] amino} -1,

A mixture of 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained.

Starting Example 7

(3R) -1- (2-Acetoxyethyl) -3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1,3-dihydro-5-phenyl-2H-1,4 benzodiazepin-2-one (3R isomer) and (3S) -1- (2-acetoxyethyl) 3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1, 12.2 g of a mixture of 3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (3S-isomer) is chromatographed on silica gel (230-400 mesh) with 20: 1 chloroform / methanol. elution. The fractions containing the desired material were combined and evaporated to dryness to give 3.32 g of pure 3S-isomer as an oil. The remaining fractions gave 8.50 g of a mixture of the 3S and 3R isomers as an oily substance. This material was repeatedly chromatographed on a silica gel column (230-400 mesh), eluting with chloroform / methanol (15: 1). This gives 1.30 g of pure 3S-isomer as oily material and 4.01 g of oily substance as 3R-isomer.

NMR (CDCl ₃ + D ₂ O) (270 MHz), delta:

3S-isomer:

1.648 (3H, s), 2.817 (1H, dd, J = 14.0 Hz, 10.8 Hz),

3.366 (1H, dd, J = 14 Hz, 6.5 Hz), 3.704 (1H, dd,

J = 10.8 Hz, 6.5 Hz), 3.927 (1H, dt, J = 15.1 Hz,

6.5 Hz), 4.07-4.20 (2H, m,), 4.660 (1H, octet, J =

13.6 Hz, 7.6 Hz, 7.6 Hz), 5.578 (1H, s), 7.19-7.64 (14H, m).

3R-isomer:

1.642 (3H, s), 2.696 (1H, dd, J = 14.0 Hz, 10.8 Hz),

3.499 (1H, dd, J = 14.0 Hz, 6.5 Hz), 3.729 (1H, dd,

J = 10.8 Hz, 6.5 Hz), 3.927 (1H, dt, J = 15.1 Hz,

6.5 Hz), 4.09-4.17 (2H, m), 4.690 (1H, octet, J =)

13.6 Hz, 7.6 Hz, 7.6 Hz), 5.571 (1H, s), 7.21-7.63 (14H, m).

Starting Example 8

The following materials can be prepared according to the procedures described in steps 6 and 7:

(3S) -l- (2-acetoxy) -3 - {[(2S) -2-amino-3-phenyl-pmpanoil] amino} -], 3-dihydro-5- (2-fluorophenyl) - 2H -], 4-benzodiazepin-2-one.

Mp: 168-170 ° C.

IR (nujol): 3410, 3360, 3325 (shoulder), 1742, 1680 (shoulder),

1667, 1610 (shoulder), 1600, 1480, 1448, 1240, 1108,

1045, 810, 781, 730, 699 cm -1.

NMR (CDCl ₃ ), delta: 1.81 (3H, s), 1.85 (2H, s), 2.84 (1H, dd, J = 10.5 Hz, 13.5 Hz), 3.33 (1H, dd, J =

13.5 Hz, 4 Hz), 3.69-4.25 (4H, m), 4.5M, δ (1H, m), 5.60 (1H, d, J = 8Hz), 6.95-7 , 9 (13H, m), 9.01 (1H, d, J = 9Hz).

(3R) -l- (2-acetoxyethyl) -3-f [(2S) -2-amino-3-phenylpropanoyl] amino} -l, 3-dihydro-5- (2-fluorophenyl) 2H -1,4-benzodiazepin-2-one.

IR (film): 3400 (shoulder), 3360, 1738, 1685 (shoulder), 1668,

1605, 1510 (shoulder), 1495, 1450, 1380, 1328, 1240,

1220, 1108, 1045, 820, 750, 700 cm -1.

NMR (CDCl ₃ ), delta: 1.80 (3H, s), 1.87 (2H, s), 2.73 (1H, dd, J = 13.5 Hz, 10.5 Hz), 3.39 (1H, dd, J =

13.5 Hz, 4 Hz), 3.7-4.25 (4H, m), 4.5-4.8 (1H, m),

5.61 (1H, d, J = 8Hz), 6.95-7.9 (13H, m), 9.04 (1H, d, J = 8Hz).

Starting Example 9

a) 4,65 (3S) -1- (2-acetoxyethyl) -3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1,3-dihydro-5-phenyl-2H A solution of -1,4-benzodiazepin-2-one and 1.43 g of phenyl isothiocyanate in 100 ml of methylene chloride is heated with steam while stirring. After removal of the solvent, methylene chloride (100 mL) was added to the residue. The above step was repeated three times and the methylene chloride was completely removed under reduced pressure to give an oily intermediate (thiourea derivative). Trifluoroacetic acid (80 ml) was added to the oil and the reaction mixture was heated in a water bath at 52 ° C for 20 minutes with stirring. The solvent was removed under reduced pressure and the residue in methylene chloride,

The mixture was triturated twice with A9 and diethyl ether and the resulting thick, red oil was chromatographed on a silica gel column using chloroform / methanol (15: 1) as eluent. Fractions containing the desired compound were combined and evaporated. The orange oily residue (2.24 g) was dissolved in ethyl acetate and washed with a small amount of aqueous sodium bicarbonate. The organic layer was separated and dried over magnesium sulfate. Removal of the solvent gave 1.35 g of (3S) -1- (2-acetoxyethyl) -3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (film): 3370, 3300, 1725, 1600 cm -1.

NMR (CDCl 3, delta: 1.66 3H, s), 2.90 (2H, broad s),

3.8-4.8 (5H, m); 7.1-7.8 (9H, m).

[α] D = -111.73 ° (0.00260 g / ml, CHCl 3).

According to the above procedure, the following compounds may be prepared:

b) (3R) -1- (2-Acetoxyethyl) -3-amino-3,3-dihydro-5-phenyl-2H-4,4-benzodiazepin-2-one.

IR (film): 3370, 3300, 1725, 1600 ^cm-first

NMR (CDCl 3, delta: 1.66 (3H, s), 2.89 (2H, broad s),

3.8-4.8 (5H, m); 7.1-7.8 (9H, m).

[a] ² d ⁶⁸ = + 123.63 ° (0.00312 g / mL, CHC1J.

c) (3S) -] - (2-Acetoxyethyl) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

IR (film): 3450 (shoulder), 3380, 3325 (shoulder), 1738, 1680,

1660 (shoulder), 16.05, 1580, 1490, 1455, 1375, 1332,

1230, 1110, 1050, 820. 760, 745 cm -1.

NMR (CDCl 3, delta: 1.81 (3H, s). 3.8-4.8 (6H, m),

6.95-7.9 (9 H, m).

[α] ²⁵ D ⁶⁸ = -57.68 '(3.10 mg / ml, CH ₂ Cl ₂ ).

d) (3R) -1- (2-Acetoxyethyl) -3-amino], 3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

IR (film): 3450 (shoulder), 3350, 3325 (shoulder), 1736, 1690 (shoulder), 1673, 1650 (shoulder), 1600, 1580, 1482, 1450,

1370, 1328, 1222, 1105,1000,815, 750cm ' ^! .

NMR (CDCl 3, delta: 1.80 (3H, s), 3.8-4.8 (6H, m),

6.95-7.3 (9H, m).

[a] = +50.52 J ² '(3.18 mg / ml CH ₂ C1 _2).

Example 4

a) 1.35 g of (3 S) -1- (2-acetoxyethyl) -3-amino-1,3-dihydro-5-phenyl-2 H -1,4-benzodiazepin-2-one in 25 ml of N, N 0.64 g of 2-indole carboxylic acid, 0.54 g of N-hydroxybenzotriazole and 0.83 g of N, N'-dicyclohexylcarbodiimide are added to a solution of dimethylformamide in dimethylformamide at room temperature with stirring. The reaction mixture was stirred for 2 hours at room temperature and then allowed to stand overnight. The resulting precipitate was filtered off and the filtrate and washings were combined. The dimethylformamide solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted twice with ethyl acetate. The extract was washed twice with brine and dried over magnesium sulfate. Removal of solvent gave 3.05 g of an oily residue which was chromatographed on a silica gel column eluting with chloroform / methanol. Using a 15: 1 mixture. The fractions containing the desired material were combined and concentrated under reduced pressure to give (3S) -1- (2-acetoxyethyl) -3 (2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H (1.90 g). -l, 4

Benzodiazepin-2-one is obtained.

IR (nujol): 3325, 3260, 1735, 1680, 1630, 1600, 1230,

745, 697 cm ^-1 .

NMR (CDCl 3, delta: 1.65 (3H, s), 3.8-4.3 (3H, m),

4.55-4.9 (1H, m), 5.84 (1H, d, J = 8.25 Hz), 7.07.8 (14H, m), 8.14 (1H, d, J = 8.25 Hz), 9.98 (1H, broad s).

Mass: m / e = 481 (M ⁺ ).

[α] β · ⁸ = -51.27 ′ (0.00340 g / ml, CHCl1).

According to the above procedure, the following compounds were prepared:

b) (3R) -] - (2-Acetoxyethyl) -3- (2-indolylcarbonylamino) -N, 3-dihydro-5-phenyl-2H-1,4-benzodiazepin2-one.

IR (nujol): 3325. 3260, 1735, 1680, 1630, 1600, 1230,

745, 697 cm ^-1 .

NMR (CDCl 3, delta: 1.65 (3H, s), 3.8-4.3 (3H, m),

4.55-4.9 (1H, m), 5.84 (1H, d, J = 8.25Hz), 7.07.8 (14H, m), 8.14 (1H, d, J = 8, 25 Hz), 10.06 (1H, broad s).

Mass: m / e = 481 (M ⁺ ).

[alpha] D = +58.90 · ⁸ '(0.00300 g / mL, CHC1 _3).

c) (3S) -1- (2-Acetoxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-], 4-benzodiazepine 2-one.

183-187 'C (decomposed).

IR (nujol): 3350 (shoulder), 3275, 1733, 1687, 1640, 1610 (shoulder), 1539, 1455, 1380, 1260, 1235, 821, 775,

750 cm ^-1 .

NMR (CDCl 3, delta: 1.8 (3H, s), 3.8-4.25 (3H, m),

4.45-4.85 (1H, m), 5.84 (1H, d, J = 8Hz), 6.9-7.9 (13H.m), 8.15 (1H, d, J = 8 Hz), 10.11 (1H, bs). Mass: m / e = 498 (M ⁺ ).

d) (3R) -1- (2-Acetoxyethyl) -3- (2-indolylcarbonylamino) -] - 3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one.

185-189 '(dec.).

IR (nujol): 3325 (shoulder), 3260. 1726, 1682, 1635, 1610 (shoulder), 1535, 1448, 1372, 1255, 1226, 820, 770,

745 cm ^-1 .

NMR (CDCl 3, delta: 1.81 (3H, s), 3.8-4.3 (3H, m),

4.55-4.85 (1H, m), 5.84 (1H, d, J = 8Hz), 6.9-7.85 (13H, m), 8.14 (1H, d, J = 8Hz) ), 10.00 (1H, broad s).

Mass: m / e = 498 (M ⁺ ).

