Benzodiazepine derivatives

The present invention has use in the treatment or prevention of emesis or pacreatitis in humans or animals.

-261.166

BCP / PE-1695

Description of the object of the invention which

FUJISAWA PHARMACEUTICAL CO., LTD. japanese, industrial, based in

4-7, Doshomachi 3-chome, Chuo-ku, Osaka-shi, Osaka 541, Japan, intends to obtain in Portugal for Process for Preparation of New Benzodiazepine Derivatives This invention relates to a process for the preparation of novel derivatives. benzodiazepine and its pharmaceutically acceptable salts.

More particularly, the invention relates to novel benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCC) antagonists and can therefore be used as therapeutic agents for emesis, pancreatitis, satiety and appetite control, pain control. , insulinoma, gastroparesis, acute obstructive cholecystitis, irritable bowel disease, pancreatic carcinoma, etc.

Benzodiazepine derivatives of the present invention may be represented by the following formula (I);

R '

AIR

<img file="PT91092B_D0001.tif" />

-NHCO ^ X

<img file="PT91092B_D0002.tif" />

(I)

<img file="PT91092B_D0003.tif" />

. '.. yf &amp; l. &lt;33

61,166 'j

Wherein R3 is halogen, heterocyclic group which may have one or more appropriate substituent (s), aryl which may have one or more appropriate substituent (s),

-NH-R4 (wherein R4 is hydrogen, lower alkanoyl or hydroxy (lower) alkyl,

-S-R6 (wherein R3 is lower alkyl, carboxy and amino substituted lower alkyl, protected and protected amino carboxy substituted lower alkyl, or pyridyl),

(Wherein R 3 is hydrogen, hydroxy protecting group, lower alkyl, lower alkenyl, lower aralkyl, lower haloalkyl, lower aminoalkyl, protected lower aminoalkyl, or lower piperazinylalkyl which may be have lower alkyl),

QQ _z

-CONH-R (wherein R is cyano, carbamoyl lower alkyl, carboxy lower alkyl, protected lower carboxyalkyl, or lower alkyl substituted by carbamoyl and aryl), or

Q __ Q,,

Wherein R is hydrogen or lower alkyl, and

Z is ₀

-C-, -CN

R¹⁰ (wherein R2 is hydroxy, lower alkoxy or amino) or

-CII

Ç / \

R¹¹ R¹²

-261.166

BCP / PE-1695

<img file="PT91092B_D0004.tif" />

τη &lt;Ί 2, (where R is carboxy or protected carboxy and R is hydrogen; or

R¹ is halogen and R¹ is halogen »

R is aryl which may have one or more appropriate substituent (s),

R is hydrogen or halogen,

R3 is hydrogen, halogen or lower alkoxy and A is lower alkylene,

In accordance with the present invention, novel benzodiazepine derivatives (I) may be prepared by the processes described in the following scheme.

Process 1

H

<img file="PT91092B_D0005.tif" />

<img file="PT91092B_D0006.tif" />

H (II) or a salt thereof (III) or a salt thereof

<img file="PT91092B_D0007.tif" />

(I) or a salt thereof

-361.166

BCP / PE-1695

Process 2

R '

<img file="PT91092B_D0008.tif" />

NH₂ + HOOC (IV) or its amino group reactant derivative or salt thereof (V) or its carboxy group reactant derivative or salt thereof

<img file="PT91092B_D0009.tif" />

(I) or a salt thereof

Process 3

<img file="PT91092B_D0010.tif" />

(la) or a salt thereof

Hydroxy protecting group elimination reaction

J

<img file="PT91092B_D0011.tif" />

(lb) or a salt thereof

Process 4

-561.166

BCP / PE-1695 / '; S' 3

<img file="PT91092B_D0012.tif" />

<img file="PT91092B_D0013.tif" />

Oxidation

<img file="PT91092B_D0014.tif" />

(Id) or your salt

Process 5

<img file="PT91092B_D0015.tif" />

(le) or a salt thereof

<img file="PT91092B_D0016.tif" />

(R¹³-) and P = C +

(X) or a salt thereof

-6-¾. 733

- $

61.166

BCP / PE-1695

R¹¹ / R¹² \ /

<img file="PT91092B_D0017.tif" />

(If) or your salt

Process 6

<img file="PT91092B_D0018.tif" />

<img file="PT91092B_D0019.tif" />

H

R⁴ + R¹⁰-NH₂ (XI) or a salt thereof _r!0

<img file="PT91092B_D0020.tif" />

<img file="PT91092B_D0021.tif" />

(Ig) or a salt thereof

-761.166

BCP / PE-1695

773

R

<img file="PT91092B_D0022.tif" />

Process 7

<img file="PT91092B_D0023.tif" />

salt

<img file="PT91092B_D0024.tif" />

Protecting group elimination reaction

Ψ amino

<img file="PT91092B_D0025.tif" />

(Ii) or a salt thereof

Process 8

<img file="PT91092B_D0026.tif" />

(lj) or a salt thereof

861.166

BCP / PE-1695 &lt;· '&lt;j? 3

Carboxy protecting group elimination reaction

J.1

<img file="PT91092B_D0027.tif" />

NHCO (ik) one of your

<img file="PT91092B_D0028.tif" />

H salt

Process 9

<img file="PT91092B_D0029.tif" />

<img file="PT91092B_D0030.tif" />

(II) or a salt thereof

Amino Protecting Group Elimination Reaction

-961.166

3CP / PS-1695

<img file="PT91092B_D0031.tif" />

Process 10

<img file="PT91092B_D0032.tif" />

<img file="PT91092B_D0033.tif" />

or its carboxy-reactive derivative or salt thereof (XIII) or its amino-reactive derivative or salt thereof

-10-1.

61.166

BCP / PE-1695

A-CONH-R⁸

<img file="PT91092B_D0034.tif" />

(In) or a salt thereof

Process 11

<img file="PT91092B_D0035.tif" />

(ip) or your salt

-1161.166

3CP / PE-1695

- I already

f .fc '

Process 12

<img file="PT91092B_D0036.tif" />

or one

<img file="PT91092B_D0037.tif" />

salt

<img file="PT91092B_D0038.tif" />

(Go) or your salt

Process 13

-1261.166

3CP / PE-1695; -&gt; 'Γκ “.0 · &lt;.. · *) * J •. ·&gt;

'4 α-νη₂

<img file="PT91092B_D0039.tif" />

<td></td><td>(Is)</td><td>(XV)</td>

<td>or</td><td>your reagent derivative</td><td>or its derivative</td>

<td>at the</td><td>amino group</td><td>reagent in the group</td>

<td>or</td><td>one your salt</td><td>carboxy or one of its</td>

salt )

A-NH-R

<img file="PT91092B_D0040.tif" />

NHCO

<img file="PT91092B_D0041.tif" />

(It) or your salt

Process 14

-1361.166

3CP / PE-1695 · ή, 4 JU.

/

Ζ *

<img file="PT91092B_D0042.tif" />

<img file="PT91092B_D0043.tif" />

(XVI) or a salt thereof

<img file="PT91092B_D0044.tif" />

Process 15

2

AOA -X

<img file="PT91092B_D0045.tif" />

(Iv)

NHCO

<img file="PT91092B_D0046.tif" />

HR or its salt (XVII) or its salt

-14-7.

61.166

BCP / PE-1695 aoa²-r¹⁶

-&gt;

<img file="PT91092B_D0047.tif" />

NHCO

<img file="PT91092B_D0048.tif" />

R (Iw) or a salt thereof

Process 16

N

R

<img file="PT91092B_D0049.tif" />

NHCO (Ix) or a salt thereof

OH

<img file="PT91092B_D0050.tif" />

O

<img file="PT91092B_D0051.tif" />

(iy) or your salt

-1561.166

BCP / PE-1695

and A are

-fc.

_D1 „2 _O3 _d4 _d6 8 _d9 _d10 _d11 _d12 wherein R, R, R, R, R, R, R, R, R, R, R each as defined above,

X is halogen, * 7 * 7

R¹ is -O-R 1 (wherein R 4 is hydroxy protecting group) or aryl having two protected hydroxy groups,

R4 is hydroxy or aryl having two hydroxy groups, R4 is (C1 -C4) alkylene,

R · ^ is aryl, r! is a heterocyclic group that has protected amino,

C 7 7 phthalimido, or -O-R · 4 (where R 4 is lower aminoalkyl),

R ^ is heterocyclic group having amino or -O-R ^ is lower aminoalkyl); is -CR ^ (where R ^ is as defined

CH ι

above, R 4 is a protected carboxy group) or, 8 o '

-CONH-R (wherein R is lower protected carboxyalkyl, R1 -C-r9 (wherein R4 is as defined above)

CH

COOH .8 * or -CONH-R4 (where R4 is lower carboxyalkyl),

Re hydrogen or lower alkyl,

R is an amino protecting group,

J is CH or N,

Q is CH or N,

X and halogen,

R3 is lower alkyl substituted by protected amino acid carboxyprotein,

<img file="PT91092B_D0052.tif" />

61.166

3CP / PE-1695 is lower alkyl substituted by carboxy and amino,

R

R

X

THE

R a

g is lower alkanoyl, is piperazinyl having lower alkyl, or

5 * *

-NH-R (wherein R is as defined above) is halogen, is lower alkylene, and is phthalimido or piperazinyl having lower alkyl.

starting compound (IV) by the following procedures.

and new and can be preparedProcess A

H

<img file="PT91092B_D0053.tif" />

(VI) or a salt thereof

R¹⁷

<img file="PT91092B_D0054.tif" />

(VII) or a salt thereof

-1761.166

BCP / PE-1695

<img file="PT91092B_D0055.tif" />

*

<img file="PT91092B_D0056.tif" />

<img file="PT91092B_D0057.tif" />

XAR¹ (III) or a salt thereof

<img file="PT91092B_D0058.tif" />

<img file="PT91092B_D0059.tif" />

Amino Protecting Group Elimination Reaction

<img file="PT91092B_D0060.tif" />

61.166

BCP / PC-1695

2 3 — .

wherein R, R, R, A and X are each as defined above,

Y is an acidic residue, and Ί 7

R¹'is a protected amino group.

Suitable pharmaceutically acceptable salts of the compound of the present invention (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and alkali metal salt. earthy (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, Ν, Ν'-dibenzylethylenediamine salt, etc. .), an organic acid salt (eg acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (eg hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like.

In the foregoing and subsequent descriptions of the present specification, suitable examples and descriptions of the various definitions which the present invention includes within its scope are explained in detail as follows.

The lower term means 1 to 6 carbon atoms unless otherwise indicated.

Suitable halogen and halogen moieties in the term lower haloalkyl may include chlorine, bromine, fluorine and iodine.

Suitable heterocyclic group may include a group-1961.166

BCP / PE-1695%

saturated or unsaturated, monocyclic or polycyclic powder containing at least one heteroatom, for example an oxygen atom, sulfur, nitrogen, etc. And an especially preferred heterocyclic group may be a heterocyclic group, for example a 3- to 8-membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example pyrrolyl, 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. β-tetrazolyl, 2H -tetrazolyl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro1,2,4-triazinyl, etc.) and the like;

saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .;

unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, henzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyrazole-5-tetrazolopyrazole-5-tzazole , etc.), dihydrotriazolopyridazinyl, etc .;

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

-2061.166

BCP / PE-1695 / *

Mod. 71-1 0000 ex. Saturated 5- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example morpholinyl, etc .;

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example benzoxazolyl, benzoxadiazolyl, etc. ;

unsaturated 3 to 8-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (for example 1,2,4 thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.;

saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolidinyl, etc .;

unsaturated 3 to 8 membered unsaturated heteromonocyclic group containing an oxygen atom, for example furyl, etc .;

unsaturated 3- to 8-membered unsaturated heteromonocyclic group containing a sulfur atom, for example thienyl, etc. ;

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl, etc., and the like, and said heterocyclic group may have one or more appropriate substituents, for example amino, amino protected, oxo, hydroxy, imino protecting group (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.

-2161.166

BCP / PE-1695

Suitable aryl and aryl moiety in the term lower aralkyl may include phenyl, naphthyl and the like.

Suitable aryl substituent which may have one or more suitable substituents for R3 may include hydroxy, protected hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc. .) and analogues.

Suitable protected hydroxy may include tetrahydroanyloxy, acyloxy, for example lower alkanoyloxy (e.g. formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, etc.) and the like

Suitable aryl substituent which may have one or more suitable substituents for R may include halogen (e.g. chlorine, bromine, fluorine and iodine) and the like.

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

Suitable lower alkyl and lower alkyl moieties under lower hydroxyalkyl, lower aralkyl, lower haloalkyl, lower aminoalkyl, protected lower aminoalkyl, lower piperazinylalkyl, lower carbamoylaloyl, lower carboxyalkyl and protected lower carboxyalkyl may include a straight or branched chain group having 1 to 6 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or analog, preferably a group of 1 to 4 carbon atoms.

-2261.166

BCP / PE-1696

- i.

:733

Suitable protected carboxy and protected carboxy moiety in the term protected lower carboxyalkyl may be a esterified carboxy group, or the like, and specific examples of the ester moiety in said esterified carboxy group may be lower alloyl ester, e.g. methyl ester, ethyl ester, propyl ester , isopropyl ester, butyl ester, isobutyl ester, tert.butyl ester, pentyl ester, bexyl ester, 1-cyclopropylethyl ester, βίο_Λ7th which may have suitable substituents, for example lower alkanoyloxyalkyl ester / for example acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, pivaloyloxyethyl ester , 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.7, lower alkanesulfonylalkyl ester /^-for example 2-mesylethyl ester, etc. or lower mono (or di or tri) haloalkyl ester, for example 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.; lower alkenyl ester / e.g. vinyl ester, allyl ester etc._x7ί lower alkynyl ester / e.g. ethinyl ester, propynyl ester etc._x7) lower mono (or di or tri) phenylalkyl ester which may have suitable substituents e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, ester 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc._x7&gt; aryl ester which may have suitable substituents / e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, ester

4-tert.butylphenyl, xylyl ester, mesityl ester, cumenyl ester, etc. or the like.

-2361.166

BCP / PE-1695

Protected amino and protected amino moiety appropriate to the term protected lower aminoalkyl may include an acylamino or amino group substituted by a conventional protecting group, for example lower aralkyl, which may have at least one suitable substituent (e.g. benzyl, trityl, etc.). ) or the like.

Suitable acyl moiety in the terms acylamino and acyloxy may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.

And suitable examples of said acyl may be lower alkanol (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);

lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);

arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.);

aroyl (e.g. benzoyl, toluyl, xylyl, naphthoyl, phthaloyl, indancarbonyl, etc.);

lower aralkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.);

lower aralkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.

-2461.166

BCP / PE-1695, Γ * ~ ι .¾ ue '.

•/235

The moiety as indicated above may have at least one suitable substituent, for example halogen (chlorine, bromine, fluorine and iodine), amino, lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, tert.butoxycarbonylamino, pentyloxycarbonylamino, hexylcarbonylamino, hexyl) or analogues.

Suitable hydroxy protecting group may include tetrahydropyranyl, acyl group, for example lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, etc.) and the like

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

4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl and the like.

Suitable lower alkoxy may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, preferably one having 1 to 4 carbon atoms.

Suitable lower alkylene may include a straight or branched chain having 1 to 6 carbon atoms, for example methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atoms.

Suitable imino protecting group may include trityl, terahydropyranyl and the like.

Suitable acid residue may include acyloxy wherein acyl moiety is as mentioned above, halogen (e.g. fluorine, chlorine, bromine and iodine) and the like.

Embodiments of the compound (I) object of the present invention are as follows.

-2561.166

B'CP / PE-1695

-1..

