MC1616A1 - IMIDAZOBENZODIAZEPINE DERIVATIVES - Google Patents

Description

1

RAN 4008/332

x 99 38 imidazobenzodiazepine derivatives

The present invention relates to imidazo-benzodiazepine derivatives which conform to the general formula:

rj /n. conhr2 \ /

r5 . i lj h

■ Y Y V r a r4 ^ \ /

î II %./'

in which r"'" represents a hydrogen atom or a lower dialkyl(inf)-aminoalkyl radical or

2

lower alkyl, r represents a hydrogen atom or a lower alkanoyl or lower alkyl radical,

3

r represents a hydrogen atom or an alkali- radical

(less than noyloxyX or hydroxy, r represents a chlorine atom,

bromine- or fluorine or a trifluoromethyl radical and R^

represents an atom of hydrogen, fluorine, or chlorine.

3

provided that a) r cannot represent a

2

hydroxy radical when r is an alkanoyl radical

3

lower and b) r represents a hydrogen atom

1

when r is a lower dialkyl (inf) aminoalkyl radical,

and their pharmaceutically acceptable salts.

The compounds of formula I above exhibit anxiolytic activity without adverse side effects on the central nervous system, for example, excessive sedation and ataxia.

The compounds of formula I were described in general terms in US patent 4,280,957, making it a broad-ranging invention. It was only later that the compounds of formula I, which are subgenres of the original invention, were found to possess activity.

2

selective anxiolytic and are therefore free from the undesirable side effects found in many commercial anxiolytic agents, for example excessive sedation, ethanol potentiation and ataxia.

5 In this document, the term "lower alkanoyl" means an acylic residue derived from a straight- or branched-chain saturated aliphatic carboxylic acid containing 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, and the like. The term "lower alkanoyloxy" means a lower alkanoyl residue having a substituted oxygen group, such as acetoxy, propionyloxy, and the like.

In this paper, the term "lower alkyl," alone or in combination, includes straight-chain and branched-chain carbon-hydrogen radicals, as well as cyclic radicals, preferably carbon-

straight-chain or branched hydrogen such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and similar.

20 The expression "pharmaceutically acceptable salts"

This refers to salts with pharmaceutically acceptable mineral or organic acids such as sulfuric, hydrochloric, nitric, methanesulfonic, and p-toluenesulfonic acids. These salts can be formed very easily by a specialist familiar with the previous technique and the nature of the compounds to be converted into salts.

A preferred category of compounds with formula I are those in which R"*" represents a hydrogen atom,

2

R represents a hydrogen atom or the ethyl radical,

4/5

30 R represents a chlorine or fluorine atom and R represents a hydrogen atom.

Particularly preferred compounds of formula I are, for example:

35

3

9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1.4] benzodiazepine-3-carboxamide,

6-(2-chlorophenyl)-4H-imidazo[1,5-a][1.4]benzodiaz pine-3-carboxamide, 5 6-(2-chlorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]

benzodiazepine-3-carboxamide,

6-(2-chlorophenyl)-4-hydroxy-4H-imidazo[1,5-a 3[1,4] benzodiazepine-3-carboxamide and

N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]

10 benzodiazepine-3-carboxamide.

According to the present invention, compounds of formula I and their pharmaceutically acceptable salts can be prepared by a process which consists of:

a) to submit a compound of general formula

15

R\./\ /C00R

.. tî Û H

W \ /iN \ /H

l i X

20 VH

.A /R4

i fi

% /*

25 in which R represents an inferior alkyl radical

14 5

rieur and R, R and R have the same meanings as above,

21

to aminolysis with an amino compound of formula H„NR

21, where R represents a hydrogen atom or a lower alkyl radical, or b) to submit a compound of general formula

35

4

< A./cocl r5 /V —'^\ /H

7 / XVI

11 y v

\H

R4

S N'

i . i

V/'

10

14 5

in which R, R and R have the same meanings as above,

21

to aminolysis with an amino compound of formula H_NR

21

15 in which R is as defined above, or c) to treat a compound of general formula

R\ ^N\ /conhr21 • •

20 yi • H

ix i X

^'\ /r4 • •

I II • •

25

1 21 4 5

in which R, R, R and R have the same meanings as above,

with a C carboxylic acid anhydride or

20 d) to treat a compound of general formula

35

5

R\ ^N\ /C0NHr21

r5 l » OCOR'

\ / Ib«

I u y-v

W V__N/ XH R4

<r i i /'

10

in which R1 represents an alkyl radical in

1 21 4 5

Cl_4 and R'R'R and R' have the same meanings as above,

with an alkali metal hydroxide or

15 e) to submit a compound of general formula

25

30

R^/Nv .COOR

\ Y \ /

RP /v jr-

OCOR 1

20 i u • ' XVIII

• v • / \

v \

J R4

S \ /

• •

I II

"v/*

11

in which R represents a hydrogen atom or

4 5

a lower alkyl radical and R, R', R and R have the same meaning as above,

21

to aminolysis with an amino compound of formula H„NR

21

in which R has the same meaning as above, f) to treat a compound of general formula

35

6

^ONHR21 R\ /*\ /OH

i II Ib,

% /\„ X

Ç=î/ \

, • r 4

^ \ /K

• i

I

'Y

11 21 4 5

10 in which R, R, R and R have the same meanings as above,

with a chloride or anhydride of carboxylic acid in or g) to treat a compound of general formula

15

R^NwC0NH2 Rx 'V /0C0R'

' 11 X

v=N/ X

T o4

THE'

20 /R

• •

I II

V/*

114 5

in which R', R', R' and R' have the same meanings as above,

with a chloride or carboxylic acid anhydride in and h) possibly, to convert a compound of formula I thus obtained into a pharmaceutically acceptable salt. 30 The general reaction schemes appearing on the four sheets A to D below are representative of the reactions for producing the compounds of formula I. In these reaction schemes, R represents a radical

11

lower alkyl, R' is a C1 alkyl radical., R and

21, v

35 Rs each represent a hydrogen atom or a radical

7

12

lower alkyl, R is a dialkyl(inf)-amino-31 radical

methyl, R is a lower alkanoyloxy or hydroxy radical, X is a halogen atom, Z is a benzy- group

12 4 5

loxycarbonyl and R, R, R and R are as defined

5 in formula I. The reactions shown on sheet A can also be carried out with the corresponding N-oxides but any N-oxide fragment present in the compounds of formula VI is removed during the VI j/II conversion.

8

Reaction Diagram A

/'hch3

\ f \ /"'

î M

\/H

xy=^ s>

y ^y i ii \ /'

ii

I

CH3 N-NO

r • n = \ f \ /

\ /'

V/ \

iii

•p4

^ \ /

i he /'

^x./"' ! "

H

^ \ /

I II * / *

T.C. JOR

_5 it f^"ZZ OR

.'H

! 5 /\ IV 4_

<y v=y

• R"*

I <1

V/'

K A A. xiv

:h->ci o

A y*4

II

% y

R3

a_.^

cugr x.^w" \ /h

I II .•

- X^î=<'\

/,' \ /R4 • / •

i li

1

V./

coor

\y-X./"

I II

/

VI

^y V=^n

I D4

/

/ \ / i H

\ /*

h

■;h2_

t?

x.^ XA î il

I p4

t' •

i u

\ y

,'vn m' h R-»

VII

0

.0-?-

' \.y i il

■s " to

J COOR

^y \=y

- R4

y s '

î m

\ /

/ * \

:x

/

r w

... cocks

R11OC''

/ "CGCR

^ xy i il % /'v

\ / \ /

.1

y \ ;<

Ç = N H

.A.A

* m

\ /*

'I

rucc-s1 ccor

A—f y i .i xy

> /'v y' \ • 9="4 NH

yy '

i M

% /'

R1 N .:CGR N .A/

R;! ^"\ \ .H

< 11

\ k; /\ /

• i—• é

x y ^y \ y /

i 'i y* /

^y v=m-- y /

9=N,

î iî

- î-?.

/ Y xui • •

> /

9

Reaction Diagram B

Rs /Nx . COOR \ y \ /

R

\ S \ /

II

V/'\

rîi-

\ /

H

?-£ XH

XII-

S

I

%./

Ia<-

XVII

R\ ^N\ /C00H

RW"X>—'3 s te i il >'

?

^ /

R4

i

R

\ ^ \ / i •

II

/ * \

Ex /k /coc1 • •

HAS

H

\ / /\

Ç=N H

Y R4

I

% /

R.1, N, CONHR21

R,

\ S \ / î II

* v/*\

lî—

S \ /

t

R4

R31

Ib

XV

XVI

10

Reaction Scheme C

Rj^VKL .COOR \ y \ /

w \

=N

/

/

H

i—

S'\ /r4 î fl

\ /' Xlla

(R'CO)20 ►

R\1^N\ /C00R

R.

\.^ \y i"

-

\ x

OCR

/

/

V/

I

% /

= N R4

H

XVIII

R

Rx1.n

\ ^ \ / he

\.^w i—1.'

CONHR

0?R'

\ /

^ \ / • •

I II

V/'

N7

R4

/

H

THE

R11 vr CONHR21

\ ^ \ /

• •

R\ ^*\ V /0H

i II V ■

• • / \

"•/VI = < XH

,R

^ \ /

• •

I b1

11

Reaction Diagram D

EtOOC ,n COOt-Bu \ 7 \ / —

R

•. Jl •

\ ^ \t/

1*1

V/'\

=ÎJ

1 R4

i u • •

v/

XIX

R12 n COOt-Bu

\ s \ / -

R5 / • i— • \ ^ \ / \.

u

X.=N/ XXII

v/

I

'V ~y

R

OH m COOt-Bu \ / \ / ~

R5 x. A—'J \ ^ \ / \

I II

v/'\.

/

y \ /

=N R4

XX

^ /

J

Cl N COOt-Bu \ ^ \ / -

R^ / • INJ

/

--u XXI .R4

I II

i •

^ / \

y i u

"v/*

t

R

R-

12

,N.

\ S \ /'

II

\y\ _/ ii—

COOMe

I II

R'

Xllb

R

R12 N CONHR'

\ S \ /

v i—î

\y \a/ i*

^ /\

^ \ /

i •

i n

\ /'

:N4

R Id

12

Stage I ^11

Compounds of formula III are prepared by nitrosation of compounds of formula II. Such nitrosation can be carried out with nitrous acid formed in situ. Among the reagents that can be used are (1) alkali metal nitrites, for example sodium nitrite, in the presence of organic or mineral acids, for example glacial acetic acid, and aqueous or non-aqueous solvents; (2) alkyl nitrites, for example methyl nitrite, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon, or, for example, dimethylformamide; and (3) a solution of gaseous nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be carried out at or below room temperature, i.e., between -20 and 25°C.

Stage VIII ^ IX

Compounds of formula IX can be produced by reacting compounds of formula VIII with dimorphopholinophosphinic chloride. The reaction of compounds of formula VIII with the phosphorylation agent to obtain compounds of formula IX is carried out by treating the compounds of formula VIII with a base strong enough to ionize the compound of formula VIII and obtain the corresponding anion. Suitable bases include alkali metal alkoxides, such as potassium β-butylate or sodium methylate, and alkali metal hydrides such as sodium hydride and alkyllithium compounds such as n-butyllithium. The reaction temperature is between 0 and 100°C, and the reaction is advantageously carried out in an inert, aprotic polar solvent, that is, a solvent that solubilizes the ambient salts of the compounds of formula VIII completely or at least partially. Preferred solvents are ethers,

For example, tetrahydrofuran or dioxane, or tertiary amides, for example dimethylformamide.

Stage III or IX ^ IV

Compounds of formula III or IX can be condensed with the anion from malonic esters of formula C to produce compounds of formula IV. The anion is produced by deprotonating the malonic esters with a suitable strong base such as an alkoxide, alkali metal amide hydride, or an alkaline earth metal amide. Preferably, the reaction of compounds of formula III or IX with the anion of the malonic ester is carried out in a solvent such as a hydrocarbon, for example, benzene, toluene, or hexane, or an ether, for example, dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, etc., at a temperature ranging from below room temperature up to 150°C, preferably between 0 and 100°C, and even better, at room temperature.

