Process for producing benzodiazepine derivatives and pharmaceutical compositions comprising same

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

In particular, a process for the preparation of novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof, which are said compounds being cololeistokinin (CCK) antagonists and thereby suitable for the treatment of emesis, pancreatitis, insomnia, gastric paresis, and affecting feelings of being stale, etc.

The benzodiazepine derivatives of the present invention have a structure of formula (I), wherein:

R is a halogen group substituted with one or more suitable substituents, a heterocyclic group substituted with one or more suitable substituents,

-NH-R^J a group of the general formula EMI123.1 wherein: hydrogen, lower alkanoyl, or lower hydroxy;

<img file="HUT50331A_D0001.tif" />

R is lower alkyl substituted with carboxyl and amino substituents

<img file="HUT50331A_D0002.tif" />

I r

lower alkyl substituted with a protected carboxyl and protected amino, lower alkyl or pyridyl

A group of the formula -0-R, wherein

R is hydrogen, hydroxy protecting group, rövidszénlánou alkyl rövidszénlánou alkenilesöpört, substituted aryl, rövidszénlánou alkyl substituted by halo, rövidszénlánou alkyl, amino-substituted, rövidszénlánou alkilosoport protected aminoosoporttal substituted rövidszénlánou Furthermore, alkyl, piperazinyl-substituted lower alkyl group which piperazinyl alalkilj alkyl group, additional short carbon (may be substituted by tubing, g

A group of formula -CONEI-R, within which

R is cyano, carbamoyl-substituted lower alkyl, carboxyl-substituted lower alkyl, protected carboxyl-substituted lower alkyl or carbamoyl and substituted-lower alkyl,

or -ZR, wherein α

R is hydrogen or lower alkyl and Z is -C (= O) -, -C (= NR) - where R is hydroxy-substituted or amino, and Z is -C (sC (R 6) -) group where

R is a carboxylic acid or protected carboxylic acid, and

R is hydrogen or

12

R and R are both halo;

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

R 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 invention are represented by the compounds of the invention. The reactions shown in FIG. In the formulas in the figures, R¹, R², R^{3 * *}, r \ R^{6 *}, R⁸, R⁹, R¹°, R¹¹, R¹² and A has the same meaning as previously defined

<img file="HUT50331A_D0003.tif" />

<img file="HUT50331A_D0004.tif" />

<img file="HUT50331A_D0005.tif" />

<img file="HUT50331A_D0006.tif" />

<img file="HUT50331A_D0007.tif" />

<img file="HUT50331A_D0008.tif" />

represents a halogen atom, φ represents a group of the formula -O-R ^

R represents a hydroxyl group protecting group or two protected hydroxyl group substituted aryl groups, represents a hydroxyl group or aryl group substituted with two hydroxyl groups, represents a C 1-5 alkylene group, represents an aryl group, represents a protected amino group or a substituted heterocyclyl group R denotes lower alkyl substituted by a protected amino group, is an amino group substituted hetero7 cyclic group, an amino group, or a group -O-R wherein

R is amino substituted c

lower alkyl,

9 is -C (= CH-R)_e ) -R, wherein o

R is as defined above, R_the denotes a protected carboxyl group - or -CONH-R - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

<td>^Rf</td><td>group within which 8 R_e denotes a protected carboxyl group a substituted lower carbonyl group, is -C (= CH-COOH) -R ^ within which She The value of R is the same as in the definition given above. g or - CONH-R ^</td>

<td></td><td>group within which g Rb is substituted with hydroxyl lower alkyl, H or lower alkyl</td>

<td>R¹⁵</td><td>alkyl, a major imino protecting group,</td>

<td>J</td><td>is CH or N,</td>

<td>Q</td><td>is CH or N,</td>

<td>X¹</td><td>is halogen,</td>

<td>R⁶the</td><td>denotes a lower carbon substituted by a protected carboxyl group and a protected amino moiety</td>

<td> /</td><td>alkyl, substituted with a carboxyl group or an amino group. toasted low carbon alkyl sweep,</td>

<td>_R5 the R¹S</td><td>denotes lower alkanoyl, denotes lower alkyl 5 substituted piperazinylsubstituted or -KH-R groups within which</td>

···· ·· • · · ·

R has the same meaning as defined above,

X² is halogen, lower alkylene and

<img file="HUT50331A_D0009.tif" />

is a piperazinyl group substituted with a phthalimide bonded or lower alkyl group

The starting material of formula IV is novel

The compound can be prepared according to the reaction scheme shown in Fig. 17 · In the formulas in Fig. 17, r \ R²and X has the same meaning as previously defined, represents an acid residue and

Y

<img file="HUT50331A_D0010.tif" />

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 with organic bases. formed salts (e.g. trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N * -dibenzylethylenediamine salt, etc.), salts with organic acids (e.g., acetate, maleate) , tartrate, methanesulfonate, benzenesulfonate, formate, toluene sulfonate, 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.) and the like.

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

Unless otherwise indicated, the term "carbon black" means a carbon chain of 1 to 6 carbon atoms.

In the halogen-substituted (lower) carbon-lower alkyl group, the halogen atom or group is 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, 1-4 nitrogen atoms.

3- to 8-membered monocyclic heterocyclic groups such as pyrrole, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, 1H-1,2,3 "Triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2Ξ-tetrazolyl, etc.), dihydrotriazinyl (e.g.

4,5-dihydro-1,2,4-triazine 1,2,5-dihydro-1,2,4-triazinyl, etc.);

<img file="HUT50331A_D0011.tif" />

ί

- a shifted 3-8 membered monocyclic ring containing 1-4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .;

unsaturated fused heterocyclic groups containing from 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. b] pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc .;

- containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms,

3-8 membered monocyclic heterocyclic groups such as oxazolyl, isooxazolyl, dihydroisooxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4 "oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and like;

- saturated 3-8 membered monocyclic heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, in the form of 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. 4 "thiadiazolyl, 1,3,4" thiadiazole, 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 ~ θ-membered, monocyclic heterocyclic groups containing oxygen, such as furyl, etc .;

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

unsaturated, fused, heterocyclic groups containing 1 to 2 sulfur 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, t-butyl, pentyl, t-pentyl, hexyl, etc.) or the like.

As used herein, the term "aryl" refers to phenyl, naphthyl and the like.

In the meaning of R, one or more suitable weeks

As used herein, a substituted substituent with a -11 substituent may include hydroxy, protected hydroxy, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, etc.). ) and the like.

Suitable protected hydroxyl groups include tetrahydropyranyloxy, acyloxy such as lower alkanoyloxy (e.g. formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy). 1-oxy, etc.) and the like ·,,

In the context of R, aryl substituted with one or more suitable substituents may be halogen (e.g., chlorine, bromine, fluorine and iodine) and the like.

Suitable lower alkanoyl alkanoyl may be formyl, aoethyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and the like.

The hydroxy-substituted lower alkyl, the aryl-substituted lower alkyl, the halogen-substituted lower alkyl, the amino-substituted lower alkyl are protected · * ··· ··· · · · · · · · · · · · ·

-12aminocsöpörttál alkilosoport substituted lower ", the substituted piperazinyl © port rövidszénlánou alkilosoport", the "lower alkilosoport karbamoilesöpörttál substituted, the substituted carboxyl group and a substituted rövidszénlánou alkilosoport rövidszénlánou the protected carboxy group in the lower alkilosoport term" mean straight or branched 1-6 carbon atoms szőnlánookat , ie methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, etc .; preferred groups are Cl-1 carbon.

In the expression "protected carboxyl-substituted lower alkyl", the protected carboxyl may be esterified carboxylic acid and the like. Said esterified carboxyl-substituted ester group may be, for example, a lower alkyl ester group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, 1-cyclopropylethyl). it may also have suitable substituent (s), such as lower alkanoyloxy (lower alkyl ester (e.g., acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl), pivaloyloxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl, pivaloyloxyethyl, 2-propionyl-13-oxyethyl, hexanoyloxymethyl ester, etc.); lower alkanesulfonyl (lower alkyl) ester (e.g. 2-mesylethyl ester, etc.), or 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, propynyl ester, etc.); one, two or three phenyl-substituted substituent lower alkyl esters which may carry additional 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-butyl benzyl ester, etc.); an aryl ester which may carry a suitable substituent (s) (e.g., above, 4-chlorophenyl, tolyl, 4-tert-butylphenyl, xylyl, mesityl, cumenyl ester, etc.) and the like .

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

As used herein, the term "acyl anionine" and "acyloxy" may mean an acyl group containing an aliphatic acyl group and an aromatic or heterocyclic ring. Examples of acyl groups include lower alkanoyl groups (e.g., boiling, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxy); carbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl groups (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl sweep (e.g. benzenesulfonyl, tosyl, etc.); aroyl groups (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indanecarbonyl, etc.); aryl-substituted lower alkanoyl groups (e.g., phenyl-acetyl, phenyl-propionyl, etc.); aryl-substituted lower alkoxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like, and the like; · »· ·· ·»

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

Suitable hydroxyl lithium protecting groups include, but are not limited to, tetrahydropyranyl liberates, aloyl liberates, such as lower alkanoyl liberates (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valaryl, isovaleryl, etc.), and the like.

Suitable lower alkenyl moieties include vinyl, allyl, 1-propenyl, 1- or 2- or 3-butenyl,

1- or 2- or 3 ~ or h-pentenyl, 1- or 2- or 3 or h- or 5 "hexanyl, etc.

Suitable lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like; carbon numbers from 1 to 4 are preferred.

Suitable lower alkylene groups may be straight or branched, having from 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, tetraraethylene, pentamethylene,

<img file="HUT50331A_D0012.tif" />

«

16 hexamethylene and the like; 1-4 carbon atoms are preferred.

Suitable "imino protecting group" include tritium 1, tetrahydropyranyl and the like.

Suitable &amp; quot; acid residues &amp; quot; include an acyloxy group in which the aoyl group is one of the foregoing, halogen (fluorine, chlorine, bromine and iodine) and the like.

Preferred compounds of formula I are those wherein

R means:

halogen, thienyl, furyl, piperazinyl substituted rövidszénlánou alkilosoporttal nilesöpört, imidazolilosoport which may be substituted tritilosoporttal, rövidszénlánou alkilosoporttal brushed substituted imidazoles, substituted imidazolilosoport, and rövidszénlánou alkilosoporttal tritilesoporttal tritilesöpörttál substituted pyrazolyl, substituted tritilesöpörttál triazolilesöpört, aminoosoporttal aminoosoporttal substituted or protected tiazölilesöpört, within this, it is more advantageous

A thiazole / amino group substituted with 17 or an acylamino group, most preferably a thiazolyl group substituted by an amino group or a lower alkanoylamino group, a two-substituted isoxazolyl group, a hydroxyl group, an oxo and a tetrahydropyranyl group; phenyl substituted with a protected hydroxy group, in particular, two acyloxy substituted phenyl groups, most preferably two lower alkanoyloxy substituted phenyl groups, two hydroxy substituted phenyl groups, two lower alkoxy substituted phenyl groups, two lower carboxyl substituted phenyl groups,

-NH-R in which

R is hydrogen, lower alkanoyl-lowered or hydroxy-substituted lower alkyl,

<img file="HUT50331A_D0013.tif" />

9

<img file="HUT50331A_D0014.tif" />

<img file="HUT50331A_D0015.tif" />

lower alkanoyl, lower alkanoyl, lower alkanoyl, lower alkanoyl, lower alkanoyl, lower alkyl and lower alkenyl; -amino-substituted lower alkyl - or R is further pyridyl,

0-R ', wherein

R 'is hydrogen, hydroxy protecting groupThis group is preferably tetrahydropyranyl or lower alkanoyl, lower alkyl, lower alkenyl, phenyl substituted lower alkyl, halogen substituted, halogen substituted, halogen substituted protected amino-substituted lower alkyl - more preferably phthalimido substituted lower alkyl - or lower alkyl substituted piperazinyl (lower alkyl), · · · · · · · · · · · · · · «· · · · ···

A group of the formula -CONH-R wherein θ

within R is cyano, carbamoyl-substituted lower alkyl, protected carboxy-lowered substituted lower alkyl

within this, an esterified carboxylic acid-substituted lower alkyl group is preferred, most preferably a lower alkoxycarbonyl-lower alkyl substituted by a carboxyl group or a carbamoyl group and a phenyl-unsubstituted lower alkyl group.

-Z-Ir is a group of the formula:

Q

R is hydrogen or lower alkyl and Z is -C (= O) -, -C (= NR 4 O) -, where R 4 is hydroxy, lower alkoxy or amino, or Z is further -C f = C (R ) Wherein R is a carboxy group or a protected carboxyl group, more preferably an esterified carboxyl group, most preferably a lower alkoxycarbonyl group, and R is a hydrogen atom,

12 or R and R are both halogen;

R is phenyl or halo-substituted phenyl;

R is hydrogen;

R 4 is hydrogen, halogen, or lower alkoxy, and ????????

A is lower alkylene.

If the 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. Compounds having a group which enables such tautomeric isomers are described in the description and claims of the invention having the structure (XVIIIA).

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

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 (III).

The salts of the compounds of the formulas II and III may be 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.). .), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth phosphorus carbonate (e.g., magnesium carbonate) ··· ··· · · · · · (Sodium, calcium carbonate, etc.), an alkali metal hydrogencarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.); diethyl acetate (e.g., sodium acetate, potassium acetate, etc.), alkaline earth phosphate (e.g. magnesium magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. hydrogen phosphate, etc.) and the like; or an organic base such as trialkylarain (e.g. trirethylamine, triethylarain, etc.), picoline, N-methylpyrrolidine, H-methylinorpholine and the like.

The solvents used for the reaction may be alcohols, IT, N-diraethyl formaride, 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 compound of formula (I) may be prepared by reacting a compound of formula (IV), or an active derivative thereof, or a salt thereof, with a compound of formula (V) or an active derivative thereof, or a salt thereof.