Preferred embodiment of r! halogen, thienyl, furyl, piperazinyl having lower alkyl, imidazolyl having trityl, imidazolyl having lower alkyl, imidazolyl having trityl and lower alkyl, pyrazolyl having trityl, triazolyl having trityl, thiazolyl having amino or protected amino (more preferably thiazolyl having amino or acylamino, most preferably thiazolyl having amino or lower alkanoylamino), isoxazolyl having hydroxy, dihydroisoxazolyl having oxo and tetrahydropyranyl, tetrazolyl, isoindolyl having two oxo groups, phenyl, phenyl having two protected hydroxy groups (more preferably phenyl having two acyloxy groups, most preferably phenyl having two lower alkanoyl groups) , phenyl having two hydroxy groups, phenyl having two lower alkoxy groups,

<img file="PT91092B_D0061.tif" />

61.166

3CP / PE-1695

5 ' *

-NH-R (wherein R is hydrogen, lower alkanoyl or lower hydroxyalkyl,

Wherein R2 is lower alkyl, carboxy and amino substituted lower alkyl, protected carboxy substituted lower alkyl and protected amino (more preferably esterified carboxy substituted lower alkyl and acylamino, most preferably diphenylalkoxy substituted lower alkyl). lower carbonyl and lower alkoxycarbonylamino), or pyridyl7, - 7

Wherein R is hydrogen, hydroxy protecting group (more preferably tetrahydropyranyl or acyl, most preferably tetrahydropyranyl or lower alkanoyl), lower alkyl, lower alkenyl, lower phenylalkyl, lower haloalkyl, lower aminoalkyl (lower protected) (preferably phthalyroidoalkyl), or piperazinyl lower alkyl having lower alkyl;

8 *

-CONH-R (wherein R is cyano, lower carbamoylalkyl, lower carboxyalkyl, lower carboxyalkyl. (More preferably esterified lower carboxyalkyl, most preferably lower alkyloxycarbonyl), or lower alkyl substituted by carbamoyl and phenyl7, or ll and Z and -C-, —C—

II

N

R¹⁰

-2761.166

BCP / PE-1695

Λ (where R¹® is hydroxy, lower alkoxy or amino) or

-C (I

11 r11 r12 (in _R11 carboxy or protected carboxy (most preferably esterified carboxy, most preferably lower alkoxycarbonyl) and

3.2 * * 3.3. * * 3.2 *

R¹ is hydrogen; or R¹ is halogen and R¹ is halogen_) 7 »

R is phenyl or halophenyl,

R is hydrogen, R4 is hydrogen, halogen or lower alkoxy, and

A is lower alkylene.

with respect to compound (I) object of the present invention, if compound (i) has the group of formula:

N

<img file="PT91092B_D0062.tif" />

said group may also exist in tautomeric form and such tautomeric equilibrium may be represented by the following scheme.

<img file="PT91092B_D0063.tif" />

NH (A) (B)

-2861.166

BCP / PE-1695

<img file="PT91092B_D0064.tif" />

Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, compounds including the group of such tautomeric isomers are represented for convenient purposes by an expression of the group of formula (A).

The processes for preparing the compound (I) object of the present invention are described in detail below.

Process I:

Í0 / 68- Χ'ΟΟΟΟΙ Ιί ΡθΙΛΙ

Compound (I) or a salt thereof may be prepared by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.

Suitable salts of compounds (II) and (III) may be those exemplified for compound (I).

This reaction is generally carried out in the presence of base.

Suitable base may include an inorganic base, for example an alkali metal hydride (eg sodium hydride, etc.), alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide, etc.), alkali metal hydroxide -earth (eg magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (eg sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (eg magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (eg sodium bicarbonate, potassium bicarbonate, etc.),

-2961.166

3CP / PE-1695

Ά alkali metal acetate (eg sodium acetate, potassium acetate etc.), alkaline earth metal phosphate (eg magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphate (eg phosphate disodium hydrogen, dipotassium hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine and the like.

This reaction is generally carried out in a solvent such as alcohol (e.g. methanol, ethanol, etc.), benzene, α, β-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not impair the reaction.

The temperature of the reaction is not important and the reaction is generally carried out at room temperature with mild heating or strong heating.

Process 2:

Compound (I) or a salt thereof may be prepared by reacting Compound (IV) or its amino-reactive derivative or salt thereof with Compound (V) or its carboxy-reactive derivative or salt thereof.

Suitable reagent derivative at the amino group of compound (IV) may include imino-type Schiff base or its tautomeric enamine-type isomer formed by reacting compound (IV) with a carbonyl compound such as aldehyde, ketone, etc .; a silyl derivative formed by reacting compound (IV) with a silyl compound such as N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by reaction of compound (IV) with tri-3061,166

BCP / PE-1695 / ^%

Ί

Mod. 71 10000 ex. Phosphorous chloride or phosgene, and the like.

Suitable salts of compound (IV) and (V) may be those mentioned for compound (I).

Suitable reagent derivative on the carboxy group of compound (V) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. 0 appropriate example may be an acid chloride, an acid azide; an acid anhydride mixed with an acid with substituted phosphoric acid (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialauylphosphoric acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (for example benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester / (CH3 vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentaclerophenyl ester, mesylphenyl ester phenylazophenyl, phenyl thioester, p-nitrophenyl thioester, · p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), an ester with an N-hydroxy compound (for example N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy- 6-chloro-1H-benzotriazole, etc.}, and anal-5161,166

BCP / PE-1695

-l JU?

- -7 logos. These reagent derivatives may optionally be chosen from them according to the type of compound (V) to be used.

The reaction is generally carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvents which do not impair the reaction. reaction. These conventional solvents may also be used in admixture with water.

When compound (V) is employed in the free acid form or salt form thereof in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as α, β'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;

N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide;

N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide;

N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide;

K, N-carbonylbis- (2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialauyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; intramolecular isoxazolium 2-ethyl-5- (m-sulfophenyl) hydroxide salt;

1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; Vilsmeier denominated reagent prepared by reaction of N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.: or the like.

-32QRlGtNAL

<img file="PT91092B_D0065.tif" />

61.166

BCP / PE-1695

The reaction may also be carried out in the presence of an inorganic or organic base, for example an alkali metal bicarbonate, lower trialauyl above, pyridine, N-lower alkyl morphine, β, β-lower dialkyl benzylamine, or the like. The temperature of the reaction is not decisive, and the reaction is generally carried out with cooling to heating.

Process 5:

Compound (1b) or a salt thereof may be prepared by subjecting Compound (1a) or a salt thereof to the hydroxy protecting group removal reaction.

The present elimination reaction is carried out according to a conventional process such as hydrolysis, reduction or the like. Hydrolysis may include a process using an acid or base or the like. These processes may be chosen according to the type of protecting groups to be removed.

Acid hydrolysis is one of the most common and preferred processes for the removal of protecting groups such as tetrahydropyranyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl or the like.

Suitable acids may include, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. The appropriate acid for the reaction may be chosen according to the protecting group to be removed and other factors.

-3361.166

BCP / PE-1695 * Λ

-Oh. 83

Hydrolysis with a base is preferably applied for the removal of the acyl group. Suitable bases may include, for example, an inorganic base such as an alkali metal (e.g. sodium, potassium, etc.), alkaline earth metal (e.g. magnesium, calcium, etc.), its hydroxide or carbonate or bicarbonate or the like. and an Organic base such as trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methyl morpholine or the like.

The reduction applicable for the elimination reaction of the present invention may include, for example, reduction using a metal (e.g. tin, zinc, iron, etc.) or a combination of metal compound (e.g. chromic chloride, chromic acetate, etc.) and an organic or inorganic acid (for example acetic acid, propionic acid, hydrochloric acid, etc.); and reduction in the presence of a metal catalyst for catalytic reduction. Suitable metal catalysts for catalytic reduction may include, for example, Raney nickel, platinum oxide, palladium on carbon and other conventional catalysts. The reaction is generally carried out in a conventional solvent such as water, dioxane, tetrahydrofuran, alcohol, α, β-dimethylformamide, or any other solvent that does not impair the reaction.

The reaction temperature is not decisive and can be chosen accordingly according to the type of protecting group and the elimination process, and the present reaction is generally carried out with cooling and heating.

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3CP / PE-1695

- i

Process 4:

Compound (Id) or a salt thereof may be prepared by subjecting compound (Ic) or a salt thereof to oxidation reaction.

Appropriate salts of compounds (Ic) and (Id) may be exemplified for compound (i).

The present oxidation reaction may be carried out by a conventional process, for example using a wetting agent such as a combination of dimethyl sulfoxide with dicyclohexylcarbodiimide, a combination of chromium trioxide with pyridine, or the like.

This reaction is generally carried out in a solvent such as benzene, α, α-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, diethyl ether or any other solvent which does not impair the reaction.

The temperature of the reaction is not decisive and the reaction is generally carried out with cooling to heating.

Process 5:

Compound (If) or a salt thereof may be prepared by reacting compound (1e) or a salt thereof with compound (X) or a salt thereof.

Suitable salts of compounds (le) and (If) may be those exemplified for compound (I).

This reaction is generally carried out in a solvent such as benzene, α, α-dimethylformamide, tetrahydrofuran, chlorofor-3561.166.

3CP / PE-1695

<img file="PT91092B_D0066.tif" />

medium, diethyl ether or any other solvent which does not impair the reaction.

The reaction temperature is not decisive and the reaction

Mod. 71-10000 ex. -89/07 is generally effected by heating to cooling.

Process 6:

Compound (1g) or a salt thereof may be prepared by reacting compound (Ie) or a salt thereof with compound (XI) or a salt thereof.

Suitable salts of compound (1g) may be those exemplified for compound (I).

This reaction is generally carried out in a solvent such as benzene, N, N-dimethylformamide, tetrahydrofuran, alcohol (e.g. methanol, ethanol, etc.), chloroform, diethyl ether or any other solvent which does not impair the reaction.

The reaction temperature is not decisive and the reaction is usually carried out with cooling to heating.

Process 7:

Compound (II) or a salt thereof may be prepared by subjecting Compound (Ih) or a salt thereof to the amino protecting group elimination reaction.

This reaction is effected substantially by the same process as that of Process A - (3), and therefore the process

-3661.166

3CP / PE-1,695

<img file="PT91092B_D0067.tif" />

and the reaction conditions are those of said Process

Process 8:

Compound (Ik) or a salt thereof may be prepared by subjecting Compound (1j) or a salt thereof to the carboxy protecting group removal reaction.

This reaction is carried out by a process substantially the same as Process 3, so the process and reaction conditions are those of Process 3.

Process 9:

Compound (Im) or a salt thereof may be prepared by subjecting Compound (II) or a salt thereof to the imino protecting group elimination reaction.

therefore the process

This reaction is carried out by a process essentially the same as that of Process A - φ, and therefore the reaction process and conditions may be those of that Process.

THE -

<img file="PT91092B_D0068.tif" />

Process 10:

Compound (in) or a salt thereof may be prepared by reacting compound (XII) or its reactive derivative on the carboxy group or salt thereof with compound (XIII) or its reactive derivative on the amino group or salt thereof.

Suitable reagent derivatives on the carboxy group

-5761.166

BCP / PS-1695

Compound (XII) may be those exemplified for compound (V).

Suitable reagent derivatives on the amino group of compound (XIII) may be those exemplified for compound (IV).

This reaction is effected by essentially the same process as that of Process 2, and therefore the reaction process and conditions may be those of said Precision.

2.

Mod. 71-10000 ex. -89/07

Process 11:

Compound (Ip) or a salt thereof can be prepared by reacting compound (10) or a salt thereof with compound (XIV) or a salt thereof.

This reaction is generally carried out in the presence of base.

An acceptable basis can in Process 1.

be one of the exemplified

This reaction is generally carried out in a solvent such as alcohol (e.g. methanol, ethanol, etc.), benzene, β, β-dimethylformamide, tetrahydrofuran or any other solvent which does not impair the reaction.

The temperature of the reaction is not decisive, and the reaction is usually carried out at room temperature with mild heating or strong heating.

<img file="PT91092B_D0069.tif" />

61.166

3CP / PE-1695

Process 12:

Compound (Ir) or a salt thereof may be prepared by subjecting Compound (Iq) or a salt thereof to removal reaction of amino protecting group and carboxy protecting group.

This reaction is carried out by essentially the same process as that of Process A - (3), and therefore the process and reaction conditions are those of said Process.

A - Ç £.

Process 15:

Compound (lt) or a salt thereof may be prepared by reacting compound (Is) or its reactive derivative in the amino group or a salt thereof with compound (XV) or its reactive derivative in the carboxy group or salt thereof.

Suitable reagent derivative in the amino group of compound (Is) may be one of those exemplified for compound (IV).

Suitable reagent derivative on the carboxy group of compound (XV) may be one of those exemplified for compound (V).

This reaction is carried out by essentially the same process as that of Process 2, and therefore the process and reaction conditions are those of said Process 2.

Process 14:

-39- 7. jJu κ · σ9

61.166 / ' /

BCP / PE-1695. , /^%

Compound (Iu) or a salt thereof may be prepared by reacting Compound (lo) or a salt thereof with Compound (XVI) or a salt thereof.

This reaction is generally carried out in a solvent such as α, β-dimethylformamide, tetrahydrofuran, or any other solvent which does not impair the reaction.

When compound (XVI) is liquid, it may be used as a solvent.

The reaction temperature is not decisive and the reaction is usually carried out at room temperature with mild heating or strong heating.

Process 15:

Compound (Iw) or a salt thereof may be prepared by reacting compound (iv) or a salt thereof with compound (XVII) or a salt thereof.

This reaction is carried out by essentially the same process as Process 1, and therefore the process and reaction conditions may be those of Process 1.

1.

Process 16:

Compound (Iy) or a salt thereof may be prepared by subjecting Compound (Ix) or a salt thereof to the imino protecting group removal reaction.

This reaction is carried out by essentially the same

-4061.166

BCP / PE-1695

<img file="PT91092B_D0070.tif" />

Process 9, and therefore the reaction process and conditions may be those of Process 9.

The processes for preparing the starting compound (IV) are explained below.

Process Compound (VIII) or a salt thereof may be prepared by reacting compound (VI) or a salt thereof with compound (VII) or a salt thereof. The process and reaction conditions may be those of Preparation 1 mentioned below.

Case A

<img file="PT91092B_D0071.tif" />

Compound (IX) or a salt thereof may be prepared by reacting compound (VIII) or a salt thereof with compound (III) or a salt thereof. This reaction is carried out by essentially the same process as Process 1, and therefore the process and reaction conditions are those of said Process 1.

Case A -:

Compound (IV) or a salt thereof may be prepared by subjecting Compound (IX) or a salt thereof to the amino protecting group elimination reaction.

Suitable salts of compound (IX) may be those exemplified for compound (I).

The elimination reaction is carried out according to a

-4161.166

BCP / PE-1695

<img file="PT91092B_D0072.tif" />

conventional process such as hydrolysis; reduction; Edman method (phenyl isocyanate method) or analogs. Hydrolysis may include a process using an acid or base or hydrazine and the like. These processes may be chosen according to the type of protecting groups to be removed.

Among these processes, hydrolysis using an acid is one of the most common and preferable for the removal of protecting groups such as substituted or unsubstituted alkoxycarbonyl, e.g. tert-pentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl, etc.). , cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.

Suitable acids include an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can be easily separated from the reaction mixture in conventional manner. for example distillation under reduced pressure, for example formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acids may be chosen according to the type of protecting group to be removed.

The elimination reaction using trifluoroacetic acid may be carried out in the presence of anisole. Hydrazine hydrolysis is currently applied for the elimination of a phthaloyl, succinyl-like amino-protecting group.

-4261.166

BCP / PE-1695

<img file="PT91092B_D0073.tif" />

Base-elimination is used for the elimination of an acyl group as trifluoroacetyl. The appropriate base may include an inorganic base and an organic base.