Example 5

a) 1.80 g of (3S) -1- (2-acetoxyethyl) -2- (2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin2-one; 0.30 g of potassium carbonate was stirred in 30 ml of 80% ethanol at 65-70 ° C for 1 hour. After cooling, the ethanol is removed under reduced pressure and water is added to the residue. The organic aqueous solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, magnesium12

It is dried over sulfate A9. Removal of the solvent gave a pale yellow amorphous powder which was chromatographed on silica gel with chloroform / ethyl acetate 3: 1 as eluent. The fractions containing the desired material were combined and evaporated

1.47 g of (3S) -1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one are obtained. in the form of a colorless amorphous powder.

IR (nujol): 3400 (shoulder), 3260, 1680, 1635, 1600, 745,

695 cm ^-1 .

NMR (CDCl ₃ ), delta: 2.7 (1H, bs), 3.65-4.3 (4H, m), 5.79 (1H, d, J = 8Hz), 7.0-7 , 9 (14H, m), 8.17 (1H, d, J = 8Hz), 10.15 (1H, broad s).

Mass: m / e = 438 (M ⁺ ).

[α] 25 D ⁶ = -59.04 ° (0.00352 mg / ml, CHCl ₃ ).

According to the above procedure, the following compounds were prepared:

b) (3R) -1- (2-Hydroxyethyl) -3- (2-indolylcarbonylamino)}, 3-dihydro-5-phenyl-2H-4,4-benzodiazepin2-one.

IR (nujol): 3400 (shoulder), 3260, 1680, 1635, 1600, 740, 695 cm @ ^-1 .

NMR (CDCl 3), delta: 2.83 (1H, bs), 3.55-4.3 (4H, m), 5.78 (1H, d, J = 8Hz), 6.9-7, Δ (14H, m), 8.18 (1H, d, J = 8Hz), 10.28 (1H, broad s).

Mass: m / e = 438 (M ⁺ ).

[ «] D ^'8 = 69.16 ° (0.00360 mg / ml in CHC1 _3).

c) (3S) -1- (2-Hydroxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4- benzodiazepin-2-one.

190-195 ° C (dec.).

IR (nujol): 3400 (shoulder), 3270, 1680 (shoulder), 1640, 1610 (shoulder), 1535, 1485, 1450, 1379, 1330, 1220, 818, 770 (shoulder), 748 cm ^-1 .

NMR (CDCl 3). delta: 2.17 (1H, s), 3.7-4.55 (4H, m),

5.79 (1H, d, J = 8Hz), 6.9-7.85 (13H, m), 8.12 (1H.d, J = 8Hz), 9.81 (1H, broad s) .

Mass: m / e = 456 (M ⁺ ).

[α] D = -1.20 ° (3.32 mg / ml, CHCl 3).

d) (3R) -] - (2-Hydroxyethyl) -3- (2-indolylcarbonylamino) -N, 3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one.

190-195 ° C (dec.).

IR (nujol): 3400 (shoulder), 3270, 1680 (shoulder), 1639, 1610 (shoulder), 1533, 1484, 1450, 1378, 1330, 1220, 818, 770 (shoulder), 745 cm ^-1 .

NMR (CDCl 3), delta: 1.91 (1H, s), 3.7-4.55 (4H, m),

5.79 (1H, d, J = 8Hz), 6.9-7.85 (13H, m), 8.08 (1H, d, J = 8Hz), 9.61 (1H, broad s) .

Mass: m / e = 456 (M ⁺ ).

[α] ^{30 D} = 0.99 ° (3.26 mg / ml, CHCl ₃ ).

Example 6

a) 3.94 mg of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one in 4 ml of N, N-dimethylformamide To a solution of the crude product was added 44 mg of sodium hydride (62% slurry in mineral oil) with stirring at 0 ° C in an ice bath.

The reaction mixture was stirred at 0 ° C to -5 ° C for one hour. 2-Methoxyethyl chloride (142 mg) was added to the reaction mixture, stirred at 6070 ° C for 6 hours and then cooled. To the cooled solution, 0.5 ml of acetic acid, 40 ml of ethyl acetate and 40 ml of water are added with stirring. The organic layer was separated, washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with chloroform. 110 mg of pure (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl- (1-methoxyethyl) -2H-1,4-benzodiazepin-2-one are obtained.

180-185 ° C (dec.).

IR (nujol): 3440, 3275, 1685, 1630, 1600, 1540,

1490 cm ^-1 .

NMR (CDCl ₃ ), delta: 3.13 (3H, s), 3.45-3.65 (2H, m),

3.80-4.50 (2H, m), 5.80 (1H, d, J = 8Hz), 7.0-7.80 (14H, m), 8.15 (1H, d, J = 8 Hz), 9.75 (1H, s).

According to the above procedure, the following compound was prepared:

b) (3R) -1-Acetylmethyl-J, 3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-4,4-benzodiazepin-2-one.

IR (nujol): 3325, 3250, 1720, 1680, 1630, 1530, 1448,

1375,740, 695 cm -1.

NMR (OMSO ₆ ), delta: 2.16 (3H, s), 4.71 (2H, s), 5.90 (1H, d, J = 7.5 Hz), 7.0-7.75 ( 14H, m), 8.09 (1H, d,

J = 7.5 Hz), 10.01 (1H, broad s).

Mass: m / e = 450 (M ⁺ ).

Example 7

0.30 g of (3RS) -1,3-dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one are dissolved. In a mixture of 1 ml of anhydrous dimethyl sulfoxide and 1 ml of benzene containing 0.056 ml of pyridine and 0.028 ml of trifluoroacetic acid. Dicyclohexylcarbodiimide (0.42 g) was added to the solution and stirred at room temperature overnight. Water was added to the solution and insoluble dicyclohexylurea was removed by filtration. The filtrate was extracted twice with ethyl acetate, and the organic phase was washed with water, aqueous sodium bicarbonate and water again, dried over magnesium sulfate and evaporated to give an oil (0.53 g). This was chromatographed on a silica gel column using chloroform / ethyl acetate 5: 1 as eluent. The fractions containing the desired material were combined and evaporated to give a white powder which was purified by washing with diisopropyl ether to give 0.20 g of pure (3RS) -1,3-dihydro-1-formylmethyl-3- (2-hydroxyethyl) -3-. (2-Indolylcarbonylamino) 5-phenyl-2H-1,4-benzodiazepin-2-one.

168 ° C (dec.).

IR (nujol): 3400 (shoulder), 3270, 1725, 1680, 1636, 1600,

1445, 1375, 745,695 cm -1.

NMR (CDCl ₃ ), delta: 4.68 (2H, s), 5.90 (1H, d, J =

7.5 Hz), 7.0-7.75 (14H, m), 8.07 (1H, d, J =

7.5 Hz), 9.66 (1H, s), 10.05 (1H, broad s).

Mass: m / e = 436 (M ⁺ ).

Example 8

0.44 g of (3RS) -1,3-dihydro-1-formylmethyl-3- (2-yn 13)

To a solution of dollylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one in 10 ml of chloroform was added 0.37 g of methoxycarbonylmethylene triphenylphosphorane and stirred for 2 hours at room temperature. The reaction mixture was concentrated and the resulting oil was chromatographed on a silica gel column using chloroform / ethyl acetate (10: 1) as eluent.

64.6 g of (3RS) -1,3-dihydro-1 - [(Z) -3-methoxycarbonyl-2-propenyl] -3- (2-indolylcarbonylamino) -5-phenyl-2H, 4-benzodiazepine 2 is obtained from the fractions which are coming down soon.

IR (nujol): 3340, 3250, 1718, 1700, 1665, 1637, 1598,

1536, 1450, 1375, 805, 740, 690 cm -1.

NMR (CDCl ₃ ), delta: 3.74 (3H, s), 5.24 (2H, dd, J

Hz and J = 1.5 Hz), 5.86 (1H, d, J = 8 Hz), 5.90 (1H, dt, J = 12.7 Hz and 1.5 Hz), 6.21 (1H , dt, J =

17.7 Hz and 6 Hz), 7.1-7.8 (14H, m), 8.13 (1H, d, J =

Hz), 9.98 (1H, bs).

291.1 mg of (3RS) -1,3-dihydro-1 - [(E) -3-methoxycarbonyl-2-propenyl] -3- (2-indolylcarbonylamino) -5-phenyl-2H-1, 4-Benzodiazepin-2-one is obtained from the subsequent fractions.

IR (nujol): 3340, 3270, 1711, 1685, 1635, 1600, 1535,

1450. 1375, 830, 772, 740, 700 cm -1.

NMR (CDCl3), delta: 3.64 (3H, s), 4.7-4.82 (2H, m),

5.87 (1H, d, J = 7.5 Hz), 5.88 (1H, dt, J = 16.5 Hz,

1.5 Hz), 6.94 (1H, dt, J = 16.5 Hz, 4.5 Hz), 7.1-7.8 (14H, m), 8.11 (1H, d, J = 7.5 Hz), 9.92 (1H, broad s).

Example 9

0.30 g of (3RS) -1-acetylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and 36.0 mg The hydrazine hydrate was refluxed in 5 mL of tetrahydrofuran for 15 hours and then concentrated to give 0.30 g of amorphous material. This material (0.30 g) was chromatographed on silica gel, eluting with 30: 1 chloroform / methanol. After the solvent was removed from the fractions containing the desired material, the residue was triturated with diisopropyl ether to give 178 g of (3RS) -1- (2-hydrazonopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) - 5-phenyl-2H-1,4-benzodiazepin2-one was obtained as a white powder.

187 ° C (dec.).

IR (nujol): 3400 (shoulder), 3250, 1680, 1630, 1600, 1528,

1450, 1374, 800, 760, 740,690 cm -1.

NMR (CDCl 3), delta: 1.53 (3H, s), 4.75 (2H, ABq),

5.90 (2H, bs), 5.87 (1H, d, J = 7.5 Hz), 7.07.75 (14H, m), 8.16 (1H, d, J = 7.5) Hz), 9.67 (1H, bs).

Mass: m / e = 464 (M ⁺ ).

J0. example

0.42 g of (3RS) -1-acetylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and 62.5 mg hydroxylamine hydrochloride was stirred in 20 ml of ethanol at room temperature for 40 hours. The reaction mixture was evaporated to dryness and the residue was chromatographed on a silica gel column with chloroform / methanol (40: 1). The fractions containing the desired product were combined and concentrated to a pale green oil which was triturated with diisopropyl ether to give (3RS) -1- (2-hydroxyiminopropyl) -1,3-dihydro-3- (2-indolylcarbonyl) 177 mg. amino) -5-phenyl-2H-1,4-benzodiazepin-2-one is obtained.

187 'C (dec.).

IR (nujol): 3400 (shoulder), 3250, 1680 (shoulder), 1635, 1600,

1532, 1450, 1375, 802, 765, 740, 695 cm -1.

NMR (CDCl 3), δ: 1.63 (3H, s), 4.75 (2H, ABq),

5.00 (1H, bs), 5.87 (1H, d, J = 7.5 Hz), 7.17, 8 (14H, m), 8.19 (1H, d, J = 7.5) Hz), 10.03 (1H, bs).

Mass: m / e = 465 (M ⁺ ).