A suitable derivative for the araine group of Compound (IV) may be a Schiff-base type imino-2 derivative or a taxitere enarain type isomer formed by carbonylation of (TV). reacting with a swept bowl 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 (trirethylsilyl) acetamide, N-trirethylsilylacetamide and the like; a derivative of compound (TV) with phosphorus trichloride or phosgene; etc

Suitable salts of the compounds (TV) and (V) are the same as the salts exemplified for the 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., diacylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), diacylphosphoric acid, e.g. ), sulfuric acid, alkylcarboxylic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid), mixed anhydrides with aromatic carboxylic acids (e.g. benzoic acid), symmetric acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, active esters such as cyanomethyl, -methyl, + dimethylimino-methyl-? - (CH2) ^ N-GH-J, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, mesic 1-phenyl, phenyl-azo-phenyl, phenylthio, p-nitrophenylthio, ρ-cresylthio, carboxymethylthio, pyranyl, piperidyl, 8-quinolylthioester, etc., with the N-hydroxy compounds (e.g., N, N-diraethylhydroxylamine, esters with hydroxy-2- (1H) -pyridone, N-hydroxy-narrowimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-c, -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 free

<img file="HUT50331A_D0016.tif" />

acid or salt thereof, it is preferable to carry out the reaction in the presence of one of the conventional condensing agents. Examples of such a condensing agent are N, TT '-dicyclohexylcarbodiimide, N-cyclohexyl-N' '-morpholinoethylcarbodiimide, N-cyclohexyl-N * - (4-diethylaminocyclohexyl) -carbodiimide, N 1 H' -. diethyl carbodiimide, N, N * -diisoporylcarbodiimide, 1-ethyl-N^,"(3-Dimethylaminopropyl) carbodiimide, N, N-carbonyl bis (2-methylimidazole), pentamethylene ketene-N-cyclohexylamine, diphenyl ketene-N-cyclohexyl-iraine, ethoxy-. acetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, diethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine , 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5^-Internal salt of (m-sulfophenyl) -isoxazole, hydroxide, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, N, N-dimethylformanide and thionyl chloride, phosgene oxychloride, etc. skilled so-called VxIsmeier 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-carbon) alkyl-1-benzylamine, and the like. The reaction temperature is not critical, and the reaction may be carried out under cooling or heating.

Process (3) (Figure 3) - The Compound (ib) or salt thereof may be prepared by removing the hydroxyl group protecting group from the Compound (Ia) or salt thereof. .

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.

Tetrahydropyranyl, benzyloxycarbonyl, substituted benzyloxycarbonyl! Hydrolysis is the most common and preferred method for the removal of 1-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 acid suitable for the reaction is selected according to the protecting group to be removed and other factors,

Acidic hydrolysis is preferably used to remove the acyl sweep. 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 - e.g. trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine,

~ 25 N-methylmorpholine, etc.

The reductive post-elimination reaction can be carried out, for example, with a metal (e.g. tin, zinc, copper, etc.) or a metal compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. , 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, N, N-dimethylformamide or other solvent which does not adversely affect the reaction.

The reaction temperature is not critical, the temperature is selected according to the protecting group and the elimination method, and cooling or heating may be employed.

Process 4 (Figure 4) - The compound of formula Xd or its salt may be prepared by oxidation of a compound of formula Xc or a salt thereof.

The salts of the compounds of the general formulas (le) and (Xd) may be those listed above for the general formula (i).

Oxidation can be accomplished using conventional techniques · ········································································· ·

They may be used, for example, using oxidizing agents such as the combination of dimethyl sulfoxide with dicyclohexylcarbodiimide or chromium trioxide with pyridine.

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

Process 5 (Figure 5) - A compound of formula (if) or a salt thereof can be prepared by reacting a compound of formula (le) 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, N, N-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) - The compound of formula (Ig) or a salt thereof can be prepared by reacting a compound of formula (le) or a salt thereof with a compound of formula (XI) ···· · ···· ··· The reaction is carried out with a compound of the formula: or a salt thereof.

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

Commonly used solvents for the reaction include benzene, Ν, ΙΊ-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 (III) or a salt thereof is prepared by removing the amino protecting group from the compound (Th) or salt thereof.

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 of formula (Ic) and its salt are prepared by removing the carboxyl protecting group from the compound of formula (Ij) or its salt.

This reaction is carried out essentially as in Process (3), therefore, the reaction mode and conditions are described therein.

<img file="HUT50331A_D0017.tif" />

Method 9 (Figure 9) - Formula (II) The compound, or salt thereof, is prepared by removing the compound or salt thereof from the compound (11).

Iminose group protecting group.

The reaction is carried out essentially as the reaction step (3) of process (17), so the method and reaction conditions are detailed there.

Process 10 (Figure 10) - A compound of formula (In) or a salt thereof can be prepared by reacting a compound of formula (XII) or a reactive derivative thereof on its carboxylic acid with a compound of formula (XIII) or a reactive derivative on its amino group 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) formed at the amino group may be the same as those exemplified for the compound of formula (IV).

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

Process 11 (Figure 11) - The compound of formula (Ip) or a salt thereof can be prepared by reacting (lo) • ·

<img file="HUT50331A_D0018.tif" />

Reacting a compound of formula (29) or a salt thereof with a compound of formula (XIV) or a salt thereof.

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

Suitable bases for process (1) are listed.

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

The reaction temperature is not critical, the reaction can be carried out at room temperature, heating is cut; even with cooling.

Process 12 (Figure 12) - The compound (Ireland) or salt thereof is prepared by removing the amino protecting group and the carboxylic acid 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 carboxylic acid salt thereof. or a salt thereof.

Suitable reactive derivatives of the compound of formula (I) 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.

Process 14 (Figure 14) - A compound of Formula (lu) or a salt thereof is prepared by reacting a compound of Formula (lo) with a compound of Formula (XVI) or a 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 (lu) or a salt thereof is prepared by reacting a compound of formula (lu) or a salt of formula (XVII)

<img file="HUT50331A_D0019.tif" />

The compound is reacted with a compound or a salt thereof.

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

Process 16 (Figure 16) - The compound of formula (ly) or salt thereof is prepared by deprotection of the imino group from the compound or salt of formula (ix).

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

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

Step (17-1) - A compound of formula (VIII) or a salt thereof can be prepared by reacting a compound of formula (VI) or a salt thereof with a compound of formula (VII).

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

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

···· · ··············································································· (32 (17 ”3 Reaction Step A - Formula IV

The compound or salt thereof is prepared by deprotecting the amino protecting group of the compound of formula IX from its salt.

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

The elimination reaction can be carried out in the usual manner, i.e., by hydrolysis, reduction, Edman's method (phenylisothiolane 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, terpentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, substituted , substituted alkylidene, substituted cycloalkylidene or the like, the most commonly and most preferably used hydrolysis process is the acidic process.

The acid used may be organic or inorganic, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. Most preferred are acids which can be readily removed by reaction in a commonly used manner such as under reduced pressure. desáYlláoióval. 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 acyl sweep such as trifluoroacetyl.

Halogen-substituted alkoxycarbonyl (e.g., trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonate 1 (e.g., benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonone 1, and the like. the reductive method is generally used to eliminate protecting groups. Reducing ash is, for example, 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 a reaction mixture of 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 moiety may generally be removed by hydrolysis. Particularly halogen-substituted alkoxycarbonyl and 8-quinolin-1-oxycarbonyl; In the case of 1-groups, the elimination is usually carried out with heavy metals such as copper, zinc, etc. - response.

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

The reaction temperature is not critical and the choice depends on the protecting group to be removed and the procedures 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 (Σ) and pharmaceutically acceptable salts thereof are cholecystokinone (CCK) antagonists and can therefore be used as medicaments for the treatment of vomiting, inflammation of the pancreas, etc. treatment.

To demonstrate the utility of the compound of formula (I), the following test procedures illustrate the CCK antagonist activity of the compound.

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

Test compound: (3RS) -1,3-Dihydro-1- (2-hydroxyethyl) -3- (2-dihydro-1-carboxylic acid) -5-fe ni 1-2H-1,4-benzodiazepin-2-one (hereinafter referred to as Test A).

- 35 ~ • ···· · · · · • · · · · · ·

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

The muscle slice is exposed to an initial tension of 0.5 g and equilibrated for 60 minutes while the bath is changed every 15 minutes. Isometric muscle-7 contraction is measured using a force transmission device. Add 3.2x10 M CCK-8 to the bath and measure the contractile force. After washing CCK-8, 1x10 M test compound was added to the bath. After 5 minutes, CCK-8 is added and the force of contraction is measured. To characterize CCK antagonism, the contraction of CCK in the absence and presence of test compound A is compared.

Test result: 91% inhibition.

The compound of formula (Z) or a pharmaceutically acceptable salt thereof can 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. »· * · · ···« ♦ · * · ··· · · · ······················································································································································sed.

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

An effective amount of an active ingredient is generally

<img file="HUT50331A_D0020.tif" />

0.01-50 mg per testulylcylogram, administered 1-4 "times daily. 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.

First example

11.75 g of (3RS) -1,3-dihydro-3-aoethoxy-5-phenyl-2H-1,4-benzodiazepin-2-one, 11.1 g of potassium phthalimide, g of sodium iodide and 80 ml The reaction mixture containing N, N-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 cm¹.

(DMSO-d₆), delta: 5.73 (1H, s, 7.30-7.70 (9H, m),

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

Second example

8.2 g (3 88) -1,3 · άϋιίάϋθ-5 ~ ίθηΐ1-3 “· ίΐΑ1ίπΐΑ.0ο-2H-1,4-benzodiazepine-2-tin, 1.0 g of hydrazine hydrate and 160 ml of tetrahydrofuran ♦ · »·

V ··· «·· ·· • ·· · · ♦ ·

After stirring at room temperature for 38 hours, 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 \

NMR (DMSO-d6), delta: 4.30 (1H, s), 5.0 (2H, bs), 7.20-7.60 (9H, m).

3 · Example

1.90 g of (3KS) -1,3-dihydro-5-phenyl-3-phthalimido-2II-1_fTo a solution of 4 "benzodiazepin-2-one in 30 ml of N, N-dimethylformamide was added 0.20 g of sodium hydride (62% suspension in mineral oil) under small stirring and cooling in an ice bath (&lt;3 ° C). ) · The reaction mixture is stirred under cooling for 10 minutes and then 1.60 g is added in one portion.

2 - [(tetrahydropyran-2-yl) oxy] ethyl bromide. The mixture was stirred at room temperature for one 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, 1.48 g of (3RS) -1,3-dihydro-5 "phenyl" 3 "phthalimido-1- 2 - ( (RS) -2-Tetrahydropyranyloxy) -ethyl-2 '-2' -1,4-benzodiazepin-2-one and (3RS) '1,3-dihydro-5' -phenyl-3-phthalimido- Yielding a mixture of N - ((SR) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepin-2-one.

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

710 cm¹.

NMR (CDC1₃), delta: 1.3-1.9 (6li, broad), 3.4-4.7 (7H, m), 6.00 (1H, s), 7.3-8.1 (13H, m) ).

4 · Example

(3RS) -1,3-Dihydro-5-phenyl-3-phthalimido- 1- [2 - ((RS) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepine-2 -one and (3RS) -1,3-dihydro-5-phenyl-3 'phthalimido-1- (2 - ((SR) -2-tetrahydropyranyloxy) ethyl) -2H-1,4-benzodiazepine. Dissolve 0.51 g of 2-in in 10 ml of chloroform and add 55 g of hydrazine hydrate at room temperature with stirring.

After stirring for 1.5 hours at room temperature, it is refluxed 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 was filtered off and the filtrate was evaporated to give 0.43 g of (3RS) -1,3 "dihydro-5-phenyl-3-amino-1-

<img file="HUT50331A_D0021.tif" />

<img file="HUT50331A_D0022.tif" />

Diazepin-2-one is obtained.

IR (nujol): 3340, 1680, 1660, 1600, 780, 760, 695 csT¹.

5th example

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 (in a 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 for 40 minutes under the same conditions, 0.39 g of 5-chloromethyl-1-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.

Using a 10: 1 mixture. 0.5 g of (3RS) -1,1'-dihydro-3- (2-indolylcarbonylamino) -5 "phenyl-1- (5-tetrazolylmethyl)" 2H-1,1'-benzodiazepine-2- ont kapunk.

M.p. 19 DEG-195 DEG C. (decomposition).

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

695 cm \

NMR (DMSO-d₆), delta: 5.42 (2H, ABq), 5.70 (1H, d, J = 8.0Hz,

6.9-8.0 (15H, m), 9.44 (1H, d, J = 8.0Hz), 11.6 (1H, broad s).

Mass: m / e = 477 (M +).

6th Example 1 To 0.19 g of N-hydroxybenzotriazole in 0.1 ml of chloroform and 0.24 g of ΤΓ, N-dicyclohexylcarbodiimide are added 0.43 g of (3RS) -1,3-dihydro-5 ′ phenyl-3-ynino-1- 2 - ((RS) -2-Tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5'-phenyl-3-minmino-1-yl. A mixture of 2 - ((SR) -2-tetralidopyranyloxy) ethyl) -2E - [1,4-benzodiazepine-2-tin at room temperature with stirring. Under these conditions, stirring is continued for 2 hours. 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. so 0.45 g (3RS) -1.3 ~ ··

Λ · »

··· · ·

«··· ·· tt

k2

-dihydro-3- (2-indolylcarbonylamino) -5 "-phenyl-1- (2 - ((RS) -2-trachloropyranyl-oxy) ethyl) -211-14-benzodiazepin-2-one and (3RS) -1,3-dihydro-3 '- (2-indolylcarbonylamino)' 5 'phenyl' 1- (2S) - ((SR) -2-tetrahydropyranyloxy) ethyl-2H- A mixture of 1,4 "benzodiazepine-2-tin is obtained.

XR (nujol); 3340, 3280, 1680, 1630, 1610 (shoulder), 750,

700 cm¹.

CHR (CDC1₃δ: 1.0-2.0 (1H, m), 3.1-4.7 (7H, w), 5.82 (111, d, J = 8Hz), 7.0-7.9 ( J4H, m), 8.13 (1H, d, J = 8Hz), 9.62 (1H, broad).