Reduction elimination is generally applied for the removal of the protecting group, for example haloalkoxycarbonyl (eg trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (eg benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. Appropriate reduction may include, for example, reduction with an alkali metal borohydrate (e.g. sodium borohydrate, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the like. metal together with a metal salt compound (e.g. chromic chloride, chromic acetate, etc.) and an inorganic or organic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); and catalytic reduction. Suitable catalysts include a conventional catalyst, for example Raney nickel, platinum oxide, palladium on carbon and the like.

Among the protecting groups, the acyl group can generally be removed by hydrolysis. In particular, the substituted halogen-alkoxycarbonyl and 8-quinolyloxycarbonyl groups are commonly eliminated by treatment with a heavy metal such as copper, zinc, etc.

The reaction is generally carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not impair the reaction.

The reaction temperature is not decisive and can be

-431 JuL. i2á3

61.166

BCP / PE-1695 is suitably chosen according to the type of amino protecting group and the aforementioned elimination process, and the reaction is generally carried out under moderate conditions, for example cooling or at a slightly elevated temperature. Among the protecting groups, the acyl group derived from λ-amino acid can be eliminated by the Edman method.

compound (I) object of the present invention and the pharmaceutically acceptable salts thereof are antagonists

CCK, and therefore useful as therapeutic agents for emesis, pancreatitis, etc. In order to show the usefulness of the compound (I) object of the present invention, the CCK antagonism of its representative compound is indicated as follows.

Mod. 71-10000 ex. 89/07

CCK receptor antagonism in isolated fundus circular muscle of guinea pig stomach / I? Experiment Compound:

(3RS) -1,3-Dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (hereinafter referred to as the test compound THE).

/ ll7 Experiment Method:

The circular muscle strip suspended in 25 ml organ bath containing Kreb bicarbonate solution (118 mM NaCl, 4.8 mM KCl, KH₂?0₄ 1.2 mM, MgSO₄, 1.2 mM, 2.5 mM CaCl 2, 25 mM NaHCO 3, 11 mM glucose and 0.1% bovine serum albumin) maintained at 37 ° C.^QC is gasified with 95% O2 and 5% CO2.

The strip is suspended under an initial tension of 0.5 g.

-4461.166

BCP / PE-1695 '' is equilibrated for 60 minutes during which the bath volume is replaced every 15 minutes. Isometric contraction is measured using a force transducer. CCK-8 (5.2 x 10'M) is added to the bath solution and the contractile force is measured. After washing off CCK-8, test compound A (1 x 10^JM) After 5 minutes, CCK-8 is added and the contractile force is measured. CCK antagonism is calculated by comparing CCK-induced contractile force in the absence or presence of test compound A.

/ “Lll7 Experiment Result Inhibition (%): 91

Mud 71 10000 ex. The compound (i) object of the present invention or pharmaceutically acceptable salts thereof may generally be administered to mammals, including humans, in the form of a conventional pharmaceutical composition such as capsule, microcapsule, tablet, granule, powder, troches, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, or the like.

The pharmaceutical composition of the present invention may contain various organic or inorganic materials which are conventionally used for pharmaceutical purposes, for example excipient (e.g. sucrose, starch, manita, sorbite, lactose, glucose, cellulose, talc, calcium phosphate, carbonate). calcium, etc.), binder (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl cellulose, calcium salt or carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.),

-45 ', Π

61.166

BCP / PE-1695. JUL

lubricant (eg magnesium stearate, talc, sodium lauryl sulfate, etc.), flavoring agent (eg citric acid, menthol, glycine, orange powders, etc.), preservative (eg sodium benzoate, sodium bisulfite, methylparaben, propyl paraben, etc.), stabilizer (eg citric acid, sodium citrate, acetic acid, etc.), suspending agent (eg methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g. water, base wax (e.g. cocoa butter, polyethylene glycol, white petrolatum, etc.).

The effective ingredient may generally be administered at a unit dose of 0.01 mg / kg to 50 mg / kg, 1 to 4 times per day. However, the aforementioned dosage may be increased or decreased depending on the age, weight, condition of the patient or the method of administration.

The following preparations and examples are given solely for the purpose of describing the present invention in more detail.

Preparation I;

A mixture of (3RS) -1,3-dihydro-3-acetoxy-5-phenyl-2H-1,4-benzodiazepin-2-one (11.75 g), potassium phthalimide (11.1 g), iodide sodium chloride (60 g) and β, β-dimethylformamide (80 ml) was stirred for 45 minutes at 90 to 95 ° C.²C. The reaction mixture was poured into cold water (1%). The precipitate was collected by filtration, washed with water and recrystallized from ethanol to give (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (8, 32 g).

-4661.166

BCP / PE-1695

<img file="PT91092B_D0074.tif" />

IR (Nujol): 3500, 3370, 3230, 1780, 1720, 1695, 1610, 1575 cm¹

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

7.97 (4H, m), 11.90 (1H, br s)

Preparation 2

A mixture of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazipin-2-one (8.2 g), hydrazine hydrate (1.08 g) and tetrahydrofuran (160 ml) was stirred for 1.0 hour at room temperature and heated at reflux for 1.5 hours. After the precipitates were filtered off, the filtrate was evaporated to small volume and the equivalent volume of diisopropyl ether was added. Precipitates were collected by filtration to give (3RS) -1,3-dihydro-3-amino-5-phenyl-2H1,4-benzodiazepin-2-one (3.64g).

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

1480 cm ¹

NMR (DMSO-d6, δ): 4.30 (1H, s), 5.0 (2H, br s), 7.20-7.60 (9H, m)

Preparation 3

To a solution of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (1.90 g) in Δ, Ν-dimethylformamide (30 ml) was added. sodium hydride (62% suspension in mineral oil; 0.20 g) is gradually maintained while stirring with cooling (&lt;3 ° C). The mixture was stirred for 10 minutes under the same conditions. To the resulting mixture was added 33%

61.166

BCP / PE-1695

<img file="PT91092B_D0075.tif" />

2- / bromide^-(tetrahydropyran-2-yl) oxyethyl (1.60 g) in one portion. The mixture was stirred at room temperature for 1 hour and at 45 ° C.⁹C for 4.5 hours and allowed to stand overnight. The resulting reaction mixture was poured into water and extracted with ethyl acetate twice. The extract was washed with water and dried over magnesium sulfate. Separation of the solvent afforded a light yellow powder, which was washed with a mixture of ethyl acetate and diethyl ether and collected by filtration to give a mixture (1.48 g) of (3 R 4 -1,3-dihydro-5). -phenyl-3-phthalid-1-yl-2- ((RS) -2-tetrahydro-pyanyloxy) ethyl-2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro 5-phenyl-3-phthalimido-1- [2 - ((SR) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepin-2-one.

IR (Nujol): 1770, 1714, 1670, 1600, 1375, 1130,

1014.710 cm^-1

NMR (CDCl₅d): 1.3-1.9 (6H, broad),

3.4-4.7 (7H, m), 6.00 (1H, s), 7.3-8.1 (13H, m)

Preparation 4

To a solution of a mixture (0.51 g) of (3RS) -1,3-dihydro-5-phenyl-3-phthalimido-1- {2 - ((RS) -2-tetrahydropyranyloxy) ethyl} -2H-1 , 4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5-phenyl-3-phthalido-1- [2 - ((SR) -2-tetrahydroimidanoxy) ethyl] -2H -1,4-Benzodiazepin-2-one in chloroform (10 ml) was added hydrazine hydrate (55 mg) at room temperature while stirring. The mixture was stirred for 1.5 hours under the same conditions and was heated at reflux for 1.5 hours. After cooling, the resulting precipitate was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in a

-48- Λ

61.166 ; \

3CP / PE-1695,? A small amount of ethanol was added and diethyl ether was added thereto. The white powder was separated again and the filtrate was evaporated to give an impure mixture (0.43 g) of (3R5) -1,3-dihydro-5-phenyl-3-amino-1 H -1 2- ( (RS) -2-Tetrahydropyranyl xi) ethyl-2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5-phenyl-3-amino-1-β 2 - ((SR) -2-tetrahydropyranyloxy) ethyl} -2H-1,4-benzodiazepin-2-one.

IR (Nujol): 3340, 1680, 1660, 1600, 780, 760,

695 cm

Example 1

To a solution of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (1.18 g) in N, N-dimethylformamide ( 10 ml) sodium hydride (62% suspension in mineral oil; 0.26 g) was added while stirring and cooling to 0 ° C in an ice-salt bath in a circulating nitrogen atmosphere. After the mixture was stirred for 40 minutes under the same conditions, 5-chloromethyl tetrazole (0.39 g) was added. The resulting mixture was stirred at room temperature for 66 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and the aqueous solution was washed with ethyl acetate. After separating a small amount of insoluble material by filtration, the separated aqueous layer was acidified with dilute hydrochloric acid.

The acidified aqueous mixture was extracted twice with ethyl acetate and the extract was washed with water and dried over magnesium sulfate. Separation of the solvent afforded an orange oil (1.27 g), which was chromatographed on silica gel with an eluent of a mixture.

-4961.166

Chloroform BCP / PE-1695 (10: 1) to give the desired pure product of (5RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- (5-tetrazolylmethyl) -2H-1,4-benzodiazepin-2-one (0.5 g).

mp: 190-195 ° C (dec)

IR (Nujol): 3350 (sh), 5250, 1680, 1655, 1600,

740,695 cm

NMR (DMSO-d₆, j): 5.42 (2H, ABq), 5.70 (1H, d, J = 8.0 Hz), 6.9-8.0 (15H, m), 9.44 (1H, d,

J = 8.0 Hz), 11.6 (1H, broad s)

Mass: m / e = 447 (M⁺)

Example 2

To a mixture of indole-2-carboxylic acid (0.19 g), N-hydroxybenzotriazole (0.16 g) and N, N-dicyclohexylcarbodiimide (0.24 g) in chloroform (10 ml) was added a mixture. (0.43 g) of (5RS) -1,3-dihydro-5-phenyl-5-amino-1 - ((RS) -2-tetrahydropyranyloxy) ethyl} -2H-1,4-benzodiazepin-2-one and (5RS) -1,3-Dihydro-5-phenyl-3-amino-1- [2 - ((SR) -2-tetrahydropyranyloxy) ethyl] -1H-1,4-benzodiazepin-2-one at room temperature while maintaining in agitation. The mixture was stirred for 2 hours under the same conditions. The resulting precipitate was filtered off. The filtrate and the combined washes were evaporated under reduced pressure and the residual oil (1.20 g) was column chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1). to give a mixture (white powder, (5RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1-2 ((RS) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepine (0.45 g) -2-one and (3RS) -1,3-dihydro-5- (2-indolylcarbonylamino) -5-phenyl-1- [2 - ((SR) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-one benzodiazepin-2-one.

-5061.166

BCP / PE-1695

IR (Nujol): 3340, 3280, 1680, 1630, 1610 (sh),

750, 700 cm¹

NMR (CDCl 3): 1.0-2.0 (6H, m), 3.1-4.7 (7H, m),

5.82 (1H, d, J = 8Hz), 7.0-7.9 (14H, m),

8.13 (1H, d, J = 8Hz), 9.62 (1H, broad)

<img file="PT91092B_D0076.tif" />

%

Example 5

To a suspension of a mixture (0.42 g) of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1-2 ((RS) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepin-2-one and (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- [2 - ((SR) -2-tetrahydropyranyloxy) ethyl] -2H-1,4-benzodiazepin-2-one in acetone (10 mL) was added 6N-hydrochloric acid (0.4 mL) while stirring at room temperature. After the clear yellow solution was stirred for 45 minutes, additional 6N-hydrochloric acid (0.4 ml) and water (1 ml) were added. The mixture was stirred for 0.5 hours at room temperature. Neutralization with aqueous sodium bicarbonate solution and acetone separation gave yellow precipitates, which were collected by filtration, washed with water and dried. 0 The crude product was purified by silica gel column chromatography with an eluent of a mixture of chloroform and ethyl acetate (5: 1) to afford (3RS) -1,3-dihydro-1- (2-hydroxyethyl) -3- (2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2one (0.28 g) pure as amorphous. This was triturated in diethyl ether to give light yellow powder.

mp: 175-175 ° C²C (dec)

IR (Nujol): 3400 (sh), 326O, 1675 (sh), 1630,

1595, 740, 690 cm '¹

NMR (CDCl₅, δ): 2.32 (1H, broad), 3.65-4.4 (4H,

-5161.166

BCP / PE-1695

m), 5.74 (1H, d, J = 8Hz), 7.05-7.7 (14H, m),

8.02 (1H, d, J = 8Hz), 9.45 (1H, broad s)

MASS: m / e = 438 (M⁺)

(5) To a solution of a mixture (1.0 g) of (3R) -1,3-dihydro-5-phenyl-3 / ((2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) ) amino7-2H-1,4-benzodiazepin-2-one and (3S) -1,3-dihydro-5-phenyl-3 / ((2s) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) amino7-2H -1,4-benzodiazepin-2-one in α, β-dimethylformamide (5 ml) was added sodium hydride (77.4 mg, 62% suspension in mineral oil) while stirring with cooling in an ice-cold bath (ca. of 3C). The mixture was stirred under the same conditions. To the resulting mixture was added 2-acetoxyethyl bromide (0.37 g) at one time with stirring and cooling. The mixture was stirred for 1.5 hours with ice cooling and 2 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate twice. The extracts were combined, washed with saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave an oil (1.29 g), which was column chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (10: 1). Fractions containing the desired compound were combined and evaporated to afford a colorless oily mixture (0.84 g) of (3R) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl-3 / ( (2s) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) amino7-2H-1,4-benzodiazapin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl -3 - [((2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) amino] -2H-1,4-benzodiazepin-2-one.

-5261.166

BCP / PE-1695

Mod. 71-1 0000 ex, 89/07

IR (net): 3400 (shoulder), 33CO, 1730, 1700 (shoulder), 1690, 1660, 1600, 745, 695 cm^-1

NMR (CLC1₅, (f): 1.40 (9H, 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 (1H, broad d), 5.51 &amp; 5.53 (1H, d &amp; d), 7.2-7.85 (14H, m)

The following compound was obtained in a manner analogous to Preparation 5 (1).

(2) Mixture of (3R) -1- (2-acetoxyethyl) -1,3-dihydro-5- (2-fluorophenyl) -3 - / ((2S) -2-tert-butoxycarbonylamino-3-phenylpropanoyl) amino7 -2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5- (2-fluorophenyl) -3- /^-((2S) -2-tert-Butoxycarbonylamino-3-phenylpropanoyl) amino]

-2H-1,4-benzodiazepin-2-one.

IR (net): 3400 (shoulder), 3320, 1730,

1700 (shoulder), 1690, 1662, 1485, 1440,

1380, 1365, 1230, 1161, 1048, 750, 695 cm¹

NMR (CLClp): 1.40 (9H, s), 1.79 (3H, s)

3.0-3.3 (2H, m), 3.8-4.8 (5H, m), 5.07 (1H, broad d, J = 7.4 Hz), 5.53, 5.55 ( 1H, dd, J = 8Hz),

6.95-7.9 (14H, m)

Preparation 6

To a solution of a mixture (0.7 g) of (3R) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl-3 / ((2S) -2-tert-butoxycarbonylamino-3 -phenylpropanoyl) amino7-2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -1,3-dihydro-5-phenyl-3 / ((2S) -2-tert) ? -butoxycarbonylamino-3-phenylpropanoyl) amino7-2H-1,4-benzodiazepin-2-one in ethyl acetate (20 ml)

-53) - ?.