//. example

a) 800 mg of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one, 790 mg of trityl-3-chloromethyl- To the reaction mixture of imidazole hydrochloride and 16 ml of Ν, Ν-dimethylformamide was added 168 mg of sodium hydride (62% suspension in mineral oil) with stirring in an ice bath at 0 ° C. The reaction mixture was stirred at 0-5 ° C for 30 minutes and then held at 70-80 ° C for 3 hours. To the cooled reaction mixture were added acetic acid (2.0 mL) and 6N hydrochloric acid (5 mL) and stir at 60 ° C for 1 hour. Pour into a cooled solution of 100 mL of ethyl acetate and 100 mL of water with stirring. The organic layer was separated, washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 20: 1 chloroform: methanol. 306.0 mg of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- (4-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one are obtained. .

195-200 ° C (dec.).

IR (nujol): 3250, 1680, 1635, 1600, 1530 cm -1.

NMR (CDCl 3). delta: 4.93 (2H, s), 5.75 (1H, d, J = .delta.)

Hz), 6.78 (1H, s), 7.0-7.85 (15H, m), 8.35 (1H, d,

J = 8 Hz), 10.35 (1H, broad s).

Mass: m / e = 474 (M ⁺ ).

According to the above procedure, the following compounds may be prepared:

b) (3RS) -N, 3-Dihydro-3- (2-indolylcarbonylamino)] - (4-imidazolylmethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine -2-one.

205-210 ° C (dec.).

NMR (CDCl 3), δ 4.85, 5.10 (2H, ABq, J = 15 Hz),

5.80 (1H, d, J = 8Hz), 6.80-7.83 (15H, m), 8.10 (1H, d, J = 8Hz), 10.10 (1H, broad s) .

Mass: m / e = 492 (M ⁺ ).

c) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino)] - [(5-methylimidazolyl-4-yl) methyl) -5-phenyl-2H-1,4-benzodiazepine -2-one.

205-210 ° C (dec.).

NMR _(DMSO-d6) delta: 1.96 (3H, s), 4.80, 5.15 (2H,

ABq, J = 15Hz), 5.55 (1H, d, J = 8Hz), 6.90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz), 11 , 58 (2H, bs). Mass: m / e = 488 (M ⁺ ).

HU 211 324 A9

d) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -N- (2-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

175-180 ° C (dec.).

NMR _(DMSO-d6) delta: 5.10 (2H, s), 5.65 (IH, d, J = 8Hz), 6.60 to 8.10 (16H, m), 9.36 ( 1H, d, J = 8Hz),

11.65 (1H, broad s), 11.90 (1H, broad s).

Mass: m / e = 474 (M ⁺ ).

e) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (3-pyrazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin2-one.

255-260 ° C (dec.).

NMR _(DMSO-d6) delta 5.03, 5.30 (2H, ABq, J = 15Hz), 5.65 (IH, d, J = 8Hz), 5.85 (IH, brs )

6.90-7.90 (15H, m), 9.43 (1H, d, J = 8Hz), 11.60 (1H, broad s), 12.55 (1H, broad s).

Mass: m / e = 474 (M ⁺ ).

f) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1 - [(1,2,4-triazol-3-yl) methyl] -5-phenyl-2H-1 , 4-benzodiazepin-2-one.

205-210 ° C (dec.).

NMR _(DMSO-d6) delta 5.10, 5.35 (2H, ABq, J = 15Hz), 5.66 (IH, d, J = 8Hz), 6.90 to 7.93 ( 15H, m),

8.23 (1H, bs), 9.40 (1H, d, J = 8Hz), 11.65 (1H, bs).

Mass: m / e = 475 (M ⁺ ) ·

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

185-190'C (dec.).

NMR _(DMSO-d6) delta: 2.63 (2H, t, J = 7Hz), 3,854,20 (IH, m), 4.20 to 4.75 (lH, m), 5.55 ( 1H, d, J = 8Hz), 6.6 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 8Hz), 11.65 ( IH, broad s).

Mass: m / e = 488 (M ⁺ ).

Example 12

Example 5 (a) Prepares (3RS) 1,3-dihydro-3- (2-indolylcarbonylamino) -1- (2-hydroxyethyl) -5- (2-fluorophenyl) - 2H-l, 4-benzodiazepin-2-one.

IR (nujol): 3240, 1670, 1630, 1530 cm -1.

NMR _(DMSO-d6) delta: 3.30-3.90 (2H, m), 3,904,40 (IH, m), 4.70-5.0 (IH, m), 5.70 (IH , d, J = 8Hz), 6.90-8.0 (13H, m), 9.50 (1H, d, J = 8Hz),

11.50 (1H, broad s).

Mass: m / e = 456 (M ⁺ ).

Example 13

The following compounds were prepared according to the procedure of Example 6 (a):

a) (3RS) -1- (2-Acetoxyethyl) -1,3-dihydro-5- (2-fluorophenyl) -3- (2-indolylcarbonyl-1-ylamino) -2H-1,4 benzodiazepin-2-one.

NMR (CDCl 3), δ: 1.80 (3H, s), 3.80-4.90 (4H, m),

5.85 (1H, d, J = 8Hz), 6.80-7.95 (13H, m), 8.10 (1H, d, J = 8Hz), 9.90 (1H, broad s) .

b) (3RS) -1- (2-Acetoxyethyl)}, 3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (nujol) 3250, 1730, 1680, 1600, 1530 cm -1.

NMR (CDCl ₃ ), δ: 7.65 (3H, s), 4.05-5.0 (4H, m),

5.87 (1H, d, J = 8Hz), 7.0-7.85 (14H, m), 8.15 (1H, d, J = 8Hz), 10.15 (1H, broad s) .

c) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-isopropylethyl) -5-phenyl-2H-1,4-benzodiazepin2-one.

M.p .: 190-193 'C.

NMR (CDCl3), delta: 0.98 (6H, d, J = 6Hz), 3.20-3.70 (3H, m), 3.80-4.40 (2H, m), 5.75 (1H, d, J = 8Hz), 7.0-7.80 (14H, m), 8.05 (1H, d, J = 8Hz), 9.66 (1H, broad s).

Mass: m / e = 480 (M ⁺ ).

d) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (3-methoxypropyl) -5-phenyl-2H-1,4-benzodiazepin2-one.

170-175 ° C (dec.).

NMR (CDCl3), delta: 1.60-1.90 (2H, m), 3.13 (3H, s), 3.05-3.35 (2H, m), 3.40-4.0 (1H, m), 4.25-4.66 (1H, m), 5.73 (1H, d, J = 8Hz), 7.0-7.75 (14H, m), 8.06 ( 1H, d, J = 8Hz), 9.60 (1H, bs).

Mass: m / e = 466 (M ⁺ ).

e) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-thienyl-ethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

165-170 ° C (dec.).

NMR (CDCl 3), δ 5.0, 5.67 (1H, ΑΒβ, J = 15 Hz),

5.80 (1H, d, J = 8Hz), 6.70-7.80 (17H, m), 8.10 (1H, d, J = 8Hz), 9.80 (1H, broad s).

Mass: m / e = 490 (M ⁺ ).

f) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1-furfuryl-5-phenyl-2H-], 4-benzodiazepin-2-one.

150-155 ° C (dec.).

NMR (CDCl3), delta: 4.96, 5.33 (2H, ABq, J = 15 Hz), 5.83 (1H, d, J = 8 Hz), 6.20 (2H, s), δ , 95-7.75 (15H, m), 8.10 (1H, d, J = 8Hz), 9.90 (1H, broad s).

Mass: m / e = 474 (M ⁺ ).

g) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-ethoxyethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one. M.p .: 205 = 210'C (dec.).

NMR (CDCl3), delta: 0.96 (3H, t, J = 7Hz), 3.35 (2H, q, J = 7Hz), 3.50-3.75 (2H, m), 3 , 80-4.20 (1H, m),

4.20-4.55 (1H, m), 5.80 (1H, d, J = 8Hz), 7.057.80 (14H, m), 8.10 (1H, d, J = 8Hz), 9, 90 (1H, bs).

h) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino)] - (2-methoxyethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine -2-one.

230-235 'C (dec.).

NMR (CDCl3), delta: 3.20 (3H, s), 3.40-3.75 (2H, m),

3.80-4.16 (1H, m), 4.20-4.55 (1H, m), 5.76 (1H, d,

HU 211 324 A9

J = 8Hz), 6.90-7.80 (13H, m), 8.10 (1H, d, J = 8Hz), 9.95 (1H, broad s).

Mass: m / e = 470 (M ⁺ ).

i) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1 - ((2-acetamidothiazol-4-yl) methyl] -5-phenyl-2H-1,4-benzodiazepine 2-one.

175-180'C (dec.).

NMR (CDCl 3), δ: 1.93 (3H, s), 4.83, 5.30 (2H, ABq, J = 15 Hz), 5.85 (1H, d, J = 8 Hz), δ, 53 (IH,

s), 6.90-7.70 (14H, m), 8.25 (1H, d, J = 8Hz), 9.56 (1H, s), 10.0 (1H, s).

k) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-bromoethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

NMR (CDCl 3), delta: 3.30-3.70 (2H, m), 3.85-4.40 (1H, m), 4.60-5.20 (1H, m), 5.83 ( 1H, d, J = 8Hz), 7.0-7.90 (14H, m), 8.15 (1H, d, J = 8Hz), 10.05 (1H, s).

l) (3RS) -1,3-Dihydro-1- [2- (2-tetrahydropyranyl) -3-oxo-2,3-dihydroisoxazol-5-yl] methyl) -3- (2-indolylcarbonylimino) - 5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (Nujol): 3260, 1700, 1682, 1630 cm ^1st

NMR (CDCl 3), delta: 1.3-2 (6H, m), 3.5-4.2 (2H, m),

4.8-5.6 (4H, ABq), 5.89 (1H, d, J = 8Hz), 7.1-7.9 (14H, m), 8.04 (1H, d, J = 8Hz), 9.7 (1H, broad s).

m) (3RS) -1,3-Dihydro-3 - [(5-chloroindol-2-yl) carbonylamino] -5-phenyl-1- (2-methoxyethyl) -2H- 1,4-Benzodiazepin-2-one.

Mp:> 260 'C.

IR (Nujol): 3350 (shoulder), 3290, 1668, 1630, 1596, 1530, 1445, 1374, 1324, 1240, 1215, 1110, 910, 759, 690 ^cm-1

NMR (CDCl 3, delta: 3.10 (3H, s), 3.45-3.75 (2H, m),

3.80-4.53 '(2H, m), 5.77 (1H, d, J = 8Hz), 6.9-7.7 (13H, m), 8.12 (1H, d, J = 8) Hz), 10.26 (1H, bs).

Mass: m / e = 487 (M ⁺ ).

"(3RS) -1,3-Dihydro-3 - [(5-methoxyindol-2-yl) carbonylamino] -5-phenyl-1- (2-methoxyethyl) -2H-1, 4-benzodiazepin-2-one.

Mp: 221-222 'C.

IR (Nujol): 3400 (shoulder), 3250, 1673, 1630, 1596, 1530, 1447, 1375, 1322, 1235, 1115, 1024, 842, 802.762, 694 ^cm-first

NMR (CDCl 3). delta: 3.11 (3H, s), 3.45-3.75 (2H, m),

3.82 (3H, s), 3.80-4.55 (2H, m), 5.78 (1H, d, J = 8Hz), 6.75-7.7 (13H, m), δ , 04 (1H, d, J = 8Hz),

9.90 (1H, bs).