7th example

0.42 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- (2 - ((RS) -2-tetrahydropyranyl-oxy) ethyl 4H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1 - [(SR) - A mixture of 2-tetrahydropyranyloxy) ethyl-2H-1,4 "benzodiazepin-2-one was prepared as a suspension in 10 µl aoetone and 0.4 ml of 6N hydrochloric acid was added at room temperature with stirring. After stirring the yellow clear solution for 45 minutes, additional 0.4 mL of 6N hydrochloric acid and mL of water were added. The reaction mixture was stirred at room temperature for half an hour. After neutralization with aqueous sodium bicarbonate solution and removal of acetone, a yellow precipitate was obtained which was collected by filtration, washed with water and dried. The Raw Space * ···

The 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-indole 1-carbonylacino) '5'-phenyl-2' -1,4- benzodiazepin-2-one was obtained as an amorphous material. Trituration with diethyl ether gave a pale yellow powder.

M.p. 17 DEG-175 DEG C. (dec.).

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

740 by 690 cm¹.

NMR (CDCl 3, delta: 2.32 (1H, broad), 3.55.4, 4.4 (4H, m),

5.74 (1H, d, J = 8Hz), 7.05-7.7 (14H, m), 8.02 (111, d, J = 8H)_Z), 9.45 (1H, broad s).

Mass: m / e = 43θ (W).

8th Example 1 (a) 1.0 g of (3R) -1,3-dihydro-5-phenyl-3 - ((2S) -2-tert-

butoxycarbonylamino-3-phenylpropanoyl) amino] -2H-1,4 * benzodiazepine "2-tin and (3S) -1,3" dihydro-5-phenyl "3" ((2S ) A mixture of -2-tert-butoxycarbonylamino-3 "phenylpropanoyl) amino] -2H-1,4" benzodiazepin-2-tin was dissolved in 5 ml N, N-dimethylformamide and 77.4 g mg (62 73 slurry in mineral oil) of sodium hydride with stirring, the reaction mixture was stirred in an ice bath for approx. Cooled to 3 ° C. Under these conditions, stirring is continued for 4θ minutes. For the reaction mixture * · ·······················································

44-0.37 g of 2-acetoxyethyl brotnide are added 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" Γ ((2S) -2-) as a colorless oil. tert-butoxycarbonyl-1-amino-3-phenylpropanoyl) amino] -2H-1,4'-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3 Resulting in a mixture of "dihydro-5" phenyl-3- (2S) -2-tert-butoxycarbonylamino-3 "phenylpropanoyl) amino] -2H-1,4" benzodiazepin-2-one.

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

1690, 1660, 1600, 745, 695 cm¹.

NMR (CDC1₃), delta: 1.40 (9Η, s), 1.62 (3H, s), 3.0-3.3 (2H, m), 3.9-4.2 (3H, m), 4, 4-4.8 (2H, m), 5.06 (111, broad, d), 5.51 and 5.53 (1H, d and d),

7.2-7.85 (14, m).

(b) According to the above procedure, the following mixture is prepared:

(3R) -1- (2-acetoxyethyl) -1,3 "dihydro-5" (2-fluorophenyl) ~ 3 "

- (((2S) -2-tert-butoxycarbonyl-amino-3'-phenyl-propanoyl) -amino] -2H-1_f 4-benzodiazepin-2-one and (3S) -1- (2-aoethoxylethyl) -1,3-dihydro-5- (2-fluorophenyl) -3 * - [((2S) -2- tert-butoxycarbonyl-awino-3 "phenyl-propanoyl) -amino] -2H-1,4"

benzodiazepin-2-one

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

9th example

1690, 1662,

1161, 1048,

1485, 1440, 1380, 1365, 1230, 750, 695 om "¹.

(3R) "1- (2-aoeoxyethyl-1,3" dihydro-5-phenyl-3 "

- [((2S) -2-tert-Butoxycarbonylamino-3'-phenylpropanoyl) amino] -2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxy) ethyl) -1,3 "dihydro-5-phenyl-3" - ((2S) -2-tert-butoxycarbonylamino-3 "phenylpropanoyl) amino] -2H-1,4-benzodiazepine 0.7 g of a mixture of 2-one is dissolved in 20 ml of ethyl acetate and hydrogen chloride gas is added to the solution under cooling and stirring. After the solution was saturated with hydrogen chloride, stirring was continued under reflux for 3 minutes and then at room temperature for 1 hour. The solution was bubbled through dry nitrogen gas to remove the

<img file="HUT50331A_D0023.tif" />

h6 hydrochloride and evaporate the solution 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-2H-1, Z).-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) ~ 3 ~ ((2S) -2-amino-3-phenylpropanoyl) - A mixture of amino] -1,3-dihydro-5-phenyl-2II-1,1'-benzodiazepine-2-tin is obtained.

10th example

(3R) ~ 1- (2-Acetoxyethyl) -3 - [((2S) -2-awino-3-phenylpropanoyl) amino] -1,3-dihydro ~ 5 '^&gt;enyl-2H-1,1'Z-benzodiazepin-2-one (3E-isomer) and (3S) -1- (2-acetoxyethyl) -3 '[((2S) -2-amino-3) 12.2 g of a mixture of phenylpropanoyl) amino] -1,3 "-dihydro-5-phenyl-2H-1,4-benzodiazapin-2-one (3S isomer) on silica gel (230 mesh). ), eluting the column with chloroform / methanol (20: 1). The fractions containing the desired material were combined and evaporated to dryness to give 3.3 g of pure 3S-isomer as an oil. The remaining fractions gave 8.50 g of a mixture of 3S and 3R isomers. This material was repeatedly chromatographed on a silica gel column (230 mesh) with chloroform / methanol, 15: 1.

<img file="HUT50331A_D0024.tif" />

eluting with a mixture. This gives 1.30 g of pure 3S isomer as an oily substance and 4.01 g of 3R isomer as an oily substance. NMR (CDC1₃ 4- D_£0) (270 MHz), delta:

3S-isomer:

1.648 (3H, s), 2.817 (1H, dd, J = 14.0IIz, 10.8I1z), 3.336 (1H, dd, J = 14Hz, 6.5Hz), 3.704 (1H, dd, J = 10, 8H_z, 6.5Hz), 3.927 (1H, dt, J = 15, 1Hz, 6.5Hz), 4.07-4.20 (2H, m), 4.660 (1H, octet, J = 13.6llz, 7, 6Hz, 7.6 (lz), 5.578 (1H, s), 7.19-17.64 (14H, m).

3R-isomer:

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

3.499 (1H, dd, J = 14.0Hz, 6.5Hz), 3.729 (1H, dd, Jss10.8Hz, 6.5Hz), 3.927 (1H, dt, J = 15.1Hz, 6.5Hz), 4 , 09-4.17 (2H, m), 4.690 (1H, octet, J = 13.6Hz, 7.6Hz, 7.6Hz), 5.571 (1H, s), 7.21-7.63 (14H, m).

11th example

The following materials can be prepared according to the procedure described in 9 and 10:

(3 S) -1- (2-Acetoxy) -3 '[((2 S) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro-5' (2-fluoro-f) enyl) -2H-1_} 4 'benzodiazepin-2-one.

M.p. 168-17 ° C.

<img file="HUT50331A_D0025.tif" />

ho TR (nujol): 3410, 3360, 3325 (shoulder), 1742, 1680 (shoulder), 1667, 1610 (shoulder), 1600, 1 ^ 80, 1448, 12 ^ 0,

1108, 1045, 810, 781, 730, 699 crn "¹.

M4R (CDCl₃), delta: 1.81 (3H, s), 1.85 (2H, s), 2.84 (1H, dd, J = 10.5Hz, 13.5Hz), 3.33 (1H, dd, J) = 13.5Hz, 4Hz), 3.69-4.25 (4H, m), 4.5-4.8 (1H, m), 5.60 (1H, d, J = 8Hz), 6.95 -7.9 (13H, m), 9.01 (1H, d, J = 9Hz).

(3R) -1- (2-Acetoxy-ethyl) -3 '- [((2S) -2-amino-3-phenyl-propanoyl) -amino] -1,3' -dihydro-5- (2-fluoro-phenyl) ) -2H-1,4-benzodiazepine-2-one.

IR (fillet): 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 = 13.5Hz, 10.5Hz), 3.39 (1H, dd, J = 13.5Hz, 4Hz), 3.7-4.25 (4H, w), 4.5-4.8 (1H, m), 5.61 (1H, d, J = 8Hz), 6.95-7.9 (13, m), 9.0Zj (1H, d, J = 8Hz).

12th Example (a) 4.65 (3S) -1 "(2-Acetoxyethyl) -3" [((2S) "2"

-amino-3-phenyl-propanoyl) -amido] -1,3-dihydro-5-phenyl-2H-1,4'-benzodiazepin-2-one and 1.43 g of phenyl isothiocyanate

100 A solution of 1 ml of ethylene chloride in water is heated with steam while stirring. After removal of solvent 100 ml ··················································

- h9 methylene chloride 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, the residue was triturated twice with methylene chloride and diethyl ether and the resulting crude red oil was chromatographed on a silica gel column using chloroform / methanol (1: 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 little aqueous sodium bicarbonate.

The organic layer was separated and dried over magnesium sulfate. Removal of the solvent gave (38) -1- (2-acetoxyethyl) -3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1.35 g).

IR (film): 3370, 3300, 1725, 1665, 1600 cm @ -1¹.

NMR (CDC1₃), delta: 1.66 (3H, s), 2.90 (211, broad s),

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

[a] 26,⁸ _ -111,73⁰ (o, 00260 g / ral, CHCl3).

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

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

<img file="HUT50331A_D0026.tif" />

ZR (filters): 3370, 3300, 1725, 1665, 1600 cm @ -1¹.

NMR (CDC1₃), delta: 1.66 (3H, s), 2.89 (2H, broad s),

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

Μ β⁶’⁸ = * 123.63 ° (0.00312 g / ml, CHCl 2).

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

IR (film): 3450 (shoulder), 3380, 3325 (shoulder), 1738, 1680, 1660 (shoulder), 1605, 1580, 1490, 1455, 1375, 1332, 1230, 1110, 1050, 820, 760, 745 cm @ -1 "¹.

Nuclear Magnetic Resonance Spectrum (ODC1), δ: 1.8 L (3H, s), 3.8-4.8 (6.1 l, m),

6.95-7.9 (9Π, m).

Γα] g⁵ = -57.68 ° (3.10 mg / ml, CH 2 Cl 2).

(d.) (3R) -1 '(2' Acoxyoxyethyl) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2TI-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, 750

MMR (CDC1₃), delta: 1.80 (3H, s), 3.8-4.8 (6H, m),

6.95-7.3 (9H, m).

FCT] |⁵ = + 50.52 ° (3.18 mg / ml, CII₂C1₂).

Example 13 · (a) 1,35e (3S) -1- (2-Acetyloxyethyl) -3'-amino-1,3 "" dihydro-5-phenyl-2H-1,4-benzodiazepine-2- on 25 ml of a solution of Ν, Ν-di in methyl formamide at room temperature

-1 cm

<img file="HUT50331A_D0027.tif" />

and 0.64 g of N-hydroxybenzotriazole and 0.83 g of 2-indole carboxylic acid are added with stirring.

N-dicyclohexylcarbodiimide. The reaction mixture was stirred for 2 hours at room temperature and then allowed to stand overnight. The precipitate formed is filtered off and the filtrate and washings are combined. The di-1-formamide solvent was evaporated under reduced pressure, and the residue was quenched with water and extracted twice with ethyl acetate. Wash the extract twice with brine,

<img file="HUT50331A_D0028.tif" />

dried with sulfate. Removal of the solvent gave 3.05 g of an oily residue which was chromatographed on a silica gel column using chloroform / methanol (15 x 1) as eluent. The fractions containing the desired material were combined and concentrated under reduced pressure to give (3S) -1- (2-aoethoxyethyl) -3 "(2-indodylcarbonylamino) -1,3-dihydro-5 (1.9 g). ~ phenyl-2H-1,4-benzodiazepin-2-one is obtained.

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

745, 697 cm ~ ¹.

1MR (CDCl 3), delta: 1.65 (3H, s), 3.8-4.3 (3H, m), 4.55-4.9 (111, m), 5.84 (1H, d, J = 8.25Hz), 7.0-7.8 (14H, m), 8.14 (1H, d., J = 8.25Hz), 9.98 (1H, broad s).

Mass: m / e = 4θ1 (M ').

Μ |⁶’⁸ = -51.27 ° (0.00340 g / ml, CHCl3).

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

• ··· · ···························································································································································· available forward Annex B 2-acetoxy-ethyl) -3- (2-indolyl-carbonyl-amino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ~. TR (txujol): 3325, 3260, 1735, 1680, 1630, 16OO, 1230,

745, 697 cm¹.

NMR (CDC1₃), delta: 1.65 (3H, a,), 3.8-4.3 (3H, m),

4.55-4.9 (1H, m), 5.84 (1H, d, J = 8.25Hz), 7.0-7.8 (14H, m), 8.14 (1H, d, J) = 8.25Hz), 10.06 (1H, broad s) ·

Mass: m / e = 481 (MH +)⁺).

+ 58.90 ° (0.00300 g / ml, CHCl₃).

(c) (3S) -1- (2-Acetoxyethyl) -3 "(2-indolylcarbonylamino) -1,3" dihydro-5- (2-fluorophenyl) -211- 1,4-benzodiazepine n-2-ol.

Mp: 183-187 ° C (dec.).

IR (nujol): 3350 (shoulder), 3275, 1733, 1687, 1640, 1610 (shoulder), 1539, 1455, 1380, 1260, 1235, 82, 775, 750 cm¹.

NMR (CDC1₃), delta: 1.80 (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 = 8Hz) ), 10.11 (1H, bs).

Mass: µl / e = 498 (M⁺).

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

·· · ···· *· • · ♦ · · · · • · · ♦· ·

185-189 ° C (dec.).

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

770, 745 is "¹.

NMR (CDC1₃), 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 = 49θ (M +)⁺).