Stage IV ^ v

The compounds of formula V are produced by decarboxylation of the compounds of formula IV by reacting the compound of formula IV with an alkali metal hydroxide such as sodium or potassium in a suitable solvent such as an alcohol, an ether, or dimethyl tallow oxide at a temperature between room temperature and ambient temperature.

COOR

COOR

14

reflux temperature, preferably between 60 and 100°C.

Stadium XIV ^V

Alternatively, a compound of formula V can also be prepared by reacting a compound of formula XIV with an acetic acid ester, i.e., CH₃COOR, in the presence of a base strong enough to remove the proton from the ester, thus producing the anion of the chosen acetic acid ester. A good example of such a base is diisopropyl-lithium amide.

Stage V-VI

Compounds of formula VI are produced by nitrosation of compounds of formula V by reacting them with nitrous acid obtained, for example, from an alkali metal nitrite, an alkyl nitrite, or a nitrosyl chloride by reaction with an organic or mineral acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids such as acetic acid, dimethylformamide, dimethyl tallow oxide, and chlorinated hydrocarbons. The reaction can be carried out at approximately room temperature, although this is not critical.

Stage VI ^ VII

Compounds of formula VII are prepared by the reduction of compounds of formula VI, for example with Raney nickel and hydrogen or with zinc and acetic acid. The reduction results in a predominant production of compounds of formula VII with a simultaneous secondary production of small quantities of several possible isometers, i.e., compounds of formulas

15

H C90R NHp „ NH

T NH2 .—COOR? )•—COOR has N^2

/" ( /N=\ i C I /—COOR

VII A VII B \m r

U VII D

Stage VII - XII

"Z-*

The compounds of formula XII are then formed by reacting the compounds of formula VII with an o-ester of 10-alkanoic acid of formula r1:lc(cor) 3

optionally in the presence of an acid catalyst, for example an organic or mineral acid such as p-15 toluenesulfonic acid, phosphoric acid, etc., at or above room temperature, i.e., between 25 and 150°C, and in this case, cyclization to compound XII occurs spontaneously. Technical equivalents of this o-ester include o-amides, for example N,N-dimethylformamide dimethyl acetal; N,N,N',N',N",N"-hexamethylmethanetriamine; nitriles, for example aceton-

20

trile; the imidates of esters, for example cfî-,-c (=nh) -0c„h.- .

3 Z D

Stage VII ^ XI

25. Compounds of formula XI can be formed by acyla-

tion of compounds of formula VII with a compound of formula

30 R13-COX or (R1;LC0)20.

35

Examples of solvents for this stage include methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in combination with an acid acceptor.

16

such as an organic or mineral base like triethylamine, pyridine, or an alkali metal carbonate. The reaction can be carried out below or above room temperature, but room temperature is preferred. Compounds with formula XI are isomeric, meaning they can exhibit either of the following stereochemical structures:

Stage XI ^XII

Compounds of formula XII can also be formed by dehydration of compounds of formula XI or their isomers with simultaneous cyclization by heating. This step can be carried out with or without a solvent, for example dimethylformamide, ethylene glycol, hexamethylphosphoric triamide, at a temperature of 100 to 300°C, preferably 150 to 250°C, for example 200°C, in the presence or absence of catalysts and water-binding agents.

Stage IX ^ X

Compounds of formula X can be formed by a condensation reaction of a compound of formula IX with an 11α-nion generated from acyl-amino-malonic esters of formula

XI A

xi b

COOR

COOR

17

10

15

20

25

30

To produce a compound of formula X, the anion is generated by deprotonation of acylaminomalonic esters with a suitable strong base such as an alkoxide, hydride, or amide of an alkali or alkaline earth metal. Preferably, the reaction of compounds of formula X with the anion of the acylaminomalonic ester is carried out in a solvent such as a hydrocarbon, for example benzene, toluene, and hexane, or an ether such as dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl tallow oxide, etc., at a temperature ranging from below room temperature up to 150°C, preferably from 0 to 100°C, and even better, at room temperature.

Stage X .XI

7*

Compounds of formula XI and their isomers are formed by decarboxylation of compounds of formula X with an alkali metal alkoxide in a solvent such as an ether, an alcohol, dimethyl sulfoxide, or dimethylformamide, above or below room temperature, but preferably at room temperature. It is not necessary to isolate compounds of formulas X and XI, but they can be converted in situ into compounds of formula XII.

Stage XII ^ XIII

Compounds of formula XIII are formed by reacting compounds of formula VII with an aldehyde of formula R^CHO. Suitable solvents for this reaction are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, dimethylformamide, dimethyl tallow oxide, etc., with or without water-binding agents, for example molecular sieves, above or below room temperature but preferably between room temperature and the reflux temperature of the solvent.

Another method for preparing a compound of formula

18

XIII in which R^" is a dialkyl radical (inf) arainoethy consists of condensing a compound of formula VII with a lower dialkylamine, for example dimethylamine, together with acrolein.

Stage XIII ^XII

Compounds of formula XIII can be converted into compounds of formula XII by in situ oxidation using oxidizing agents such as manganese dioxide, air or oxygen, etc.

Another method for preparing compounds of formula XII involves reacting a compound of formula IX with a protected amino-malonic ester of formula

^.COOR

® C NHZ

^ COOR

to convert the compound corresponding to formula X, but in which R^ is a benzyloxy radical, thus obtained into a compound corresponding to formula XI as described above regarding the X → XI stage, and to subject the compound thus obtained to treatment with hydrobromidric acid in glacial acetic acid, obtaining a compound of formula VII. It is not necessary to isolate the intermediates of formulas X and XI. The compound of formula VII thus obtained can be further converted into the final compound of formula XII by passing through the aforementioned reaction stages VII → XIII and XIII → XII.

According to yet another process, compounds of formula XII, in which R"'" represents a hydrogen atom, can be prepared by reacting a compound of formula III or IX, or a compound corresponding to formulas III and IX but bearing in position 2 another transient group such

19

that the dialcoxy group (inf) phosphono-0PO (O-alkyl) ^

with an isocyanoacetate of formula CSN-CH₂-COOR in the presence of a base strong enough to generate the isocyanoacetate anion in an inert solvent such as dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, or any other suitable organic solvent. All that is required of the organic solvent at this stage is that the starting materials be soluble in it and that the solvent not interfere with the subsequent reaction. The reaction temperature may vary between approximately -40°C and room temperature, preferably between approximately 0°C and room temperature.

The bases are strong enough to form the anion

15 of the isocyano-acetate are notably the alkali metal alkoxides such as potassium β-butylate or sodium methylate and the alkali metal hydrides such as sodium hydride and the alkali metal amides such as lithium amide or diisopropyl-li-20 thium amide.

Stage XII-XV

Compounds of formula XV are formed by hydrolyzing those of formula XII with the corresponding acids, preferably with 25 hydroxides of alkali metals such as sodium or potassium. Hydrolysis is conveniently carried out in an inert solvent. Suitable solvents include alcohols (methanol, ethanol), ethers (dioxane, tetrahydrofuran), and dimethylformamide, in combination with water. It is preferable to carry out this step at a temperature between ambient and the boiling point of the reaction mixture.

Stage XII or IV ^Ia

The compounds can be produced by direct aminolysis of compounds of formula XII (with an amino compound of for

20

21

mule H^NR) or by conversion of XV to acid chloride XVI, for example by treatment with phosphorus pentachloride, and the subsequent reaction with an amino compound of formula

5. Stage XII is conveniently carried out in an inert or solvent-free soil. Suitable solvents include hydrocarbons (hexane, toluene); ethers (tetrahydrofuran); alcohols (methanol, ethanol); dimethylformamide, dimethyl sulfoxide, and hexamethyl-10 phosphoric triamide. This stage is preferably carried out at a temperature between approximately 50 and 200°C, and even better, between approximately 100 and 150°C, under atmospheric pressure or higher.

Stage XV—>Ia, via XVI, is conveniently carried out in an inert solvent. Suitable solvents include hydrocarbons (hexane, toluene); ethers (tetrahydrofuran); and chlorinated hydrocarbons (methylene chloride, chlorobenzene). This reaction is preferably carried out at a temperature between approximately -20°C and the boiling point of the reaction mixture, and even better, between approximately 0 and 50°C.

Stadium the _>XVII

Compounds of formula XVII are formed by converting the corresponding compounds of formula la into their N-oxides. This conversion is carried out by oxidizing a compound of formula la with an organic peracid. A conventional organic peracid, such as peracetic acid, perpropionic acid, m-chloroperbenzoic acid, etc., can be used for this purpose. The oxidation can be carried out at room temperature or at a temperature above or below room temperature.

Stage XVII ^Ib

35 We can then use compounds of formula XVII

to prepare compounds of formula Ib by known processes such as, for example, the Polonovski grouping using an acid anhydride to form the lower alkanoyloxy radical which can be converted to a hydroxy radical by treatment with an alkali metal hydroxide such as sodium hydroxide. An example of such a Polonovski grouping is found in US patent 3,296,249.

Stage XIIa vXVIII

The compounds of formula XVIII are formed by reacting the N-oxide of formula Xlla with a carboxylic acid anhydride, preferably acetic anhydride, in the absence or presence of an inert organic solvent such as xylene or toluene, at a reaction temperature between approximately 100°C and the boiling point of the solvent mixture used, the preferred reaction temperature being approximately the boiling point of the chosen solvent. It should be noted that the reaction can also be carried out without a solvent, that is, in the anhydride alone.

Stage XVIII >Ib"

The compounds of formula Ib" p, are formed by reaction of the compound of formula XVIII with ammonia or a lower alkylamine, for example preferably methyla-

mine or ethylamine, within an alcohol in prefer

The reaction can be carried out in the form of methanol or, if desired, in the amine reagent itself. The reaction temperature can vary between approximately 0 and 100°C, with a preference for room temperature.

Stage Ib" ^Here

The compounds of formula Ib" are reacted with an alkanoic acid chloride or anhydride in the presence of an acid acceptor such as pyridine. In fact-

2

the compound of formula Iç in which R can still react

22

is a hydrogen atom, with a lower alkanoic acid chloride or anhydride, for example, chloride or

* 2

acetic anhydride, we can convert the R substituent

of hydrogen in a lower alkanoyl radical. Preferably, the reaction is carried out under reflux.

Stage XIX ^XX

The compound of formula XIX is prepared by techniques analogous to those described for the preparation of compounds of formula XII starting from the compound of formula V previously described. The diester of formula XIX can be reduced using sodium borohydride in a boiling alkanool, for example ethanol, to obtain the compound of formula XX.

Stage XX > XXI

The compound of formula XX can be reacted with thionyl chloride to convert the hydroxy substituent into a chloro substituent.

Stage XXI ^ XXII

The compound of formula XXI can be reacted with a lower dialkylamine, for example dimethylamine, at about 100°C to obtain the compound of formula XXII.

Stage XXII y XIIb

The t-butyl ester substituent of the compound of formula XXII can be converted into a methyl ester by reaction with methanolic sulfuric acid.

Stage XXIIb s, Id

The conversion of formula XIIb can be carried out as previously described for stage XIIla, for example by reacting this compound with a methanolic ammonia solution in the presence of ammonium chloride or a

alkylamine in the presence of its hydrochloride.

The compounds of formula I are active anxiolytic agents. This activity can be confirmed by the following tests using the preferred compounds of the invention.

It will be noted that the compounds of the invention are inactive or relatively inactive in the rotating rod test, which highlights muscle relaxation, but they are highly active in the antimetrazol test which demonstrates anxiolytic activity.

Rotating rod test

The procedure is a modification of that described by N.W. Dunham and T.S. Miya: J.A. Ph. A. Sci. Ed. 4_6, 208 (1957). CF-1 mice are selected based on their ability to remain for two minutes on a rod 30 mm in diameter rotating at 16 revolutions per minute. Groups of eight mice for each dosage are placed on the rotating rods 30 minutes after drug administration and observed for two minutes. Those unable to remain on the rod for a full two minutes are considered affected by the drug. The number of mice unable to remain on the rotating rod is converted into a percentage of the total number in each dosage group. Logarithmic survey paper is used to plot this percentage against the dose, and the ED50 is determined by the method of L.C. Miller and M.L. Tainter: Proc. Soc. Exp. Biol. Med.5_7,26 (1944).