Mass: m / e = 482 (M ⁺ ).

o) (3RS) -1- (3-Bromopropyl) -3- (2-indolylcarbonylamino) -5-phenyl-1,3-dihydro-2H-], 4-benzodiazepin2-one.

IR (nujol): 3400 (shoulder), 3250, 1675, 1633, 1600, 1530, 1445, 1375, 1242, 800, 742, 692 cm -1.

NMR (CDCl 3, delta: 1.8-2.3 (2H, m), 2.95-3.4 (2H, m), 3.8-4.75 (1H, dl, J = 13.8 Hz) , 6.6 Hz) 4.354.65 (1H, dt, J = 13.8 Hz, 6.6 Hz), 5.77 (1H, d, J =

Hz), 7.0-7.7 (14H, m), 815 (1H, d, J = 8Hz),

9.97 (1H, broad s).

Example 14 (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1 - [(2-acetamidothiazol-4-yl) methyl] -5-phenyl-2H-1, The reaction mixture of 4-benzodiazepin-2-one, 13 ml of methanol, 8 ml of tetrahydrofuran and 0.8 ml of concentrated hydrochloric acid was stirred at 70 ° C for 7 hours, cooled and the pH was adjusted to pH 5 with 5% aqueous sodium bicarbonate. = 7.0. Under cooling, 100 ml of water and 100 ml of ethyl acetate are added to the reaction mixture. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 2: 1 ethyl acetate / chloroform, to give (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1 - [(2-aminothiazole-4). yl) methyl] -5-phenyl-2H-1,

4-Benzodiazepin-2-one is obtained.

200-205 'C (dec.).

NMR _(DMSO-d6) delta 4.80, 5.06 (2H, AB q, J =

Hz), 5.60 (1H, d, J = 8Hz), 6.06 (1H, s), 6.75 (2H, broad s), 6.90-7.95 (14H, m), 9 , 40 (1H, d, J =

Hz).

Mass: m / e = 506 (M ⁺ ).

Example 75

a) 0.47 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1 - [(E) -3-methoxycarbonyl-2-propenyl] -5-phenyl2H-1, The reaction mixture of 4-benzodiazepin-2-one, 15 ml of tetrahydrofuran, 7.5 ml of methanol and 1 ml of aqueous sodium hydroxide solution was stirred at room temperature for 1 hour and then cooled. Water (100 mL) and ethyl acetate (100 mL) were added to the cooled reaction mixture and the pH was adjusted to 4.0 by stirring with 6N hydrochloric acid. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform / methanol (1: 1). 80 mg (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1 - [(E) -3-carboxy-2-propenyl] -5-phenyl-2H-1,4-benzodiazepine We get a -2-on.

175-180 ° C (dec.).

NMR _(DMSO-d6) delta: 3.13 (2H, d, J = 7.5Hz),

5.20-5.66 (1H, m), 5.66 (1H, d, J = 8Hz), 6.907.90 (15H, m), 9.55 (1H, d, J = 8Hz), 11.58 (1H, broad s).

Mass: m / e = 478 (M ⁺ ).

b) Preparing (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1 - [(Z) -3-carboxy-2-propenyl] -5-phenyl according to the above procedure. 2H-l, 4-benzodiazepin-2-one. 230-235 'C (dec.).

NMR _(DMSO-d6) delta: 5.12 (2H, d, J = 4.5 Hz), 5.68 (IH, d, J = 8Hz), 5.75 to 6.30 (lH, m), 6.95-7.90 (15H, m), 9.55 (1H, d, J = 8Hz).

Mass: m / e = 478 (M ⁺ ).

Example 16

0.3 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamine)

A9 no) -1- (2-bromoethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one and 3.0 ml of 1-methylpiperazine were stirred at room temperature for 4 hours and then stirred at room temperature for 20 hours. Add diisopropyl ether (mL). The precipitate was collected by filtration and dissolved in dilute hydrochloric acid. The solution was adjusted to pH 7 with aqueous sodium bicarbonate solution and the precipitate was collected by filtration (0.20 g) of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- [2 - (4-Methyl-1-piperazinyl) -ethyl] -5-phenyl-2H-1,4-benzodiazepin-2-one.

135-140'C (dec.).

IR (nujol): 3230, 1670, 1635, 1600, 1530 cm -1.

NMR (CDCl ₃ ), delta: 2.0-2.70 (13H, m), 3.60-4.10 (1H, m), 4.30-4.90 (1H, m), 5.83 (1H, d, J = 8Hz),

7.0-7.90 (14H, m), 8.20 (1H, d, J = 8Hz), 10.10 (1H, broad s).

Example 17 (3RS) -1-Formylmethyl-3- (2-indolylcarbonylamino) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2 (0.5 g) in ml of ethanol -one and 144.1 mg of methoxyamine hydrochloride were stirred at room temperature for 3 hours. After removal of the solvent, ethyl acetate and dilute aqueous sodium bicarbonate solution were added to the residue. The organic layer was washed twice with water and dried over magnesium sulfate. Removal of the solvent left 0.56 g of an amorphous material which was chromatographed on silica gel, eluting with chloroform / ethyl acetate. The fractions containing the desired material were combined and evaporated. The resulting glass was stirred in diisopropyl ether overnight (0.34 g) of (3RS) -1- (2-methoxyiminoethyl) -3- (2-indolylcarbonylamino) -5-phenyl-1,3-dihydro -2H-1,4-benzodiazepin-2-one as a white powder (1: 1 mixture of E and Z isomers).

169-174 ° C (dec.).

IR (nujol): 3400 (shoulder), 300, 1690, 1640, 1600, 1535,

1490, 1450, 1379, 1040, 850, 820, 772, 747,

699 cm ^-1 .

NMR (CDCl ₃ ), delta 3.72 and 3.87 (3H, each s),

4.6-4.7 and 4.75-4.85 (2H, each dd, J =

5.4 Hz, 3 Hz), 5.80 (1H, d, J = 8 Hz), 6.62 and 7.05 (1H, each t, J = 5.4 Hz), 7.07-7, 7 (14H, m),

8.03 (1H, d, J = 8Hz), 9.78 (1H, broad s).

Mass: m / e = 465 (M ⁺ ).

Example 18

212.9 mg of (3RS) -1,3-dihydro-1 - {[2- (2-tetrahydropyranyl) -3-oxo-2,3-dihydroisoxazol-5-yl] methyl} -3- (2 To a suspension of indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one in 4 ml of methanol was added 2N hydrochloric acid at room temperature and with stirring. 1 ml of tetrahydrofuran was added to the reaction mixture to give a clear solution which was stirred at room temperature for 30 minutes. The solution was evaporated to dryness, and the resulting yellow powder was washed with stirring in ether overnight, collected by filtration and dried to give (3RS) -1,3-dihydro-1 - [(3-hydroxyisoxazol-5-yl) methyl] 149.1 mg. 3- (2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one as a yellow powder.

M.p. 207 'C (dec.).

NMR (DMSO-d 6), delta: 5.24 (2H, ABq, J = 15 Hz,

25.5Hz), 5.67 (1H, d, J = 8Hz), 5.70 (1H, s), 7.07.85 (14H, m), 9.52 (1H, d, J = 8 Hz), 11.61 (1H, broad s).

Mass: m / e = 491 (M ⁺ ).

Example 19

The following compounds were prepared according to the procedure of Example 6 (a):

a) (3RS) -1- [2- (2-Chloroethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-], 4-benzodiazepine 2-one.

NMR (CDCl 3), delta: 3.20-4.60 (8H, m), 5.80 (1H, d, J = 8Hz), 7.0-7.80 (14H, m), 8.15 (1H, d, J = 8Hz), 10.20 (1H, broad s).

b) (3RS) -1- (2-Vinyloxyethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one .

210-215'C (dec.).

NMR (CDCl 3), delta: 3.75-4.0 (4H, m), 4.0-4.20 (1H, m), 4.30-4.65 (1H, m), 5.76 ( 1H, d, J = 8Hz), 6.05-6.35 (1H, m), 7.0-7.75 (14H, m), 8.03 (1H, d, J = 8Hz), 9 , 53 (1H, broad s).

Mass: m / e = 464 (M ⁺ ).

c) (3RS) -1- (2-Benzyloxyethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2- you.

195-200 'C (dec.).

NMR (CDCl 3) delta 3.55-3.80 (2H, m), 3.8 (M, 20 (1H, m), 4.20-4.55 (1H, m), 4.30 (2H, s), 5.75 (1H, d, J = 8Hz), 6.96-7.80 (14H, m), 8.06 (1H, d, J = 8Hz), 9.95 (1H, broad s).

d) (3RS) -1- (3,4-Dimethoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

220-225 'C (dec.).

IR (Nujol): 3300, 3200, 1680, 1635, 1590, 1525, 1505 ^cm-first

NMR (CDCl 3) delta 3.40 (3H, s), 3.75 (3H, s), 4.70, 5.75 (2H, ABq, J = 15 Hz), 5.90 (1H, d, J = 8 Hz),

6.45-6.65 (3H, m), 7.10-7.80 (14H, m), 8.20 (1H, d, J = 8Hz), 9.98 (1H, broad s).

e) (3RS) -1- (3,4-Diacetoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

f) (3RS) -] - Benzyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

145-150 ° C (dec.).

IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm ^1st

NMR (CDCl 3), δ: 4.88, 5.68 (2H, ABq, J = 15 Hz),

5.93 (1H, d, J = 5Hz), 7.0-7.80 (19H, m), 8.25 (1H, d, J = 8Hz), 10.08 (1H, broad s) .

Mass: m / e = 484 (M ⁺ ).

HU 211 324 A9

g) (3RS) -1- (2-Phthalimidoethyl) -, 3-dihydm-3- (2-indolylcarbonylamino) -5-phenyl-2H -}, 4-benzodiazepin-2-one.

IR (nujol): 3400, 3250, 1770, 1712, 1678, 1646 cm -1. NMR _(DMSO-d6) delta: 3.6-A, 8 (4H, m), 5.60 (1H, d,

J = 8Hz), 7.0-8.0 (18H, m), 9.50 (1H, d, J = 8Hz),

11.45 (1H, bs).

h) (3RS) -] - (2-Methylthioethyl) -, 3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one.

Mp 149-156 ° C.

IR (nujol): 3380 (shoulder), 3270, 1672, 1635, 1595, 1530,

1445, 1375, 1320, 740, 690 cm ^-1 .

NMR (CDCl ·), delta: 1.98 (3H, s), 2.63 (2H, t, J

7.5 Hz), 3.88 (1H, dt, J = 13.5 Hz, 7.5 Hz), 4.63 (1H, dt, J = 13.5 Hz, 7.5 Hz), 5, 80 (1H, d, J =

8.4 Hz), 7.0-7.8 (14H, m), 8.11 (1H, d, J = 8.4 Hz),

9.93 (1H, broad s).

Mass: m / e = 469 (M ⁺ ).

Example 20

287 mg of (3RS) -1- (3,4-diacetoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one, A mixture of methanol (5 ml), tetrahydrofuran (5 ml), water (1 ml) and aqueous potassium carbonate (5 ml) was stirred at 0 ° C to -5 ° C for 1 hour and then adjusted to pH 1-2 with 6N hydrochloric acid. . Ethyl acetate (50 mL) and water (50 mL) were added with stirring. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 4: 1 chloroform / ethyl acetate. 155 mg of (3RS) -1- (3,4-dihydrobenzyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one are obtained. 165-170 ° C (dec.).