Example 14 (a) 1.80 g of (3S) -1- (2-acetoxyethyl) -2- (2-indolyl)

-carbonylamino) -1,3-dihydro-5-phenyl-2II-1,4-benzodaze &lt;_&gt;pin-2-one and 0.30 g of potassium carbonate were stirred in 30 ml of 80 'h ethanol at 65-7θ ° 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 and dried over magnesium sulfate. 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 desired fractions were combined and evaporated to give (3S) -1- (2-hydroxyethyl) -3- (2-indol-1-carbonylamino) -1,3 "dihydro-5" phenyl-2II (1.47 g). 1,4-Benzodlazepin-2-one is obtained as a colorless amorphous powder.

···· · ···· ·· ·· ··· ····· • · » ·♦ · • · · · · · · ·· ··· · ·· ··

- 54 IR (ttujol) x 3400 (shoulder), 3260, 1680, 1635, 1600, 745,

695 cm¹.

NMR (CDCl₃), delta: 2.7 (1H, broad s), 3.65-4.3 (4H, m)_f

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 / es 43θ (M⁺)·

fx]^26,8= -59.04 ° (0.00352 mg / ml, CHCl 1)₃).

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

(b) (3R) -1- (2-Hydroxyethyl) -3- (2-indolylcarbonyl)

amino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

Dl (nujol): 3400 (shoulder), 3260, 1680, 1635, 1600, 740, 695 cm ¹.

NMR (CDC1₃), delta: 2.83 (1H, broad s), 3.55-4.3 (4H, tn),

5.78 (1H, d, J = 8Hz), 6.9-7.8 (14H, m), 8.18 (1H, d, J = 8Hz), 10.28 (1H, broad s).

Mass: m / e = 438 (MH +)⁺).

gT]²⁶»⁸ = 69.16 ° (0.00360 g / ml, CIIC1)₃).

(o) (3S) -1- (2-Hydroxyethyl) -3,2-indole-1-carbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4- benzodiazepin-2-one.

190-195 ° C (dec.).

IR (nujol): 3400 (shoulder), 3270, 1680 (shoulder), 164, 1610, (shoulder), 1535, 1485, 1450, 1379, 1330, 1220, 818, 770 (shoulder), 748 cm¹.

* • · · · · · · ···· ·· ·· ·· ·· • · · · · &lt;• · · · · · · · · · · β ·· ·· · ·

- 55 NMR (CDCl₃), 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 / es 456 (M + H)⁺).

[ajjj⁵ _ -i_r20 ° (3.32 mg / ml, CHCl 3).

(d) (3R) -1- (2-Hydroxyethyl) -3- (2-indol-1-carbonyl)

-amino) -1,3 'dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2-one.

M.p. 19 DEG-195 DEG C. (decomposition).

IR (nujol): 3400 (shoulder), 3270, 1680, (shoulder), 1639, 1610 (shoulder), 1533, 1484, 1/150_t 1378, 1330, 1220, 818, 770 (shoulder), 745 cm¹.

NMR (CDCl₃), delta: 1.91 (1H, s), 3.7-4.55 (4H, m), 5.79 (1H, d, Js = 8Hz), 6.9-7.85 (13H, tn ), 8.08 (111, d, J = 8Hz), 9.61 (1H, broad s).

Mass: m / e = 456 (MH +)⁺).

[aj q⁵ = 0.99 ° (3.26 mg / ml, ClCl 1)₃).

Example 15 (a) 3.94 rag (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -5-phenyl '2H-1,4-benzodiazepin-2-ol in 4 mL N To a solution of N in dimethyl fortnamide was added 44 mg of sodium hi dide (62 'ο slurry in mineral oil) with stirring at 0 ° C in an ice bath. The reaction mixture was stirred at 0 ° to -5 ° C for 1 hour. 142 mg of 2-methoxyethyl chloride are added

Λ 9 9 · «« «·· · · • 99 9 9 99.

The reaction mixture was stirred at 60-7 ° C for 6.0 hours and then cooled. To the cooled solution was added 0.5 ml of acetic acid, 40 ml of ethyl acetate and 40 ml of water. The organic layer was separated, washed with aqueous carbonate and water, magnesium sulfate dish dried and evaporated · The residue was chromatographed on silica gel eluting with chloroform · 110 mg pure (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- (2- methoxyethyl) -2H-1,4-benzodiazepithi-2-one ·

18 DEG-185 DEG C. (decomposition).

IR (Nujol); 3440, 3275, 1685, 1630, 10000, 1540, 1490 cm¹. NMR (CDC1₃), 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 = 8Hz) ), 9.75 (1H, s).

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

(b) (3R) -1-aoethylmethyl-1,3-dihydro-3- (2-indolyl)

-carbone 1-amino) -5'-phenyl 1-2H-1,4-ten ten-odiazepin-2-one. IR (nujol): 3325, 3250, 1720, 1680, 1630, 1530, 1448,

1375, 740, 695 cm¹.

NMR (DMSO-d₆), delta: 2.16 (3H, s), 4.71 (2H, s), 5.90 (1H, d, J = 7.5H)_Z), 7.0-7.75 (14H, m), 8.09 (111, d, J = 7.5IIz), 10.01 (1H, broad s).

•♦4· ♦

♦ *· &lt; · · * · • ·· · • · · · • «· «·

M / e = 450 (M + H)⁺).

16th example

0.30 g of (3RS) -1,3-dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonyl-1-amino) -5-phenyl-2H-1,4-benzodiazepine 2-one is dissolved in a mixture of 1 ml of anhydrous dimethylsulfoxide and 1 ml of benzene containing 0.056 ml of pyridine and 0.028 ml of trifluoroacetic acid. 0.42 g of dicyclohexylcarbodiiside are added to the solution and stirred at room temperature overnight. insoluble dicyclohexylurea is 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 0.53 g of an oil. This was chromatographed on a silica gel column using chloroform / ethyl acetate (5: 1) as eluent.

1-form 1-methyl-3- (2-indolylcarbonylamino) -5-phenyl-2H-

- 1,4-benzodiazepin-2-one

168 ° C (dec.).

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

1445, 1375, 745, 695 cm¹.

Nuclear Magnetic Resonance Spectrum (CDC1), δ: 4.68 (211, s), 5.90 (1H, d, J = 7.5, 2z), 7.0-7.75 (14Π, m), 8.07 (111, d., J = 7.5 Hz), 9.66 (111, s),

- 58 10.05 (1Η, wide s). Mass: m / s 436 (M +)⁺).

17th example

0.44 (3RS) -1,3-Dihydro-1-formyl-methyl-3 '- (2-indolylcarbonylamino) -5' phenyl-2H-1,4-benzodiazepin-2-one prepared in 10 ml chloroform Methoxycarbonylmethylene triphenylphosphorane (0.37 g) was added to the solution and stirred at room temperature for 2 hours. The reaction mixture was concentrated and the resulting oil was chromatographed on silica gel using chloroform / ethyl acetate (10: 1) as eluent.

64.6 g of (3RS) -1,3 "dihydro-1- (f) (Z) -3-methoxycarbonyl-2-propenyl) -3- (2-indolylcarbonylamino) -5" phenyl-2H ~ -1_t4 'on bezodlazepine-2 was obtained from the upstream fractions. IR (nujol): 3340, 3250, 1718, 1700, 1665, 1637, 1598,

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

NMR (CDC1₃), delta: 3.74 (3H, s), 5.24 (2H, dd, J = 6) and

J = 1.5Hz), 5.86 (1H, d, Js = 8Hz), 5.90 (1H, dt, J = 12.7Hz, and 1.5Hz), 6.21 (1H, dt, J = 17.7Hz and 6Hz), 7.1-7.8 (14H, m), 8.13 (1H, d, J = 8Hz),

9.98 (1H, broad s).

291.1 mg of (3RS) -1,3-dihydro-1 - [(E) -3-wetoxycarbonyl-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 οπΓ¹.

NMR (CDC1₃), delta: 3.64 (3H, s), 4.7-4.82 (2H, m), 5.87 (1H, d, Jc7.5Hz), 5.88 (1H, dt, J = 16 , 5Hz, 1.5Hz), 6.94 (1H, dt, J = 16.5Hz, 4.5Hz), 7.1-7.8 (14H, w), 8.11 (1H, d, J = 7.5Hz), 9.92 (1H, broad s) ·

0.30 g of (3RS) -1-aoethylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one; Hydrazine hydrate (0 mg) was refluxed in THF (5 mL) for 15 hours and evaporated to give 0.30 g of amorphous material. This material (0.30 s) 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 in diisopropyl ether to give (3RS) -1- (2-hydrazonopropyl) -1,3-dihydro-3 '(2-indolylcarbonylamino) 17 g. ) -5-phenyl-2H-1,4-benzodiazepin-2-one as a white powder.

187 ° C (dec.).

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

1450, 1374, 800, 760, 740, 690 cm¹.·

NMR (CDC1₃), delta; 1.53 (3H, s), 4.75 (211, A13q), 5.90 (211, broad s), 5.87 (1H, d, J = 7.5Hz), 7.0-7.75 (1411, w), 8, 16 (111, d, J = 7.5Hz), 9.67 (1H, broad 5). Mass: m / e = 4⁺).

·· · example

0.42 g of (3RS) -1-aoethylmethyl-1,3 "-dibro-3" (2-indolylcarbonylamino) -5-phenyl-2H-1,4 "benzodiazepin-2-one and 62, 5 mg of hydroxylamine hydrochloride was stirred in 20 ml of ethanol at room temperature for 4 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 evaporated to give a pale green oil which was triturated with diisopropyl ether to give (3RS) -1- (2-hydroxy-lminopropyl) -177 mg._r 3“^,dihydro-3 '- (2-indolylcarbonylamino) -5-phenyl-2' * -1,4-benzodiazepln-2-one is obtained.

187 ° C (dec.).

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

1532, 1450, 1375, 802, 765, 740, 695 om¹.

RMR (CDC1₃), delta: 1.63 (3H, s), 4.75 (2H, ABq), 5.00 (1H, broad s), 5.87 (1H, d, J = 7.5Hz), 7.1 -7.8 (14H, m), 8.19 (1H, d, J = 7.5), 10.03 (1H, broad s).

Mass: m / e = 465 (MH +)⁺).

20th example (a) 800 rag (3RS) -1_fFrom 3-Dihydro-3 "(2-indoll1-carbonylamino) -5-phenyl-2II-1,4" benzodiazepln-2-one, 79θ mg

1-trityl-3 ', 6'-methyl-imidazole hydrochloride and 16 ml

For the reaction mixture consisting of 1J, N-dimethylfuramide, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Add in ice bath at 0 ° C

168 mg of sodium hydride (62% suspension in mineral oil) · A. The reaction mixture is stirred at 0-5 ° C for 30 minutes and then kept at 7-08 ° C for 3 hours. To the cooled reaction mixture are added 2.0 ml of acetic acid and 5 ml of 6N hydrochloric acid, and the mixture is stirred at 60 ° C for 1.0 hour. · The cooled solution is poured into a mixture of 100 mL of ethyl acetate and 100 mL of water while stirring. · The organic phase is separated and washed three times with water. dried over magnesium sulfate and evaporated. 4 "imidazolylmethyl) -5" phenyl-211,1,4-benzodiazepin-2-one was obtained.

M.p. 195-100 ° C (dec.).

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

NMR (CDCl3, delta: 4.93 (2H, s), 5.75 (1H, d, J = 811z),

6.78 (111, s), 7.0-7.85 (15H, m), 8.35 (1H, d, J = 8_z), 10.35 (1H, broad s).

Mass: tn / es 474 (M⁺).

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

(b) (3RS) -1,3-Dihydro-3- (2-indolylcarbonyl-1-amino) -1- (4-imidazolylmethyl) -5 '(2-fluorophenyl) ) -2II-1,4 "benzodiazepin-2-one.

Mp: 205-210 ° C (dec.).

NMR (CDCl₃)_t delta: 4.85, 5.10 (2H, ABq, J = 15Hz), 5.80 (1H, d, J = 8Hz), 6.80-7.83 (15H, m), 8.10 (1H , d, J = 8H_Z), 10.10 (1H, bs).

Mass: m / es 492 (M + H)⁺).

(c) (3RS) - 1,3-dihydro-3- (2-indolylcarbony-amino) -

-1- (5-methylimidazol-4'-yl) -ethyl] -5'-phenyl-2H-1,4-benzo4 diazepin-2-one.

205-210 ° C (dec.).

NMR (DMSO-d_She), delta: 1.96 (3H, s), 4.80, 5.15 (2H, ABq, J = 15IIz), 5.55 (1H, d, J = 8Hz), 6.90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz), 11.58 (2H, broad s). Mass: m / es 488 (M + H)⁺).

(d) (3RS) -1,3 "Dihydro-3" (2-indolyl-1-carbonylamino) -1- (2-imidazolylmethyl) -5-phenyl 1-211-1_r4-benzodiazepin-2-one. 175-18 ° C (dec.).

NMR (DMSO-d₆), delta: 5.10 (2Π, s), 5.65 (1H, d, J = 8Hz),

6.60-8.10 (16H, m), 9.36 (111, d, J = 811z),

11.65 (1H, broad s), 11.90 (1H, broad s). Mass: m / e = 474 (MH +)⁺).

(e) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -

-1- (3'-pyrazolyl-ethyl) -5'-phenyl-2H-1,4-benzodiazepin-2-one. 255-260 ° C (dec.).

NMR (DMSO-d_She), delta: 5.03, 5.30 (2Ii, ABq, J = 15Hz), 5.65 (1H, d, J = 81Is), 5.85 (1H, broad s), 6.90-7, 90 • · · · · · · · · ·

- 63 15Η, m), 9.43 (1H, d, J = 8Hz), 11.60 (1H, broad s), 12.55 (1H, broad s) ·

Mass: m / e = 474 (MH +)⁺).

(f) (3RS) -1,3-Dihydro-3- (2-indol-1-carbonylamino) -1 '- (1,2,4-triazol-3-yl) methyl] -5- phenyl-2II-1,4-benzodlazepin-2-one,

Op .: 205-210 (decomposed).