The purpose of the test is to control chemical compounds to determine their effect on muscle tone and/or muscle coordination, especially muscle relaxants, sedatives or stimulants.

24

Standardized drug activity DE5q (m9/kg p.o.)

Chlorpromazine

10.0

+

0.5

Methotrimeprazine

3.8

+

0.4

Chlordiazepoxide

33.5

+

8.0

Diazepam

7.4

+

0.9

Results :

Compounds

9-chloro-6-(2-chlorophenyl)-4H-imidazo [L,5-a] [1,4Jbenzodiazepine-3-carboxamide

62-chlorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

6-(2-chlorophenyl)-4-hydroxy-4H-imidazo[1,5-a]£1,4]benzodiazepine-3-carboxamide

N-acetyl 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4] benzodiazepine-3-carboxamide acetyl ester

DE50 (mg/kg p.o.)

>200

>200

>200

>200

>200

Intravenous antimetrazol test

Brief description: For this test, male CF-1 mice, aged 45 to 54 days, are housed in an enclosure for one week and then deprived of food for approximately 24 hours. The test compound, dispersed in 5% acacia, is administered orally to three mice at 1/10th of the lethal dose in the TSP test. One hour later, metrazol is administered intravenously at 70 mg/kg (convulsive dose 100 mg/kg), and the animals are observed for 30 seconds.

25

This concerns protection against seizures. If the compound is active orally, three animals are used for each dosage. The dosage at which 50% of the animals are protected from seizures is expressed as ED50.

Measurements taken:

the number protected from seizures.

Calculations:

If the drug is active and three mice are used per assay, the approximate ED50 value is calculated using the method of Miller and Tainter (Proc. Soc. Exp. Biol. Med. 57:261, 1944). If six or more mice are used per assay, the ED50 values and 95% fiducial limits are calculated using a computer program according to the method of D.J. Finney ("Probit Analysis", Cambridge University Press, Cambridge, UK, 1971).

The test estimates anticonvulsant agents and is considered to predict anxiolytic activities.

Results :

Medicine

Standardized drug activity

DE50 (mg/kg p.o.)

Chlordiazepoxide Diazepam

Sodium phenobarbital

19

3.9 1.0

Compounds

9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4Ibenzodiazepine-3-carboxamide

N-acetyl-6-(2-chlorophenyl)-4H-imidazo[l,5-a]Il,4]benzodiazepine-3-carboxamide

DE5q (mg/kg p.o.)

0.97

1.3

26

10

Compounds (continued) DE50 P-o.)

6-(2-chlorophenyl)-l-methyl-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxamide 5,1

6-(2-chorophenyl)-4-hydroxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide 0.86

6-(2-chorophenyl)-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carbaxamide 7,4

The imidazobenzodiazepines listed above are useful as pharmaceutical products and are characterized by their activity as selective anxiolytic agents. These compounds can be used in the form of conventional pharmaceutical compositions.

For example, these compounds can be mixed with inert, organic or mineral pharmaceutical vehicles suitable for parenteral or enteral administration, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols, petrolatum, or the like. They can be administered in conventional pharmaceutical forms, such as solid forms, for example, tablets, coated tablets, capsules, suppositories, or the like, or in liquid forms, for example, solutions, suspensions, or emulsions. Furthermore, pharmaceutical compositions containing the compounds of the invention can be subjected to conventional pharmaceutical treatments, such as sterilization, and can contain common pharmaceutical excipients, such as preservatives, stabilizers, emulsifying agents, salts for adjusting osmotic pressure, or buffers. The compositions may also contain other therapeutically active substances. A suitable pharmaceutical dosage unit may

27

Containing approximately 0.1 to 500 mg of the final imi-dazo-benzodiazepine products, with a dosage ranging from approximately 0.1 mg to 100 mg, is preferred for oral administration, while for parenteral administration, a dosage of approximately 0.1 to 50 mg is preferred. However, for any given individual, specific dosages should be determined according to individual needs and the qualified judgment of the practitioner or person monitoring the treatment. It is understood that the dosages indicated are merely examples and in no way limit the implementation of the invention.

The term "dosage unit" used in this paper refers to pharmaceutically separated units suitable as unit doses for administration to mammals and containing, each, a predetermined amount of the active substance calculated to produce the desired therapeutic effect in combination with the necessary diluent or pharmaceutical vehicle.

The following examples serve to illustrate invention 20 without in any way limiting its scope:

Example 1

Nine g (0.08 mol) of potassium p-butylate is added to a solution of 19 g (0.07 mol) of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 350 mL of 25-dimethylformamide, cooled to 5°C. After stirring for 5 minutes under nitrogen, 18.1 g of diethyl chlorophosphate is added and the mixture is stirred for 10 minutes. Next, 12.7 g (0.112 mol) of ethyl isocyanoacetate is added to 150 mL of dimethylformamide, followed by 12.6 g of 30-t-potassium butyrate. After stirring without cooling for 1 hour, the reaction mixture is acidified with glacial acetic acid and divided between toluene and a saturated sodium bicarbonate solution. The organic layer is dried and evaporated. Crystallization in ethyl ether of 6-(2-chlorophenyl)-4H-

28

imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic, P. F -225-227°C. For analysis, it is recrystallized in a mixture of methylene chloride and ethyl acetate, leaving off-white crystals, PiF 226-228°C.

5

Example 2

2.5 g (23 mmol) of potassium t-butylate is added to a solution of 5.08 g (20 mmol) of 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 75 mL of 10-tetrahydrofuran, cooled to 0°C. After 5 minutes of stirring, 4.3 mL (30 mmol) of diethyl chlorophosphate is added, and stirring continues under nitrogen for 15 minutes. Then, a solution of 3.4 mL (32 mmol) of ethyl isocyanoacetate is added, followed immediately 15 minutes later by 3.5 g (32 mmol) of potassium t-butylate. The mixture is stirred at room temperature for 2 hours, acidified with glacial acetic acid, and divided between water and methylene chloride. The organic layer is dried and evaporated, and residue 20 is crystallized in ether to obtain the ethyl ester of 6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid. For analysis, it is recrystallized in ether at 197-198 °C.

25 Example 3

4.5 g (40 mmols) of potassium t-butylate is added to a solution of 11 g (35 mmols) of 5-(2-bromophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 300 mL of dimethylformamide, cooled in ice water. With stirring under nitrogen, 7.6 mL (9 g, 52 mmols) of diethyl chlorophosphate is added. After stirring for 5 minutes, 7.9 g (70 mmols) of ethyl isocyanoacetate and 7.8 g (70 mmols) of potassium t-butylate are added. The mixture is stirred at room temperature for 2 hours, acidified with glacial acetic acid, and divided between the

Toluene and water. The organic layer is washed with water, dried, and evaporated. The residue is filtered through silica gel buffer using a 10% (v.) solution of ethyl acetate in methylene chloride. The filtrate is evaporated, and the residue is crystallized in ether to give the ethyl ester of 6-(2-bromophenyl)-4H-imidazo[1,5-a][1,4]-benzo-diazepine-3-carboxylic acid, P.F. 230–232°C. The analytical sample is recrystallized in a mixture of methylene chloride and ethyl acetate, yielding colorless crystals with the same P.F.

The starting benzodiazepin-2-one in example 3 is prepared as follows (examples 4 to 8):

Example 4

17.5 g (0.15 mol) of boron trichloride is dissolved in 100 mL of methylene chloride and added, after cooling over ice, to a solution of 27.45 g (0.15 mol) of N-(phenyl)benzylamine in 400 mL of methylene chloride. After adding 15.1 g (0.15 mol) of triethylamine, the mixture is heated under reflux for 2 hours. While cooling over ice water, a solution of 27.75 g (0.15 mol) of 2-bromoben-...zaldehyde and 19.7 g (0.195 mol) of triethylamine in 400 mL of methylene chloride is then slowly added. After stirring at room temperature for 18 hours, the reaction mixture is washed with a 10% aqueous sodium carbonate solution, dried, and evaporated. The oily residue is dissolved in 1 liter of methylene chloride, and 32 g of chloroacetyl chloride are added to the ice-cooled solution. A layer of a 10% aqueous sodium carbonate solution is applied to the mixture, and the two-phase product is vigorously shaken for 30 minutes. The organic phase is then dried and evaporated. Crystallization in an ethyl acetate/ether mixture separates a byproduct.

30

which is removed by filtration. The filtrate is evaporated and the residue is crystallized in ether, yielding three collections of N-[2-[(2-bromophenyl)hydroxymethyl]-phenyl]-N-(phenylmethyl)-2-chloroacetamide. This material is oxidized without further purification. An analytical sample is obtained by recrystallization in a mixture of methylene chloride and hexane, melting at 163–166°C. NMR (CDC1) shows a mixture of two rotamers.

Example 5

A mixture of 27.7 g (62 mmol) of N-[2-[(2-bromophenyl)-hydroxymethyl]phenyl]-N-(phenylmethyl)-2-chloroacetamide, 140 g of manganese dioxide, and 1.4 liters of methylene chloride is stirred at room temperature for 5 hours. The manganese dioxide is removed by filtration through Celite, and the filtrate is evaporated. Crystallization of the residue in 2-propanol gives N-[2-(2-bromobenzoyl)phenyl]-N-(phenylmethyl)2-chloroacetamide, mol.P. 120–123°C.

Example 6

A mixture of 16.7 g (37.5 mmol) of N-[2-(2-bromobenzoyl)phenyl]-N-(phenylmethyl)2-chloroacetamide, 3.45 g (53 mmol) of sodium azide, and 200 ml of dimethylformamide is heated to 65-76°C for 45 minutes, then divided between water and methylene chloride. The organic layer is dried and evaporated, and the residue is crystallized in an ether/hexane mixture to obtain 2-azido-N-[2-(2-bromobenzoyl)-phenyl]-N-(phenylmethyl)acetamide, mol.f. 93-95°C.

Example 7

A mixture of 14.8 g (33 mmol) of 2-azido-N-[2-(2-bromobenzoyl)phenyl]-N-(phenylmethyl)acetamide, 200 ml of hydrogen, was heated under atmospheric pressure for 1.5 hours.

4-trahydrofuran, 350 mL of ethanol, and 15 g of Raney nickel are used. The catalyst is filtered, and the filtrate is heated under reflux for 30 minutes after the addition of 10 mL of glacial acetic acid. The solution is evaporated, and the residue is divided between methylene chloride and a 10% aqueous sodium carbonate solution. The organic phase is dried, evaporated, and the residue is crystallized in 2-propanol, yielding 5-(2-bromophenyl)-1,3-dihydro-1-(phenylmethyl)-2H-1,4-benzodiazepin-42-one as a colorless product, molten at 132–134°C. For analysis, the product is recrystallized in 2-propanol, molten at 135–138°C.

:: Example 8

A solution of 6.6 g (16.3 mmol) of 5-(2-bromophenyl)-1,3-dihydro-1-(phenylmethyl)-2H-1,4-benzodiazepin-2-one in 125 mL of concentrated sulfuric acid is heated in a steam bath for 12 minutes. The cooled mixture is poured onto ice and alkalized with ammonia. The precipitate is extracted with a mixture of methylene chloride and ethanol. The extracts are dried and filtered through silica gel buffer using a 5% (v/v) ethanol-methylene chloride solution for washing. The filtrate is evaporated and the residue is crystallized in a mixture of methylene chloride/ethyl acetate/hexane to give 5-(2-bromophenyl)-1,3-dihydro-2H-l,4-benzo-diazepin-2-one in the form of colorless crystals, P.F 220-222°C.

Example 9

The reaction of 8 g (26.3 mmol) of 1,3-dihydro-5-(2-trifluoromethylphenyl)-2H-1,4-benzodiazepin-2-one with potassium t-butylate and diethyl chlorophosphate, followed by treatment with ethyl isocyanoacetate anion, gives, after crystallization in a mixture of methylene chloride and ether, the ethyl ester

32

d1 6-[2-(trifluoromethyl)phenyl]4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid. This product is recrystallized from a mixture of methylene chloride and d1-ethanol for analysis and melts at 236-238°C.