61.166

To cool down, tertiary hydrogen chloride was added to a stirred ice bath. After the solid was saturated with hydrogen chloride, the mixture was stirred for 30 minutes at the same temperature and for 1 hour at room temperature. After separation of the hydrogen chloride by passing bubbles of nitrogen gas, the mixture was evaporated under reduced pressure. To the residue was added water and the mixture was neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the extract was washed with water and dried with magnesium sulfate. Solvent separation afforded a mixture (0.57 g) of (3R) -1- (2-acetoxyethyl) -3- /^-((2S) -2-amino-3-phenylpropanoyl) amino7-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- (2-acetoxyethyl) -3 / ((2S) -2-amino-3-phenylpropanoyl) amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.

Preparation 7

A mixture (12.2 g) of (3R) -1- (2-acetoxyethyl) -3 - / ((2S) -2-amino-3-phenylpropanoyl) amino-1,3-dihydro-5-phenyl-2H -1,4-benzodiazepin-2-one (3R- isomer) and (3S) -1- (2-acetoxyethyl) -5- / ((2S) -2-amino-3-phenylpropanoyl) amino7 -1,3 -dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (3S- isomer) was subjected to silica gel column chromatography (230-400 mesh) with an eluent of a mixture of chloroform and methanol ( 20: 1). Fractions containing the compound object of the present invention were combined and evaporated to dryness to give pure 3S-isomer (3.32 g) as an oil. From the other fractions, an oily mixture (8.50 g) of 3S- isomer and 3R- isomer was obtained. The oily mixture was rechromatographed on silica gel (230-400 mesh) with an eluent of a mixture of chloroform and methanol (15: 1) to give a pure 3S-isomer.

-5461.166

Oily BCP / PE-1695 (1.50 g) and an oily pure 5R-isomer (4.01 g).

Mod. 71-10000 ex. 89/07

NMR (CDCl1)₅ + D₂0.05) 270 MHz:

5S-isomer

1.648 (5H, s), 2.817 (1H, dd, J = 14.0Hz, 10.8Hz), 5.556 (1H, dd, J = 14Hz, 6.5Hz), 5.704 (1H, dd, J = 10.8Hz) 6.5 Hz),

5.927 (1H, dt, J = 15.1 Hz, 6.5 Hz),

4.07-4.20 (2H, m), 4.660 (1H, octet, J = 15.6Hz, 7.6Hz, 7.6Hz), 5.578 (1H, s), 7.19-7.64 (14H , m)

5R-isomer

1.642 (5H, s), 2.696 (1H, dd, J = 14, CHz, 10.8Hz), 5.549 (1H, dd, J = 14.0Hz, 6.5Hz), 5.729 (1H, dd, J = 10 , 8Hz, 6.5Hz),

5.927 (1H, dt, J = 15.1 Hz, 6.5 Hz),

4.09-4.17 (2H, m), 4.690 (1H, octet, J = 15.6Hz, 7.6Hz, 7.6Hz), 5.571 (1H, s), 7.21-7.65 (14H , m)

Preparation 8

The following compounds were obtained according to preparation methods analogous to those of Preparations 6 and 7.

(5S) —1- (2-Acetoxyethyl) -5- (((2S) -2-amino-5-phenylpropanyl) amino-1,5-dihydro-5- (2-fluorophenyl) -2H-1, 4-benzodiazepin-2-one.

mp: 168-17030

IR (Nujol): 5410, 5560, 5525 (sh), 1742, 1680 (sh), 1667, 1610 (sh), 1600, 1480, 1448, 1240, 1108, 1045, 810, 781, 750, 699 cm^-1

-5561.166

BCP / PE-1695

- 7. JoL.

Mod. 71 10000 ex. - 89/07

NMR (CLClp): 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-Acetoxyethyl) -3 - [((2s) -2-amino-3-phenylpropanoyl) amino] -1,3-dihydro-5 - (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

IR (Film): 3400 (sh), 3360, 1738, 1685 (sh),

1668, 1605, 1510 (sh), 1495, 1450, 1380, 1328, 1240, 1220, 1108, 1045, 820, 750, 700 cm¹

NMR (CDCl1)₃, (f): 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, m),

4.5-4.8 (1H, m), 5.61 (1H, d, J = 8Hz),

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

(1) A solution of (3S) -1- (2-acetoxyethyl) -3 - / ((2s / -2-amino-3-phenylpropanoyl) amino-1,3-dihydro-5-phenyl-2H- 1,4-Benzodiazepin-2-one (4.65 g) and phenyl isothiocyanate (1.43 g) in methylene chloride (100 ml) was heated on a steam bath while stirring. methyl chloride (100 ml) was added to the residue The procedure described above was repeated three times. Then methylene chloride was separated completely under reduced pressure to give an oily intermediate (thiourea derivative). Trifluoroacetic acid (80 ml) was added to the oil and the mixture was heated in a water bath adjusted to 52 ° C while stirring for 20 minutes. The solvent was separated

<img file="PT91092B_D0077.tif" />

61.166

BCP / PE-1695 under reduced pressure and the residue was treated with methylene chloride and diethyl ether twice respectively to give a viscous red oil, which was subjected to silica gel column chromatography with an eluent of a chloroform mixture. and methanol (15IL). Fractions containing the desired compound were combined and evaporated to afford an orange oil (2.24 g). The oil was dissolved in ethyl acetate and washed with a small amount of aqueous sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Separation of the solvent afforded (3S) -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 cm¹NMR (CDCl1)₅H): 1.66 (3H, s), 2.90 (2H, br s),

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

Z &lt;7p⁶’⁸ : -111.735 (0.00260 g / ml, CHCl3)

The following compounds were obtained analogously to Preparation 9 (1).

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

IR (Film): 3370, 3300, 1725, 1665, 1600 cm¹NMR (CDCl1)₅, Q: 1.66 (3H, s) 2.89 (2H, br s),

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

ZX7 ^^6,8 : 123.632 (0.00312 g / ml, CHCl3) (3) (3S) -1 - (- Acetoxyethyl) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4 -benzodiazepin-2-one

IR (Film): 3450 (sh), 3380, 3325 (sh), 1738,

1680, 1660 (sh), 1605, 1580, 1490, 1455,

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3CP / PE-1695

Mod. 71 10000 ex. 89/07

1375, 1332, 1230, 1110, 1050, 820, 760,

745 cm^-1

NMR (CDCl1)₅, δ): 1.81 (3H, s), 3.8-4.8 (6H, m),

6.95-7.9 (9H, m) [delta]: -57.682 (3.0 mg / ml, CH₂C1₂) (4) (3R) -1- (2-Acetoxyethyl) -3-amino-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

IR (Film): 3450 (sh), 3350, 3325 (sh), 1736,

1690 (sh), 1673, 1650. (sh), 1600, 1580, 1482, 1450, 1370, 1328, 1222, 1105, 1000, 815,

750 cm¹

NMR (CDCl3): 1.80 (3H, s), 3.8-4.8 (6H, m),

6.95-7.9 (9H, m)

Z ^ 7p⁵ : 50.522 (3.18 mg / ml, CH₂C1₂)

Example 4 (1) To a solution of (3S) -1- (2-acetoxyethyl) -3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1.35 g) In β, β-dimethylformamide (25 ml) were added indole-2-carboxylic acid (0.64 g), N-hydroxybenzotriazole (0.54 g) and N, β'-dicyclohexylcarbodiimide (0.83 g). ) while stirring at room temperature. The mixture was stirred for 2 hours at the same temperature and allowed to stand overnight. The resulting precipitates were filtered off and the filtrate and washings were combined. The solvent (α, β-dimethylformamide) was evaporated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution twice and dried over magnesium sulfate. Solvent separation provided an oil

-5861.166

BCP / PE-1695 (3.05 g) which was subjected to silica gel column chromatography with an eluent of a mixture of chloroform and methanol (15: 1). Fractions containing the desired product were combined and evaporated under reduced pressure to give (5S) -1- (2-acetoxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one (1.90 g).

IR (Nujol): 3325, 3260, 1735, 1680, 1630, 1600,

1250, 745, 697 cm^-1

NMR (CDCl3?): 1.65 (3H, s), 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),

9.98 (1H, br s)

MASS: m / e = 481 (M⁺)

Z ~ ^ 7p^6,8 : -51.272 (0.00340 g / ml, CHCl3)

The following compounds were obtained in a manner analogous to that of Example 4 (1).

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

IR (Nujol): 3325, 3260, 1735, 1680, 1630, 1600,

1250, 745, 697 cm^-1

NMR (CDCl1)₃Δ): 1.65 (3H, s), 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, br s)

MASS: fn / e = 481 (M⁺)

£ 7p⁶’⁸ : 58.902 (0.00300 g / ml, CHCl3

-5961.166

3CP / PE-1695

<img file="PT91092B_D0078.tif" />

' % ;7 ./

Mod. 71-10000 ex. (3) (3S) -1- (2- (2-Acetoxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-one benzodiazepin-2-one mp: 183-187 ° C (deo)

IR (Nujol): 3350 (sh), 3275, 1733, 1687, 1640,

1610 (sh), 1539, 1455, 1380, 1260, 1235, 821,

775, 750 cm¹

NMR (CDCl1)₃t): 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, broad s)

MASS: m / e = 498 (M⁺) '(4) (3R) -1- (2-Acetoxyethyl) -3- (2-indolylcarhonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one one mp: 185-189²C (dec)

IR (Nujol): 3325 (sh), 3260, 1726, 1682, 1635,

1610 (sh), 1535, 1448, 1372, 1255, 1226, 820,

770,745 cm^-1

NMR (CDCl1)₃cf): 1.81 (3H, s), 3.8-4.3 (3H, m),

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

MASS: m / e = 498 (M⁺)

Example 5 (1) A mixture of (3S) -1- (2-acetoxyethyl) -3- (2-indolicarbonylamino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 1.80 g) and potassium carbonate (0.30 g) in

-6061,166 '··' -V

BCP / PE-1695/85% aqueous ethanol (50 mL) was heated to 65 to 7020 ° C for 1 hour while stirring. After cooling, ethanol was separated under reduced pressure, and to the residue was added water. The aqueous mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. Separation of the solvent afforded a light yellow amorphous powder, which was chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (5: 1).

The fractions containing the desired product were combined and evaporated to give (5S) -1- (2-hydroxyethyl) -5- (2-indolylcarbonylamino) -1,5-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one. 2-one (1.47 g) as a colorless amorphous powder.

IR (Nujol): 5460 (shoulder), 5260, 1680, 1655,

1600, 745, 695 cm^-1

NMR (CDCl 3, δ): 2.7 (1H, br s), 5.65-4.5 (4H, m),

5.79 (1H, d, J = 8Hz), 7.0-7.9 (14H, m),

8.17 (1H, d, J = 8Hz), 10.15 (1H, br s)

MASS: m / e = 458 (M⁺) /λ.71)⁶’⁸ : -59.04 2 (0.00552 g / ml, CHCl3)

The following compounds were obtained in a manner analogous to that of Example 5 (1).

(2) (5R) -1- (2-Hydroxyethyl) -5- (2-indolylcarbonylamino) -1,5-dihydro-5-phenyl-2H-1,4-benzodiezepin-2-one.

IR (Nujol): 5400 (shoulder), 5260, 1680, 1655,

1600, 740, 695 cm^-1

NMR (CDCl1)₅, (R): 2.83 (1H, br s), 5.55-4.5 (4H, m),

5.78 (1H, d, J = 8Hz), 6.9-7.8 (14H, m),

-6161.166

BCP / PE-1695 £ Jul AJ

8.18 (1H, d, J = 8Hz), 10.28 (1H, br s) MASS: m / e = 438 (M⁺)

?? - ??,⁶*⁸ : 69.162 (0.00360 g / ml, CHCl3₅) (3) (3S) -1- (2-Hydroxyethyl) -3- (2-indolyl carbonyl ami.

no) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp: 190-195 ° C² C (dec)

IR (Nujol): 3400 (sh), 3270, 1680. (sh), 1640,

1610 (sh), 1535, 1485, 1450, 1379, 1330, 1220, 818, 770 (sh), 748 cm¹

NMP (CDC1₃δ): 2.17 (1H, s), 3.7-4.55 (4H, m),

5.79 (1H, d, J = 8Hz), 6.9-7.85 (13H, m),

8.12 (1H, d, J = 8Hz), 9.81 (1H, broad s)

MASS: m / e = 456 (M⁺)

Zk7p⁵ : -1.202 (3.32 mg / ml, CHCl₅) (4) (3R) -1- (2-Hydroxyethyl) -3- (2-indolylcarbonylamino) -1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp : 190-195² C (dec)

IR (Nujol): 3400 (sh), 3270, 1680. (sh), 1639, 1610 (sh), 1533, 1484, 1450, 1378, 1330, 1220, 818, 770 (sh), 745 cm¹

NMR (CLC1₃cf): 1.91 (1H, s), 3.7-4.55 (4H, m),

5.79 (1H, d, J = 8Hz), 6.9-7.85 (13H, m),

8.08 (1H, d, J = 8Hz), 9.61 (1H, broad s)

MASS: m / e = 456 (M⁺)

P_7f)⁵ : 0,99² (3.26 mg / ml, CHCl3)

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3CP / PE-1695

<img file="PT91092B_D0079.tif" />

Example 6 (1) To a solution of (3RS) -1,3-dihydro-3- (2-indolyl carbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (394 mg) in N, N-dimethylformamide (4ml) was added sodium hydride (62% suspension in mineral oil, 44 mg) while stirring at 0 ° C.^sC in an ice bath. The mixture was stirred for 1.0 hour at 0 to -5 ° C.^sC. 2-Methoxyethyl chloride (142 mg) was added. The mixture was stirred for 6.0 hours at 60 to 70 ° C.⁹C and cooled.

To the cooled reaction mixture was added acetic acid (0.5 mL), ethyl acetate (40 mL) and water (40 mL) while stirring. The organic layer was separated, washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with chloroform as eluent to give pure (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1- (2-methoxyethyl) -2H product. -1,4-benzodiazepin-2-one (110 mg).

mp: 180-185 ° C⁹C (dec)

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

1490 cm ¹

NMR (CDCl1)₃a): 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)

The following compound was obtained in a manner analogous to that of Example 6 (1).

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

-6361.166

BCP / PE-1695

IR (Nujol): 3325, 3250, 1720, 1680, 1630, 1530, 1448, 1375, 740, 695 cm^-1

NMR (DMSO-d6, d): 2.16 (3H, s), 4.71 (2H, s),

5.90 (1H, d, J = 7.5 Hz), 7.0-7.75 (14H, m), 8.09 (1H, d, J = 7.5 Hz), 10.01 (1H, broad s)

MASS: m / e = 45O (M⁺)

Example 7 (3RS) —1,3-Dihydro-1- (2-hydroxyethyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.30 g) was It was dissolved in a mixture of anhydrous dimethyl sulfoxide (1 mL) and benzene (1 mL) containing pyridine (Q056 mL) and trifluoroacetic acid (0.028 mL).

After addition of dicyclohexylcarbodiimide (0.42 g) the mixture was stirred overnight at room temperature. Water was added and insoluble dicyclobexylurea was filtered off. The filtrate was extracted with ethyl acetate twice and the organic layer was washed with water, aqueous sodium bicarbonate and water respectively. The extract was dried over magnesium sulfate and evaporated to give an amorphous oil (0.53 g) which was column chromatographed on silica gel with a mixture of chloroform and ethyl acetate (5: 1) as eluent. Fractions containing the materials of the present invention were combined and evaporated to a white powder, which was purified by washing with diisopropyl ether to give (3RS) -1,3-dihydro-1-formylmethyl-3-one. Pure (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.20 g).

mp: 1682 ° C (dec)

IR (Nujol): 3400 (shoulder), 3270, 1725, 1680,

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BCP / PE-1695

<img file="PT91092B_D0080.tif" />

1635, 1600, 1445, 1375, 745, 695 cm

NMR (CDCl1)₅δ): 4.68 (2H, s), 5.90 (1H, d,

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

J = 7.5 Hz), 9.66 (1H, s), 10.05 (1H, broad s)

MASS: m / e = 436 (M⁺)

Example 8

To a solution of (3RS) -1,3-dihydro-1-formylmethyl-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.44 g) in chloroform (10 ml) was added methoxycarbonylmethylene triphenylphosphorane (0.37 g). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a residual oil, which was column chromatographed on silica gel with a mixture of chloroform and ethyl acetate (10: 1) as eluent.