NMR (DMSO-d₆), delta: 5.10, 5.35 (211, ABq, J = 15Hz), 5.66 (1H, d, J = 8Hz), 6.90-7.93 (15H, m), 8.23 (1H, bs), 9.40 (111, d, J = 8Hz), 11.65 (1H, bs) ·

Mass: m / es 475 (M⁺).

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

135-119 ° C (dec.).

NMR (DMSO-d_She), delta: 2.63 (2H, t, J = 7Hz), 3.85-4.20 (111, m), 4.20-4.75 (1H, m), 5.55 (1H, d) , J = 8Hz),

6.6 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 8llz),

11.65 (1H, broad s).

Mass: m / e = 488 (MH +)⁺).

21st example

In accordance with the procedure of Example 14 (a), (3RS) -1,3 "dihydro-3- (2-indolylcarbonyl-awino) -1- (2-hydroxy-1) -5" is prepared. (2-Fluoro-phenyl) -2H-1,1'-benzodiazepin-2-one

<img file="HUT50331A_D0029.tif" />

- 64 TR (nujol): 3240, 1670, 1630, 1530 on¹.

NMR (DMSO-d₆), delta: 3.3Ο-3.9θ (2H, n), 3.90-4.40 (1H, n), 4.70-5.0 (1H, m), 5.70 (1H, d) , J = 8Hz),

6.90-8.0 (13H, m), 9.50 (1H, d, J = 8Hz), 11.50 (1H, broad s).

Mass: m / ea 456 (M + H)⁺),

22nd example

The following compounds were prepared according to the procedure of Example 15 (a):

(a) (3 &amp; amp; S) -1- (2-Acetoxyl-ethyl) -1,3-dihydro-5- (2-fluoro-3-phenyl) -3- (2-indolylcarbonylamino) -2H-1 4-benzodiazθpin-2-one.

NMR (CDC1₃), delta: 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) -1,3-dihydro-3- (2-itidolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2- you.

IR (nujol): 3250, 1730, 1680, 1600, 1530 cm¹.

NMR (CDCl3), delta: 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) '.

(e) (3RS) -1,3-Dihydro-3- (2-indole-1-carboxylic acid) -1- (2-isopropylethyl) -5-phenyl-2H -1 h-benzodiazepin-2-one.

• · · ·· • ·

M.p. 19 ° -193 ° C,

NMR (CDCl₃)_t delta: 0.98 (6H, d, J = 6llz), 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 (1) , J = 8H_Z), 9.66 (1H, broad s).

Mass: m / es 480 (M⁺).

(d) (3RS) -1,3-Dihydro-3- (2-indolylcarbonyl-axnino) -1- (3-methoxy-propyl) -5-phenyl-2H-1,4-benzodiazepin-2-one . Mp 177-175 ° C (dec.),

NMR (CDC1₃), 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 (111, m), 5.73 (1H, d, J = 8Hz), 7.0-7.75 (14H, m), 8.06 (1H, d, J) = 8H_Z), 9.60 (111, broad s).

Mass: m / e = 466 (MH +)⁺).

(e) (3RS) -1,3-Dihydro-3- (2-indol-1-carboxylic acid) -

- 1- (2-thienylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one.

165-17 ° C (dec.).

NMR (CDC1₃), delta: 5.0, 5.67 (211, ABC, J = 15IIz), 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 / es 490 (M⁺).

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

15 DEG-155 DEG C. (dec.).

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

NMR (CDCl /₃δ delta: 4.96, 5.33 (2H, ABq, Je 15Hz), 5.83 (1H, d, JkBHz), 6.20 (2H, s), 6.95-7.75 (15H, n) ), 8.10 (1H, d, J = 8Hz), 9.90 (1H, broad s).

Mass: m / e = 474 (M +).

(g) (3RS) -1,3 * -Dihydro-3- (2'-methylol-carbonyl-anino) -1- (2-ethoxy-ethyl) -5-phenyl-2H-1,4'-benzodiazepine -2-one.

Mp: 205-210 ° C (dec.).

NMR (GDC1₃), 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), 7.05-7.80 (1411, m), 8.10 (1H , d, J = 8H_Z), 9.90 (1H, bs).

(h) (3RS) -1,1-Dihydro-3- (2-indol-1-carbonyl-1-amino) -1- (2-ethoxyethyl) -5- (2-fluorophenyl) - 2H-1,4-benzodiazepin-2-one.

Melting point: 23 DEG-235 DEG C. (decomposition).

NMR (CDC1₃), delta: 3.20 (j1, s), 3.40-3.75 (2H, m),

3.80-4.16 (1H, m), 4.20-4.55 (1H, m), 5.76 (1H, d, J3Hz), 6.90-7.80 (13H, m), 8.10 (1H, d, Jt = 8Hz), 9.95 (1H, broad s).

Mass: m / o 470 (M + H)⁺).

(i) (3RS) -1,3-Dihydro-3 '- (2-indolylcarbonylamino) -

-1- (2-acetamido-thiazol-4-yl) methyl -5'- phenyl -211-1,4-benzodlazepin-2-one,

175-110 ° C (dec.).

· * «

HMR (CDC1₃), delta: 1.93 (3H, s), 4.83, 5.30 (2H, ABq,

J = 15Hz), 5.85 (1H, d, J = 8Hz), 6.53 (1H, s),

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

(k) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (2-bromo-6'-ethyl) -5'-ethyl-2H-1,4-betisodiazepine 2-one. NMR (CDC1₃), delta: 3.30-3.70 (2H, m), 3.85-4.40 (1H, m),

?, 60-5.20 (1H, m), 5.83 (1H, d, J = 8Hz), 7.0-7.90 (14H, m), 8.15 (1H, d, J = 8Hz), 70.05 (1H, s).

(1) (3HS) -1,3 "Dihydro-1- [2- (2-tetrahydropyranyl) -3-OXO-2,3" dihydroisoxazole-5-yl] methyl "-3" (2-indolylcarbonyl) -aEnno) -5-phenyl-1,4-benzodiazepin-2-one. IR (nujol): 3260, 1700, 1682, 1630 cm "¹.

NMR (CDC1₃), delta: 1.3-2 (6H, m), 3.5-4.2 (2H, m),

4, θ-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).

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

&gt; 260 ° C, im (mole): 3350 (shoulder), 3290, 1668, 1630, 1596, 1530, 1445, 1374, 1324, 1240, 1215, 1110, 910, 759, 690 cm¹.

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

- 68 NMR (CDCl₃), delta: 3.10 (3H, s), 3.45-3.75 (2H, m),

3.80-4.53 (2H, m), 5.77 (1H, d, J = 8.0Hz),

6.9-7.7 (13H, m), 8.12 (1H, d, J = 8.0Hz), 10.26 (1H₍ sharp s).

Mass: m / e = 487 (MH +)⁺).

(ti) (3RS) -1,3 "dihydro-3" [(5 "methoxyindol-2-yl) carbonyl-1-amino] -5-phenyl-1- (2-methoxyethyl) - 2H-1,4-benzodiazepl n-2-one ·

M.p. 22-222 ° C.

TR (nujol): 3400 (shoulder), 3250, 1673, 1630, 1596, 1530, 1447, 1375, 1322, 1235, 1115, 1024, 842, 802, 762, 694 cm¹.

NMR (ODC1₃), delta: 3.11 (3H, s), 3.45-3.75 (2H, m),

3.82 (311, s), 3.80-4.55 (211, m), 5.78 (111, d, J = 8.0Hz), 6.75-7.7 (13H, m), 8.04 (111, d, Jts8, CH2), 9.9θ (1H, broad s).

Mass: m / e = 4θ2 (M +)⁺).

(o) (3RS) - 1- (3-Bromo-propyl) -3- (2-indol-1-carbonyl-amino) -5-phenyl-1,3-dihydro-2H-1 , 4-benzodiazepin-2-oti.

TR (nujol): 3400 (shoulder), 325θ, 1675, 1633, 1600, 1530, 1445, 1375, 1242, 800, 742, 692 om¹.

NMR (CDC1₃), delta: 1.8-2.3 (2H, m), 2.95-3.4 (211, m),

3.8-4.75 (1H, dt, J = 13.8Hz, 6.6Hz), 4.35-4.65 (1H, dt, J = 13.8Hz, 6.6Hz), 5.77 ( 1H, d, J = 8Hz), 7.0-7.7 (14H, tn), 8.15 (1H, d, J = 811z), 9.97 (111, broad s).

23rd Example 3 (3RS) -1,3-Dihydro-3- (2-dihydro-1-carbonyl-1-amino) -1- (2-acetamidothiazol-4-yl) methyl] - The reaction mixture of 5'-phenyl-2H-1,4-benzodiazepin-2-oneb61, 13 ml of methanol, 8 ml of tetrahydrofuran and 0.8 ml of concentrated hydrochloric acid was stirred for 7.0 hours at 7θ ° C, cooled and aqueous sodium bicarbonate solution to pH7.0. 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-r (2-aminothiazole). 4'-yl) -methyl] -5-phenyl-2H-1,4-benzodiazepin-2-one is obtained.

M.p. 2000-250 ° C (dec.).

iam (DMSO-d₆), delta: 4.80, 5, θ6 (2H, ABq, J = 15Hz), 5.60 (1H, d, J = 8llz), 6.06 (1H, s), 6.75 (2H, broad s), 6.90-7.95 (14H, m), 9.40 (1H, d, J = 8). Mass: m / ee 5θ6 (M +)⁺).

24th (a) 0.47 g of (3RS) -1,3-dihydro-3- (2-indolylcarbonylaraino) -1 - ((E) -3-methoxycarbonyl-2-propenyl) -5 " phenyl-2II-1,4 "benzodiazepine-2-tin, 15 ml tetrahydrofuran

The reaction mixture, consisting of 7.5 ml of methanol and 1 ml of aqueous sodium hydroxide solution, was stirred at room temperature for 1.0 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 tin 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 of (3RS) -1,3-dihydro-3 '- (2-indolylcarbonylamino) -1 - [(E) -3-carboxyl-2-propenyl-5' phenyl-2H-1, 4-Benzodiazepin-2-one is obtained. 175-18 ° 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). , 6.90-7.90 (15H, m), 9.55 (1H, d, J = 8), 11.58 (1H, broad s).

Mass: m / es 47θ (M⁺).

(b) According to the above procedure, (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1-l (Z) -3-carboxy-2-propenyl] -5- phenyl-2H-1,4-benzodiazepin-2-one.

23 DEG-235 DEG C. (dec.).

NMR (DMSO-d₆), delta: 5.12 (211, d, J =, 4Hz), 5.68 (111, d, J = 8Hz), 5.75-6.30 (1H, m), 6.95-. 7.90 (15H, m), 9.55 (1H, d, J = 8Hz).

Mass: m / e = 478 (MH +)⁺).

···· · ···· ·· ·· • ·· · · · · • · · ·· · • · 4 · 4 9 9

999 9 99 99

25th example

0.3 g of (3RS) -1,3-dihydro-3 '- (2' indolylcarbonylamino) -1- (2-bromoethyl) -5-phenyl-2H-1,4 'benzodiazepine-2 and 3.0 ml of 1-wetylpiperazine were stirred at room temperature for 4.0 hours and then 20 ml of diisopropylether were added. The precipitate was collected by filtration and dissolved in dilute hydrochloric acid. The solution was adjusted to pHss7 with aqueous sodium bicarbonate solution and the precipitate was collected by filtration (0.20 g of (3RS) -1,3-dihydro-3- (2-yolinolylcarbonylamino) -1- [2- ( 4-methyl-1-piperazinyl) ethyl-5-phenyl-2H-1,4-benzodlazepin-2-one is obtained.

135 - 14 ° C (dec.).

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

NMR (cr) Cl₃), delta: 2.0-2.70 (13Π, m), 3.60-4.10 (1H, m),

4.30-4.90 (1H, Ei), 5.83 (1H, d, J = 8Hz), 7.0-7.90 (14H, m), 8.20 (111, d, J = 8Hz) ), 10.10 (1H, bs).

2h. example in ml ethanol 0.5 s (3RS) - 1-formylmethyl-3 '

- (2-Indyl-1-carcinone-1-amino) -5-phenyl-1,3-dilyl-dro-2H-1,4-benzodiazepin-2-one and 144.1 mg of methoxyamine -hydrochloride was stirred at room temperature for 3 hours. After removal of the solvent, ethyl acetate and a dilute aqueous sodium bicarbonate solution were added to the residue.

··«'« • ·· · · · · · • · · ·· · • «······ &gt; ·· ··· · ·· ··

The organic layer was washed twice with water and dried over magnesium sulfate. After removal of the solvent, 0.5 g of an amorphous material remained, 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.

IR (nujol): 3400 (shoulder), 3.00, 1690, 1640, 1600, 1535, 1490, 1450, 1379, 1040, 850, 820, 772, 747, 699 cm ¹.

NMR (CDC1₃), delta: 3.72 and 3, θ7 (3H, each s),

4.6-4.7 and 4.75-4.85 (2H, each dd, J = 5.4Hz, 3i2), 5.80 (1H, d, J = 8Hz), 6.62 and 7.05 (1Π, each t, ​​J = 5.4Hz), 7.07-7.7 (14H, in), 8.03 (1H, d, J = 8Hz), 9.78 (1H, broad s).

Mass: m / es 465 (M⁺).

27th example

212.9 mg (3RS) -1,3-dihydro-1- [[2- (2-tetrahydropyranyl) -3-oxo-2,3-dihydro-isoxazol-5-yl] -αιβΐ11) · -3- (2-ind to a slurry of oilylcarbonyl-anino) -5-phenyl-1,4-benzodiazepine-n-2-one in 4 ml of methanol at room temperature • ♦ »1 ·

Λ • • · «« t t t t t · · · · · ·

- 73 ml and 2N hydrochloric acid are added with stirring. 1 ml of tetrahydrofuran is added to the reaction mixture to give a clear solution which is 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, (149.1 mg. -methylj -3 "(2-indole 1-carbonyl-1-amino) -5-phenyl-1,4-benzodiazepine-2-one as a yellow powder ·

Mp 20 ° C (decomposition) ·

NMR (DMSO-d₆), delta: 5.24 (211, ABq, J = 15Hz, 25.5Hz),

5.67 (1H, d, J = 8Hz), 5.70 (1H, s), 7.0-7.85 14H, m), 9.52 (111, d, J = 8Hz), 11.61 (1H, wide s) ·

Mass: ra / e = 491 (M⁺)·

28th example

The following compounds were prepared according to the procedure of Example 15 (a):

(a) (3RS) -1- [2- (2-Chloroethoxy) ethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5'-phenyl-2II-1,4- benzodiazepin-2-one.