5

Example 10

A solution of 0.82 g (3 mmol) of 8-fluoro-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 20 mL of tetrahydrofuran is cooled to -10°C and stirred under nitrogen before adding 0.4 g (3.56 mmol) of potassium t-butylate. After 5 minutes, 0.61 g (0.51 mL, 3.56 Mmol) of diethyl chlorophosphate is added, and stirring continues for 10 minutes. Then, 0.4 mL of ethyl isocyanoacetate is added, followed by 0.4 g (3.56 mmol) of potassium t-butylate. Cooling is stopped and the mixture is stirred for 30 minutes. It is acidified with acetic acid and divided between methylene chloride and a sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue in ether gives the ethyl ester of 9-fluoro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid. It is recrystallized in a mixture of ethyl acetate and hexane for analysis and melts at 215-217°C.

25 The starting benzodiazepin-2-one from example 10 is obtained by the intermediation of indole as follows (examples 11 to 15).

Example 11

30 We add, drop by drop, at a temperature of -20 to

5°C a solution of 30.4 g (0.44 mole) of sodium nitrite in 200 ml of water to a mixture of 44.4 g (0.4 mole) of 3-fluoraniline in 160 ml of concentrated hydrochloric acid.

After the addition is complete, solution 35 is stirred for 15 minutes at a temperature of -5 to 0°C and

<=k

33

Pour into a mixture prepared as follows: Dissolve 90 g (0.4 mol) of 2-acetyl-3-(2-fluorophenyl)propionic acid methyl ester in 320 mL of methanol and cool the solution to -50°C. Add a solution of 76 g (1.9 mol) of sodium hydroxide in 200 mL of water while maintaining the temperature below -5°C. After combining the two mixtures below 0°C, stir the reaction mixture without cooling for 45 minutes. Dilute with water, extract with methylethylene chloride, dry the extracts, and evaporate. Dissolve the red oil in one liter of methanol and saturate the solution with hydrochloric acid. After heating under reflux for 2 hours, the solution is diluted with water and the precipitated crystals are collected. Recrystallization in a mixture of ether and hexane yields the methyl ester of 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid. The analytical sample is purified by silica gel filtration using methylene chloride as the solvent. Crystallization in a mixture of methylene chloride and hexane gives colorless crystals, molten at 158-160°C.

Example 12

A mixture of 2550 g (0.174 mol) of 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid methyl ester, 39 g (0.7 mol) of potassium hydroxide, 150 mL of water, and 1.5 L of methanol is heated under reflux for 2 hours. The mixture is acidified with glacial acetic acid and partially evaporated. The hot solution is diluted with 30 L of water, and the product is crystallized by seeding.

After cooling, the crystals are collected and aspirated to dryness. Recrystallization in a mixture of ether and hexane yields 6-fluoro-3-(2-fluorophenyl)1H-indole-2-carboxylic acid as a colorless product, 35 p.f. at 215–218°C. The analytical sample is then recrystallized.

4

34

in the same solvents and the P.F remains unchanged.

Example 13

34.8 g (0.127 mol) of 6-fluoro-3-5 (2-fluorophenyl)-1H-indole-2-carboxylic acid is converted to acid chloride using 37.1 g (0.178 mol) of phosphorus pentachloride in 3 liters of methylene chloride by stirring for 1 hour at room temperature. Ammonia is then added until the reaction mixture remains alkaline. A layer of water is applied and the mixture is stirred for 1 hour. The organic phase is separated, dried, evaporated, and the residue is crystallized in a mixture of ethyl acetate and hexane to obtain 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxamide, PF 191-193°C. 15 For analysis, we recrystallize in the same solvents and obtain colorless crystals, P.F 195-197°C.

Example 14

A 5 g (18.4 mmol) solution of 6,20-fluoro-3-(2-fluorophenyl)-1H-indole-2-carboxamide is added to

100 mL of tetrahydrofuran is dissolved in a suspension of 5 g of lithium-aluminum hydride in 150 mL of ether. This mixture is heated under reflux in nitrogen for 6 hours and then stirred at room temperature for 16 hours. The excess reagent is decomposed by the careful addition of 25 mL of water. After dilution with ether, the mineral matter is filtered and washed with methylene chloride. The filtrate is dried and evaporated. The residue is dissolved in ether and treated with an ethanolic solution of HCl. The precipitated crystals are collected and washed with ether to leave 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-methanamine hydrochloride as a colorless product. The analytical sample is recrystallized in a mixture of ethanol and ether and melts at 241-245°C (dec).

35

Example 15

A mixture of 8.4 g (28.5 mmol) of 6-fluoro-3-(2-fluorophenyl)-1H-indole-2-methanamine hydrochloride, 84 mL of acetic acid, 8.4 mL of water, and 8.4 g of chromium chloride is stirred for 2 hours in a cold water bath. The mixture is poured into ice water, alkalized with ammonia, and extracted with methylene chloride. The extracts are dried and left to stand for 48 hours after the addition of 10 mL of acetic acid. The methylene chloride solution is washed with aqueous bicarbonate, dried, and evaporated. The residue is chromatographed on 100 g of silica gel using a 1:1 (v/v) mixture of methylene chloride and ethyl acetate for elution. Crystallization of the combined fractions containing the product in a mixture of ethyl acetate and d1-hexane gives 8-fluoro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one as off-white crystals, molten at 175-177°C. For analysis, recrystallization in the same solvents yields colorless crystals, molten at 177-179°C.

t.Example 16

The ethyl ester of 6-(2-chlorophenyl)-9-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is similarly obtained by reacting 5-(2-chlorophenyl)-8-fluoro-1,3-dihydro-2H-1,4-benzodiazepine-2-one with potassium β-butylate and diethyl chlorophosphate, followed by a reaction with the ethyl isocyanoacetate anion as described in Example 9. It is crystallized in ether and recrystallized for analysis in ethyl acetate. The melting point of the colorless crystals is 213–215°C.

The starting material for example 16 is prepared by an indole oxidation as described later (examples 17-21):

36

Example 17

The ethyl ester of 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid is prepared as described in Example 11 by coupling the diazonium salt of 3-fluoraniline with the sodium salt of the ethyl ester of 2-acetyl-3-(2-chlorophenyl)propionic acid and subsequently heating with an ethanolic HCl solution. It is then crystallized in a mixture of ethanol and water. The analytical sample is recrystallized in hexane to leave colorless crystals, PF 123-125°C.

Example 18

3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid is similarly obtained as described in Example 12 by alkaline hydrolysis of the ethyl ester. It is crystallized in an ether/hexane mixture and recrystallized for analysis in the same solvents to obtain off-white crystals / PF 198-200°C.

Example 19

3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxylic acid is converted to 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxamide as described in Example 13 using the phosphate pentachloride/ammonia process. It is crystallized in an ethyl acetate/hexane mixture and recrystallized for analysis in the same solvents, yielding colorless crystals, PF 208-211°C.

Example 20

An 11 g (38 mmole) solution of 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-carboxamide in 250 ml of tetrahydrofuran is added to a suspension of 6.5 g of lithium-aluminum hydride in 500 ml of tetrahydrofuran.

After heating under reflux for 1 hour, the excess reagent is decomposed by careful addition of 40 ml of water.

37

The mineral matter is separated by filtration, and the filtrate is dried and evaporated. The residue is treated with an ethanolic solution of HCl and with ether. The precipitate is collected, and 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-methanamine hydrochloride is left as crystals, molten at 242-245°C. The analytical sample is recrystallized in an ethanol/ether mixture, molten at 252-255°C.

Example 21

5-(2-chlorophenyl)-8-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one is prepared as described in Example 15 by the oxidation of 3-(2-chlorophenyl)-6-fluoro-1H-indole-2-methanamine hydrochloride with chromium trioxide. It is purified by silica gel filtration using a mixture of methylene chloride and ethyl acetate (1:1 by volume), and crystallization in ethyl acetate/hexane gives colorless crystals. Melting point: 239-242°C.

Example 2.2

A solution of 13.8 g (35 mmol) of (1,l-dimethyl)ethyl ester of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid is stirred at room temperature for 16 hours in 50 mL of trifluoroacetic acid. The reagent is evaporated azeotropically with toluene. The residue is stirred with ethyl acetate and water, and the precipitated crystals are collected, leaving 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid, molten at 257–259°C. The filtrate is extracted with dilute ammonia, and the extract is acidified with acetic acid. The precipitate is collected to give a second harvest which is recrystallized in a mixture of methanol and ethyl acetate. The analytical sample is recrystallized in the same solvents, at a boiling point of 258-260°C.

Example 2 3

A solution of 3.2 g (7.5 mmol) of (1,1-dimethyl)ethyl ester of 9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4-benzodiazepine-3-carboxylic acid in 30 mL of trifluoroacetic acid is left to stand at room temperature for 90 minutes. The reagent is evaporated under reduced pressure and finally azeotropically with toluene. The residue is dissolved in methylene chloride, washed with water, dried, and evaporated. Crystallization in ethanol gives 9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4-benzodiazepine-3-carboxylic acid as a colorless product. For analysis, we recrystallize in ethanol, P.F 264-265°C.

Example 24

A solution of 6.3 g (16.5 mmol) of ethyl ester of 6-(2-chlorophenyl)-9-fluoro-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylic acid is heated in 200 mL of hexanormal HCl for 8 hours in a steam bath. After evaporation to dryness, the residue is stirred with 150 mL of water, 6 g of sodium acetate, and 6 mL of acetic acid for

1 hour at room temperature. The precipitated crystals are collected, washed with water, aspirated to dryness, and recrystallized in a methanol/ethyl acetate mixture to leave 6-(2-chlorophenyl)-9-fluoro-4H-imidazo[1,5-a].[1,4]benzodiazepine-3-carboxylic acid as a colorless product, PF 270-272°C.

Example 25

A solution of 2.6 g (7 mmol) of ethyl ester of 9-fluoro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4-Ibenzodiazepine-3-carboxylic acid is heated for 8 hours in a steam bath in 100 ml of hexanormal HCl. After evaporation to dryness, the residue is stirred with 50 ml of water.

2 g of sodium acetate and 2 ml of acetic acid. We re-

39

collect the precipitated acid, wash with water and aspirate to dryness. Recrystallize in a mixture of methanol and ethyl acetate to obtain the acid 9-fluoro-6-(2-fluorophenyl)-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxy-5 league, P.F 255-257°C (dec)'.

10

Example 26

A solution of 16.9 g (45 mmol) of (1,1-dimethyl)ethyl ester of 6-(2-fluorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid is left to stand at room temperature for 90 minutes in 60 mL of trifluoracetic acid. The reagent is evaporated under reduced pressure, and the residue is dissolved in 250 mL of methylene chloride. A layer of 15% aqueous sodium acetate solution is then applied. After 30 minutes of vigorous stirring, the precipitated crystals are filtered out, and the mixture is aspirated to dryness. After vacuum drying for 16 hours, the product is recrystallized in a mixture of methanol and ethyl acetate to obtain 6-(2-fluorophenyl)-20 4H-imidazo[1,5-a ] [1,4]benzodiazepine-3-carboxylic acid, in the form of colorless crystals, P.F 241-243°C.

Example 27

(A) A mixture of 5 g (13.7 mmol) of ethyl ester of 6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 5 g of ammonium chloride, and 100 ml of methanol containing 20% (vol) ammonia is heated in a steel bomb at 100°C for 25–18 hours. Most of the solvent is evaporated, and the residue is diluted with water. The crystals are collected, aspirated to dryness, and recrystallized in a mixture of methylene chloride and ethanol to obtain 6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide as colorless crystals, PF 310–314°C. 35 (b) The same compound is also obtained by treatment

40

of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxylic acid with phosphorus pentachloride followed by ammonia treatment of the non-isolated acid chloride.

Example 28

(A) A mixture of 1.5 g (4.3 mmol) of ethyl ester of 6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 1.5 g of ammonium chloride, and 20 mL of a 20% by volume methanolic ammonia solution is heated in a steel bomb at 100°C for 18 hours. The usual treatment and crystallization in a methanol/ethanol/methylene chloride mixture gives 6-(2-

fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbo-xamide in the form of colorless crystals, P.F>300°C.

(B) The same compound is also obtained by treating 6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxylic acid with phosphorus pentachloride, followed by ammonia treatment of the chloride of the unisolated acid.