(3RS) -1,3-Dihydro-1- (Z) -3-methoxycarbonyl-2-propenyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine 2-one (64.6 mg) from the above fractions.

IR (Nujol): 3340, 3250, 1718, 1700, 1665, 1637,

1598, 1536, 1450, 1375, 805, 740, 690 cm ¹NMR (CLC1₅, δ): 3.74 (3H, s), 5.24 (2H, dd, J = 6Hz,

1.5Hz), 5.86 (1H, d, J = 8Hz), 5.90 (1H, dt, J = 12.7Hz, 1.5Hz), 6.21 (1H, dt, J = 12, 7Hz, 6Hz), 7.1-7.8 (14H, m), 8.13 (1H, d, J = 8Hz), 9.98 (1H, broad s)

(3RS) -1,3-Dihydro-1- (E) -3-methoxycarbonyl-2-propenyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2 -one (291.1 mg) from the last fractions.

-6561.166

30Ρ / ΡΞ-1695

<img file="PT91092B_D0081.tif" />

IR (Nujol): 3340, 3270, 1711, 1685, 1635, 1600, 1535, 1450, 1375, 830, 772, 740, 700 cm^-1

NMR (CLC1₅δ): 3.64 (3H, s), 4.7-4.82 (2H, m),

5.87 (1H, d, J = 7.5Hz), 5.88 (1H, dt, J = 16.5Hz, 1.5Hz), 6.94 (1H, dt, J = 16.5Hz, 4, 5Hz),

7.1-7.8 (14H, m), 8.11 (1H, d, J = 7.5 Hz),

9.92 (1H, broad s)

Mod. 71 10000 ex. 89/07

Example 9

A mixture of (3RS) -1-acetylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.30 g) and hydrazine hydrate (36.0 mg) in tetra 15-idrofuran (5 ml) was refluxed for 15 hours and concentrated to give an amorphous material (0.30 g).

This material (0.30 g) was chromatographed on silica gel with a mixture of chloroform and methanol (30: 1). After the solvent was separated from the objective compound containing fractions, the residue was sprayed into diisopropyl ether to give (3R3) -1- (2-hydrazinopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5 -phenyl-2H-1,4-benzodiazepin-2-one (white powder, 178 mg).

mp: 187² C (dec)

IR (Nujol): 3400 (shoulder), 3250, 1680, 1630,

1600, 1528, 1450, 1374, 800, 760, 740, 690 cm^-1

NMR (CDCl1)₃δ): 1.53 (3H, s), 4.75 (2H, A3q),

5.90 (2H, broad s), 5.87 (1H, d, J = 7.5 Hz), 7.0-7.75 (14H, m), 8.16 (1H, d, J = 7, 5Hz),

9.67 (1H, broad s)

MASS: m / e = 464 (M⁺)

-6661.166

BCP / PE-1695

-7.JULJS3%

Example 10

A mixture of (3RS) -1-acetylmethyl-1,3-dihydro-3- (2-indolicarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.42 g), and Hydroxylamine (62.5 mg) in ethanol (20 mL) was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and the residue was subjected to silica gel column chromatography with an eluent of a mixture of chloroform and methanol (40: 1). Fractions containing the objective product were combined and evaporated to give a pale green oil, which was sprayed on diisopropyl ether to afford (3P.S) -1- (2-hydroxyiminopropyl) -1,3-dihydro-3- ( 2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (177 mg).

mp: 187² C (dec)

IR (Nujol): 3400 (shoulder), 3250, 1680 (shoulder),

1635, 1600, 1532, 1450, 1375, 802, 765, 740,

695 cm ¹

NMR (CDCl1)₅d): 1.63 (3H, s), 4.75 (2H, Abq),

5.00 (1H, broad s), 5.87 (1H, d, J = 7.5 Hz),

7.1-7.8 (14H, m), 8.19 (1H, d, J = 7.5 Hz),

10.03 (1H, broad s)

MASS: m / e = 465 (M⁺)

Example 11 (1) To a mixture of (3RS) -1,3-dihydro-3- (2-indolyl carbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (800 mg) 1-Trityl-4-chloromethylimidazole (790 mg) and β, β-dimethylformamide (16 ml) were added sodium hydride (62% suspension in mineral oil, 168 mg) keeping

-6761.166

BCP / PE-1695 i

Ϊ

Mod. 71 -10000 ex. - 89/07 stirring and cooling to 0 ° C²C in an ice bath. The mixture was stirred for 30 minutes at 0 to 5 ° C.^sC and heated to 70 to 80 ° C²For 3.0 hours, to the cooled reaction mixture was added acetic acid (2.0 ml) and 6N hydrochloric acid (5 ml). The mixture was stirred for 1 hour at 60 ° C.⁹C. The cooled reaction mixture was poured into a mixture of ethyl acetate (100 mL) and water (100 mL) while stirring. The organic layer was separated, washed with water three times, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (20: 1) to give (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- (4-imidazolylmethyl) -5-phenyl-2H-1,4-benzo diazepin-2-one (306.0 mg).

mp: 195-200 °⁹ C (dec)

IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm -1.¹NMR (CLC1₅, d): 4.93 (2H, s), 5.75 (1H, d, J = 8Hz),

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

MASS: m / e = 474 (M⁺)

The following compounds were obtained in a similar manner to Example 11 (1).

(2) (3RS) —1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (4-imidazolylmethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp: 205-210²C (dec)

NMR (CDCl 3, 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)

MASS: m / e = 492 (M⁺)

-6861.166

3CP / PE-1695:? 3S (3) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- / (5-methylimidazol-4-yl) methyl7-5-phenyl-2H-1 4,4-benzodiazepin-2-one mp: 205-210 ° C? C (dec)

NMR (DMSO-d6, 6): 1.96 (3H, s), 4.80, 5.15 (2H,

ABq, J = 15Hz), 5.55 (1H, d, J = 8Hz), 6.90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz), 11.58 ( 2H, s)

MASS: m / e = 488 (M⁺) (4) (3RS) -1,3-Dihydr0-3- (2-indolylcarbonylamino) -1- (2-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 175-1802 ° C C (dec)

NMR (DMSO-d6, j): 5.10 (2H, s), 5.65 (1H, d,

J = 8Hz), 6.60-8.10 (16H, m), 9.36 (1H, d,

J = 8Hz), 11.65 (1H, br s), 11.90 (1H, br s)

MASS: m / e = 474 (M⁺) (5) (3RS) —1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (3-pyrazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 255-2602 ° C C (dec)

NMR (EMSO-d₆, J): 5.03, 5.30 (2H, ABq, J = 15Hz),

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

6.90-7.90 (15H, m), 9.43 (1H, d, J = 8Hz),

11.60 (1H, br s), 12.55 (1H, br s),

MASS: m / e = 474 (K⁺) (6) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (1,2,4-triazol-3-yl) methyl7-5-phenyl-2H-1,4-one benzodiazenin-2-one mp: 205-210 ° C (dec.)

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

-6961.166 _ - _Λ ~ '· 3ΐ. jpj

BCP / PE-1695 /; 'fi ii 3' / '

Ls 1

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

8.25 (1H, br s), 9.40 (1H, d, J = 8Hz),

11.65 (1H, br s)

MASS: m / e = 475 (M⁺) (7) (3RS) -1,5-Dihydro-5- (2-indolylcarbonylamino) -1-_j/^-2- (4-imidazolyl) ethyl7-5-phenyl-2H-1,4-benzodiazepin-2-one mp: 185-1902 C (dec.)

NMR (EMSO-d 6): 2.65 (2H, t, J = 7Hz), 5.85-4.20 (1H, m), 4.20-4.75 (1H, m), 5, 55 (1H, d, J = 8Hz),

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

MASS: m / e = 488 (M⁺)

Example 12

The following compound was obtained in a similar manner to Example 5 (1).

(3RS) -1,3-Ohydro-3- (2-indolylcarbonylamino) -1- (2-hydroxyethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

IR (Nujol): 3240, 1670, 1630, 1530 cm^-1

NMR (EMSO-d₆, /): 3.30-3.90 (2H, m), 3.90-4.40 (1H, m), 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, br s)

MASS: m / e = 456 (M⁺)

<img file="PT91092B_D0082.tif" />

61.166

3CP / P3-1695

Example 15

The following compounds were obtained in a similar manner to Example 6 (1).

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

NMR (CDCl1)₅a): 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, br s) (2) (3RS) -1- (2-Acetoxyethyl) -1,3-dihydro-3- (2-indo) : lilcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one

IR (Nujol): 3250, 1730, 1680, 1600, 1530 cm¹NMR (CDCl1)₃6.65: 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, br s) (3) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (2-isopropoxyethyl) -5-phenyl-2H-1,4-Benzodiazepin-2-one mp: 190-193 ° C

NMR (CLC H13.6): 0.98 (6H, d, J = 6Hz), 3.20-3.70 (3H, m), 3.80-4.40 (2H, m), 5.75 (1H, d,

J = 8Hz), 7.0-7.80 (14H, m), 8.05 (1H, d J = 8Hz), 9.66 (1H, br s)

MASS: m / e = 480 (M⁺) (4) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (3-methoxypropyl) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 170-175 ° C⁹ Ç

-7161.166

3CP / PB-1695 °;

<img file="PT91092B_D0083.tif" />

NMR (CLC1₅, J): 1.60-1.90 (2H, m), 5.15 (5H, s), 5.05-5.55 (2H, m), 5.40-4.0 (1H, m ), 4.25-4.65 (1H, m), 5.75 (1H, d, J = 8Hz), 7.0-7.75 (14H, m), 8.06 (1H, d, J = 8Hz), 9.60 (1H, br s)

MASS: m / e = 466 (M⁺) (5) (5RS) —1,5-Dihydro-5- (2-indolylearbonylamino) -1- (2-thienylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 165-1702 ° C C (dec)

NMR (CDCl₅d): 5.0, 5.67 (2H, ABq, J = 15 Hz),

5.80 (1H, d, J = 8Hz), 6.70-7.80 (17H, m),

8.10 (1H, d, J = 8Hz), 9.80 (1H, br s)

MASS: m / e = 490 (M⁺) (6) (3RS) -1,5-Dihydro-5- (2-indolylearbonylamino) -1-furfuri-5-phenyl-2H-1,4-benzodiazepin-2-one mp: 150-155 ° C (dec. )

NMR (CLC1₅t): 4.96, 5.55 (2H, ABq, J = 15Hz),

5.85 (1H, d, J = 8Hz), 6.20 (2H, s) 6.95 - 7.75 (15H, m), 8.10 (1H, d, J = 8Hz), 9.90 (IH, br s)

MASS: m / e = 474 (M⁺) (7) (5RS) -1,5-Bihydro-5- (2-indolylcarbonylamino) -1- (2-ethoxyethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 205-2102 ° C C (dec)

NMR (CDCl1)₃, /): 0.96 (5H, t, J = 7Hz), 3.55 (2H, q, J = 7Hz), 5.50-5.75 (2H, m), 5.80-4.20 (1H, m), 4.20-4.55 (1H, m), 5.80 (1H, d, J = 8Hz),

7.05-7.80 (14H, m), 8.10 (1H, d, J = 8Hz),

9.90 (1H, br s)

-7261.166

3CP / PE-1695 &lt;* '.--. Η

JL.

(8) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (2-methoxyethyl) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one mp : 230-2352 C (dec)

NMR (CDCl1)₅t): 3.20 (3H, s), 3.40-3.75 (2H, m),

3.80-4.16 (1H, m), 4.20-4.55 (1H, m), 5.76 (1H, d, J = 8Hz), 6.90-7.80 (13H, m ),

8.10 (1H, d, J = 8Hz), 9.95 (1H, br s)

MASS: m / e = 47O (M⁺) (9) (3RS) -1,3-Dihydr0-3- (2-indolylcarbonylamino) -1- / (2-acetamidothiazol-4-yl) methyl7,5-phenyl-2H-1,4-benzodiazepin-2-one one mp: 175-180 ° C (dec)

NMR (CDCl1)₃, ά); 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, m), 8.25 (1H, d, J = 8Hz),

9.56 (1H, s), 10.0 (1H, s) (10) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (2-bromoethyl) -5-phenyl 2H-1,4-ben zodiazepin-2-one

NMR (CDCl1)₅, j): 3.30-3.70 (2H, m), 3.85-4.40 (1H, m), 4.60-5.20 (1H, m), 5.83 (1H, d, J = 8Hz), 7.0-7.90 (14H, m), 8.15 (1H, d, J = 8Hz),

10.05 (1H, s) (11) (3RS) -1,3-Dihydro-1- [2- (2-tetrahydropyranyl) -3-OXO-2,3-dihydroisoxazol-5-yl] methyl7-3- ( 2-indolylcarbonyl amino) -5-phenyl-1,4-benzodiazepin-2-one

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

-7361.166 . 7

30Ρ / ΡΕ-1695 / / *

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

4.8-5.6 (4H, A3q), 5.89 (1H, d, J = 8Hz),

7.1-7.9 (14H, m), 8.04 (1H, d, J = 8Hz),

9.7 (1H, br s) (12) (3RS) -1,3-Dihydro-3- / (5-chloroindol-2-yl) carbonyl amino7-5-phenyl-1- (2-methoxyethyl) -2H-1,4-benzodiazepin-2-one mp&gt; 2602 ° C

IR (Nujol): 3350 (sh), 3290, 1668, 1630, 1596,

1530, 1445, 1374, 1324, 1240, 1215, 1110, 910,

759, 690 cm ¹

NMR (CDCl1)₃t): 3.10 (3H, s), 3.45-3.75 (2H, m),

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

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

10.26 (1H, br s)

MASS: m / e = 487 (M⁺) (13) (3RS) -1,3-Dihydro-3- / (5-methoxyindol-2-yl) carbonylamino7-5-phenyl-1- (2-methoxyethyl) -2H-1,4-benzodiazepin-2-one one mp: 221-2222 C

IR (Nujol): 3400 (sh), 3250, 1673, 1630, 1596, 1530, 1447, 1375, 1322, 1235, 1115, 1024,

842, 802, 762, 694 cm¹

NMR (CDCl1)₅Δ): 3.11 (3H, s), 3.45-3.75 (2H, m),

3.82 (3H, s), 3.80-4.55 (2H, m), 5.78 (1H, d, J = 8.0 Hz), 6.75-7.7 (13H, m), 8.04 (1H, d, J = 8.0Hz), 9.90 (1H, br s)

MASS: m / e = 482 (M⁺)

-7461.166

BCP / PE-1695!&gt;

'hi. 353

5?