NMR (CDC1₃), delta: 3.20-4.60 (811, m), 5.80 (1H, d,

Jss8llz), 7.0-7.80 (14H, tn), 8.15 (111, d, J = 8Hz), 10.20 (111, broad s).

··· ♦ · ·· «· · · ················································· (b) 3RS) - 1- (2-Vinyloxy-ethyl) -1,3-dlhydro-3- (2-indolylcarbonylamino) -5'-phenyl-2H-1,4^-benzodiazepin-2-one.

M.p. 21 DEG-215 DEG C. (dec.).

UMR (CDC1₃), 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 = 8llz)_f 9.53 (1H, broad s).

Mass: m / es 464 (M + H)⁺).

(o) (3RS) -1- (2-Benzyloxyethyl) -1,3-dihydro-3- (2-indyl-1-caxyloxycarbonylamino) -5-phenyl 1-2II - 1,4 ** benzodiazepine on n-2-one.

195-200 ° C (dec.).

NMR (CDCl₃), delta 3.55-3.80 (211, m), 3.80-4.20 (1H, m), 4.20-4.55 (1H, m), 4.30 (2H, s) ), 5.75 (1H, d, J = 81), 6.96-7.80 (14H, m), 8.06 (1H, d, J = 8_Z), 9.95 (Hi, broad s).

(d) (3RS) -1- (3,4-Dimethoxybenzyl) -1,3-dihydro-3- (2-indole-1-carbonyl-1-amino) -5-phenyl-1- 2H-1,4-benzodiazepine-2-one

220-225 ° C (dec.).

TR (nujol): 3300, 3200, 1680, 1635, 1590, 1525, 1505 cm¹.

NMR (CDC1₃), delta: 3.40 (311, s), 3.75 (3H, s), 4.7 ^ 5.75 (2II, ABq, Js15Hz), 5.90 (111, d, Jx = 8llz),

<img file="HUT50331A_D0030.tif" />

- 75 6.45-6.65 (3Η, 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-

- (2-1-Ndolylcarbonyl-1-amino) -5-ethyl-1-2H-1,4-benzodiazepin-2-one.

(f) (3RS) -1-Benzyl-1,3-dihydro-3- (2-inolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one.

145 - 15 ° C (dec.).

IR (nujol): 3250, 1680, 1635, 1600, 1530 cm¹.

NMR (CDC1₃), delta: 4.88, 5.68 (211, ABq, J = 15Hz), 5.93 (1H, d, J = 5Hz), 7.0-7.80 (19I-I, m), δ , 25 (1H, d, J = SH2), 10.08 (1H, broad s).

Mass: m / e = 4θ4 (M +)⁺).

(g) (3RS) -1- (2-phthalimidoethyl) -1,3-dihydro-3- (2-

-1-indolylcarbonyl-1-amino) -5-phenyl-1-2H-1,4-benzodiazepthi-2-one. IR (nujol): 3400, 3250, 1770, 1712, 1678, 1646 cm¹.

NMR (DMSO-d₆), delta: 3.6-4.8 (4H, m), 5.60 (1H, d, J = 8Hz), 7.0-8.0 (18H, m), 9.50 (1H, d) , J = 8llz), 11.45 (1H, broad s).

(h) (3RS) -1- (2-Methylthioethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2 -οη. M.p. 149-156 ° C.

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

1445, 1375, 1320, 740, 690 cm¹.

NMR (CDC1₃), delta: 1.98 (3H, s), 2.63 (2H, t, J = 7.5Hz),

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

J = 13.5Hz, 7.5Hz), 5.80 (1H, d, J = 8.4Hz), 7.0-7.8 (1Z, 1H), 8.11 (1H, d, J = 8 , 4Hz), 9.93 (1H, broad s).

Weight: m / ea 469 (M) ·

29th example

287 mg (3BS) -1- (3,4-diacetoxybutyl) -1,3-dihydro-3- (2-indol-1-carbonyl-1-amino) -5-phenyl-1-2II-1, A reaction mixture of 4 "benzodiazepin-2-one, 5 ml methanol, 5 ml tetrahydrofuran, 1 ml water and 5 ml 1N aqueous potassium carbonate was stirred for 1 hour at 0 ° to 5 ° C and then stirred at pH 6 with 6N hydrochloric acid. pII = 1-2. While stirring, 5θ ml of ethyl acetate and 50 ml of water are added. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with chloroform / ethyl acetate (4: 1). 155 mg of (3RS) -1- (3,4-dihydrobenzyl) -3 "- (2-indol-1-carbonylamino) -5-phenyl-1-2II-1,4" benzodiazepin-2-one are obtained.

165-17 ° C (dec.).

NMR (CDCl₃-DMSO-d₆), delta: 4.75, 5.35 (2H, ABq, J = 15Hz),

5.75 (1H, d, J = 8Hz), 6.20-6.60 (3H, m), 6.90-7.70 (14H, m), 8.35 (2H, broad s), δ , 96 (1H, d, J = 811z), 11.46 (1H, broad s).

Mass: l / ee 516 (1I⁺).

····

- 77 Example 30

To a mixture of 792.1 g of carbon tetrachloride in 20 ml of methylene chloride is added, while stirring and at room temperature, 2.70 g of triphenylphosphine, followed by 0.90 g of (3RS) -1-fortnylmethyl-1,3-dihydro-3- (2-indolyl- carbonylamino) -5-phenyl-2H-1,4-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 and evaporated to give a red oil which was chromatographed on a silica gel column eluting with 20: 1 chloroform / ethyl acetate. The fractions containing the desired material were combined and evaporated to dryness to give 0.20 g of a glass which was pulverized in diisopropyl ether. 138.8 mg of (3RS) -1-3.3 "dichloro-2-propenyl) -1,3" dihydro-3 "(2-indolylcarbonylamino) -5-fetyl-211-1,4-benzodiazepine Received -2 ​​as a yellow powder.

149-152 ° C (dec.).

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

1378, 742, 694 cm "¹.

NMR (CDC1₃), delta: 4.53 (1H, dd, J = 15Hz, 7.2Hz), 4.77 (1H, dd, J15HZ and 7.2Hz), 5.93 (1H, 'dd, J = 7, 2IIz and 7, θΗζ), 5.77 (1H, d, J = 7.8Hz), 7.0-7.7 (14Π), 7.99 (1Π, d, J = 7.8Hz) .

9.67 (1H, broad s).

···· · ···· ·· ·· • · · · · · · • · · · * ·

Mass: m / e = 5θ3 (M +)⁺).

31st example

Preparation of (3RS) -1- [2- (2-hydroxy-ethylamino) -ethyl] -1,3-dihydro-3- (2-indyl-1-carbonylamino) -5 "as described in Example 25 · phenyl-2H-1,4-benzodiazepin-2-one ·

125-130 ° C (dec.).

TR (Nujol): 3250, 1680, 1630, 1600, 1535 cm¹. NMR (CDC1₃), 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 = 811z), 10.20 (1H , wide s).

32nd example

700 tng (3RS) -1- {2- (2-Chloroethoxy) -ethyl] -1,3-dihydro-3- (2-indole-1-carbonyl-1-amino) -5-phenyl-1 The reaction mixture, consisting of 2II-1,4-benzodiazepin-2-one, 610 mg of potassium oxaphthalimide and 5 ml of N, NdItylformers, is refluxed for 7 hours at 80-9 ° C. The reaction mixture was poured into 100 ml of cold water and extracted with ethyl acetate. The extract extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS) -1- [2- (2-phthalimidoethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonyl) 0.9 g. amino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

···· · ···· ·· · · • · · · · · · • · « · · ·

- 79 33 · Example

500 mg of (3RS) -1- [2- (2-chloroethoxy) ethyl] -1,3-dihydro-3 '- (2-indol-1-carbonylamino) -5-phenyl-2H-1,4' - Benzodiazepin-2-one was stirred in 5.0 ml of 1-methylpperazine at 70 ° C for 5.0 hours, then 30 ml of diisopropyl ether was added to the reaction mixture. The resulting precipitate was filtered off and the filtrate was evaporated. and dry it, 0.43 g of (3RS) -1- [2- (2- (4'-methyl-1-piperazinyl) ethoxy] ethyl] -1,3 '-dihydro-3- (2-indole-1-carbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

100-105 ° C (dec.).

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

NMR (CDC1₃), delta: 2.15-2.60 (13H, m), 3.35-4.50 (6H, m),

5.80 (1H, d, J8Hz), 7.0-7.85 (14H, m), 8.15 (1H, d, J = 8H)_Z), 10.10 (1H, bs).

Mass: m / e = 564 (MH +)⁺).

34th Example (a) 1.04 g of (3RS) -1- (2-phthalimidoethyl) -1,3 "dihydro-3- (2-indolylcarbonylanino) -5" phenyl-2II-1,4- Benzodiazepin-2-one and I30 me hydrazine hydrate were stirred in 10 N, N-dimethyltinnamide for 3 hours at 70 ° C, followed by addition of 130 mg hydrazine hydrate. The reaction mixture was heated at 80 ° C for 12.5 hours. THE

The extract was washed with water, dried, and the solvent was evaporated under reduced pressure to give 1.03 g of a viscous oil which was chromatographed on a silica gel column with chloroform / methanol (50: 1). The fractions containing the desired material were combined and evaporated to give (3RS) -1- (2-aminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H (0.76 g). Obtained as 1,4-benzodlazepi n-2-one as an oil, stirred in ether overnight to give the product as a crystalline powder of 456.2 grams.

IR (nujol): 3260, 1690, 1660, 1620 cra "¹.

NMR (CDC1₃), 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 (1Π, wide s).

(b) According to the above procedure, (3RS) -1- [2- (2-aminoethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonyl-1-atnino) ~ 5 is prepared. Phenyl-2H-1,4-benzodiazepin-2-one · m.p. 130-135 ° C (dec.).

TR (nujol): 3250, 1680, 1640, 1600, 1540 cm¹.

NMR (CDC1₃), delta: 2.30 - 2.80 (211, 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 (MH +)⁺).

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

81 Example 35

0.66 g of (3R) -1,2-((2R) -2-tert-butoxycarbonylamino) -2-benzhydryloxycarbonyl-ethylthio) ethyl] -1,3 "-dihydro -3- (2-Indolylcarbonyl-1-amino) -5 "phenyl-2 H -1,4" benzodiazepin-2-one and (3 S) -1- (2 - ((2 R) -2-ter butoxycarbonyl-amino-2-benzhydryl-oxycarbonyl-1-thio) -ethyl] -1,3-dihydro-3- (2-indolylcarbonyl) -amino) -5 " phenyl-2II-1,4-benzodiazepin-2-one, 0.6 ml anisole,

The reaction mixture, consisting of 1.5 tl of trifluoroacetic acid and 15 ml of dichloromethane, was stirred at room temperature for 3.0 hours. After removal of the solvent, the residue was stirred in ethyl acetate (5 ° C) 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 "- (2R) -2-amino-2-carboxyethylthio) ethyl] -1,3" dihydro ~ 3 "(2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1-f2 - ((2R) -2-amino-2-carboxyethyl). thio) -ethyl-1,3-dihydro-3- (2-indole-1-carbonyl-1-amino) -5-phenyl-1-2II-1,4-benzodiazepin-2-one.

190-195 ° C (dec.).

NMR (CDC1₃ + 001), delta: 2.60-3.10 (4'H, m), 4.0-4.40 (211, m), 4.60-5.0 (1H, m), 5.96 (1H, s), · · · ·

6.65-8.15 (14Η, m).

Mass: m / es 541 (M + H)⁺).

36 · example

350 mg of (3RS) -1- N - (ethoxyl-carbonylmethyl) carbamoyl-ethyl] -1,3-dihydro-3- (2-indolylcarbonyl) amino-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 4.0 hours, then 50 ml of water and 5θ ml of ethyl acetate were added.

<img file="HUT50331A_D0031.tif" />

hydrochloric acid is adjusted to pII = 1-2. 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) carbamoyltaethyl-1,3-dihydro-3 '(2-indole-1-carbonylamino) -5' phenyl (204 mg). 2II-1,4-benzodiazepin-2-one was obtained.

170-175 ° C (dec.).

NMR (DMSO-d₆), delta: 3.77 (211, d, J = 5Hz), 4.65 (2Η, s),

5.73 (1H, d, J = 8llz), 6.9-7.80 (1411, m), 8.5c (1H, tri, J = 5Hz), 9.45 (1H, d, J188z), 11.65 (111, broad s).

37th example (a)

452 g (3RS) -1-Icarboxymethyl 1-1,3-dihydro-3- (2 ~

-indolyl-carbonyl-amino) -5-phenyl-1-2H-1,1'-benzodiazep⁴n ·· ·· ·· · · · · · · · · · · · · ·

To a reaction mixture of -2-tin, 135 mg of 1-hydroxybenzotriazole and 5 ml of N, N-dimethylformate at 20 ° C was added 206 mg of N, N * -dicyclohexylcarbodylmide under stirring. The reaction mixture was stirred for 1.0 hour at room temperature and then 74 mg of glycinamide hydrochloride and 120 mg of triethylamine were 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 to give 180 mg of (3RS) -1- [1-carbacoylthetyl) carbanoylmethyl] -1,3-dihydro-3 '- (2-indolylcarbonylamino) -5. -phenyl-2H-1,4 "benzodiazepin-2-one. TH (nujol): 3270, 1680, 1665, 1630, 1600, 1540 cm¹. NMR (DMSO-d_She), delta: 3.65 (211, d, Js5IIz), 4.65 (211, s),

5.73 (1H, d, J = 8Hz), 6.90-7.80 (14H, m), 8, b (&amp; gt; (1H, t, J = 5Hz), 9.48 (1H, d, J = 8Hz), 11.65 (1H, s).