Example 29

Three g (7.3 mmol) of ethyl ester of 6-(2-bromophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid is heated in a steam bath with 100 mL of hexanormal HCl for 8 hours. After evaporation under reduced pressure, the residue is stirred with 150 mL of water, 2 mL of acetic acid, and 1.5 g of sodium acetate for one hour at room temperature. The precipitate is filtered, and the aspirated fluid is aspirated to dryness. Recrystallization in a mixture of methanol and ethyl acetate yields a colorless acid with a boiling point of 265–268°C. This material is converted into an amide using the same technique with phosphorus pentachloride and ammonia as in example 31, and 6-(2-bromophenyl)-4H-imidazo[1,5-a][1,4] are obtained.

benzodiazepine-3-carboxamide in the form of crystals which melt at 307-309°C, after crystallization in the mixture of methylene chloride and ethanol.

Example 30

The ethyl ester of 6-[(2-trifluoromethyl)phenyl]-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is converted to 6-[2-(trifluoromethyl)phenyl]-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as described in Example 27 by heating in a methanolic ammonia solution in the presence of ammonium chloride. It is then recrystallized in a methylene chloride/ethanol mixture, yielding colorless crystals at a boiling point of 295-296°C.

Example 31

A mixture of 2.3 g (6 mmol) of 9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4-Ibenzodiazepine-3-carboxylic acid, 1.6 g (7.6 mmol) of phosphorus pentachloride, and 75 mL of methylene chloride is stirred at room temperature for 90 minutes. Ammonia is then bubbled through the solution until it becomes alkaline. Water is added, and the two-phase mixture is stirred for 1 hour. The product is extracted with methylene chloride containing 10% by volume of ethanol. The extracts are dried, evaporated and crystallized in a mixture of methylene chloride and ethanol to obtain 9-chlor-ro-6-(2-chlorophenyl)4H-imidazot1,5-a]t1,4]benzodiazepine-3-carboxamide in the form of colorless crystals, P.F 278-280°C.

Example 32

(A) 2.4 g of 9-fluoro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is converted to an amide using the phosphorus pentachloride and ammonia technique described in Example 31 to obtain 9-fluoro-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]-

benzodiazepine-3-carboxamide is crystallized in a mixture of methylene chloride and ethanol. For analysis, it is recrystallized in the same solvents to obtain colorless crystals, P*F 283-286°C.

(B) This amide is also obtained by reaction of the ethyl ester with a mixture of ammonia and ammonium chloride.

Example 33

3.3 g of 6-(2-chlorophenyl)-9-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is converted to 6-(2-chlorophenyl)-9-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide by the phosphorus pentachloride/ammonia technique (see example 31) to obtain the final product, P.F 295-297°C, after crystallization in a mixture of methylene chloride and ethanol.

Example 34

Two g (6 mmol) of 6-(2-chlorophenyl)-4H-imidazo[1,5-al[1,4-1-benzodiazepine-3-carboxylic acid are reacted in 400 mL of methylene chloride with 1.7 g (8 mmol) of phosphorus pentachloride and then treated with methylamine, yielding a crude amide which is filtered through silica gel buffer using a 5% (v/v) ethanol solution in methylene chloride. Crystallization of the evaporated filtrate in a mixture of ethyl acetate and hexane gives 6-(2-chlorophenyl)-N-methyl1-4H-imidazo[1,5-al[1,4-1-benzodiazepine-3-carboxamide as colorless crystals, molten at 216–219°C.

Example 3.5

Two g of 6-(2-chlorophenyl)-4H-imidazo[1,5-α1[1,4β1benzodiazepine-3-carboxylic acid] are converted to chloride and reacted with ethylamine as described in Example 34. The product is purified by chromatography.

43

on 50 g of silica gel using a 1:1 by volume mixture of methylene chloride and ethyl acetate. The clean evaporated fractions are recrystallized in ethanol and 6-(2-chlorophenyl)-N-ethyl-4H-imidazo-5 [1,5-a][1,4]benzodiazepine-3-carboxamide is obtained as colorless crystals, P.F 211-212°C.

Example 36

The reaction of 1.5 g (4.45 mmoles) of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid with 1.3 g (6.25 mmoles) of phosphorus pentachloride in 150 ml of methylene chloride and subsequent treatment with excess isopropylamine gives 6-(2-chlorophenyl)-N-(1-methylethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide. The analytical sample is purified by filtration through a silica gel buffer using a mixture of ethyl acetate and methylene chloride (1:1 by volume) and crystallized in a mixture of ethyl acetate and ether to give colorless crystals, P.F 218-221°C.

Example 37

9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is converted to acid chloride as described in Example 31 and reacted in situ with an excess of ethylamine. Crystallization in a mixture of methylene chloride and ethanol gives 9-chloro-6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as a colorless product, MF 198-200 °C.

'Example 38'

52.8 mL (0.5 mol) of 3-chloraniline is added in several portions to 142.5 mL (1.125 mol) of 2,35-chlorobenzoyl chloride heated to 120°C. The mixture is heated to

10

15

20

25

30

44

The mixture is heated to 180-200°C, and then 87.2 g (0.64 mol) of zinc chloride is added in several portions. After the addition, the mixture is heated for 90 minutes at 200-205°C. The evolution of hydrochloric acid gas ceases at this point. After cooling to 120°C, 500 mL of trinormal HCl is added, and the mixture is refluxed. The HCl is decanted, and this process is repeated two more times. The residue is dissolved by heating with 500 mL of acetic acid. This solution is combined with 300 mL of concentrated HCl, and the mixture is heated under reflux for 18 hours. The solvents are removed under reduced pressure, and the residue is divided between methylene chloride and water. The organic layer is washed with a trinormal sodium hydroxide solution, dried, and evaporated. The residue is passed through 300 g of silica gel using toluene. Crystallization of the fractions containing the product in ethanol yields (2-amino-4-chlorophenyl)-(2-chlorophenyl)methanone as yellow crystals in two harvests. The analytical sample is recrystallized in ethanol, mol.W. 104-106 °C.

Example 39

A mixture of 25 g (0.1 mol) of (2-amino-5-fluorophenyl)-(2-chlorophenyl)methanone, 9 g of hydroxylamine sulfate, 120 mL of ethanol, and a 2-chloroacetaldehyde solution, prepared by heating a mixture of 20 g of chloroacetaldehyde dimethylacetal and 20 mL of 1.5 N HCl under reflux for 10 minutes, is divided between water and methylene chloride. The organic layer is washed with a saturated sodium bicarbonate solution, dried, and evaporated. Crystallization of the residue in a mixture of ether and hexane gives 2-chloromethyl-4-(2-chlorophenyl)-6-fluoro-1,2-dihydroquinazoleine 3-oxide in two harvests. The analytical sample is recrystallized in a mixture

45

ethyl acetate/ether/hexane to obtain yellow crystals, P.F 138-141°C.

Example 40

5. 7-3-oxide is obtained in a yield of 78%

Chloro-2-chloromethyl-4-(2-chlorophenyl)-1,2-dihydroquina-zolein is produced by reacting (2-amino-4-chlorophenyl)-(2-chlorophenyl)methanone with 1-hydroxylamine sulfate and 2-chloroacetaldehyde as described in Example 10. The analytical sample is recrystallized in a mixture of methylene chloride and ethanol, yielding yellowish crystals at a boiling point of 197-198°C. In this case, the 1,2-dihydro derivative is isolated for analysis before oxidation, as described in Example 42.

15

Example 41

A solution of 2-chloroacetaldehyde, prepared by heating 200 g of 2-chloro-1,1-dimethoxyethane in 200 mL of 1.5 N HCl under reflux for 5 minutes, is added to a mixture of 231 g (1 mole) of (2-amino-phenyl)(2-chlorophenyl)methanone, 90 g of hydroxylamine sulfate, and 1.1 liters of ethanol. After stirring at room temperature for 2 hours, the reaction mixture is diluted with water, the precipitated crystals are collected, washed in water, and aspirated to dryness to leave the crude 2-chloro-methyl-4-(2-chlorophenyl)-1,2-dihydroquinazoleine 3-oxide, which is then directly oxidized as follows. A solution of this material is stirred in 1.4 liters of methylene chloride with 600 g of manganese dioxide for 2 hours. The manganese dioxide is separated by filtration, the filtrate is concentrated, and crystallized by adding ether to obtain 2-chloromethyl-4-(2-chlorophenyl)quinazoleine 3-oxide in the form of yellow crystals. For analysis, it is recrystallized in a methylene chloride/ether/hexane mixture, PF 167-168°C.

46

Example 42

The oxidation of 24 g (70 mmol) of 7-chloro-2-chloromethyl-4-(2-chlorophenyl)-1,2-dihydroquinazoleine 3-oxide in 300 ml of methylene chloride with 50 g of manganese dioxide gives 7-chloro-2-chloromethyl-4-(2-chlorophenyl)quinazoleine 3-oxide, MF 159-162°C. The analytical sample is recrystallized in a mixture of tetrahydrofuran and ethanol to leave light yellow crystals, MF 161-162°C.

Example 4.3

At -50°C, 193 mL of a 1.55 M (0.3 mol) solution of butyllithium in hexane is added to 200 mL of a 2 M solution of diisopropylamine in tetrahydrofuran. Ethyl acetate is slowly added while maintaining the temperature below -45°C. After this addition, a 30.5 g (0.1 mol) solution of 2-chloromethyl-4-(2-chlorophenyl)quinazoleine 3-oxide is added to 200 mL of tetrahydrofuran. Cooling is stopped, and the mixture is stirred for 2 hours under nitrogen. It is acidified by adding 30 mL of acetic acid, and the toluene is partitioned off with water. The organic phase is dried and evaporated. Crystallization of the residue in ether gives the 4-ethyl ester oxide of 5-(2-chlorophenyl)-1,3-dihydro-2H-benzodiaze-pin-2-ylidene-acetic acid, a sample of which is recrystallized in a mixture of methylene chloride and ether for analysis, P.F 172-174°C.

Example 44

At -50°C, a solution of n-butyllithium in hexane (406 mL, 1.6 M; 0.65 mol) is added to a 2 M solution of diisopropylamine in tetrahydrofuran (400 mL, 0.8 mol). After stirring under nitrogen for 10 minutes, 108 mL (0.8 mol) of t-butyl acetate is added, maintaining the temperature between -40 and -50°C. After the addition,

47

stir the mixture for 10 minutes while cooling it to -60°C. Then, a solution of 57.7 g (0.2 mol) of 2-chloromethyl-3-oxide is added all at once.

4-(2-fluorophenyl)quinazoleine in 750 mL of 5-tetrahydrofuran. Cooling is stopped and the mixture is stirred for 2.5 hours. After acidification with glacial acetic acid, the reaction mixture is divided between water and toluene. The organic layer is dried and the mixture is concentrated. The product is crystallized by dilution with 10⁻¹'hexane, collected, and washed with a little ether to leave the 4-(1,1-dimethyl)ethyl oxide ester of 4-(1,1-dimethyl)ethyl acid.

5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-yl-deneacetic acid, P-F 184-186°C. For analysis, it is recrystallized in ethanol, yielding colorless crystals, P.F

15 186-188°C (dec).

Example 45

The reaction of 61 g (0.2 mol) of 2-chloromethyl-4-(2-chlorophenyl)quinazoleine 3-oxide with the 20-t-butyl acetate anion (see Example 44) gives the 4-oxide of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid, MF 229-231°C (dec). The analytical sample is recrystallized in a mixture of methylene chloride and ethanol.

25

Example 46

The reaction of 20 g (0.059 mol) of 3-oxide of 7-chloro-2-

chloro-methyl-4-(2-chlorophenyl)quinazoleine with the anion of

See β-butyl acetate (example 44) which gives the 4-oxide of 30 (1,1-dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid, which is crystallized in ether. For analysis, it is recrystallized in ether, PF 197-199°C.

qh

48

Example 47

145 ml of phosphorus trichloride is added in three portions over 15 minutes to a solution of 145 g (0.376 mol) of 4-oxide of (1,1-dimethyl)ethyl 5 of 5-(2-chlorophenyl)-1,3-dihydro-2H-l,4-benzodiaze-pin-2-ylidene-acetic acid in 1.5 litre of methylene chloride cooled in ice water. After 15 minutes of further stirring, the mixture is evaporated under reduced pressure. The residue is divided between methylene chloride and a 10% aqueous solution of sodium carbonate. The organic phase is dried, evaporated, and the (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid is left as a yellow oil. A 2 g sample is passed over silica gel using a 10% (v/v) solution of ethyl acetate in methylene chloride. Crystallization in a mixture of methylene chloride and ethanol yields off-white crystals, with a melting point of 170–173°C.