NMR (CDCl ₃ -DMSO-d ₆ ), delta: 4.75, 5.35 (2H, ABq,

J = 15 Hz), 5.75 (1H, d, J = 8 Hz), 6.20-6.60 (3H, m), 6.90-7.70 (14H, m), 8.35 ( 2H, bs), 8.96 (1H, d, J = 8Hz), 11.46 (1H, bs).

Mass: m / e = 516 (M ⁺ ).

Example 21

To a stirred mixture of carbon tetrachloride (792.1 g) in methylene chloride (20 mL) was added triphenylphosphine (2.70 g) at room temperature followed by (3RS) -1-formylmethyl-1,3-dihydro-3- (0.90 g). (2-indolylcarbonyl) amino-5-phenyl-2H-l, 4-benzodiazepin-2-one.

The reaction mixture was stirred for 6 hours at room temperature. The methylene chloride was evaporated and water was added to the residue, acidified with dilute hydrochloric acid and extracted twice with ethyl acetate. The extract was dried over magnesium sulfate, concentrated and the resulting red oil was chromatographed on a silica gel column eluting with chloroform / ethyl acetate (20: 1). The fractions containing the desired material were combined and evaporated to dryness to give 0.20 g of a glass which was triturated with diisopropyl ether. 138.8 mg of (3RS) -1- (3,3-dichloro-2-propenyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2- obtained as a yellow powder.

149-152 ° C (dec.).

IR (nujol): 3400 (shoulder), 3550, 1680, 1640, 1535, 1450,

1378,742,694 cm -1.

NMR (CDCl ₃ ), delta: 4.53 (1H, dd, J = 15 Hz, 7.2 Hz),

4.77 (1H, dd, J = 15 Hz and 7.2 Hz), 5.93 (1H, dd, J = 7.2 Hz and 7.8 Hz), 5.77 (1H, d, J = 7.8 Hz), 7.07 (14H, m), 7.99 (1H, d, J = 7.8 Hz), 9.67 (1H, broad s).

Mass: m / e = 503 (M ⁺ ) ·

Example 22

Preparation of (3RS) -1- [2- (2-Hydroxyethylamino) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl as described in Example 16. 2H-l, 4-benzodiazepin-2-one. 125-130 ° C (dec.).

IR (nujol): 3250, 1680, 1630, 1600, 1535 cm -1.

NMR (CDCl ₃ ) delta 2.45-2.85 (4H, m), 3.30-3.50 (2H, m), 3.50-3.90 (1H, m), 4.20 -4.60 (1H, m),

5.80 (1H, d, J = 8Hz), 7.0-7.80 (14H, m), 8.25 (1H, d, J = 8Hz), 10.20 (1H, broad s) .

Example 23

700 mg of (3RS) -1- [2- (2-chloroethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine A reaction mixture of 2-one, 610 mg of potassium phthalimide and 5 ml of Ν, Ν-dimethylformamide was heated at 80-90 ° C for 7 hours. The reaction mixture was poured into 100 ml of cold water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS) -1- [2- (2-phthalimidethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonyl) 0.9 g. amino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

Example 24

500 mg of (3RS) -1- [2- (2-chloroethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine 2-one was stirred in 5.0 ml of 1-methylpiperazine at 70 ° C for 5 hours and then 30 ml of diisopropyl ether was added to the reaction mixture. The precipitate formed is filtered off and the filtrate is evaporated. The residue was washed with water and dried to give (3RS) -1 {2- [2- (4-methyl-1-piperazinyl) ethoxy] ethyl} -1,3-dihydro-3- (2-indolyl) 0.43 g. carbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

M.p. 100-105 C (dec.).

IR (nujol): 3250. 1690, 1635, 1600, 1540 cm -1.

NMR (CDCl ₃ ), delta: 2.15-2.60 (13H, m), 3.35-4.50 (6H, m), 5.80 (1H, d, J = 8Hz), 7, 0-7.85 (14 H, m),

8.15 (1H, d, J = 8Hz), 10.10 (1H, broad s).

Mass: m / e = 564 (M ⁺ ).

Example 25

a) 1.04 g of (3RS) -1- (2-phthalimidoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazole pine. 2-one and 130 mg of hydrazine hydrate were stirred in 10 ml of N, N-dimethylformamide at 70 ° C for 3 hours, followed by addition of additional 130 mg of hydrazine hydrate. The reaction mixture was heated at 80 ° C for 12.5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was removed under reduced pressure

The residue was evaporated to give 1.03 g of a viscous oil, which was chromatographed on a silica gel column with chloroform / methanol 50: 1 as eluent. The fractions containing the desired material were combined and evaporated to give 0.76 g of (3RS) -1- (2-aminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H. -1,4-benzodiazepin-2-one was obtained as an oil which was stirred in ether overnight to give the product as a crystalline powder (456.2 mg).

IR (nujol): 3260, 1690, 1660, 1620 cm -1.

NMR (CDCl ₃ ), delta: 3.3-3.8 (3H, m), 4.0-4.4 (1H,

m), 5.83 (1H, d, J = 8Hz), 6.12 (2H, broad t),

7.1-7.9 (14H, m), 8.20 (1H, d, J = 8Hz), 9.85 (1H, broad s).

b) According to the above procedure, (3RS) -] - [2- (2-aminoethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl- 2H -], 4-benzodiazepin-2-one.

130-135 ° C (dec.).

IR (Nujol): 3250, 1680, 1640, 1600, 1540 ^cm-first

NMR (CDCl ₃ ), delta: 2.30 - 2.80 (2H, m), 3.0 - 4.0 (5H,

m), 4.30-4.70 (1H, m), 5.80 (1H, s), 7.07-7.80 (14H, m).

Mass: m / e = 481 (M ⁺ ).

Example 26

0.66 g of (3R) -1- {2 - [(2R) -2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio] ethyl} -1,3-dihydro-3 (2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- {2 - [(2R) -2-tert-butoxycarbonylamino-2- benzhydryloxycarbonyl-ethylthio] -ethyl} -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one, 0 The reaction mixture, anisole (6 ml), trifluoroacetic acid (1.5 ml) and dichloromethane (15 ml) was stirred at room temperature for 3 hours. After removal of the solvent, the residue was stirred in ethyl acetate (50 mL) and water (50 mL). The mixture was adjusted to pH 6-7 with 5% aqueous sodium bicarbonate solution with stirring. The organic phase is separated off and concentrated. The resulting precipitate was collected by filtration, washed with water and dried to give 0.20 g of (3R) -1- (2 - [(2R) -2-amino-2-carboxyethylthio] ethyl} -1,3-dihydro- 3- (2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- {2 - [(2R) -2-aminocarboxyethyl] thio] ethyl} -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

190-195 ° C (dec.).

NMR (CDCl ₃ + DCl), delta: 2.60-3.10 (4H, m). 4.04.40 (2H, m), 4.60-5.0 (1H, m), 5.96 (1H, s), 6.658.15 (14H, m).

Mass: m / e = 541 (M ⁺ ).

Example 27

350 mg of (3RS) -1- [N- (ethoxycarbonylmethyl) carbamoylmethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) 5-phenyl-2H-1,4 The reaction mixture of benzodiazepin-2-one, 10 ml of tetrahydrofuran and 0.65 ml of 1N aqueous sodium hydroxide solution was stirred at room temperature for 4 hours, then 50 ml of water and 50 ml of ethyl acetate were added. The pH of the reaction mixture was adjusted to pH 1-2 with stirring with IN hydrochloric acid. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from tetrahydrofuran to give (3RS) 1- [N- (carboxymethyl) carbamoylmethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H- (204 mg). 1,4-benzodiazepin-2-one.

170-175 ° C (dec.).

NMR (DMSO-d 6), delta: 3.77 (2H, d, J = 5Hz), 4.65 (2H, s), 5.73 (1H, d, J = 8Hz), 6.9-. 7.80 (14 H, m),

8.50 (1H, tri, J = 5Hz), 9.45 (1H, d, J = 8Hz),

11.65 (1H, broad s).

Example 28

a) 452 g of (3RS) -1-carboxymethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one, 135 mg of 1-hydroxy- To the reaction mixture of benzotriazole and 5 ml of Ν, Ν-dimethylformamide was added 206 mg of Ν, Ν'-dicyclohexylcarbodiimide at 5 ° C with stirring. After stirring for 1 hour at room temperature, 74 mg of glycinamide hydrochloride and 120 mg of triethylamine are added at 5 'C. The mixture was stirred for 3.0 hours at room temperature. The precipitate was filtered off and the filtrate was poured into ethyl acetate and water. The resulting precipitate was collected by filtration, 180 mg of (3RS) -1- [N- (carbamoylmethyl) carbamoylmethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl -1,4-benzodiazepin-2-one.

IR (nujol): 3270, 1680, 1630, 1600, 1540 cm -1.

NMR _(DMSO-d6) delta: 3.65 (2H, d, J = 5Hz), 4.65 (2H,

s), 5.73 (1H, d, J = 8Hz), 6.90-7.80 (14H, m), 8.40 (1H, t, J = 5Hz), 9.48 (1H, d, J = 8Hz), 11.65 (1H, s). Mass: m / e = 508 (M ⁺ ).

According to the above procedure, the following compounds were prepared:

b) (3RS) -] - [N- (Ethoxycarbonylmethyl) carbamoylmethyl] -], 3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-4,4-benzodiazepine. 2-one.

c) (3R) -] - {N - [(S) -] - Carbamoyl-2-phenylethyl] carbamoylmethyl] -, 3-dihydro-3- (2-indolylcarbonylamino) ) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- (N - [(} S) -carbamoyl-2-phenylethyl] -carbamoylH-methyl) -3-dihydro- Mixture of 3- (2-indolylcarbonylamino) -5-phenyl2H-1,4-benzodiazepin-2-one.

165-170 ° C (dec.).

IR (Nujol): 3230, 1680, 1650, 1600, 1525 cm ^1st

NMR _(DMSO-d6) delta: 2.65-3.20 (2H, m), 4,304,90 (3H, m), 5.67 (IH, d, J = 8Hz), 7,0- 7.80 (19H, m), 8.25-8.50 (1H, m), 9.37-9.57 (1H, m),

11.65 (1H, broad s).

Mass: m / e = 598 (M ⁺ ).

Example 29

1.53 g of (3RS) -1-carboxymethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one in 30 ml of methylene chloride suspension

With stirring and cooling in an ice bath, 1.29 g of oxalyl chloride are added. The reaction mixture was stirred at room temperature for 3.5 hours. The solvent and excess oxalyl chloride were removed under reduced pressure and the residue was triturated with ether to give the hydrochloride as an orange powder, which was collected by filtration, washed with ether and dried under reduced pressure. To a solution of 0.17 g of cyanamine and 0.42 g of tritylamine in 20 ml of methylene chloride is added 0.5 g of the powder obtained above with stirring at room temperature. After stirring for 2 hours at room temperature, methylene chloride (50 ml) was added and the mixture was washed with dilute hydrochloric acid and water. After drying over magnesium sulfate, the organic phase is concentrated under reduced pressure. The residue was chromatographed on a silica gel column eluting with ethyl acetate / n-hexane / acetic acid (2: 1: 0.1). The product was stirred in ether to give 0.14 g of (3RS) -1- [N (cyano) -carbamoylmethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H 1,4-Benzodiazepin-2-one is obtained in the form of a pale orange powder.