Mass: m / e = 508 (M + H)^h).

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

(b) (3RS) -1-N- (Ethoxycarbonylmethyl) carbamoylmethyl-1,3 "dihydro-3" (2-indolylcarbonylamino) -5-phenyl-2H-1,4 benzodiazepin-2-one.

(c) (3R) -1-HT - ((1S) -1-Carbamoyl-2-phenylethyl) -carbamoylmethyl-1,3 "dihydro-3" (2-indolylcarbonyl-awino) • · · «

- 84 -5-phenyl-2H-1₁4-Benzodiazepin-2-one and (3S) -1-CN - ((1S) -1-carbemol-2-phenylethyl) carbamoylmethyl] -1,3-dihydro-3- (2-indole) -carbonyl-amino) -5 * -phenyl 1-2H-1,4-benzodiazepin-2-one ·

Mp: 165-17 ° C (dec.).

TR (nujol): 3230, 1680, 1650, 1600, 1525 cttT¹.

NMR (DMS0-d₆), delta: 2.65-3.20 (2H, m), 4.30-4.90 (3H, m),

5.67 (1H, 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 / ec 598 (M + H)⁺).

38th example

1.53 g of (3RS) -1-carboxymethyl-1,3-dihydro-3- (2-indol-1-carbonyl-axnino) -5-phenyl-1,2-one-1,4 "benzodiazepine- 2- in 30 ml of ethylene chloride. To the slurry of the suspension prepared under 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 cyanoamine and 0.42 g of triethylamine in 20 ml of ethylene chloride is added with stirring at room temperature, 5 g of the powder obtained above. The reaction mixture was stirred for 2 hours at room temperature, oil

<img file="HUT50331A_D0032.tif" />

add 5θ ml of methylene chloride and wash with dilute hydrochloric acid and wash with water. After drying over magnesium sulfate, the organic phase is concentrated under reduced pressure. The residue is chromatographed on a silica gel column, eluting with ethyl acetate / n-hexane / acetic acid (2: 1: 0.1). The resulting product was stirred in ether to give 0.14 g of (3RS) "1" [N- (cyano) -carbamoylmethyl] -1,3 "dihydro-3- (2-indolylcarbonyl-1-amino) -5" phenyl 1-2II-1,4-benzodiazepin-2-one is obtained in the form of a pale orange powder.

225-260 ° C (dec.).

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

1305 by 745 cm "¹.

NMR (DM50-d_She), delta: 4.77 (2Π, s), 5.75 (1H, d, J = 8Hz), 7.0-7.9 (14H, m), 9.52 (1H, d, J = 8Hz) ), 11.50 (1H, broad s),

39th example

0.52 g of (3RS) -1- (3-bromopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5'-phenyl-2H-1,4-benzodiazepine-2- to a solution of 3 ml of 1 N, N-dimethylformamide in dichloromethane is added a solution of sodium methoxylate in methanol, prepared from a solution of 0.48 g of methanol 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.

<img file="HUT50331A_D0033.tif" />

With stirring, the reaction mixture is poured onto water containing a few drops of acetic acid. / with an ethyl acetate, Eluting with 20: 1 · The resulting 330 mg glass was stirred in diisopropyl ether overnight to give 248.1 g of (3RS) -1- (3'-methylthiopropyl) -1,3-dihydro-2- (2- Indole 1-carbonyl-1-amino) -5-phenyl-2 '-1,4'-benzodiazepin-2-one is obtained in the form of a white powder.

M.p. 216-221 ° C.

IR (nujol): 3430, 3260, 1673, 1638, 10000, 1532, 1450,

1375, 1270, 800, 778, 739, 695 cm "¹.

NMR (GDC1₃), delta: 1.7-2.0 (211, m), 1.9 (3H, s),

2.25-2.45 (2H, m), 3.7-4.0 (111, dt, J = 13.8Hz, 6.6Hz), 4.4-4.7 (1H, dt. J = 13.8Hz, 6.6Hz),

5.83 (1H, d, J = 7, SH2), 7.1-7.8 (14H, m), 8.17 (1H, d, J = 7.8IIz), 10.01 (11i, broad s). Mass: m / e = 4θ2 (M +)⁺).

Example 4θ (a) (3RS) -1- (2-Bromoethyl) -1,3-dihydro-3- (2-indol-1-carbonyl-1-amino) -5'-phenyl-2II-1 (501 mg). , 4-benzodiazepin-2-one, -, 12 g of triethylamine, 0.13 mg of 4-mercaptopyridine and 6 ml of 1,1', N-dimethylformamide. ··· · «· · · · · · · · · ·

The mixture 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-indolylcarbonylamino) -5" phenyl-2H-1, 4-Benzodiazepin-2-one is obtained.

Melting point: 15 DEG-155 DEG C. (decomposition).

IR (nujol): 3230, 1680, 1630, 1600, 1570, 1530 cm¹. NMR (CDCl₃)_t delta: 3.0-3.30 (2H, m), 3.70-4.10 (1H, m),

4.40-4.80 (1H, ra), 5.80 (1H, d, J = 8llz), 7.0-7.80 (16H, m), 8.10 (1H, d, J = 8Hz) ), 8.25-8.45 (2H, m), 10.05 (1H, broad s). Mass: ια / e = 531 (M⁺).

(b) According to the above procedure, (3R) -1- [2 - ((2R) -2-tert-butoxycarbonylamino-2-benzhydryloxycarbonyl-ethylthio) -ethyl] -1- , 3-Dihydro-0-3- (2-indyl-1-carbonylamino) -5-fetyl 1-211-1,4-benzodiazepine-2-tin is the major source of (3S) -1-f2 - ((2R) -2-tert-Butoxycarbonylamino-2-benzhydryloxycarbonyl-ethylthio) -ethyl] -1,3 "dihydro-3" (2-methyl-1-carbonyl-1-anino) -5- a mixture of enyl-211-1,4-benzodiazepine-2-tin.

NMR (CDC1₃), delta; 1, Ζ | Ο (911, s), 2.20-3.10 (4H, τη),

3.50-4.0 (1H, m), h, 20 -, 70 (2H, ni),

<img file="HUT50331A_D0034.tif" />

t

5.15-5.45 (1H, m), 5.80 (1H, d, J = 8Hz), 6.90 (1H, s), 7.10-7.85 (24H, m), δ, 15 (1H, d,

J = 8Hz), 9.75 (1H, broad s).

41 «Example

434 mg of (3RS) -1- (2-arainoethyl) -1,3-dihydro-3 '- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and To a solution of 222 mg of triethylamine in 4 ml of methylene chloride was added dropwise 172.8 mg of acetyl chloride under 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 g of a brown oil which was chromatographed on silica gel eluting with chloroform / methanol (30: 1). The fractions containing the desired material were combined and evaporated. The resulting amorphous material was pulverized with ether overnight. The crystalline powder was collected by filtration, washed with ether, 327.1 mg of (3RS) -1- (2-acetylaminoethyl) -1,3 "dihydro-3" (2-indolylcarbonylamino) -5 "phenyl -2H-1,4-benzodiazepin-2-one.

167-175 ° C (dec.).

TR (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 ts 479 (MH +)⁺)_e

42 · example

1.0 g of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-211-1,4-benzodiazepin-2-one and 1.28 g of 1-trityl-4 To a suspension of 25-chloroethylimidazole hydrochloride in 25 ml of N, N-dimethylformamide was added 0.36 g of sodium hydride (40'a suspension in oil) under ice-bath cooling and stirring, followed by stirring for 1 hour. After addition of 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 thus obtained was chromatographed on a silica gel column, eluting with chloroform / ethyl acetate (20: 1). 1.3θg of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3'-phthalimido-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepine We receive 2 ·

NMR (DI-lS0-d_She), delta: 5.08 (211, ABq), 5.75 (1Π, s),

6.7-7.7 (2911, m).

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

43 · example

19.96 g of (3RS) -1,3 "dihydro-5- (2-fluorophenyl) -3" phthalitnido-1- (1-trityl-4 "imidazolyl) methyl-2II-1,4" - To a suspension of benzodiazepin-2-one in 200 ml of tetrahydrofuran is added a solution of 1.38 &amp; hydrazine hydrate in 10 ml of methanol. The reaction mixture was cooled in an ice bath, the precipitate was filtered off, and the filtrate and washings were concentrated under reduced pressure. The residue was dissolved in chloroform and the mixture was filtered. The filtrate was concentrated to give an oily residue (19.30 g) which was chromatographed on silica gel using chloroform / methanol (30: 1) as eluent. 9.97 g of (3RS) -1,3-dihydro-5 '- (2-fluorophenyl) -3-atenyl-1- (1-trityl-3' imidazolyl) methyl-2II-1 4-Benzodiazepin-2-one is obtained.

NMR (CDC1₃), delta: 2.42 (2H, broad s), 4.49 (1H, s),

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

Example 44 (a) 591.7 mg of (3RS) -1,3 "dihydro-5" (2-fluorophenyl) -3-amino-1- (1-trityl-4 "imidazolyl) methyl-2H- To a solution of 1,4 "benzodiazepin-2-one in 2 ml of ethyl acetate at room temperature was added 129.3 mg of (s) - (+) - nandulic acid in h ml of ethyl acetate under stirring, λ • · ·

- 91 "precipitated gel was added to the solution by adding 0.2 ml of methanol. · 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) -methyl-2H-1,4-benzodiazepln-2-one as the crystalline salt of (S) - (+) - manic acid.

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

From the filtrate, (3 H) -1,3-dihydro-5 '- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2 H -1,4-benzodiazepine-2 and (3^s) A mixture of ~ 1,3-dihydro-5- (2'-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2 '-1,4-benzodiazepin-2-one is obtained. .

(b) The (3S) -1,3 ”dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) -methyl-1-2ΙΙ-1 prepared above, The (S) - (+) - mandelic acid salt of 4-benzodiazepin-2-one is suspended in a mixture of water and ethyl acetate. The pH of the resulting mixture was adjusted to p1 = 7-8 with stirring with aqueous sodium bicarbonate. The organic phase was separated, washed with water and evaporated to dryness to give 181.4 mg (38) - 1,3-dihydro-5- (2-fluorophenyl) -J-99 ······ ··· · · · • · · ·

yielding amino-1- (1-trityl-4'-imidazolyl) methyl-2H-1,4-benzodiazepln-2-one.

[.alpha.] D @ 25 = -35.34 DEG (O = 0.846 in methanol).

Example 45 (a) 1.57 g of (3R) -1,3 "dihydro-5" (2-fluoro-f_enyl) "3-amino-1- (1-trityl-4" -iridazolyl) methyl-2H-1,4-benzodiazepin-2-one and (3S) -1,3-dihydro-5- (2-fluoro- fen.il) -3-

- which is a mixture of no-1- (1-trityl-4-iraidazolyl) methyl-2II-1,4-benzodiazepin-2-one ([α] D = + 14.4 °), ), dissolved in a mixture of 5.3 mL of ethyl acetate and 0.5 mL of methanol. To the solution was added 34 [mu] g of (R) - (-) - mandelic acid in 20 ml of ethyl acetate with stirring at room temperature. To the reaction mixture was added diisopropyl ether (0.5 mL), stirred for 2 hours, and allowed to stand overnight. The precipitate was collected by filtration, washed with ethyl acetate and diisopropylether, closed as a white powder.

685.6 mg of (3R) -1,3 "dihydro-5- (2-fluorophenyl) -3-amino-1-

The (R) - (-) - mandelic acid salt of (1-trityl-4 'iraidazolyl) methyl-2' -1,4-benzodiazepin-2-one is obtained.

[α] D = + 33.60 ° (o = 0.848, methanol).

(b) A (3R) -1,3 "Dihydro-5" (2-fluorophenyl) -3 "aratno-1- (1- trieth 1-4" imidazole 1) -methyl 1-211-1 4-Benzodiazepin-2one is prepared as described in Example 44 / b.

-1,3-Dihydro-5 "(2-fluoro-ene 1) -3" -amino-1- (1-thiazol-4-imidazolyl) methyl-2H-1,4 "benzodiazepine-2 on (R) - (-) - mandelic acid salt.

[α] 22 D + 37.91 ° ​​(o = 0.844, methanol).

46th example

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

(a) (3S) -1,3-Dihydro-1- (1-trityl-4 "imidazolyl) -tneyl-3- (2-indol-1-carbonyl 1-amino) -5" (2 -fluorophenyl) -2II-1,4 "benzodiazepin-2-one.

(NMR (CDC1₃), delta: 5.085 (2H, ABq), 5.76 (111, d, J = 7.9 Hz), (b)

6.3-8.0 (3011, m), 8.10 &lt;11-1, d, Js7.9Hz), 9.8 1 (1Π, s).

(3R) ~ 1,3-Dihydro-1- (1-trityl-4-imidazolyl) -methyl 1-3- (2-indolylcarbonyl-1-amino) -5- (2-fluoro- phen 1) -2Π-1,4-benzodiazepin-2-one «

NMR (DMS0-d₆), delta: 5.11 (2H, ABq), 5.64 (1Π, d, J = 8.0Hz), (o)

6.7-8.0 (30Η, ta), 9.55 (1Π, d, J = 8.0II)_z), 11.66 (1Π, s).

(3RS) -1,3-Dihydro-3 '- (2-indole 1-carbonyl-1-araino) -1- (4'-imidazolylmethyl) -5'-onyl-2'-1,4-benzodiazepine-2- you.

IR (nujol): 3250, 1680, 1635, 160c, 1530 cm¹.