20 Example 4 8

Over 15 minutes, 126 mL of phosphorus trichloride is added in three portions to a solution of 126.5 g (0.343 mol) of 4-oxide of (1,1-dimethyl)ethyl ester of 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin 25-2-ylidene-acetic acid in 1.3 L of methylene chloride cooled in ice water. After 30 minutes of further stirring, the solution is evaporated, and the residual oil is divided between the methylene chloride and a 10% aqueous sodium carbonate solution. The organic layer is washed with the carbonate solution, dried, and evaporated. Crystallization of the residue in methanol gives the (1,1-dimethyl)ethyl ester of 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid in crystalline form, P.F 154-157°C. The analytical sample is recrystallized in methanol, P.F 155-157°C.

Example 49

The (1,1-dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid is obtained by treating 4-oxide of (1,dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid with phosphorus trichloride as described in Example 47. It is crystallized in ether and recrystallized for analysis in a mixture of methylene chloride and ethanol giving colorless crystals, P.F 158-160°C.

Example 50

Over 15 minutes, 53 mL of phosphorus trichloride is added in two portions to an ice-cooled solution of 53.4 g (0.138 mol) of 4-(1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid in 650 mL of methylene chloride. After stirring for a further 15 minutes, the solvent is evaporated under reduced pressure, and the residue is divided between methylene chloride and a 10% aqueous solution of sodium carbonate. Following treatment, the residue is treated with 12.45 g (0.18 mol) of sodium nitrite in 350 mL of glacial acetic acid. Dilution with water, filtration, and recrystallization in a mixture of tetrahydrofuran and ethanol yields the (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid as light yellow crystals, with a boiling point of 229–230°C. For analysis, the product is recrystallized in a mixture of methylene chloride and ethanol, with the boiling point remaining unchanged.

Example 51

Over 15 minutes, 25 ml of phosphorus trichloride is added in three portions to a solution of 25.2 g (0.07 mol) of 4-ethyl ester oxide of 5-(2-chloride)

50

(rophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid is mixed in 250 mL of ice-cooled methylene chloride. After 15 minutes of stirring at room temperature, the mixture is evaporated, the residue is divided between methylene chloride and a 10% aqueous sodium carbonate solution, the organic phase is dried and evaporated, and then the residue is dissolved in 150 mL of glacial acetic acid and treated with 6.8 g of sodium nitrite in two portions. The mixture is stirred for 1 hour, diluted with water, the precipitate is collected by filtration, washed with water, and aspirated to dryness. Recrystallization in a mixture of tetrahydrofuran and ethanol gives the ethyl ester of 5-(2-chlorophenyl)-a-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, in the form of yellowish crystals, P.F 245-248°C (dec).

Example 52

Four grams (58 mmols) of sodium nitrite are added to a solution of 19 g (47 mmols) of (1,1-dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylidene-acetic acid in 150 mL of glacial acetic acid. After stirring at room temperature for 30 minutes, the solution is diluted with water, the precipitated crystals are collected, washed with water, and aspirated to dryness. Recrystallization in a mixture of methylene chloride and ethanol yields (1,1-dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, with a melting point of 208–210°C.

Example 5 3

A suspension of 35.7 g (0.1 mol) of 4-ethyl ester oxide of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidene-acetic acid in 225 ml of glacial acetic acid is treated with 9.75 g (0.14 mol) of sodium nitrite in two portions over 10 minutes. After

51

After 1 hour of stirring at room temperature, the crystalline product is further precipitated by dilution with water and collected by filtration. It is washed with water and aspirated to dryness. Recrystallization in a mixture of 5-tetrahydrofuran and ethanol yields the 4-ethyl ester oxide of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid as off-white crystals, with a boiling point of 262-264°C (dec). A second collection is obtained from the mother liquor.

10

Example 54

The reaction of 70.4 g (0.2 mol) of (1,1-dimethyl)ethyl ester of 5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid with 19.3 g (0.28 mol) of sodium nitrite in 425 mL of glacial acetic acid gives the (1,1-dimethyl)ethyl ester of 5-(2-fluorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid as a product solvatized in 1 M ethanol, PF 214–216°C (dec). For analysis, the product is recrystallized in a mixture of methylene chloride and ethanol.

Example 55

We hydrogenated under atmospheric pressure for 2 hours a mixture of 17 g (42.5 mmols) of (1,1-dimethyl-25 thyl)ethyl ester of 5-(2-chlorophenyl)-a-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, 240 ml of tetrahydrofuran, 120 ml of methanol, 17 g of Raney nickel and 3 ml of a methanolic (20% vol.) ammonia solution. The catalyst is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in 100 mL of ethyl acetate. The solution is treated with 6.8 mL (50 mmol) of dimethylformamide dimethylacetal and heated under reflux for 5 minutes. After the addition of 100 mL of hexane, the product is crystallized by cooling and collected to allow the (1,1-dimethyl)ethyl ester of 6-

52

(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in the form of beige crystals. The analytical sample is recrystallized in a mixture of methylene chloride and ethyl acetate to form colorless crystals, PF 247-249°C.

Example 56

Hydrogen is reacted with Raney nickel for 3 hours, as described in Example 55, resulting in a solvatized product: (1,1-dimethyl)ethyl ester of 5-(2-fluorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid (38.2 g, 0.09 mol) in ethanol (1 M). The crude hydrogenation product is dissolved in 200 mL of ethyl acetate. After the addition of 19 mL of dimethylformamide dimethylacetal, the mixture is heated under reflux for 5 minutes. The product is crystallized by adding 500 ml of hexane and cooling to allow the (1,1-dimethyl)ethyl ester of 6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxylic acid to form crystals, PF 216-219°C. The analytical sample is recrystallized in a mixture of ethyl acetate and hexane, PF 218-220°C.

Example 57

A mixture of 31 g (0.08 mol) of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid 4-ethyl ester oxide, 600 mL of tetrahydrofuran, 300 mL of ethanol, 12 mL of methanol containing 20% ammonia, and 31 g of Raney nickel is heated under atmospheric pressure until hydrogen consumption ceases (2 hours). After filtration and evaporation, the residue is dissolved in 150 mL of ethyl acetate. 16 mL of dimethylformamide dimethylacetal is added, and the mixture is heated under reflux for 5 minutes. The product crystallizes and is collected after cooling. It is washed with ether, yielding 6-(2-)ethyl ester 5-oxide.

53

chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic, P.F 245-248°C. For analysis, it is recrystallized in a mixture of methylene chloride and ethyl acetate, the melting point remaining unchanged.

5

Example 58

A mixture of 12 g (0.03 mol) of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-α-(hydroxyimino)-10 3H-1,4-benzodiazepine-2-acetic acid, 200 mL of tetrahydrofuran, 100 mL of ethanol, 3 mL of a 20% methanolic ammonia solution, and 23 g of Raney nickel is hydrogenated for 90 minutes at atmospheric pressure. The catalyst is filtered, and the filtrate is evaporated under reduced pressure. The yellow residue is dissolved in 400 mL of 15-methylethylene chloride and treated with 5 mL (0.09 mol) of acetaldehyde. After 20 minutes of stirring at room temperature, 12 g of manganese dioxide is added, and stirring is continued for 30 minutes. The manganese dioxide is filtered and the filtrate is evaporated. Crystallization of residue 20 in ethyl acetate gives the (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, P.F. 250-253°C. The analytical sample is recrystallized in ethyl acetate, with the P.F. remaining unchanged.

25

Example 59

As in Example 58, 11 g of 4-ethyl ester oxide of 5-(2-chlorophenyl)-a-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid are hydrogenated, and the crude hydrogenation product is dissolved in 350 mL of methylene chloride. 5.5 mL of acetaldehyde is added, and the solution is stirred for 20 minutes. After the addition of 11 g of manganese dioxide, stirring is continued for 30 minutes. The manganese dioxide is removed by filtration through Celite, and the filtrate is evaporated. The crystallization of

The residue in ethyl acetate gives the 5-ethyl ester oxide of 6-(2-chlorophenyl)-l-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid, P.F 221-224°C. The analytical sample is recrystallized in a mixture of methylene chloride and ethyl acetate to obtain colorless crystals, P.F 224-226°C.

Example 60

Hydrogen is evaporated at atmospheric pressure until hydrogen absorption ceases (1-2 hours) using a mixture of 5 g (12.6 mmol) of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, 100 mL of tetrahydrofuran, 50 mL of ethanol, 2 mL of methanol containing 20% ammonia, and 5 g of Raney nickel. After filtration and evaporation, the residue is dissolved in 200 mL of methylene chloride and stirred for 20 minutes, then 2 mL of propionaldehyde is added. The solution is treated with 5 g of manganese dioxide, stirred for a further 20 minutes, the manganese dioxide is removed by filtration through Celite, the filtrate is evaporated and the residue is crystallized in ether to obtain the (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-ethyl-4H-imidazo[1,5-a][1,4] benzodiazepine-3-carboxylic acid which is recrystallized in a mixture of ethyl acetate and hexane for analysis, P.F 211-213°C.

Example 61

A mixture of 15 g (35 mmol) of (1,1-dimethyl)ethyl ester of 8-chloro-5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, 150 mL of tetrahydrofuran, 75 mL of methanol, 15 g of Raney nickel, and 5 mL of a 20% (v/v) methanolic ammonia solution was evaporated under atmospheric pressure for 2.5 hours (after which hydrogen consumption ceased). The catalyst was filtered, and the filtrate was evaporated under

55

At reduced pressure, the residue is dissolved in 200 mL of ethyl acetate and the solution is treated with 10 mL of dimethylformamide dimethylacetal. After heating under reflux for 5 minutes, the solvent is evaporated and the residue is crystallized in ether to obtain the ester.

(1,1-dimethyl)ethyl of 9-chloro-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, P.F 232-234°C. The analytical sample is purified by silica gel chromatography using a 10 1:1 by volume mixture of methylene chloride and ethyl acetate and crystallized in ethanol, P.F 234-236°C.

Example 6.2

A solution of 10 g (24.5 mmol) of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-α1λ4]benzodiazepine-3-carboxylic acid in 50 mL of trifluoracetic acid is left to stand overnight while slowly bubbling nitrogen through the mixture. The mixture is evaporated under reduced pressure and finally azeotropically with toluene. The residue is divided between dilute ammonia and ethyl acetate. The ammonia extracts are acidified with acetic acid and partially evaporated. The precipitated crystals are collected and washed with water, leaving 6-(2-chlorophenyl)-25l-methyl-4H-imidazo(l,5-a]l,4]benzodiazepine-3-carboxylic acid as colorless crystals. Recrystallization in a mixture of methanol and ethyl acetate yields a product that melts at 272–274°C.

30 Example 6 3

The reaction of 6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid (18.8 g, 53 mmols) with 15.6 g (75 mmols) of phosphorus pentachloride in 2 liters of methylene chloride and subsequent treatment with excess gaseous ammonia gives

56 a the 6-(2-chlorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4Jbenzo-diazepine-3-carboxam± which is recrystallized in a mixture of methylene chloride and ethanol. The analytical sample is recrystallized in a tetrahydrofuran/ethanol mixture, P.F 318-321°C.

Example 64

Using the phosphorus pentachloride/ethylamine process of Example 63, 2.8 g (8 mmol) of 6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid is converted to 6-(2-chlorophenyl)-N-ethyl-1-methyl-4H-imidazo[1,5-e][1,4]benzodiazepine-3-carboxamide crystallized in a mixture of methylene chloride and d-ethyl acetate. The analytical sample is recrystallized in the same solvents, at 240-242°C.

Example 65

The treatment of 1.85 g (5 mmol) of 6-(2-chlorophenyl)-l-ethyl-4H-imidazo[1,5-a]C1,4]benzodiazepine-3-carboxylic acid obtained by cleaving the t-butyl ester in the final product of Example 60 with trifluoroacetic acid with 1.47 g (7 mmol) of phosphorus pentachloride in 200 ml of methylene chloride for 1 hour and the subsequent reaction with ammonia gives 6-(2-chlorophenyl)-l-ethyl-4H-imidazo[1,5-a][l,4]benzodiazepine-3-carboxamide as a colorless product, P.F 288-290°C, crystallized in a tetrahydrofuran/ethanol mixture.