// (14) (3RS) -1- (3-Bromopropyl) -3- (2-indolylcarbonyl-amino) -5-phenyl 1-1,3-dihydro-2H-1,4-tenzodiazepin-2-one

IR (Nujol): 3400 (sh), 3250, 1675, 1633, 1600, 1530, 1445, 1375, 1242, 100, 742, 692 cm¹

NMR (CDCl1)₃(1): 1.8-2.3 (2H, m), 2.95-3.4 (2H, 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, m), 8.15 (1H, d, J = 8Hz), 9.97 (1H, br s)

Example 14

A mixture of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- / (2-acetamidothiazol-4-yl) methyl7-5-phenyl-2H-1,4-benzodiazepin-2-one , methanol (13 ml), tetrahydrofuran (8 ml) and concentrated hydrochloric acid (0.8 ml) were stirred for 7.0 hours at 70 ° C, cooled and adjusted to pH 7.0 with 5% aqueous solution. Sodium bicarbonate, to the mixture were added water (100 ml) and ethyl acetate (100 ml) with cooling. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of ethyl acetate and chloroform (2: 1) to give (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- / (2 -aminothiazol-4-yl) methyl7-5-phenyl-2H-1,4-benzodiazepin-2-one.

mp: 200-205 ° C (dec)

NMR (DMSO-d6, d): 4.80, 5.06 (2H, ABq, J = 15Hz),

5.60 (1H, d, J = 8Hz), 6.06 (1H, s), 6.75 (2H, br s), 6.90-7.95 (14H, m), 9.40 (1H , d, J = 8Hz),

11.65 (1H, s)

MASS: m / e = 506 (M⁺)

-7561.166

30P / PS-1695%

Example 15 (1) A mixture of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- / (E) -3-methoxycarbonyl-2-propenyl7-5-phenyl-2H-1,4 -benzodiazepin-2-one (0.47 g), tetrahydrofuran (15 ml), methanol (7.5 ml) and 1N aqueous sodium hydroxide (1 ml) were stirred for 1.0 hour at room temperature and cooled. To the cooled reaction mixture were added water (100 mL) and ethyl acetate (100 mL) and the mixture was adjusted to pH 4.0 with 6N hydrochloric acid, washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (1: 1) to give (3RS) -1,3-dihydro-3- (2-indiolylcarbonylamino) -1- /^- (E) -3-Carboxy-2-propenyl-5-phenyl-2H-1,4-benzodiazepin-2-one (80 mg).

mp: 175-1802 ° C (dec)

N4R (DMSO-d6): 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 = 8Hz), 11.58 (1H, br s)

MASS: m / e = 478 (M⁺)

The following compound was obtained in one manner. similar to that of Example 15 (1).

(2) (3RS) -1,3-Dihydr0-3- (2-indolecarbonylamino) -1- (Z) -3-carboxy-2-propenyl7-5-phen1-2H-1,4-benzodiazepin-2-one 2-one mp: 230-2352 ° C (dec)

NMR (DMSO-d₆α): 5.12 (2H, d, J = 4.5Hz), 5.68 (1H, 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 (M⁺)

<img file="PT91092B_D0084.tif" />

61.166

BCP / PE-1695

Example 16

A mixture of (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -1- (2-bromoethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.3 g) and 1-methylpiperazine (3.0 ml) was stirred for 4.0 hours at room temperature and diisopropyl ether (20 ml) was added. The resulting precipitates were collected by filtration and dissolved in dilute hydrochloric acid. The solution was adjusted to pH 7 with aqueous sodium bicarbonate solution and the resulting precipitates were collected by filtration to give (3RS) -1,3-dihydro-3- (2-indolylcarbonylamino) -? / 2- (4-methyl-1-piperazinyl) ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.20 g).

mp: 135-140 ° C (dec)

IR (Nujol): 3230, 1670, 1635, 1600, 1530 cra^-1NMR (CDCl 3, δ): 2.0-2.70 (13H, m), 3.60-4.10 (1H, m), 4.30-4.90 (1H, m), 5.83 ( 1H, d, J = 8Hz) 7.0-7.90 (14H, m), 8.20 (1H, d, J = 8Hz),

10.10 (1H, br s)

Example 17

A mixture of (3RS) -1-formylmethyl-3- (2-indolylcarbonylamino) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (0.5 g) and methoxyamine hydrochloride (144.1 mg) in ethanol (5 ml) was stirred for 3 hours at room temperature. After separation of the solvent, ethyl acetate and a dilute aqueous sodium bicarbonate solution were added to the residue. The organic layer was washed with water twice and dried over magnesium sulfate. Separation of the solvent afforded an amorphous material (0.56 g), which was subjected to co-77-

<img file="PT91092B_D0085.tif" />

61.166

3CP / PE-1695 column on silica gel, eluting with a mixture of chloroform and ethyl acetate (10: 1). The fractions containing the desired product were combined and evaporated to give a glassy material which was stirred in diisopropyl ether overnight to afford (3RS) -1- (2-methoxyiminoethyl) -3- (2-indolylcarbonylamino). ) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1: 1 mixture of de- and Z- isomers, 0.34 g) as a white powder.

mp: 169-1742 C

IR (Nujol): 3400 (sh), 3300, 1690, 1640, 1600,

1535, 1490, 1450, 1379, 1040, 850, 820, 772,

747, 699 cm^-1

NMR (CLC1₅cf): 3.72 and 3.87 (3H each s),

4.6-4.7 and 4.75-4.85 (2H, each dd, Q = 5.4 Hz,

3 Hz), 5.80 (1H, d, J = 8Hz), 6.62 and 7.05 (1H, each t, ​​J = 5.4Hz), 7.07-7.7 (14H, m), 8 .03 (1H, d, J = 8Hz), 9.78 (1H, br s)

MASS: m / e = 465 (M⁺)

Example 18

To a (3RS) -1,3-dihydro-1- [2- (2-tetrahydropyranyl) -3-oxo-2,3-dihydroisoxazol-5-yl] methyl] -3- (2-indolylcarbonylamino) -5 suspension -phenyl-1,4-benzodiazepin-2-one (212.9 mg) in methanol (4 ml) was added 2N hydrochloric acid while stirring at room temperature. Tetrahydrofuran (1 ml) was added to give a clear solution which was stirred at the same temperature for 30 minutes. The reaction mixture was evaporated to dryness to afford a yellow powder, which was washed with ether by stirring overnight, collected by filtration and dried to give (3RS) -1,3-dihydro. -1- / (3-hydroxyisoxazol-5-yl) -3- (2-indolylcarbonylamino) -7861,166

3CP / PE-1695

-5-phenyl-1,4-benzodiazepin-2-one (149.1 mg) as a yellow powder.

mp: 200 °⁹C (dec)

NMR (EMSO-d6, δ): 5.24 (2H, A3a, J = 15Hz, 25.5Hz),

5.67 (1H, d, J = 8Hz), 5.70 (1H, s), 7.0-7.85 (14H, m), 9.52 (1H, d, J = 8Hz), 11, 61 (1H, broad s)

MASS: m / e = 491 (M⁺)

Example 19

The following compounds were obtained in a similar manner to Example 6 (1).

(1) (3RS) -1- / 2- (2-Chloroethoxy) ethyl7-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one

NMR (CLCl1 Cf): 3.20-4.60 (8H, m), 5.80 (1H, d,

J = 8Hz), 7.0-7.80 (14H, m), 8.15 (1H, d, J = 8Hz), 10.20 (1H, br s) (2) (3RS) -1- ( 2-Vinyloxyethyl) -1,3-dihydro-3- (2-indorylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 210-215 ° C⁹C (dec)

NMR (CLC1₅,: 3.75-4.0 (4H, m), 4.0-4.20 (1H, m),

4.30-4.65 (1H, m), 5.76 (1H, d, J = 8Hz),

6.05-6.35 (1H, m), 7.0-7.75 (14H, m),

8.03 (1H, d, J = 8Hz), 9.53 (1H, br s)

MASS: m / e = 464 (M⁺)

-7961.166

BCP / PE-1695

- ί.

(3) (3RS) -1- (2-Benzyloxyethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzadiazyl-pin-2-one mp: 195-2002 ° C (dec)

NMR (CDCl₃, (f): 3.55-3.80 (2H, m),

3.80-4.20 (1H, m), 4.20-4.55 (1H, m),

4.30 (2H, s), 5.75 (1H, d, J = 8Hz),

6.96-7.80 (14H, m), 8.06 (1H, d, J = 8Hz),

9.85 (1H, br s) (4) (3RS) -1- (3,4-Dimethoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-one benzodiazepin-2-one mp: 220-2252 ° C (dec.)

IR (Nujol): 3300, 3200, 1680, 1635, 1590, 1525,

1505 cm ¹

NMR (CI) C1₅,: 3.40 (3H, s), 3.75 (3H, s),

4.70, 5.75 (2H, ABq, J = 15Hz),

5.90 (1H, d, J = 8Hz), 6.45-6.65 (3H, m),

7.10-7.80 (14H, m), 8.20 (1H, d, J = 8Hz),

9.98 (1H, br s) (5) (3RS) -1- (3,4-Diacetoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phen (1,2H-1,4) -benzodiazepin-2-one (6) (3RS) -1-Benzyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 145: 1502 C (dec)

IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm¹NMR (CDCl1)₅,: 4.88, 5.68 (2H, ABq, J = 15Hz),

5.93 (1H, d, J = 5Hz), 7.0-7.80 (19H, m),

8.25 (1H, d, J = 8Hz), 10.08 (1H, br s)

MASS: m / e = 484 (M⁺)

<img file="PT91092B_D0086.tif" />

61.166

3CP / PE-1695

4 'S' (7) (3RS) -1- (2-Phthalimidoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one

IR (Nujol): 3400, 3250.1770, 1712, 1678, 1646 cm^-1NMR (DMSO-d6, cf): 3.6-4.8 (4H, m), 5.60 (1H, d,

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

11.45 (1H, broad s) (8) (3RS) -1- (2-Methylthioethyl) -1,3-dihydro-3- (2-indolylcarbonylamino-5-phenyl-2H-1,4-yl) benzodiazepin-2-one mp: 149-1565 ° C

IR (Nujol): 3380 (sh.), 3270, 1672, 1635, 1595, 1530, 1445, 1375, 1320, 740, 690 cm¹

NMR (CDCl3): 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 = 8.4 Hz), 7.0-7.8 (14H, m),

8.11 (1H, d, J = 8.4Hz), 9.93 (1H, br s)

MASS: m / e = 469 (M⁺)

Example 20

A mixture of (3RS) -1- (3,4-diacetoxybenzyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (287 mg) , methanol (5 mL), tetrahydrofuran (5 mL), water (1 mL) and 1N aqueous potassium carbonate (5 mL) were stirred for 1.0 hour at 0 to 5 ° C.² C was then adjusted to pH 1 to 2 with 6N hydrochloric acid. To the mixture was added ethyl acetate (50 mL) and water (50 mL) while stirring. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an eluent of a mixture of chloroform and acetate.

-8161,166

3CP / PS-1695

<img file="PT91092B_D0087.tif" />

) ethyl (4: 1) to give (3RS) -1- (3,4-dihydroxybenzyl) -3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (155 mg ).

mp: 165-1702 ° C (dec)

NMR (CDCl3 -PMSO-d6, d): 4.75, 5.35 (2H, A3q,

J = 15Hz), 5.75 (1H, d, J = 8Hz), 6.20-6.60 (3H, m),

6.90-7.70 (14H, m), 8.35 (2H, br s), 8.96 (1H, d, J = 8Hz), 11.46 (1H, br s)

MASS: m / e = 516 (M⁺)

Example 21

To a solution of carbon tetrachloride (792.1 mg) in methylene chloride (20 ml) was added triphenylphosphine (2.70 g) while stirring at room temperature. To the resulting mixture was added (3RS) -1-formylmethyl-1,3-dihydro-3- (2-indoliylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.90 g) . The mixture was stirred for 6 hours at room temperature.

From the reaction mixture, methylene chloride was evaporated off. Water was added to the residue. The mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate twice. The extract was dried over magnesium sulfate and evaporated to give a red oil, which was column chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (20: 1). Fractions containing the objective compound were combined and evaporated to dryness to give a glassy material (0.20 g), which was sprayed on diisopropyl ether to give (3RS) -1- (3,3-dichloro-2-one). propenyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (138.8

-8261.166

BCP / PE-1695 mg) as a yellow powder, mp: 149-1522 ° C (dec.)

IR (Nujol): 3400 (sh.), 3550, 1680, 1640, 1535, 1450, 1378, 742, 694 cm¹

NMR (ECC1₅, J: 4.53 (1H, dd, J = 15Hz, 7.2Hz),

4.77 (1H, dd, J = 15Hz, 7.2Hz), 5.93 (1H, dd, J = 7.2Hz, 7, SHz), 5.77 (1H, d, J = 7.8Hz) , 7.0-7.7 (14H, m), 7.99 (1H, d, J = 7.8 Hz),

9.67 (1H, hr s)

MASS: m / e = 503 (M⁺)

Example 22

The following compound was obtained in a similar manner to Example 16.

(3RS) -1- / 2- (2-hydroxyethylamino) ethyl7-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one mp: 125-1302 ° C C (dec)

IR (Nujol): 3250, 1680, 1630, 1600, 1535 cm^-1NMR (CPC1₅, J ·): 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, H = 8Hz), 7.0-7.80 (14H, m),

8.25 (1H, d, J = 8Hz), 10.20 (1H, br s)

Example 23

A mixture of (3RS) -1- / 2- (2-chloroethoxy) ethyl7-1,3-dihydro-3- (2-indolecarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (700 potassium phthalimide (610 mg)

-8361.166

3CP / PE-1695 λαΟ • Q □ and Ν, Ν-dimethylformamide (5 ml) was kept stirring for 7 hours at 80-90 ° C^and C. The reaction mixture was poured into cold water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS) -1- / 2-phthalimidoethoxy) ethyl7,3-dihydro-3- (2-indolylcarbonylamino) -5 -phenyl-2H-1,4-benzodiazepin-2-one (0.9 g).

Example 24

Mod. 71 10000 ex. 89/07

A mixture of (3RS) -1- / 2- (2-chloroethoxy) ethyl7-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (500 mg) and 1-methylpiperazine (5.0 ml) was kept under stirring at 70 ° C.⁹ G for 5.0 hours. Then diisopropyl ether (30 ml) was added to the reaction mixture. After the resulting precipitate was filtered off, the filtrate was evaporated. The residue was washed with water and dried to afford (3RS) -1- / 2- (4-methyl-1-piperazinyl) ethoxy-7-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl -2H-1,4-benzodiazepin-2-one (0.43 g).

mp: 100-105 °² C (dec)

IR (Nujol): 3250, 1690, 1635, 1600, 1540 cm^-1NMR. (CDCl₅, (f): 2.15-2.60 (13H, m),

3.35-4.50 (6H, m), 5.80 (1H, d, J = 8Hz), 7.0-7.85 (14H, m), 8.15 (1H, d, J = 8Hz) ), 10.10 (1H, br s)

MASS: m / e = 564 (M⁺)

Example 25 (1) A mixture of (3RS) -1- (2-phthalimidoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one ( 1.04 g) and hydrazine hydrate (130 mg)

-8461.166

BCP / PE-1695

Mod. 71-10000 ex. 89/07¹ in Ν, Ν-dimethylformamide (10 ml) was heated to 70 ° C.⁹ 0 while stirring for 3 hours. Additional hydrazine hydrate (130 mg) was added. The resulting mixture was heated at 80 ° C and 12.5 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated off under reduced pressure to afford a viscous oil (1.03 g), which was purified by silica gel column chromatography with an eluent of a mixture of chloroform and methanol (50: 1). Fractions containing the desired product were combined and evaporated to give (3RS) -1- (2-aminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin -2-one (0.76 g) as an amorphous oil, which was sprayed into ether by stirring overnight to afford crystalline powder (456.2 mg).

IR (Nujol): 3260, 1690, 1660, 1620 cm^-1

NMR (CDCl1)₃, 4): 3.3-3.8 (3H, m), 4.0-4.4 (1H, m),

20 5.83 (1H, d, J = 8Hz), 6.12 (2H, broad t),

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

9.85 (1H, broad s)

The following compound was obtained in a similar manner to Example 25 (1).