<img file="HUT50331A_D0035.tif" />

- 94 diazepin-2-on ·

NMR (CDC1₃), d δ: 4.85, 5.10 (2H, ABq, J = 15Hz), 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) -1-f ( 5-methylimidazol-4 "yl)" methyl-5 "Γθηί1 ~ 2ΙΙ-1,4-benzodiazepin-2-one ·

NMR (DMS0-d₆), delta: 1.96 (3Π, s), 4.80, 5.15 (211,

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) -1,3-Dihydro-1- (4-iridazolylmethyl) -3- (2-indolylcarbonyl-1-amino) -5 '- (2-fluorophenyl) -211 - 1,4 "benzodiazepit-2-one.

NMR (DMSO-d₆), delta: 5.04 (2H, ABq), 5.63 (1H, d, J = 7.9 Hz),

6.9-8.2 (15Π, m), 9.58 (111, d, J = 7.9Hz), 11.65 (1H, s), 11.92 (111, s).

(g) (3R) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5 "- (2-fluorophenyl) -2II-1,4 benzodiazepin-2-one.

NMR (DMSO-d_She), delta: 5.04 (2H, ABq), 5.62 (111, d,

J = 7.9Hz), 6.9-8.3 (15Π, m), 9.58 (1H, d, J = 7.9Hz),

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

(h) (3R8) ~ 1,3 'Dilydro-3- (2-indolylcarbonyl-eunino) -

- Your 1- (2-writer is olylmethyl) ~ 5 "phenyl 1-2.1-1, 1 &lt;benzodiazepin-2-one * ···· ··

- 95 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 = 811z), 11.65 (1H, broad s), 11.90 (1H, broad s).

(J) (3RS) -1,3-Dilyldro-3- (2-1-indole 1-carbonyl-1-amino) -

- 1- (3-pyrazolylmethyl) -5 "phenyl-2H-1,4-benzodiazepine-2-οη.

NMRfDMSO-d₆), delta: 5.03, 5.30 &lt;2H, ABq, J = 15Hz),

5.65 (1H, d, J = 8Hz), 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).

(k) (3RS) -1,3 "Dihydro-3- (2-1-diphenylcarbonylamino) -1 - ((1,2,4-triazol-3-yl) ethyl) - 5 "phenyl-2H-1,4-benzodiazepin-2-one.

11MR (DMS0-d₆), delta: 5.10, 5.35 (2H, ABq, Js15Hz), 5.66 (1H, d, JsSlIz), 6.90-7.93 (15Π, m), 8.23 ​​(111, broad s), 9.40 (111, d, J = 811z), 11.65 (111, broad s).

(1) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -

- 1- [2- (4'-imidazolyl) -ethyl] -5'-phenyl-2 '-1,4-benzodiazepin-2-one.

l&gt; IR (DMS0-d_She), delta: 2.63 (211, t, J = 71 Iz), 3.85-4.20 (111, _n), 4.20-4.75 (1Π, οι), 5.55 (1Π, d, J = 8lease),

6.60 (1H, s), 6.93-7.85 (15H, m), 9.43 (111, d, J = 811z), 11.65 (1H, broad).

• · «· · ································································ · · · · · · · · · · · · · · · · · · · · · · ·

- 96 T (m) (3 S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylanilino) -5- (2-fluoro-phenyl) ) -211-1,4-benzodiazepin-2-one hydrochloride.

NMR (DMSO-d₆), delta: 5.33 (2H, ABq), 5.69 (1H, d, J = 7.6 µz),

7.0-8.0 (15H, n), 9.05 (1H, s), 9.60 (1H, d, Js7.6Hz), 11.74 (1H, s), 14.73 (1H, bs).

47th example

0.79 g of (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2II-1,4- benzodiazepin-2-one, 0.22 g of 2-indole carboxylic acid, 0.18 g of l.^TThe reaction mixture consisting of hydroxybenzotriazole, 0.28 g of dicyclohexylcarbodiylide and 8 ml of N, IT-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 an oily liquid which was chromatographed on silica gel using chloroform / methanol 30: 1 as eluent. 0.97 g of (3S) -1,3-dihydro-1- (1-trityl-4'-imidazole) -methyl-3- (2-indolylcarbonyl-amino) -5- (2-fluoro) -phenyl) -2II-1,4-benzodiazepin-2-one as an amorphous substance.

M 7) 3 - -32.47 ° (c = 0.85, methanol).

···· · ···· ·· ·· • ·· · · · · » • '· ♦ ·· · • · · · · · · ·* ·»· · ·» ··

NMR (CDCl₃)_f delta: 5.085 (2H, ABq, 5.76 (1H, d), J = 7.9Hz),

6.8-8.0 (30Η, m), 8.10 (1H, d, J = 7.9Hz), 9.81

48th example

0.81 g of (3R) -1,3-dihydro-1- (1-trityl-4-imidazolyl) -methyl-3 'amino-5' (2-fluorophenyl) -2II-1,4 Benzodiazepin-2-one, 0.23 g of 2-indole carboxylic acid and 0.19 g of N-hydroxybenzotriazole in 8 ml of N, N-dimethylformamide are added with stirring at room temperature. 0.27 g of 1-ethyl-3 '(3-dinethylaminopropyl) carbodiimide hydrochloride and 0.14 g of triethylamine. The reaction mixture was stirred at room temperature for 4 hours. While stirring, ethyl acetate and water were added. Hátrium hydrogen

with an aqueous solution of carbonate, adjust the pH of the reaction mixture to, for example, In 8. 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- (2-1-dihydro-1-carboxyl-aryl) -5. ~ (2-fluorophenyl) -2H-1,4 "

Benzodiazepin-2-one is obtained.

Rf = 41.58 ° (c = 0.856, methanol).

Π (Olt⁵ Od ^), delta: 5.11 (211, «Jq), 5.64 (Hi, d, J = 8, u .._tK),

<img file="HUT50331A_D0036.tif" />

»), 9,55 ( ¹ , d,

Ε, σΐζ)

<img file="HUT50331A_D0037.tif" />

···· · ···· ·· ·· • ·· · · · · ·

4 · ·· · • · · · · · · • 4 ·»· · ·· ··

- 98 49 · example

1.0 S (3S) -1,3-Dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolyl-carbonylamino) -5 '- (2-fluorophenyl) - To a solution of 2II-1,4-benzodiazepin-2-one in 10 ml of N, N-dinyldinylformamide is added 7 ml of 6N hydrochloric acid under ice-cooling and stirring. 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 using chloroform / methanol (20: 1) as eluent. (3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluoro-) as a yellow crystalline powder Phenyl 1) -211-1,4-benzodiazepin-2-one is obtained.

ss + 24.68 ° (c = 0_t64, chloroform).

HMR (DMSO-d₆), delta: 5.04 (2H, ABq), 5.63 (UI, d, J = 7.9Hz),

6.9-8.2 (1511, m), 9.58 (1H, d, J = 7.9 Hz), 11.65 (111, s), 11.92 (111, s).

50th example

Example 3 (3R) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluoro-f) was prepared as described in Example 49. e ni 1) -211-1,4-benzodiazepin-2-one.

Rf = -26.40 ° (o = 0.64, chloroform).

NMR (DMS0-d₆), delta: 5.04 (2H, ABq), 5.62 (1H, d, J = 7.9Hz),

6.9-8.3 (15H, m), 9.58 (111, d, J = 7.9Hz), 11.66 (1H, s), 11.93 (1H, s).

51st example

15.1 tag (3S) -1,3 "dihydro-1- (4-imidazolylmethyl) -3" (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1, To a solution of 4-benzodiazepin-2-one in 5 ml of methanol is 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 to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonyl) 197.1 mg. amino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride.

m.p. = -35.94 ° (c = 0.612, methanol).

214-218 ° C (dec.)₆), delta:

5.33 (2H, ABq), 5.69 (1H, d, J = 7.61Iz),

7.0-8.0 (15H, m), 9.05 (111, s), 9.60 (111, d,

J = 7,6n_c), 11.74 (1H, s), 14.73 (1H, broad s).

100

52nd example

24-6 mg of (3S) -1,3 "dihydro-1- (4-imidazolylmethyl) -3- (2-indole-1-carbonylamino) -5- (2-fluorophenyl) -2H-1, To a solution of 4-benzodiazepin-2-one in 10 ml of methanol is added 75.0 mg of L - (+) - tartaric acid at room temperature. After stirring for a few minutes, the reaction mixture is made up to 2 ml. The resulting pale yellow powder was collected by filtration, washed twice with diisopropyl ether and dried to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indole-1-carbonyl) amino (235.3 mg). ) -5- (2-fluorophenyl) -211-1,4-benzodiazepin-2-one-1 (+) - tartrate.

M.p. 17 DEG-175 DEG C. (dec.).

NMR (DMSO-d₆), delta: 4.31 (211, s), 5.07 (211, s), 5.63 (111, d, J = 7.7Hz), 6.9-8.1 (1511, m), 9.58 (1H, d, J = 7.7Hz), 11.65 (1H, s).

53rd example

As described in Examples 51 and 52, (3S) -1,3 "dihydro-1- (4-imidazolylmethyl) -3" (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2U-1,4-benzodiazepin-2-one is reacted with methanesulfonic acid to give (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indole 1-carbonyl) -amino) -5- (2-fluorophenyl) -21H-l''-benzodiazepine-4'-one methanesulfonate.

[α] D = -31.32 (c = G, 632, methanol).

101

136-139⁰C (dec.).

NMR (DMSO-d₆), delta: 2.39 (3H), 5.33 (211, ABq), 5.69 (1H, d, J = 7.7Hz), 7.0-7.8 (15H, m), δ, 99 (1H,

s), 9.58 (1H, d, J = 7.7nz), 11.68 (1H, s),

14.26 (1H_f wide).

54th example

The following compounds were prepared as described in Example 13 (a):

(a) (3RS) "1,3" Dihydro-3- (2-indolylcarbonylamino) -

-1- (4'-imidazolylmethyl) -5 "phenyl-2II-1,4-benzodiazepin-2-one · IR (nujol): 3250, 1680, 1635, 1530 cm¹.

(b) (3RS) -1,3 "dihydro-3" (2-indolylcarbonylamine) -

- 1- (4-imidazol-1-yl) -5- (2-fluorophenyl) -211- 1,4-benzodiazepin-2-one.

CHR (CDC1₃), delta: 4.85, 5.10 (211, ABq, J = 15Hz), 5.80 (1Π, d, J = 81 Iz), 6.80-7.83 (15H, ni), 8.10 (1H, d, JsoIIz), 10.10 (1ΪΙ, broad s).

(c) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -

- 1- (5-methylimidazol-4-yl) ethyl] -5-phenyl 1-211-1,4-benzodiazepin-2-one.

NMR (d DlíSO₆), delta: 1.96 (311, s), 4.80, 5.15 (211, ABq, J = 15 MHz), 5.55 (111, d, J = 81 Iz), 6.90-8, 15 (15Π, m), 9.33 (11i, d, J = 8Jz), 11.58 (2Π, broad s).

(d) (JS) -1,3-Dihydro-1- (4-iridazole-methyl) -3- (2-

- • 1 'l; arbunil-att-^:.iio) - '*&gt; - (; .'- luor-í'eni l) -2 1,4-

- · 'irr'. 'Od' e; c-; r. -2 · or.

102

NMR (DMSO-dg), delta: 5.04 (2H, ABq), 5.63 (1H, d, J = 7.9Hz), 6.9-8.2 (15H, m), 9.58 ( 1H, d, J = 7.9Hz), 11.65 (1H, s), 11.92 (1H, s).

(e) (3R) -1,3-Dihydro-1- (4-imidazolylidene) -3- (2-indolylcarbonyl-awino) -5 "(2-fluorophenyl) ) -2H-1,4-benzodiazepin-2-one.

NMR (DMSO-d6), δ: 5.04 (211, ABq), 5.62 (1H, d, J = 7.9Hz), 6.9-8.3 (15H, m), 9.58 ( 1H, d, J = 7.9Hz), 11.66 (1H, s), 11.93 (1H, e).

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

M-IR (DIIS-d_She), delta: 5.10 (2Π, s), 5.65 1H, d, J = 8Hz),

6.60-3.10 (16Π, m), 9.36 (111, d, J = 8Kz), 11.65 (11-1, broad s), 11.9θ (111, broad s).

(g) (3HS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -

- 1 - ((3-pyridazol-2-yl) -1-methyl) -5-phenyl-1,2-1,4-benzodiazepin-2-one. 1 H NMR (DMSO-d 6), δ 5.03, 5.30 (2H, ABq, J = 15 II),

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

6.90-7.90 (15H, m), 9.43 (11II, d, J = 8Hz), 11.60 (1H, bs), 12.55 (1H, bs).

(h) (3RS) -1,3-Dihydro-3- (2-indolylcarbonyl-1-amino) -1- [1,2,4-triazol-3'-yl] -ethyl] -5-phenyl-2'L -1.4 ~^,benzodiazepin-2-one.

103

NMR (DMSO-d₆), delta: 5.10, 5.35 (2H, ABq, J = 15Hz),

5.66 (1H, d, J = 8Hz), 6.90-7.93 (15H, m), 8.23 ​​(1H, broad s), 9.40 (1H, d, J = 8Hz), 11 , 65 (1H, bs) · (1) (3RS) -1,3 ”dih ± dr 0-3- (2-indolylcarbonyl-1-amino) -1- [2- (4-imidazolyl-ethyl) - 5-phenyl-2H-1,4-benzodiazepin-2-one.

NMR (DMS0-d₆), delta: 2.63 (2H, t, J = 7Hz), 3.85-4.20 (1H, _She), 4.20-4.75 (1H, m), 5.55 (1H, d, J = 811z), 6.60 (111, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 811z), 11.65 (1H, broad s).

(j) (3 S) -1,3-Dihydro-1- (4-imidazol-1-yl-ethyl) -3 "(2-dihydro-1-amino) -5" (2 -fluorophenyl) -211-1,4-benzodiazepin-2-one hydrochloride.

ll-IR (DIIS-d₆), delta: 5.33 (211, ABq), 5.69 (1H, d, Je7.6L-Iz), 7.0-8.0 (15H, m), 9.05 (1H, s),

9.60 (111, d, J = 7.6Hz), 11.74 (111, s), 14.73 (1Π, broad s).