56 b

Example 66

A mixture of 1 g (2.5 mmol) of 5-oxy-5 of ethyl ester of 6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,5-a][1,U]benzodiazepine-3-carboxylic acid, 1 g of ammonium chloride and 20 ml of a 20% by volume methanolic ammonia solution is heated in a steel bomb at 95-100°C for 18 hours. The reaction mixture is diluted with water, the product is filtered, aspirated to 10 dryness, and recrystallized in a mixture of methylene chloride and methanol to obtain 5-oxide of 6-(2-chlorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxamide as a colorless product, P.F 307-310°C (dec.).

(A) 1.55 g (9 mmol) of 2-chlorobenzoic acid is added to a solution of 2 g (5.9 mmol) of 6-(2-chlorophenyl)-UH-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in 500 ml of methylene chloride. After overnight rest at room temperature, the solution is washed with a saturated aqueous solution of sodium bicarbonate and dried.

15

Example 67

57

and evaporates. The crystalline residue is recrystallized in a mixture of methylene chloride/methanol and 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]ben-^zodiazepine-3-carboxamide is obtained as a colorless product P.F 301-304°C (dec)-.

(B) A mixture of 3 g (7.6 mmol) of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid 5-oxide of ethyl ester, 3 g of ammonium chloride, and 75 mL of a 20% by volume methanolic ammonia solution is heated in a steel bomb at 100°C for 18 hours. The reaction mixture is diluted with water, the product is filtered, aspirated to dryness, and recrystallized in a mixture of methylene chloride and methanol to obtain 6-(2-chlorophenyl)-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxamide 5-oxide in the form of crystals identical to those in paragraph (A).

Example 6 8

3.36 g (10 mmol) of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4lbenzodiazepine-3-carboxamide] is refluxed in 125 ml of acetic anhydride for 90 minutes, with 50 ml of the reagent distilled. The solution is evaporated, finally azeotropically with xylene, and the residue is crystallized in ethyl acetate to obtain N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4lbenzodiazepine-3-carboxamide, which is recrystallized in a tetrahydrofuran/ethyl acetate/hexane mixture to leave colorless crystals, PF 178-180°C.

Example 69

1.57 g (9 mmol) of m-chloroperbenzoic acid is added to a solution of 2.3 g (6 mmol) of N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in 125 ml of methylene chloride. After 24 hours at room temperature, the solution is washed with a

58

saturated sodium bicarbonate solution, we dry and evaporate. Crystallization of the residue in a mixture of methylene chloride and methanol gives N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzo-5 diazepine-3-carboxamide 5-oxide as a colorless product, P.F 275-278°C (dec).

Example 7 0

A solution of 1.8 g (4.5 mmol) of N-acetyl-6-(2-chloro-10-phenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide is heated under reflux for 90 minutes in 150 mL of acetic anhydride. The solution is then evaporated azeotropically with xylene. The residue is crystallized in a mixture of ethyl acetate and ether, yielding the crude product, 4-acetyloxy 15 N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide. The solution is purified by passing it through silica gel buffer using a 10% (v/v) solution of ethyl acetate in methylene chloride. Evaporation and crystallization in the ethyl acetate/hexane mixture gives colorless crystals that melt at 170-173°C.

Example 71

A 1 g (3 mmol) suspension of 6-(2-chlorophenyl)-1-methyl 25 4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide 5-oxide is heated under reflux for 1 hour in

75 mL of acetic anhydride. A portion (25 mL) of the solvent is removed by separation in a Dean-Stark trap. After evaporation to dryness, the residue is chromatographed on 30 g of silica gel using a 1:1 by volume mixture of methylene chloride and ethyl acetate for elution. The clean fractions of the product are combined and evaporated. Crystallization of the residue in ether gives N-acetyl-4-acetyloxy-6-(2-chlorophenyl)-1-methyl-4H-imi-dazo[1,5-a1[1,4]benzodiazepine-3-carboxamide as 35 colorless crystals, molten at 176-180°C. NMR (CDCl₂) indicates

59

a mixture of two rotamers in a ratio of about 1:1 (limited range of a seven-element nucleus).

Example 7 2

8.5 mL (17 mmol) of a binormal sodium hydroxide solution is added to a 0.75 g (1.7 mmol) solution of 4-acetyloxy-N-acetyl-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in 25 mL of methanol. After stirring at room temperature under nitrogen for 90 minutes, the solution is buffered with carbon dioxide and diluted with water. The precipitated crystals are filtered, the solution is washed with water, and the aspirated solution is dried. Recrystallization in a mixture of methylene chloride and methanol gives 6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-[1,5-a][1,4lbenzodiazepine-3-carboxamide as colorless crystals, P.F 305-308°C. (dec).

Example 73

A 3.4 g (7.5 mmol) solution of N-acetyl-4-acetyloxy-6-(2-chlorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide in 40 mL of methanol is treated with 37.5 mL of a binormal sodium hydroxide solution. After stirring under nitrogen for 1 hour at room temperature, the solution is acidified with glacial acetic acid and diluted with water. The precipitate is collected by filtration and recrystallized in a mixture of methylene chloride and methanol to obtain 6-(2-chlorophenyl)-4-hydroxy-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as colorless crystals, molten at 305-307°C.

Example 74

(A) The mixture is stirred for 15 minutes until all solids have dissolved, and then left to stand at room temperature for 18 hours.

60

40.2 g (0.109 mol) of ethyl ester of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 35.6 g (0.165 mol) of 80% m-chloroperbenzoic acid, and 1 liter of methylene chloride. After washing with 10% aqueous sodium carbonate solution,

The methylene chloride is dried and evaporated. Crystallization of the residue in 300 ml of boiling ethyl acetate gives the 5-ethyl ester oxide of 6-(2-chlorophenyl)-4H-imidazot1,5-a]C1,4]benzodiazepine-3-carboxylic acid, 10 P.F 242-245°C.

(B) This compound is also obtained in a yield of 56% by reacting 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide with a base, followed by a reaction with di-15 ethyl chlorophosphate and ethyl isocyanoacetate.

Example 75

A mixture of 10 g (0.026 mol) of 5-ethyl ester 20 of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 140 mL of acetic anhydride is stirred and refluxed for 1 hour. The solution is then concentrated to a small volume, diluted with ether, and cooled over ice. Filtration and washing with ether yield the ethyl ester 25 of 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, with a boiling point of 190–192°C. The analytical sample is recrystallized in a mixture of ethyl acetate and hexane and melts at 192-195°C.

30 Example 76

A mixture of 9.5 g (0.022 mol) of ethyl ester of 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 35 and 95 ml of a 20% ammonia in methanol solution is shaken in a hermetically sealed flask for 2-3 hours at room temperature.

Ht

61

Filtration and washing with methanol gives 6—(2— chlorophenyl)-4-hydroxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, P.F 306-308°C.

5 Example 77

A mixture of 3 g (0.007 mol) of ethyl ester of 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 45 mL of a 20% methylamine solution in ethanol is shaken in a tightly closed flask for 18 hours at room temperature. The product is filtered, washed with ethanol and ether, and yields 6-(2-chlorophenyl)-4-hydroxy-N-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, with a melting point of 258–260°C. Recrystallization for analysis in a mixture of tetrahydrofuran and ethanol gives colorless crystals that melt at 260–262°C.

Example 78

(A) A mixture of 2 g of 4-acetyloxy-6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, 30 mL of methanol, and 4 mL of a trinormal sodium hydroxide solution is shaken at room temperature for 30 minutes. The solution is divided between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer is dried and evaporated. Crystallization of the residue in methylene chloride/ethyl acetate gives 6-(2-chlorophenyl)-N-ethyl-4-hydroxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as colorless crystals, P.F 246-248°C.-30 (B) A mixture of 0.43 g of ethyl ester of 4-acetyloxy-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 10 mL of ethanol containing 20% by volume of ethylamine is stirred at room temperature for 24 hours. The solvent is evaporated and the residue is recrystallized in an ethylene chloride/ethyl acetate mixture.

Cx

62

to obtain 6-(2-chlorophenyl)-N-ethyl-4-hydroxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as a colorless product, P.F 246-248°C.

Example 79

A solution of 5.4 g of 6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxamide 5-oxide is heated at 100°C for 18 hours in 70 ml of acetic anhydride. The reagent is evaporated under reduced pressure, the residue is crystallized in an ethyl acetate/ether/hexane mixture, and then recrystallized in an ethyl acetate/hexane mixture to obtain 4-acetyloxy-6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide as colorless crystals, molten at 145-150°C.

Example 80

A mixture of 6.5 g (0.017 mol) of 6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, 4.75 g (0.22 mol) of 80% pure m-chloroperbenzoic acid, and 250 mL of methylene chloride is stirred until all the material is dissolved. The solution is left to stand at room temperature for 18 hours.

After washing with a 10% aqueous sodium carbonate solution, the mixture is dried and the methylene chloride is evaporated. The residue is chromatographed on silica gel using a 1:19 ethanol/methylene chloride mixture. The fractions containing the product are combined and evaporated. Crystallization in ethanol gives 6-(2-chlorophenyl)-N-ethyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide 5-oxide, molten at 175-180°C.

Example 81

A mixture of 7.95 g (0.02 mol) of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl-α-(hydroxyimino-) acid was hydrogenated under atmospheric pressure for 2.5 hours.

63

3H-1,4-benzodiazepine-2-acetic acid, 8 g of Raney nickel, 150 mL of tetrahydrofuran, 75 mL of ethanol, and 2 mL of a 20% ammonia-methanol solution. The catalyst is filtered and the filtrates evaporated. Residue 5 is dissolved in 200 mL of toluene, treated with 5.16 g (0.06 mol) of pivaldehyde, and stirred for 1 hour. After adding 8 g of manganese dioxide, stirring is continued for 30 minutes. Manganese dioxide is filtered, the filtrates are evaporated, and they are crystallized in a mixture of ether and hexane to obtain the (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid, with a melting point of 194-197°C. Recrystallization for analysis in a mixture of ethyl acetate and hexane gives a product with a melting point of 195-197°C.

Example 82

The mixture is left to stand at room temperature for 2 hours, and then a solution of 1.1 g (2.5 mmol) of (1,1-dimethyl)ethyl ester of 6-(2-chlor-20 rophenyl)-1-(1,1-dimethylethyl)-4H-imidazo[1,5-a][1,4]ben- is evaporated.

3-benzodiazepine-3-carboxylic acid is dissolved in 10 ml of trifluoroacetic acid. The oils are distilled azeotropically with toluene, then crystallized in boiling ethyl acetate. Recrystallization in a methanol/ethyl acetate mixture yields 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imi-dazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid.

Example 8 3

The mixture is treated with 0.38 g (1.8 mmol) of phosphorus pentachloride 30, and then a suspension of 0.56 g (1.4 mmol) of 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is stirred for 1 hour in 75 mL of methylene chloride. Gaseous ammonia is bubbled through the solution until it remains alkaline. After the addition of 25 mL of water and

10 ml of ethanol and stirring for 1 hour, the methylene chloride phase is separated, dried and evaporated. Recrystallization in the methylene chloride/ethanol mixture gives 6-(2-chlorophenyl)-1-(1,1-dimethylethyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, P.F 275-278°C.

Example 84

A mixture of 7.95 g (0.02 mol) of (1,1-dimethyl)ethyl ester of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, 8 g of Raney nickel, 150 mL of tetrahydrofuran, 75 mL of ethanol, and 2 mL of ammonia in a 20% methanol solution was hydrogenated at atmospheric pressure for 2.5 hours. The catalyst was filtered out, and the filtrates were evaporated. The residue was dissolved in 200 mL of methylene chloride, treated with 4.32 g (0.06 mol) of butytaldehyde, shaken for 1 hour in an open-bottom flask, and then evaporated. The residue was chromatographed on silica gel buffer using a 1:9 mixture of ethyl acetate and methylene chloride. The fractions containing the product are combined and evaporated. Crystallization in ether gives the (1,1-dimethyl)-ethyl ester of 6-(2-chlorophenyl)-1-propyl-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid, with a melting point of 176-179°C. For analysis, recrystallization in ether gives a product with a melting point of 178-180°C.