225-260 ° C (dec.).

IR (nujol): 2170. 1680, 1640, 1600, 1540, 1460, 1380,

1305.745 cm -1.

NMR _(DMSO-d6) delta: 4.77 (2H, s), 5.75 (1H, d, J =

Hz), 7.0-7.9 (14H, m), 9.52 (1H, d, J = 8Hz),

11.50 (1H, bs).

Example 30

0.52 g of (3RS) -1- (3-bromopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one 3 To a solution of 1 ml of NN-dimethylformamide is added a solution of sodium methane thiolate in methanol prepared from 0.48 g of methane thiol in 30% methanol and 3.0 ml of 1N sodium hydroxide in methanol. The reaction mixture was stirred for 6 hours and allowed to stand for 37 hours.

While stirring, the reaction mixture was poured into water containing a few drops of acetic acid. Extract twice with ethyl acetate, combine the extracts, wash three times with water, and dry over magnesium sulfate. The solution was evaporated to give 0.59 g of a yellow oil which was chromatographed on a silica gel column, eluting with 20: 1 chloroform / ethyl acetate. The resulting glass (330 mg) was stirred in diisopropyl ether overnight to give (3RS) -1- (3-methylthiopropyl) -1,3-dihydro-2- (2-indolylcarbonylamino) -5- (24RS). phenyl-2H1.4-benzodiazepin-2-one is obtained in the form of a white powder. 216-221 'C.

IR (nujol): 3430, 3260, 1673, 1638, 1600, 1532, 1450,

1375, 1270, 800, 778, 739, 695 ^cm-first

NMR (CDCl 3), δ: 1.7-2.0 (2H, m), 1.9 (3H, s),

2.25-2.45 (2H, m), 3.7-4.0 (1H, dt, J = 13.8Hz,

6.6 Hz), 4.4-4.7 (1H, dt, J = 13.8 Hz, 6.6 Hz), 5.83 (1H, d, J = 7.8 Hz), 7.1 -7.8 (14H, m), 8.17 (1H, d,

I = 7.8 Hz), 10.01 (1H, broad s).

Mass: m / e = 482 (M ⁺ ).

Example 31

a) 501 mg from (3RS) -1- (2-bromoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin2-one, A reaction mixture of 12 g of triethylamine, 0.133 mg of 4-mercaptopyridine and 6 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into water and ethyl acetate. The organic layer was separated, washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. 0.19 g of (3RS) -1- [2- (4-pyridylthio) ethyl] -1,3-dihydro-3- (2-indo] ylcarbonyl] amino) -5-phenyl-2H-1 4-Benzodiazepin-2-one is obtained.

150-155 ° C (dec.).

IR (nujol): 3230, 1680, 1630, 1600, 1570, 1530 cm -1. Nuclear Magnetic Resonance Spectrum (CDC1-0, delta: 3.0-3.30 (2H, m), 3.70-4.10 (1H, m), 4.40-4.80 (1H, m), 5.80 (1H, d, J = 8Hz), 7.0-7.80 (16H, m), 8.10 (1H, d, J = 8Hz), 8.258.45 (2H, m), 10.05 (1H, broad s).

Mass: m / e = 531 (M ⁺ ) ·

b) According to the above procedure, (3R) -1- {2 - [(2R) -2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio] ethyl} -1,3 dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- {2 - [(2R) -2-tert-butoxy] -carbonyl) -amino-2-benzhydryloxycarbonyl-ethylthio] ethyl} -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4- a mixture of benzodiazepin-2one.

NMR (CDCl3), delta: 1.40 (9H, s), 2.20-3.10 (4H, m),

3.50-4.0 (1H, m), 4.20-4.70 (2H, m), 5.15-5.45 (1H, m), 5.80 (1H, d, J = 8 Hz), 6.90 (1H, s), 7.107.85 (24H, m), 8.15 (1H, d, J = 8Hz), 9.75 (1H, broad s).

Example 32

434 mg of (3RS) -1- (2-aminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and 222 mg To a solution of triethylamine in 4 mL of methylene chloride was added dropwise 172.8 mg of acetyl chloride while cooling in an ice-water bath. Stirring is continued for 4 hours under the same conditions. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water and dried over magnesium sulfate. Evaporation of the solvent gave 672.2 mg of a brown oil which was chromatographed on silica gel eluting with 30: 1 chloroform / methanol. The fractions containing the desired material were combined and evaporated. The resulting amorphous material was pulverized with ether overnight. The crystalline powder is collected by filtration, washed with ether, 327.1 mg of (3RS) -1- (2-acetylaminoethyl)], 3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl- 2H-1,4-benzodiazepin-2-one was obtained.

167-175 ° C (dec.).

IR (nujol): 3250, 1690, 1672, 1635 cm -1.

NMR _(DMSO-d6). delta: 2.25 (3H, s), 3.6-4.4 (4H, m), 5.59 (1H, d, J = 8Hz), 6.9-7.9 (14H, m) , 9.48 (1H, d, J = 8Hz), 11.48 (1H, broad s).

Mass: m / e = 479 (M ⁺ ).

Starting Example 10

1.0 g of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-2H-1,4-benzodiazepin-2-one and 1.28 g of 1-trityl-4-chloro- ME20

To a suspension of A9 -yl imidazole hydrochloride in 25 ml of Ν, Ν-dimethylformamide was added 0.36 g of sodium hydride (40% suspension in oil) under ice-cooling and stirring, followed by stirring under further cooling. After adding 0.5 ml of acetic acid, the reaction mixture is poured into 100 ml of water. The aqueous solution of sodium bicarbonate was adjusted to pH 7 with stirring. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 2.22 g of a yellow powder. The material was chromatographed on a silica gel column eluting with chloroform / ethyl acetate (20: 1). 1.38 g of (3RS) 1,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one are obtained. NMR _(DMSO-d6) delta: 5.08 (2H, ABq), 5.75 (1H, s);

6.7-7.7 (29 H, m).

Starting Example 11

19.96 g of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepine-2 A solution of 1.38 g of hydrazine hydrate in 10 ml of methanol is added to a suspension of 200 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 0.5 hour and then the resulting clear solution is refluxed for 2 hours with stirring. The reaction mixture was cooled in an ice bath and the precipitate was filtered off. The filtrate and washings were evaporated under reduced pressure. The residue was dissolved in chloroform and the mixture was filtered. The filtrate was evaporated

19.30 g of an oily residue are obtained, which is chromatographed on silica gel using chloroform / methanol 30: 1 as eluent. 9.97 g of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-3-imidazolyl) methyl-2H-1,4-benzodiazepine We win 2.

NMR (CDCl 3), delta: 2.42 (2H, bs), 4.49 (1H, s),

5.06 (2H, s), 6.8-8.0 (25H, m).

Starting Example 12

a) 591.7 mg of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepine A solution of (S) - (+) - mandelic acid (129.3 mg) in ethyl acetate (4 ml) was added at room temperature to a solution of -2-ethyl acetate (2 ml) with stirring. The precipitating gel was dissolved in methanol (0.2 mL). To the clear solution was added 4 mL of ethyl acetate and three drops of diisopropyl ether. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The resulting precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether. Drying gave 202.2 g of a white powder, which was recrystallized from ethyl acetate to give (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) -. to the (S) - (+) - mandelic acid salt of methyl 2H1.4-benzodiazepin-2-one as a crystalline material.

[α] D 20 = -33.33 ° (c = 0.846, methanol).

From the filtrate, (3R) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one and a mixture of (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one obtained.

b) (3S) -1,3-Dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl2H-1,4-benzodiazepine-2 on (S) - (+) - mandelic acid salt is suspended in a mixture of water and ethyl acetate. The pH of the resulting mixture was adjusted to pH 7-8 with stirring with aqueous sodium bicarbonate. The organic phase was separated, washed with water and evaporated to dryness to give (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl (181.4 mg). 2H1, 4-benzodiazepin-2-one.

[α] D = -35.34 (C = 0.846, methanol).

Starting Example 13

a) 1.57 g of (3R) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4- benzodiazepin2-one and (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one mixture ((a) = + 14.4 *) obtained as described in Example 44 a) was dissolved in a mixture of 5.3 ml of ethyl acetate and 0.5 ml of methanol. 342.7 mg of (R) - (-) - mandelic acid in 20 ml of ethyl acetate are added to the solution at room temperature with stirring. To the reaction mixture was added diisopropylether (0.5 mL), stirred for 2 hours and allowed to stand overnight. The precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether, dried as a white powder.

685.6 mg of (3R) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin2-one ( R) - (-) - J-mandelic acid salt.

[.alpha.] D @ 20 = + 33.60 DEG (c = 0.848, methanol).

b) (3R) -1,3-Dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one (3R) -1,3-Dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1 is prepared as described in Example 12 b). 4-Benzodiazepin-2-one (R) - (-) mandelic acid salt.

["] D = +37.91 '(c = 0.844, methanol).

Example 33

The following compounds were prepared as described in Example 15 a):

a) (3S) -1,3-Dihydro-1 - (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H1.4- benzodiazepine -2-one.

NMR (CDCl 3), δ 5.085 (2H, ABq), 5.76 (1H, d,

J = 7.9 Hz), 6.8-8.0 (30H, m), 8.10 (1H, d, J =

7.9 Hz), 9.81 (1H, s).

b) (3R) -], 3-Dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indothylcarbonylamino) -5- (2-fluorophenyl) -2H1.4- benzodiazepin-2-one.

NMR _(DMSO-d6) delta: 5.11 (2H, ABq), 5.64 (1H, d,

J = 8.0 Hz), 6.7-8.0 (30H, m), 9.55 (1H, d, J =

8.0 Hz), 11.66 (1H, s).

c) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -N- (4-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (nujol): 3250, 1680, 1635, 1600, 1530 cm -1.

HU 211 324 A9

d) (3RS) -], 3-Dihydro-3- (2-indolylcarbonylamino) 1- (4-imidazolyl-melyl) -5- (2-fluorophenyl) -2H-1,4-benzene benzodiazepin-2-one.

NMR (CDCl 3), δ: 4.85, 5.10 (2H, ABq, J = 15 Hz),

5.80 (1H, d, J = 8Hz), 6.80-7.83 (15H, m), 8.10 (1H, d, J = 8Hz), 10.10 (1H, broad s) .

e) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -11 (5-methylimidazolyl-4-yl) methyl] -5-phenyl-2H-1,4-benzodiazepine-2 -you.

NMR _(DMSO-d6) delta: 1.96 (3H, s), 4.80, 5.15 (2H, ABq, J = 15Hz), 5.55 (1H, d, J = 8Hz),

6.90- 8.15 (15H, m), 9.33 (1H, d, J = 8Hz), 11.58 (2H, broad s).

f) (3S) -], 3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one.

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.63 (1H, d, J = 7.9Hz), 6.9-8.2 (15H, m), 9, 58 (1H, d, J =

7.9 Hz), 11.65 (1H, s), 11.92 (1H, s).

g) (3R) -], 3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-], 4-benzodiazepine. 2-one.