(2) (3RS) -1- [2- (2-Aminoethoxy) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

mp: 130-135 ° C⁹ C (dec)

IR (Nujol): 3250, 1680, 1640, 1600, 1540 cm^-1

NMR (CDCl1)₃, U); 2.30-2.80 (2H, m), 3.0-4.0 (5H, m), 4.30-4.70 (1H, m), 5.80 (1H, s),

7.0-7.80 (14H, m)

-8561.166

BCP / PE-1695

Jo3

MASS: m / e = 481 (M⁺)

Example 26

Mixture of a mixture (0.66 g) of (3RS) -1- / 2 - ((2R) -2-tert.butoxycarbonylamino-2-benzhydryloxycarbonylethylthio) ethyl7,3-dihydro-3- (2-indolylcarbonylamino ) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- / 2 - ((2R) -2-tert.butoxycarbonylamino-2-benzbhydryloxycarbonylethylthio) ethyl7-1,3-dihydro 3- (2-Indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one, anisole (0.6 mL), trifluoroacetic acid (1.5 mL) and dichloromethane (15 mL) were stirred. for 3.0 hours at room temperature. After separation of the solvent, the residue was mixed with ethyl acetate (50 mL) and water (50 mL). The mixture was adjusted to pH 6-7 with 5% aqueous sodium bicarbonate solution while stirring. The organic layer was separated and concentrated. The resulting precipitate was collected by precipitation, washed with water and dried to give a mixture (0.20 g) of (3R) -1- / 2 ((2R) -2-amino-2-carboxyethylthio). ) Ethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one and (3S) -1- / 2 - ((2R) -2-amino -2-carboxyethylthio) ethyl7-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

mp: 190-195² C (dec)

NMR (CDCl3 +: 2.60-3.10 (4H, m),

4.0-4.40 (2H, m), 4.60-5.0 (1H, m),

5.96 (1H, s), 6.65-8.15 (14H, m)

MASS: m / e = 541 (M⁺)

Example 27

A mixture of (3RS) -1- / N- (ethoxycarbonylmethyl) carbamide

-8661.166

3CP / RE-1695

C 1-3-ylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (350 mg), tetrahydrofuran (10 ml) and hydroxide 1N aqueous sodium chloride (0.65 ml) was stirred for 4.0 hours at room temperature, and then water (50 ml) and ethyl acetate were added thereto. The mixture was adjusted to pH 1-2 with 1 N hydrochloric acid while stirring. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated. 0 The residue was crystallized from tetrahydrofuran to afford (3RS) -1- / N- (carboxymethyl) carbamoylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one. one (204 mg).

Mod. 7M0000ex. -89/07 mp: 170-175² 0 (dec.)

NMR (DM30-d₆, J): 3.77 (2H, d, J = 5Hz),

4.65 (2H, s), 5.73 (1H, d, J = 8Hz),

6.90-7.30 (14H, m), 8.50 (1H, tri, J = 5Hz),

9.45 (1H, d, J = 8Hz), 11.65 (1H, trs)

Example 28 (1) To a mixture of (3RS) -1-carboxymethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-1-2H-1,4-benzodiazepin-2-one (452 ​​mg ), 1-hydroxybenzotriazole (135 mg) and N, N-dimethylformamide (5 ml) were added N, N'-dicyclohexyl carbodiimide (206 mg) at 5 ° C while stirring. The mixture was stirred for 1.0 hour at room temperature, and glycine amide hydrochloride (74 mg) and triethylamine (120 mg) were added to the reaction mixture at 5 ° C. The mixture was stirred for 3.0 hours at room temperature. room temperature. The precipitates were filtered off and the filtrate was poured into a mixture of ethyl acetate and water. The resulting precipitates were selected by filtration to obtain (3RS) -1- / N- (carbamoylmethyl) -car-8761,166.

3CP / PE-1695.089 bamoylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (180 mg).

IR (Nujol): 3270, 1680, 1665, 1630, 1600,

1540 cm ¹

NMR (DMSO-d6, δ): 3.65 (2H, d, J = 5Hz), 4.65 (2H, s), 5.73 (1H, d, J = 8Hz), 6.90-7 , 80 (14H, m), 8.40 (1H, tri, J = 5Hz), 9.48 (1H, d, J = 8Hz), 11.65 (1H, s)

MASS: m / e = 508 (M⁺)

The following compounds were obtained in a similar manner to Example 28 (1).

(2) (3RS) -1- / N- (ethoxycarbonylmethyl) carbamoylmethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (3) (3R) -1- / N- ((1S) -1-Carbamoyl-2-phenylethyl) carbamoylmethyl-1,3-dihydro-3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1 , 4-benzodiazepin-2-one and (33) -1- / N - ((1S) -1-carbamoyl-2-phenylethyl) carbamoylmethyl7-1,3-dihydro-3- (2-indolylcarbonylamino) -5- phenyl-2H-1,4-benzodiazepin-2-one mp: 165-170 ° C (dec.)

IR (Nujol): 3230, 1680, 1650, 1600, 1525 cm^-1NMR (DMSO-d6, d): 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, br s)

MASS: m / e = 598 (M⁺)

-8861.166

BCP / P3-1695

-.1.-43 fi

Mod 71 10000 ex. - 89/07

Example 29

To a suspension of (3RS) -1-carboxymethyl-1,3-hydroxy-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (1.53 g) in Methylene (30 ml) was added oxalyl chloride (1.29 g) while stirring and cooling in an ice bath. The mixture was stirred for 3.5 hours at room temperature. 0 The solvent and excess oxalyl chloride were separated under reduced pressure and the residue was triturated in ether to give an acid chloride as an orange powder, which was collected by filtration, washed with ether and dried under reduced pressure. The well (0.5 g) was added to a solution of cyanoamine (0.17 g) and triethylamine (0.42 g) in methylene chloride (20 ml) while stirring at room temperature. The mixture was stirred for 2 hrs at the same temperature. To the reaction mixture was added methylene chloride (50 ml) and the mixture was washed with dilute hydrochloric acid and water. After being dried over magnesium sulfate, the organic layer was evaporated under reduced pressure. 0 The residue was subjected to silica gel column chromatography eluting with a mixture of ethyl acetate, n-hexane and acetic acid (2: 1: 0.1) to obtain the desired product, which was stirred. in ether to give (3R3) -1- [N- (cyano) carbamoylmethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one as of a light orange powder (0.14 g).

mp: 255-2602 c (dec)

IR (Nujol): 2170, 1680, 1640, 1600, 1540,

1460, 1380, 1305, 745 cm^-1

NMR (DMSO-d₆, J): 4.77 (2H, S), 5.75 (1H, d,

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

J = 8Hz), 11.50 (1H, broad s)

-8961.166

BCP / PE-1695. λ ..

'' '-r ·

Ί “- /

Ύ

Example 50

To a solution of (3RS) -1- (3-bromopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.52 g ) in β, β-dimethylformamide (3 ml) was added methanolic sodium methanethiolate prepared from 30% methanolic methanethiol (0.48 g) and IM methanolic sodium hydroxide (3.0 ml). The mixture was stirred for 6 hours and allowed to stand for 37 hours.

The reaction mixture was poured into water containing a few drops of acetic acid while stirring and extracted with ethyl acetate twice, and the extracts were combined, washed with water three times and dried over magnesium sulfate. The solvent was evaporated to dryness to give yellow oil (0.59 g) which was column chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (20: 1) to afford a material. vitreous (330 mg). This material was stirred in diisopropyl ether overnight to afford (3RS) -1- (3-methylthiopropyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-f θη yl-2H- 1,4-benzodiazepin-2-one (248.1 mg) as a white powder.

mp: 216-2212 c

IR (Nujol): 3430, 3260, 1673, 1638, 1600, 1532,

1450, 1375, 1270, 800, 778, 739, 695 cm¹

NMR (CDCl3 .d): 1.7-2.0 (2H, m), 1.9 (3H, s),

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

5.83 (1H, d, J = 7.8Hz), 7.1-7.8 (14H, m),

8.17 (1H, d, J = 7.8Hz), 10.01 (1H, br s)

MASS: m / e = 482 (M⁺)

-9061.166

BCP / PE-1695 ϊ

Example 31 (1) A mixture of (3RS) -1- (2-bromoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one ( 501 mg), triethylamine (0.12 g), 4-mercaptopyridine (0.133 g) and α, β-dimethylformamide (6 ml) were kept stirring overnight at room temperature. The reaction mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated, washed with water three times, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with an ethyl acetate eluent to give (3RS) -1-^-2- (4-pyridylthio) ethyl-1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (0.19 g) mp: 150-1559 ° C (dec.)

IR (Nujol): 3230, 1680, 1630, 1600, 1570, 1530 cm¹

NMR (CDCl1)₃, t): 3.0-3.30 (2H, m), 3.70-4.10 (1H, m), 4.40-4.80 (1H, m), 5.80 (1H, d); , J = 8Hz), 7.0-7.80 (16H, m), 8.10 (1H, d, J = 8Kz),

8.25-8.45 (2H, m), 10.05 (1H, br s)

MASS: m / e = 531 (M⁺)

The following compound was obtained in a similar manner to Example 31 (1).

(2) Mixture of (3R) -1- [2- (2R) -2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio) ethyl] -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl -2H-1,4-benzodiazepin-2-one and (3S) -1- / 2 - ((2R) -2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio) ethyl] -1,3-dihydro-3- (2 -indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one.

-9161.166

BCP / PE-1695

NMR (CLC1₅1.5): 1.40 (9H, s), 2.20-3.10 (4H, m), 3.50-4.0 (1H, m), 4.20-4.70 (2H, m) ),

5.15-5.45 (1H, m), 5.80 (1H, d, J = 8Hz),

6.90 (1H, s), 7.10-7.85 (24H, m), 8.15 (1H, d, J = 8Hz), 9.75 (1H, br s)

Example 32

To a solution of (3RS) -1- (2-aminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepin-2-one (434 mg) and Triethylamine (222 mg) in methylene chloride (4 ml) Acetyl chloride (172.8 mg) was added dropwise with cooling in ice water bath and stirring. The mixture was stirred for 4 hours under the same conditions. After the solvent was evaporated off under reduced pressure, water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water, then dried over magnesium sulfate. The solvent was evaporated off to give a brown oil (672.2 mg), which was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (30: 1). The fractions containing the desired product were combined and evaporated to give an amorphous product, which was sprayed into ether by stirring overnight. The crystalline powder was collected by filtration and washed with ether to give (3RS) -1- (2-acetylaminoethyl) -1,3-dihydro-3- (2-indolylcarbonylamino) -5-phenyl-2H-1 4,4-benzodiazepin-2-one (327.1 mg).

mp: 167-175 ° C⁹ C (dec)

IR (Nujol): 3250, 1690, 1672, 1635 cm¹

NMR (DMSO-d6.6): 2.25 (3H, s), 3.6-4.4 (4H, m),

5.59 (1H, d, J = 8Hz), 6.9-7.9 (14H, m), 9.48

-9261,166 '- 3CP / PE-1695. · ./ $

(1H, d, J = 8Hz), 11.48 (1H, broad s)

MASS: m / e = 479 (M⁺)

Preparation 10

Mod. 71-10000ex. -89/07

To a suspension of (3RS) -1,3-dihydro-5- (2-fluorophenyl) phthalimido-2H-1,4-benzodiazepin-2-one (1.0 g) and 1-trityl-4-hydrochloride Chloromethylylidazole (1.28 g) in N, N-dimethyl formamide (25 ml) was slowly added sodium hydride (40% suspension in mineral oil, 0.36 g) while stirring and cooling in a bath. ice, and the mixture was stirred at the same temperature for one hour and then at room temperature for 17 hours. After adding acetic acid (0.5 ml), the reaction mixture was poured into water (100 ml). The mixture was adjusted to pH 7 with an aqueous sodium bicarbonate solution while stirring. The resulting precipitates were collected by filtration, washed with water and dried under reduced pressure and heating to give a yellow powder (2.22 g).

The powder was purified by silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (20: 1) to give (3RS) -1,3-dihydro-5- (2-fluorophenyl ) -3-Phthalimido-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one (1.38 g).

NMR (DMSO-d6): 5.08 (2H, ABq), 5.75 (1H, s),

6.7-7.7 (29H, m)

Preparation II

To a (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-phthalimido-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one suspension (19.96 g) in tetrahydrofuran (200 ml)

-9361.166

3CP / PE-1695

Mod. 71-10000 ex. A solution of hydrazine hydrate (1.38 g) in methanol (10 ml) was added. The mixture was stirred at room temperature for 0.5 hours and then the clear solution was refluxed for 2 hours with stirring. The reaction mixture was cooled in an ice bath and the precipitates were filtered off. The filtrate and washings were evaporated under reduced pressure. The residue was dissolved in chloroform and the mixture was filtered. The filtrate was evaporated to give an oil (19.30 g) which was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (30: 1) to afford (3RS) -1,3-dihydro. -5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one (9.97 'g).

NMR (CD01₅d): 2.42 (2H, broad s), 4.49 (1H, s), 5.06 (2H, s), 6.8-8.0 (25H, m)

(12) To a solution of (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-one benzodiazepin-2-one (591.7 mg) in ethyl acetate (2 ml) was added a solution of (S) - (+) - mandelic acid (129.3 mg) in ethyl acetate (4 ml) keeping in stirring at room temperature. The precipitated gel was dissolved by the addition of methanol (0.2 ml). To the clear solution was added ethyl acetate (4 ml) and diisopropyl ether (three drops). The mixture was stirred for 2 hours and allowed to stand overnight. The resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried to give a white powder (202.2 mg), which was recrystallized from ethyl acetate to afford 9461,166.

BCP / PE-1695 cation (3RS) -1,3-Dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl) (S) - (+) - mandelic acid salt 4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one. in the form of crystals.

/\7|⁴ = -33.335 (C = 0.866, CH3 OH)

Additionally, a mixture of (3R) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trithi-4-imidazolyl) methyl-2H-1 was obtained from the filtrate. 4-benzodiazepin-2-one and (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin -2-one.

Mod. 71-10000 ex. -89/07 b

(2) (3S) -1,3-Dihydr0-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl (S) - (+) - mandelic acid salt -2H-1,4-benzodiazepin-2-one obtained in Preparation 12 (1) was suspended in a mixture of water and ethyl acetate. The resulting mixture was adjusted to pH.

7-8 with an aqueous sodium bicarbonate solution while stirring. The organic layer was separated, washed with water and evaporated to dryness to give (3RS) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl). 4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one (181.4 mg).

/ “* 7p⁴ = -35.34 δ (C = 0.866, CH3 OH)

(13) A mixture of (/ ^ 7 ^ = +14.4⁹) (1.57 g) of (3R) —1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin -2-one and (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazoli methyl-2H-1,4-benzodiazepin-2-one obtained in Preparation 12 (1) was dissolved in a mixture of ethyl acetate

-9561.166

3CP / PE-1695

-'UL.

ί ί

(5.3 ml) and methanol (0.5 ml). To this solution was added a solution of (R) - (-) - mandelic acid (342.7 mg) in ethyl acetate (20 ml) while stirring at room temperature. To this mixture was added diisopropyl ether (0.5 ml) and the resulting mixture was stirred for 2 hours and allowed to stand overnight. The precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried to give (3R) -1,3-dihydro-5-R (-) - mandelic acid salt. (2-fluorophenyl) -3-amino-1- (1- (1-trityl-4-imidazolylmethyl) -2H-1,4-benzodiazepin-2-one (white paddle, 685.6 mg).

/7_7|,⁴ = + 33.602 (0 = 0.848, CH₃OH) (2) (3R) -1,3-Dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-1,2H-1,4-benzodiazepine -2-One Treating (3R) -1,3-Dihydr0-5- (2-fluorophenyl) -3-amino-1- (1-trithi-4-imidazolyl) (E) - (-) - Mandelic acid salt ) methyl-2H, 1,4-benzodiazepin-2-one in a manner analogous to Preparation 12 (2).

= +37.915 (0 = 0.844, CH3 OH)

Example 33

The following compounds were obtained in analogous manner to Example 6 (1).