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.62 (1H, d, J = 7.9 Hz). 6.9-8.3 (15H, m), 9.58 (1H, d, J =)

7.9 Hz), 11.66 (1H, s), 11.93 (1H, s).

h) (3RS) -], 3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-imidazolylmethyl) -5-phenyl-2H-], 4-benzodiazepin-2-one .

NMR _(DMSO-d6) delta: 5.10 (2H, s). 5.65 (1H, d, J = 8Hz). 6.60-8.10 (16H, m), 9.36 (1H, d, J = 8Hz),

11.65 (1H, broad s), 11.90 (1H, broad s).

7) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (3-pyrazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin2-one.

NMR _(DMSO-d6) delta 5.03, 5.30 (2H, ABq, J = 15Hz), 5.65 (1H, d, J = 8Hz), 5.85 (1H, br s )

6.90-7.90 (15H, m), 9.43 (1H, d, J = 8Hz), 11.60 (1H, broad s), 12.55 (1H, broad s).

k) (3RS) -], 3-Dihydro-3- (2-indolylcarbonylamino) 1 - [(}, 2,4-triazol-3-yl) methyl] -5-phenyl-2H-1 , 4-benzodiazepine-2-one.

NMR _(DMSO-d6) delta 5.10, 5.35 (2H, ABq, J = 15Hz), 5.66 (1H, d, J = 8Hz), 6.90 to 7.93 ( 15H, m),

8.23 (1H, bs), 9.40 (1H, d, J = 8Hz), 11.65 (1H, bs).

I) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1 -1- (4-imidazolyl) ethyl] -5-phenyl-2H-1,4-benzodiazepine-2- you.

NMR _(DMSO-d6) delta: 2.63 (2H, t, J = 7Hz), 3,854,20 (1H, m), 4.20 to 4.75 (1H, m), 5.55 ( 1H, d, J = 8Hz), 6.60 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 8Hz), 11.65 ( 1H, broad).

m) (3S) -], 3-dihydro] - (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-4,4-benzodiazepine; 2-one hydrochloride.

NMR (DMSO-cy, delta: 5.33 (2H, ABq), 5.69 (1H, d,

J = 7.6Hz, 7.0-8.0 (15H, m), 9.05 (1H, s), 9.60 (1H, d, J = 7.6Hz), 11.74 (1H , s), 14.73 (1H, broad s).

Example 34

0.79 g of (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin2-one, A reaction mixture of 0.22 g of 2-indole carboxylic acid, 0.18 g of hydroxybenzotriazole, 0.28 g of dicyclohexylcarbodiimide and 8 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight and filtered. The filtrate and washings were diluted with ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 1.12 g of a viscous oil, which was chromatographed on silica gel, eluting with 30: 1 chloroform / methanol. 0.97 g of (3 S) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one is obtained as an amorphous material.

[α] D = -32.47 ° (c = 0.85, methanol).

NMR (CDCl ₃ ), delta: 5.085 (2H, ABq), 5.76 (1H, d, J = 7.9 Hz), 6.8-8.0 (30H, m), 8.10 (1H, d, J =

7.9 Hz), 9.81 (1H, s).

Example 35

0.81 g of (3R) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3-amino-5- (2-fluorophenyl) -2H-1,4-benzodiazepine To a solution of 2-one, 0.23 g of 2-indolecarboxylic acid and 0.19 g of N-hydroxybenzotriazole in 8 ml of Ν, Ν-dimethylformamide is added 0.27 g of l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride and 0.14 g triethylamine. The reaction mixture was stirred at room temperature for 4 hours. Ethyl acetate and water were added with stirring. The pH of the reaction mixture was adjusted to pH 8 with aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The separated organic layer and the ethyl acetate extract were combined, washed twice with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 1.0 g of (3R) -1,3-dihydro-1- (1-trityl-3-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluoro). (phenyl) -2H-1,4-benzodiazepin-2-one is obtained.

[.alpha.] D @ 20 = + 41.58 DEG (c = 0.856, methanol).

NMR (DMSCHi _6). delta: 5.11 (2H, ABq), 5.64 (1H, d,

J = 8.0 Hz), 6.7-8.0 (30H, m), 9.55 (1H, d, J =

8.0 Hz), 11.66 (1H, s).

Example 36

1.0 g of (3S) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) - To a solution of 2H1,4-benzodiazepin-2-one in 10 ml of Ν, Ν-dimethylformamide was added 7 ml of 6N hydrochloric acid under ice-cooling and stirring. The temperature of the reaction mixture was raised to 50 ° C and stirred for 2 hours 22

HU 211 324 A9 us. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture with stirring, and the pH was adjusted to pH 8 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. Removal of the solvent gave 1.20 g of a viscous oil, which was chromatographed on silica gel eluting with chloroform / methanol (20: 1). (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1, 601.5 mg as a yellow crystalline powder. 4-Benzodiazepin-2-one is obtained. [α] D = + 24.68 ° (c = 0.64, chloroform).

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.63 (1H, d, J = 7.9Hz), 6.9-8.2 (15H, m), 9, 58 (1H, d, J =

7.9 Hz), 11.65 (1H, s), 11.92 (1H, s).

Example 37

Example 3 (3R) 1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) - 2H-1,4-benzodiazepin2-one.

[Α] D ⁼ -26.40 (c = 0.64, chloroform).

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.62 (1H, d, J = 7.9Hz), 6.9 to 8.3 (15H, m), 9, 58 (1H, d, J =

7.9 Hz), 11.66 (1H, s), 11.93 (1H, s).

Example 38

215.1 mg of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine To a solution of 2-oh in 5 ml of methanol was added 0.1 ml of 6N hydrochloric acid under cooling. Evaporate the clear yellow solution to dryness under reduced pressure. The residue was triturated with ether to give a yellow powder which was collected by filtration and washed twice with ether,

197.1 mg of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one hydrochloride was obtained.

[α] D ⁼ -35.94 (c = 0.612, methanol).

214-218 ° C (dec.).

NMR _(DMSO-d6) delta: 5.33 (2H, ABq), 5.69 (1H, d, J = 7.6Hz), 7.0-8.0 (15H, m), 9, 05 (1H, s),

9.60 (1H, d, J = 7.6 Hz), 11.74 (1H, s), 14.73 (1H, broad s).

Example 39

246 mg of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2 of l-(+) tartaric acid (75.0 mg) at room temperature. After stirring for a few minutes, the reaction mixture was concentrated to 2 ml. The resulting pale yellow powder was collected by filtration, washed twice with diisopropyl ether and dried (235.3 mg. (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5). - (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one -1 - (+) - tartrate.

170-175 ° C (dec.).

NMR _(DMSO-d6) delta: 4.31 (2H, s), 5.07 (2H, s);

5.63 (1H, d, J = 7.7 Hz), 6.9-8.1 (15H, m), 9.58 (1H, d, J = 7.7 Hz), 11.65 (1H , s).

Example 40

As described in Examples 38 and 39, (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) 5- (2-fluorophenyl) - 2H-1,4-Benzodiazepin-2-one is reacted with methanesulfonic acid to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) 5- ( 2-fluorophenyl) -2H-1,4-benzodiazepin-2-one methanesulfonate.

[α] D = -31.32 (c = 0.632, methanol).

136-139'C (dec.).

NMR _(DMSO-d6) delta: 2.39 (3H), 5.33 (2H, ABq);

5.69 (1H, d, J = 7.7 Hz), 7.0-7.8 (15H, m), 8.99 (1H, s), 9.58 (1H, d, J = 7, 7Hz), 11.68 (1H, s),

14.26 (1H, broad).

Example 41

The following compounds were prepared as described in Example 4 (a):

a) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (4-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

IR (nujol): 3250, 1680, 1635, 1530-1.

b) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (4-imidazolylmethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine -2-one.

NMR (CDCl 3), δ: 4.85, 5.10 (2H, ABq, J = 15 Hz),

5.80 (1H, d, J = 8Hz), 6.80-7.83 (15H, m), 8.10 (1H, d, J = 8Hz), 10.10 (1H, broad s) .

c) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -JC-5-methylimidazolyl-4-yl) methyl] -5-phenyl-2H-1,4-benzodiazepine-2- you.

NMR _(DMSO-d6) delta: 1.96 (3H, s), 4.80, 5.15 (2H,

ABq, J = 15Hz), 5.55 (1H, d, J = 8Hz), 6.90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz), 11 , 58 (2H, bs).

d) (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one.

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.63 (1H, d,

J = 7.9 Hz), 6.9-8.2 (15H, m), 9.58 (1H, d, J =

7.9 Hz), 11.65 (1H, s), 11.92 (1H, s).

e) (3R) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one.

NMR _(DMSO-d6) delta: 5.04 (2H, ABq), 5.62 (1H, d, J = 7.9Hz), 6.9 to 8.3 (15H, m), 9, 58 (1H, d, J =

7.9 Hz), 11.66 (1H, s), 11.93 (1H, s).

f) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- (2-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

NMR _(DMSO-d6) delta: 5.10 (2H, s), 5.65 (1H, d, J = 8Hz), 6.60 to 8.10 (16H, m), 9.36 ( 1H, d, J = 8Hz),

11.65 (1H, broad s), 11.90 (1H, broad s).

HU 211 324 A9

g) (3RS) -N, 3-Dihydro-3- (2-indolylcarbonylamino) 1- (3-pyrazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin2-one.

NMR _(DMSO-d6) delta 5.03, 5.30 (2H, AB q, J =

Hz), 5.65 (1H, d, J = 8 Hz), 5.85 (1H, broad s),

6.90-7.90 (15H, m), 9.43 (1H, d, J = 8Hz), 11.60 (1H, broad s), 12.55 (1H, broad s).

h) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1 (1,2,4-triazol-3-yl) methyl] -5-phenyl-2H-1,4 benzodiazepin-2-one.

NMR _(DMSO-d6) delta 5.10, 5.35 (2H, AB q, J =

Hz), 5.66 (1H, d, J = 8Hz), 6.90-7.93 (15H, m),

8.23 (1H, bs), 9.40 (1H, d, J = 8Hz), 11.65 (1H, bs).

i) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) 1- [2- (4-imidazolyl-ethyl) -5-phenyl-2H-1,4-benzodiazepine-2- you.

NMR _(DMSO-d6) delta: 2.63 (2H, t, J = 7Hz), 3,854.20 (IH, m), 4.20 to 4.75 (lH, m), 5.55 (IH, d, J =

Hz), 6.60 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 8Hz), 11.65 (1H, broad s).

j) (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine 2-one hidmklorid.

NMR _(DMSO-d6) delta: 5.33 (2H, ABq), 5.69 (IH, d,

J = 7.6 Hz), 7.0-8.0 (15H, m), 9.05 (1H, s), 9.60 (1H, d, J = 7.6 Hz), 11.74 (1H, s), 14.73 (1H, broad s).

Starting example 13 for a solution of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (25 g) in Ν, Ν-dimethylformamide (625 mL) sodium hydride (60% suspension in mineral oil) was added gradually over 30 minutes with stirring and cooling in an ice bath. The mixture was stirred under the same conditions for 0.5 hours and at ambient temperature for a further 0.5 hours. To the cooled mixture was added dropwise chloroacetonitrile (4.98 mL) dissolved in N, N-dimethylformamide (10 mL) in an ice bath over 10 minutes. After stirring at the same temperature for 20 minutes, the mixture was stirred at room temperature for 16.5 hours.

Acetic acid (10 mL) was added dropwise to the reaction mixture in an ice bath. The resulting mixture was evaporated in vacuo and the residue was poured into a mixture of water (1000 mL) and ethyl acetate (800 mL) with vigorous stirring. After adjusting the pH of the mixture to 8.0, the organic layer was separated, washed twice with water, dried over magnesium sulfate and evaporated. The resulting oil was purified by silica gel column chromatography using chloroform / methanol (25: 1) as eluent. The fractions containing the expected product were combined and concentrated in vacuo to give (3RS) -1-cyanomethyl-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (26.69 g).

NMR _(DMSO-d6) delta: 5.07 (2H, ABq, J = 20.6 Hz,

17.8 Hz). 5.82 (1H, s), 7.25-8.82 (13H, m).

Starting Example 14 (3RS) -1-Cyanomethyl-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (100.0 g) and sodium azide (46). 4 g) Dissolve in 1-methyl-2-pyrrolidone (1.74 L) and add triethylamine hydrochloride (49.1 g) while stirring. The mixture was heated in an oil bath at 145 ° C and stirred for 4 hours. While cooling and stirring, the reaction mixture was poured into 5% hydrochloric acid (4.8 L). The resulting precipitate was collected by filtration and dried under vacuum at 50 ° C for 5 hours to give (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-1 - [(1H-tetrazol-5-yl) methyl]. 2H-1,4-benzodiazepin-2-one (100.39 g) is obtained.

NMR (DMSO-d 6), delta: 5.43 (2H, s), 5.84 (1H, s),

7.2-8.0 (14 H, m).

Starting Example 75 (3RS) -1,3-Dihydro-5-phenyl-3-phthalimido-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one ( 100 g) and trityl chloride (61.96 g) were dissolved in Ν, Ν-dimethylformamide (1.8 L) and triethylamine (36.1 ml) was added dropwise with stirring and cooling in an ice bath. The mixture was stirred at the above temperature for 10 minutes and then stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (181) with stirring and the resulting precipitate was collected by filtration, washed several times with water and dried under vacuum at 60 ° C for 8 hours. (3RS) -1,3-Dihydro-5-phenyl-3-phthalimido-1 - [(1-trityl-1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one is obtained (128). 2 g).

NMR (CDCl ₃ ), delta: 5.45 (2H, ABq, J = 33.6 Hz,

16.4 Hz), 5.98 (1H, s), 6.9-7.95 (28H, m).

Starting Example 76 (3RS) -1,3-Dihydro-5-phenyl-3-phthalimido-1 - [(1-tritylH-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepine-2- (128 g) was dissolved in tetrahydrofuran and hydrazine monohydrate (10.43 ml) was added at room temperature and the precipitate formed was filtered off. The filtrate and washings were evaporated in vacuo and the residue dissolved in dichloromethane. After filtering off the insoluble material, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N sodium hydroxide solution and water. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated to about 300 mL. The residue was stirred at room temperature. The resulting precipitate was collected by filtration of (3RS) -3-amino-1,3-dihydro-5-phenyl-1- (1-trityl-1H-tetrazol-5-yl) methyl] -2H1,4-benzodiazepin-2-one yield (53.6 g).

IR (nujol): 3380, 1680, 1600, 1560 cm -1.

NMR (CDCl ₃ ), delta: 2.71 (1H, s), 4.55 (1H, s), 5.46 (2H, ABq, J = 16.2 Hz, 50.8 Hz), 6.90 -7.50 (24 H, m).

Starting Example 7 (3RS) -3-Amino-1,3-dihydro-5-phenyl-1 - [(1-trityl-1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepine-2 Ontone (5.76 g) and N-tert-butoxycarbonyl-L-phenylalanine (2.79 g) are dissolved in Ν, Ν-dimethylformamide (100 ml) and 1-hydroxybenzotriazole (1, 42 g), 124

Ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.01 g) and triethylamine (1.7 ml) were added while stirring at room temperature. The mixture was stirred under the same conditions for 2 hours and then poured into aqueous sodium bicarbonate solution. The resulting precipitate was collected by filtration and washed with water. The collected precipitate was dissolved in ethyl acetate and washed with brine. The organic layer was separated and dried over magnesium sulfate. The solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (29 mL) and 4N hydrochloric acid in ethyl acetate (29 mL) was added dropwise at 0 ° C. After stirring for 2 hours under the same conditions, the mixture was diluted with ether (29 mL) and the resulting precipitate was collected by filtration. The methanolic solution of the collected precipitate was neutralized with ethanolic ammonia solution. The mixture was evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel using chloroform / methanol (5: 1) as eluent.

The fractions containing the expected compound were combined and evaporated to give an oil which was crystallized from methanol-ethyl acetate to give (3S) -3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1,3-dihydro- 5-Phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (1.86 g) was prepared. IR (nujol): 1670, 1600, 1520 cm -1.

NMR _(DMSO-d6) delta, 2.91 (IH, dd, J = 8.5Hz,

13.9 Hz), 3.21 (1H, dd, J = 4.0 Hz, 13.9 Hz), 41.5 (1H, dd, J = 4.0 Hz, 8.5 Hz), 5, 26 (1H, s), 5.36 (1H, d, J = 8.0 Hz), 7.15-7.68 (14H, m), 7.92 (1H, d, J =

8.2 Hz), 9.75 (1H, d, J = 8.0 Hz).

Fractions containing the expected other compound were treated in the same way with (3R) -3 - {[(2S) -2-amino-3-phenylpropanoyl] amino} -1,3-dihydro-5-phenyl-1 - [(1H) -tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (1.29 g) was obtained.

IR (nujol): 1670, 1600, 1620 cm -1.

NMR _(DMSO-d6) delta: 2.95 to 3.22 (2H, m), 4.24 (IH, t,

J = 7.2 Hz), 5.20 (2H, ABq, J = 15.7 Hz, 37.6 Hz),

5.37 (1H, d, J = 8.2 Hz), 7.21-7.69 (15H, m), 7.94 (1H, d, J = 8.2 Hz), 9.74 (1H , d, J = 8.2 Hz).

Starting Example 18 (3S) -3 - {[(2S) -2-Amino-3-phenylpropanoyl] amino} 1,3-dihydro-5-phenyl-1 - [(1H-tetrazol-5-yl) - methyl] -2H1.4-benzodiazepin-2-one (12 g) and triethylamine (3.83 mL) were dissolved in tetrahydrofuran (240 mL) and phenyl isothiocyanate (2.99 mL) was added at room temperature. After stirring for 4 hours at room temperature, the solvent was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S) -3 - {[(2S) -2- (N'-phenyl) thioureido] -3-phenylpropanoyl} amino-1,3-dihydro-5-phenyl-1 [( 1H-Tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (14.26 g) is obtained.

[α] D = -60.00 ° (c = 0.5, CH ₃ OH).

NMR _(DMSO-d6) delta, 3.05 (IH, dd, J = 7.2Hz,

Hz), 3.20-3.40 (1H, m), 5.30-5.60 (4H, m), 7.007.92 (21H, m), 9.66 (1H, d, J = 8, 1 Hz), 9.83 (1H, s).

Starting Example 19 (3S) -3 - {[(2S) -2- [N '- (Phenyl) thioureido] -3-phenylpropanoyl] amino} -1,3-dihydro-5-phenyl-1 - to a solution of [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one (14.10 g) in tetrahydrofuran (84.6 ml) dropwise at 60 ° C with ethyl acetate (84.6 mL) of 4N hydrochloric acid was added. After stirring for 10 hours under the same conditions, the resulting precipitate was collected by filtration, and the collected precipitate was suspended in chloroform and stirred for 1 hour at room temperature. The expected product is collected by filtration (3S) -3-amino-1,3-dihydro-5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one hydrochloride (7.15 g) was obtained.

[tt] g = -122.6 '(c = 0.5, CH ₃ OH).

IR (nujol): 3210, 2600, 1950, 1700, 1595, 1540 cm -1. NMR _(DMSO-d6) delta, 5.19 (IH, d, J = 3.9 Hz), 5.49 (IH, ABq, J = 16.6 Hz, 19.2 Hz), 7.20 -8.00 (10H, m), 9.24 (2H, s).

Mass (FAB): 334 (M ⁺ + 1).

Starting Example 20

The following compounds were prepared as described in Starting Examples 18 and 19.

(3R) -3-Amino-1,3-dihydro-5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one trifluoroacetate . NMR _(DMSO-d6) delta, 5.11 (IH, s), 5.37 (2H, s);

7.22-7.99 (10 H, m).

Mass (FAB): 334 (M ⁺ + 1).

Example 42

A mixture of indole-2-carboxylic acid (2.18 g), N, N-dimethylformamide (52 mg), thionyl chloride (1.0 mL) and anhydrous dichloromethane (22 mL) was heated under reflux for 1 hour. a solution of indolylcarbonyl chloride is obtained.

On the other hand, (3S) -3-amino-1,3-dihydro-5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepin-2-one hydrochloride and dichloromethane anhydrous (50 mL) was added dropwise triethylamine (7.45 mL). The above solution of 2-indolylcarbonyl chloride solution is added dropwise at a temperature below 10 ° C with stirring and cooling. After stirring for 2 hours under the same conditions, the mixture was washed with hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was recrystallized from ethanol to give (3 S) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1, 4-Benzodiazepin-2-one is obtained (5.3 g).

[?] D = -157.6 '(c = 0.5, DMSO).

IR (nujol): 3420, 3350, 3125, 1670, 1630, 1600,

1535 cm ¹ .

NMR (DMSO-d6, delta: 5.47 (2H, ABq, J = 16.4 Hz,

28.1 Hz), 5.72 (1H, d, J = 8.0 Hz), 7.02-7.90 (15H, m), 9.56 (1H, d, J = 8.0 Hz) , 11.64 (1H, s).

This compound is a selective CCK-A receptor antagonist and is pharmaceutically superior to the racemic compound.

Example 43

The following compound was prepared by reacting the compound of Example 42.

As described in Example A9, (3R) -3-amino-1,3-dihydro-5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepine-2-one. on-trifluoroacetate is reacted with 2-indolylcarbonyl chloride:

(3R) -1,3-Dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1 - [(1H-tetrazol-5-yl) methyl] -2H-1,4-benzodiazepine-2 -you.

[?] D ⁴ = 40.0 ° (c = 0.5, CHjOH).

IR (Nujol): 3250, 1640, 1600, 1535 cm ^1st

NMR (DMSO-d 6), delta: 5.31 (2H, ABq, J = 15.8 Hz,

30.5 Hz), 5.66 (1H, d, J = 8.1 Hz), 7.02-7.94 (15H, m), 9.47 (1H, d, J = 8.1 Hz) , 11.66 (1H, s).

Claims (3)

PATENT CLAIMS Compounds of formula (1) and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable carriers. 3. A method of treating or preventing cholecystokinin-mediated diseases comprising: a The compound of claim 1, or a pharmaceutically acceptable salt thereof, is administered to a human or animal.