(1) (3S) -1,3-Dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylearbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one 2-one

-96 ~ Z; JJlZP Í'J6'S

61.166

BCP / PE-1695

NMR (CDCl1)₅3 ): 5.085 (2H, A3q), 5.76 (1H, d, J = 7.9Hz), 6.8-8.0 (30H, m), 8.10 (1H, d, J = 7.9Hz) ), 9.81 (1K, s) (2) (3R) -1,3-Dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl ) -2H-1,4-benzodiazepin-2-one

NMR (DMSO-d6, δ): 5.11 (2H, A3q), 5.64 (1H, d, J = 8, CHz), 6.7-8.0 (30H, m), 9.55 (1H, d J = 8.0 Hz), 11.66 (1H, s)

Mod. 71 10000 ex. (3) (3RS) -1,1-Dihydro-3- (2-indolicarbonylamino) -1- (4-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one

IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm¹ (4) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (4-imidazolylmethyl) -5- (2-fluorophenyl) -2H1,4-benzodiazepin-2-one

NMR (CBCl3?): 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 = 8Kz), 10.10 (1H, broads) (5) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- / (5-methylimidazole -4-yl) methyl / -5-phenyl-2H1,4-benzodiazepin-2-one.

NMR (DMSC-d₆, J); 1.96 (3H, s), 4.80, 5.15 (2H, ABq, J = 15Hz), 5.55 (1H, d, J = 8Hz),

6.90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz),

11.58 (2H, br s)

-9761.166

30Ρ / ΡΞ-1695 (6) (3S) -1,3-Bihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -1,4-benzodiazepine 2-one

NMR (BMSO-d6): 5.04 (2H, A3q), 5.63 (1H, d, J = 7.9Hz), 6.9-8.2 (15H, m), 9.58 ( 1E, d J = 7.9Hz), 11.65 (1E, s), 11.92 (1E, s) (7) (3R) -1,3-Bihydro-1- (4-imidazolylmethyl) -3- (2-Indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

NMR (DMSO-d6): 5.04 (2H, A3q), 5.62 (1H, d, J = 7.9Hz), 6.9-8.3 (15H, m), 9.58 ( 1H, d, J = 7.9 Hz), 11, bb (lE, s), 11.93 (1H, s) (8) (3RS) -1,3-Bihydro-3- (2-indolylcarbonylamino) -1 - (2-imidazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one

NMR (BMS0-d6): 5.10 (2E, s), 5.65 (1E, d, J = 8Hz), 6.60-8.10 (16H, m), 9.36 (1E, d, J = 8Hz), 11.65 (1H, br s), 11.90 (1H, br s) (9) (3RS) -1,3-Bihydro-3- (2-indolylcarbonylamino) -1- ( 3-pyr3zolimethyl) -5-phenyl-2d-1,4-benzodiazepin-2-one

NMR (BMSO-d6): 5.03, 5.30 (2H, A3q,

J = 15Hz), 5.65 (IE, d, J = 8Hz), 5.85 (1E, br s), 6.90-7.90 (15E, m), 9.43 (1E, d, J = 8Ez), 11.60 (1H, br s), 12.55 (1E, br s)

-9861.166

3CP / P3-1695

-1.

L. 233 (10) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- / (1,2,4-triazol-3-yl) methyl7-5-phenyl-2H1,4- benzoa zepin-2-one

NMR (DMSO-d6, d): 5.10, 5.35 (2H, ABq,

J = 15Hz), 5.66 (1H, d, J = 8Hz), 6.90-7.93 (15H, m), 8.23 ​​(1H, br s), 9.40 (1H, d, J = 8Hz), 11.65 (1H, br s) (11) (3RS) -1,3-Bihydro-3- (2-indolylcarbonylamino) -1- / 2- (4-imidazolyl) ethyl7-5-phenyl- 2H-1,4-benzodiazepin-2-one

NMR (DMSO-d6, J: 2.63 (2H, t, J = 7Hz), 3.85-4.20 (1H, m), 4.20-4.75 (1H, m),

5.55 (1H, d, J = 8Hz), 6.60 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d)

J = 8Hz), 11.65 (1H, br s) (12) (33) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-) hydrochloride fluorophenyl) -2H-1,4-benzodiazepin-2-one

NMR (DMSO-d6, d): 5.33 (2n, ABq), 5.69 (1H, d, J = 7.6 Hz), 7.0-8.0 (15H, m), 9.05 ( 1H, s), 9.60 (1H, d, J = 7.6 Hz), 11.74 (1H, s),

14.73 (1H, broad s)

Example 34

A mixture of (3S) -1,3-dihydro-5- (2-fluorophenyl) -3-amino-1- (1-trityl-4-imidazolyl) methyl-2H-1,4-benzodiazepin-2-one ( 0.79 g), indole-2-carboxylic acid (0.22 g),

-99 'ί Λ (ΐ_ ί &lt;? $ 3

61.166 ; /

3CP / PE-1695 /

N-hydroxybenzotriazole (0.18 g) and N, N'-dicyclohexylcarbodiimide (0.28 g) in N, N-dimethylformamide (8 ml) were stirred at room temperature overnight and filtered. The filtrate and washings were diluted with ethyl acetate. The mixture was washed with aqueous sodium bicarbonate solution. The separated organic layer was washed with water and dried over magnesium sulfate. The solvent was separated under reduced pressure to give a viscous oil (1.12 g), which was chromatographed on silica gel with an eluent of a chloroform-methanol (30: 1) mixture to give (3S) -1. 1,3-dihydro-1- (1-trityl -4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (amorphous substance, 0.97 f).

/ Tc?²³ = 32.472 (0 = 0.85, CH₃OH)

NMR (CDCl₃α): 5.085 (2H, ABq), 5.76 (1H, d, J = 7.9 Hz), 6.8-8.0 (30H, m), 8.10 (1H, d,

J = 7.9 Hz), 9.81 (1H, s)

Example 35

To a solution of (3R) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3-amino-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (0.81 g), indole-2-carboxylic acid (0.23 g), and N-hydroxybenzotriazole (0.19 g) in N, N-dimethylformamide (8 ml) were added 1-ethyl-3 hydrochloride - (3-dimethylaminopropyl) carbodiimide (0.27 g) and triethylamine (0.14 g) while stirring at room temperature. The reaction mixture was stirred for 4 hours at room temperature. To the reaction mixture was added ethyl acetate and water while stirring. The mixture was adjusted to pH 8 with an aqueous sodium bicarbonate solution. The organic layer was separated and extracted at ca-10061.166.

3CP / PS-1695 aqueous layer with ethyl acetate. The separated organic layer and extract were combined, washed with water twice and dried over magnesium sulfate. The solvent was separated under reduced pressure to give (3R) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) - 2H-1,4-benzodiazepin-2-one (1.0 g).

Γ / 7²^ = +41.589 (0 = 0.856, CH₃OH)

NMR (BMSO-d 6): 5.11 (2H, ABq), 5.64 (1K, d,

J = 8, QHz), 6.7-8.0 (30H, m), 9.55 (1H, d, J = 8, CHz), 11.66 (1H, s)

Mod. 71 10000 ex. - 89/07

Example 56

To a solution of (35) -1,3-dihydro-1- (1-trityl-4-imidazolyl) methyl-3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin -2-one (1.0 g) in N, N-dimethylformamide (10 ml) was added hydrochloric acid (7 ml) while stirring and cooling in an ice bath. The mixture was heated to 50 ° C.^and 0 and stirred for 2 hours. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture while stirring. The mixture was adjusted to pH 8 with an aqueous sodium bicarbonate solution. The separated organic layer was washed with water and dried.

Separation of the solvent afforded a viscous oil (1.20 g), which was chromatographed on silica gel with an eluent of a mixture of chloroform and methanol (20: 1) to afford (35) -1,3-dihydro-1. - (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (601.5 mg) as a yellow crystalline powder.

-10161.166

BCP / PS-1695

<img file="PT91092B_D0088.tif" />

/&gt; 7p⁰ = +24.682 (0 = 0.64, CHCl3)

NMR (DMSO-d6, δ): 5.04 (2H, A3q), 5.63 (1H, d,

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

J = 7.9 Hz), 11.65 (1H, s), 11.92 (1H, s)

- 7 ί¹?

¹ cul. Oob

Example 37

The following compound was obtained in a manner analogous to that of Example 36.

(3R) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzoadizepin-2-one / 7 |⁵ = -26.402 (0 = 0.64, CH01₇)

NMR (DMSO-d6, d): 5.04 (2H, A3q), 5.62 (1H, d, J = 7.9Hz), 6.9-8.3 (15H, m), 9.58 ( 1H, d, J = 7.9 Hz), 11.66 (1H, s), 11.93 (1H, s)

Example 38

To a solution of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one ( 215.1 mg) in methanol (5 ml) was added 6N-hydrogen chloride solution in ether (0.1 ml) with cooling. The light yellow solution was evaporated to dryness under reduced pressure. The residue was triturated in ether to give yellow powder, which was collected by filtration and washed twice with ether to afford (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- ( 2-Indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (197.1 mg).

-10261.166

BCP / PE-1695

<img file="PT91092B_D0089.tif" />

f = -35.942 (0 = 0.612, CH3 OH) mp: 214-2189 c (dec.)

NMR (DMSC-d6, δ): 5.33 (2H, ABq), 5.69 (1H, d, J = 7.6Hz), 7.0-8.0 (15H, m), 9.05 ( IH, s),

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

Example 39

To a solution of (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (246 mg) in methanol (10 ml) was added L - (+) - tartaric acid (75.0 mg) at room temperature. After being stirred for a few minutes, the mixture was concentrated to 2 ml.

The resulting light yellow salt was collected by filtration, washed with diisopropyl ether twice and dried to afford (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-) L - (+) tartrate. indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one (235.3 mg).

mp: 170-1752 ° C (dec)

NMR (EMS0-d₆, J): 4.31 (2H, s), 5.07 (2H, s),

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

9.58 (1H, d, J = 7.7Hz), 11.65 (1H, s)

Example 40

The following compound was obtained by reacting (3S) -1,3-dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2K-1,4-benzodiazepin-2-one. 2-one with methanesulfonic acid in analogous ways to Examples 38 and 39.

-10361.166

3CP / PE-1695

<img file="PT91092B_D0090.tif" />

<img file="PT91092B_D0091.tif" />

(33) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl-2H-1,4-benzodiazepin-2-one) methanesulfonate |^{3 4 *} = -31.32 ° (C = 0.632, CH₃OH) mp: 136-139⁹ 0 (dec.)

NMR (DMSO-d 6, α): 2.39 (3H), 5.33 (2H, A3q),

5.69 (1H, d, J = 7.7Hz), 7.0-7.8 (15H, m),

8.99 (1H, s), 9.58 (1H, d, J = 7.7Hz), 11.68 (1H, s), 14.26 (1H, broad)

Example 41

The following compounds were obtained analogously to Example 4 (1).

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

IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm^-1 (2) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (4-imidazolylmethyl) -5- (2-fluorophenyl) -2K-1,4-benzodiazepin-2-one.

NMR (CDCl₅δ): 4.85, 5.10 (2H, ASq, 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) (3) (3RS) —1,3-Lihydro-3- (2-indoliylcarbonylamino) -1- / (5-methylimidazole -4-yl) methyl7-5-phenyl-2H-1,4-benzodiazepin-2-one

-10461.166

3CP / P2-1695

NMR (DMSO-d 6): 1.96 (3H, s), 4.80, 5.15 (2H, Abc, J = 15Hz), 5.55 (1H, d, J = 8Hz), (6 90-8.15 (15H, m), 9.33 (1H, d, J = 8Hz),

11.58 (2H, br s)

- /.

(4) (3s) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one one

NMR (DMSO-d6, δ): 5.04 (2H, A3q), 5.63 (1H, d, J = 7.9Hz), 6.9-8.2 (15H, m), 9.58 (1H, d, J = 7.9Hz), 11.65 (1H, a), 11.92 (1H, s) (5) (3R) -1,3-Dihydro-1- (4-imidazolylmethyl) - 3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one

NMR (DMSO-d₆, J): 5.04 (2H, A3q), 5.62 (1H, d, J = 7.9 Hz), 6.9-8.3 (15H, m), 9.58 (1H, d, J = 7.9Hz), 11.66 (1H, s), 11.93 (1H, s) (6) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- (2-imidazolylmethyl) ) -5-phenyl-2H-1,4-benzodiazepine-2-one

NMR (DMSO-d6, δ): 5.10 (2H, s), 5.65 (1H, d, J = 8Hz), 6.60-8.10 (16H, m), 9.36 (1H, d, J = 8Hz), 11.65 (1H, br s), 11.90 (1H, br s) (7) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- ( 3-pyrazolylmethyl) -5-phenyl-2H-1,4-benzodiazepin-2-one

-10561.166

3CP / PZ-1695

<img file="PT91092B_D0092.tif" />

- /.

• Λ (8) (9) (10)

NMR (DMSO-d6, δ): 5.03, 5.30 (2H, ASq,

J = 15Hz), 5.65 (1H, d, J = 8Hz), 5.85 (1H, br s), 6.90-7.90 (15H, m), 9.43 (1H, d,

J = 8Hz), 11.60 (1H, br s), 12.55 (1H, br

s) (3RS) -1,3-Dihydro-3- (2-indolylcarbonylamino) -1- /^-(1,2,4-triazol-3-yl) methyl7-5-phenyl-2H • 1,4-benzodiazepin-2-one

NMR (DMSO-d₆(f): 5.10, 5.35 (2H, A3q, J = 15Hz), 5.66 (1H, d, J = 8Hz), 6.90-7.93 (15H, m),

8.23 (1H, br s), 9.40 (1H, d, J = 8Hz),

11.65 (1H, br s) (3RS) -1,3-Bihydro-3- (2-indolylcarbonylamino) -1- / 2- (4-imidazolyl) ethyl7,5-phenyl-2H-1,4-benzodiazepin -2-one

NMR (DMS0-d₆, J): 2.63 (2H, t, J = 7Hz),

3.85-4.20 (1H, m), 4.20-4.75 (1H, m),

5.55 (1H, d, J = 8Hz), 6.60 (1H, s), 6.93-7.85 (15H, m), 9.43 (1H, d, J = 8Hz),

11.65 (1H, br s)

(3S) -1,3-Dihydro-1- (4-imidazolylmethyl) -3- (2-indolylcarbonylamino) -5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one hydrochloride

NMR (BMSO-d6, δ): 5.33 (2H, ABq), 5.69 (1H, d, J = 7.6 Hz), 7.0-8.0 (15H, m),

9.05 (1H, s), 9.60 (1H, d, J = 7.6 Hz),

11.74 (1H, s), 14.73 (1H, broad s)

-106 • J: Jlit.

’^ctj3

61.166

3CP / PS-1695 filing of the corresponding applications for the invention described above was made in Great Britain on July 7, 1988.² 8816207.8; on August 31, 1988 under No. 8820560.4 and on October 7, 1983 under No.²8825660.9.

- R 3 IVI II TIP 3 3 1 ^ .- Process for the preparation of new benzodiazepine derivatives of formula:

Mod. 71 10000 ex. -89/07

<img file="PT91092B_D0093.tif" />

wherein is halogen, heterocyclic group which may have one or more appropriate substituent (s), aryl which may have one or more appropriate substituent (s),

-NH-R^J (wherein R3 is hydrogen, lower alkanoyl or hydroxy-lower allyl),

-S-r6 (θπι where R ^ is lower alkyl, carboxy-substituted lower alkyl and amino, protected carboxy-substituted lower aloyl and protected amino or pyridyl), * 7 * 7

-O-R '(where R' is hydrogen, hydroxy protecting group, lower alkyl, lower alkenyl, ar-lower alkyl, halo-lower alkyl, amino-lower alkyl, amino-lower alkyl protected, or

-107 /.

61.166 ' . 1

3CP / PE-1695