Example 85

A solution of 1.9 g (4.3 mmol) of (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is left to stand at room temperature for 2 hours in 20 mL of trifluoracetic acid, then evaporated and distilled azeotropically with toluene. Crystallization in methanol/ethyl acetate, followed by recrystallization in the same solvents, gives the acid

65

6-(2-chlorophenyl)-l-propyl-4H-imidazo[1,5-a][1,4l-benzo-diazepine-3-carboxylic, P.F 271-273°C.

Example 86

5. A suspension of 1.1 g (2.8 mmol) of 6-(2-chlorophenyl)-1-propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 125 mL of methylene chloride is treated with 0.78 g (3.7 mmol) of phosphorus pentachloride and stirred for 1 hour. Gaseous ammonia is bubbled through the solution at 10°C until it remains alkaline. After adding 50 mL of water and 25 mL of ethanol, the mixture is stirred for 1 hour, the methylene chloride layer is separated, the solution is dried, and the solution is evaporated. Recrystallization in methylene chloride gives 6-(2-chlorophenyl)-1-15 propyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide, P.F 290-292°C.

Example 87

(A) 50 ml of a normal hydroxide solution is added

20 g of sodium is added to a solution of 5 g of 2-chloromethyl-4-(2-chlorophenyl)quinazole 3-oxide in 250 ml of tetrahydrofuran. After 3 hours of stirring at room temperature, the mixture is acidified by the addition of glacial acetic acid and evaporated to a small volume. The mixture is then divided between 25 g of methylene chloride containing 10% ethanol and an aqueous solution of sodium bicarbonate. The organic layer is dried and evaporated, and the residue is recrystallized in the methylene chloride and ethanol mixture to obtain 5-(2-chlorophenyl)-1,3-dihydro-2H-3O-1,4-benzodiazepin-2-one 4-oxide as colorless crystals, molten at 231-232°C.

(B) This compound is also prepared in a yield of

88% by oxidation of 5-(2-chlorophenyl)-1,3-dihydro~2H-l,4-benzodiazepin-2-one with m-chloroperbenzoic acid in 35% methylene chloride.

66

Example 88

A solution of 27 g (0.1 mol) of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzo-diazepin-2-one in 400 ml of tetrahydrofuran is cooled over ice water. After the addition of 13 g (0.115 mol) of potassium t-butylate,

The mixture is stirred for 5 minutes under nitrogen. Then, 18 mL (0.125 mol) of diethyl chlorophosphate is added, and stirring continues for 10 minutes. After the addition of 26.4 g (0.2 mol) of dimethyl malonate and 22.4 g (0.2 mol) of potassium t-butylate, the mixture is stirred without cooling for 2 hours and then acidified by treatment with 20 mL of acetic acid. The mixture is then divided between toluene and a sodium bicarbonate solution. The organic layer is separated, dried, and evaporated. Crystallization of the residue in ether yields yellowish crystals, with a melting point of 133–138°C. For analysis, the product is purified by passing it through silica gel buffer using 5% (v/v) ethyl acetate in methylene chloride for elution. Crystallization in 20 1'ether gives a pure material which is the dimethyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidenepropanedioic acid, P.F 135-138°C.

Example 89

25 A mixture of 9 g (23.4 mmol) of dimethyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylidenepropanedioic acid, 6.6 g (0.117 mol) of potassium hydroxide, and 300 mL of methanol is refluxed under nitrogen for 3 hours. Most of the solvent 30 is removed under reduced pressure, and the residue is divided between water and methylene chloride. The organic phase is separated, dried, and evaporated to leave only the oily methyl ester of 5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ylideneacetic acid. 35 This material is dissolved in 50 mL of glacial acetic acid and

°t

67

The solution is treated with 1.96 g (28 mmol) of sodium nitrite. After stirring at room temperature for 1 hour, the mixture is diluted with water, the precipitate is filtered, the mixture is washed with water, and the aspirated fluid is allowed to dry. Recrystallization in a mixture of methylene chloride and ethanol gives the methyl ester of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid as yellow crystals, with a boiling point of 246–248°C.

Example 9 0

A mixture of 8 g of 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid methyl ester, 200 mL of tetrahydrofuran, 80 mL of methanol, 14 g of Raney nickel, and 2 mL of a 20% (v/v) ammonia solution in methanol is hydrogenated at atmospheric pressure for 2 hours. The catalyst is filtered out, and the filtrate is evaporated. The residue is dissolved in 100 mL of methylene chloride and heated with 20 mL of a 20% (v/v) dimethylamine solution in tetrahydrofuran and 4 mL of acrolein. After 20 minutes of stirring at room temperature, 14 g of activated manganese dioxide is added, and stirring is continued for 30 minutes. Manganese dioxide is separated by filtration on Celite and the filtrate is evaporated. Crystallization of the residue in the mixture of ethyl acetate and ether gives the methyl ester of 6-(2-chlorophenyl)-l-[(2-dimethylamino)ethyl]-4H-imidazo[l,5-a][1,4]benzodiazepine-3-carboxylic acid which is recrystallized in a methanol/ethyl acetate/ether mixture to give colorless crystals, P.F 170-172°C.

Example 91

A mixture of 3 g of methyl ester of 6-(2-chlorophenyl)-1-[2-(dimethylamino)ethyl]-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylic acid, and 3 g of ammonium chloride is heated in a steel bomb at 100°C for 18 hours.

68

nium and 75 ml of methanol containing 20% by volume of ammonia. The solvent is partially evaporated, and the residue is divided between methylene chloride and aqueous ammonia. The organic phase is dried and evaporated. The residue is crystallized in a methanol/ethyl acetal mixture to leave the 6-(2-chlorophenyl)-1-[2-(dimethylamino)ethyl]-

^-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide. The analytical sample is recrystallized in the same solvents, giving off-white crystals, P.F 257-10 260 °C.

Example 9 2

A mixture of 1.9 g of 1-ethyl-3-(1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-dicarboxylic acid, 100 mL of ethanol, and 1 g of sodium borohydride is heated under reflux for 15 minutes. The solvent is partially evaporated, and the residue is partitioned between water and methylene chloride. The organic phase is dried and evaporated. Crystallization of the residue in a mixture of methylene chloride and ethyl acetate yields the (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-(hydroxymethyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid. For analysis, it is recrystallized in a mixture of methanol and ethyl acetate and colorless crystals are obtained, P.F 25 253-254°C (dec).

Example 93

Six g of (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-(hydroxymethyl)-4H-imidazo[1,5-α][1,4]-benzodiazepine-3-carboxylic acid are added to 30 mL of thio-30 nyl chloride. After stirring at room temperature for 1 hour, the reagent is evaporated, and the residue is divided between methylene chloride and a 10% aqueous solution of sodium carbonate containing ice. The organic phase is dried and evaporated. The residue is crystallized in a mixture of methylene chloride and ether, yielding

Of

The (1,1-dimethyl)ethyl ester of 1-(chloromethyl)-6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, P.F 190-194°C (dec). The analytical sample is purified by chromatography over a 30-fold greater quantity of silica gel using 10% by volume of ethyl acetate in methylene chloride for elution and crystallized in a mixture of ethyl acetate and hexane to obtain colorless crystals, P.F 194-195°C (dec).

Example 94

A mixture of 3 g of (1,1-dimethyl)ethyl ester of 1-(chloromethyl)-6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 40 mL of tetrahydrofuran containing 20% by volume of dimethylamine is heated in a steel bomb at 100°C for 3 hours. The solvent is evaporated, and the residue is divided between methylene chloride and a 10% aqueous sodium carbonate solution. The organic layer is then dried and evaporated. Crystallization of the residue in a mixture of ethyl acetate and ether gives the (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo[l,5-a][1,4]benzodiazepine-3-carboxylic acid, MF 192-195°C. Recrystallization of the analytical sample in a mixture of ethyl acetate and hexane yields colorless crystals, MF 198-200°C.

Example 95

A mixture of (1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 40 mL of methanol, and 5 mL of concentrated sulfuric acid is left to stand at room temperature for 24 hours. The mixture is then divided between methylene chloride and dilute ammonia under ice. The methylene chloride layer is separated, dried, and evaporated. The residue is passed through a buffer of

70

Silica gel is prepared using 5% ethanol in methylene chloride. Evaporation and crystallization in a mixture of ethyl acetate and ether yields, in two harvests, the methyl ester of 6-(2-chlorophenyl)-1-[(dime-5-thylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid. The analytical sample is recrystallized in ether, and its melting point is 184-185°C. A variant with a lower melting point (166-169°C) is also observed.

Example 96

A mixture of 2.5 g of methyl ester of 6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 2.5 g of ammonium chloride, and 40 mL of methanol containing 20% ammonia is heated in a steel bomb at 100°C for 18 hours. The solvent is partially evaporated, and the residue is partitioned between methylene chloride and water. The organic phase is dried and evaporated. The residue is chromatographed on 50 g of silica gel using 5% by 20% ethanol in methylene chloride for elution. Crystallization in a mixture of ethyl acetate and ether gives 6-(2-chlorophenyl)-1-[(dimethylamino)rti-: thyl]-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxamide in the form of colorless crystals, P.F 228-230°C.

25

Example 97

At atmospheric pressure, hydrogen is heated until hydrogen consumption ceases (2 hours). A mixture of 4 g (10 mmol) of (1,1-dimethyl)ethyl ester, 5-(2-chlorophenyl)-α-(hydroxyimino)-3H-1,4-benzodiazepine-2-acetic acid, 50 ml of tetrahydrofuran, 20 ml of ethanol, 1 ml of methanol containing 20% by volume of ammonia, and 5 g of Raney nickel is added. The catalyst is filtered, the filtrate is evaporated, the residue is dissolved in 100 ml of methylene chloride, and the mixture is treated with 2.5 g of glyoxa-

71

The mixture is stirred in an open flask for 18 hours at room temperature. It is filtered through silica gel buffer using 5% by volume of ethyl acetate in methylene chloride for washing. The filtrate is evaporated, and the residue is crystallized in ether to obtain the 1-ethyl-3-(1,1-dimethyl)ethyl ester of 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-1,3-dicarboxylic acid. The analytical sample is recrystallized in a mixture of ethyl acetate and hexane to obtain colorless crystals, molten at 185-187°C.

Example A

6-(2-chlorophenyl)-4-hydroxy-4H-imidazotl,5-a 1 tl,43benzodiazepine-3-carboxamide (reduced to a particle size on the order of microns) can be used as an active ingredient in the following compositions:

a) Composition of tablets (Direct Compression)

N"

Ingredients

mq/tablet

1.

Active ingredient

0.1

0.5

5.0

10.0

25, 0

2.

Lactose

85.4

85.5

81.0

103.0

112.5

3.

Avicel

30.0

30.0

30.0

45.0

60.0

4.

Modified starch

8

7.5

7.5

10.0

15, 0

5.

Magnesium Stearate

1.5

1.5

1.5

2.0

2.5

Total

125

125

125

170

"215

Procedure:

1. Mix numbers 1 to 4 in a suitable blender for 10 to 15 minutes.

2. Add the magnesium stearate (No. 5) to the previous mixture and mix for 4 minutes. Compress in a suitable press.

72

b) Tablet composition (Compression)

Direct)

No.

Ingredients

mg/tablet

1.

Active ingredient

10.0

20, 0

40.0

2.

Lactose

182, 0

172.0

216, 0

3.

Microcrystalline Cellulose

60.0

60.0

80.0

4.

Modified starch

15.0

15.0

20.0

5.

Corn starch

30.0

30, 0

40.0

6.

Magnesium Stearate

3.0

3.0

4.0

Total

300

300

400

Procedure:

1. Mix Nos. 1 to 5 in a suitable blender for 1 to 15 minutes.

2. Add #6 and mix for 5 minutes. Compress in a suitable press.

c) Composition of the capsules

No.

Ingredients

mg/capsule

1.

Active ingredient

0.1

0.5

5.0

o o

1—l o m

CM

2.

Lactose

183.9

183.5

179.0

218.0

257, 0

3.

Starch

30.0

30.0

30.0

50.0

o o

4.

Talc

5.0

5.0

5.0

o o i—i

15.0

5.

Magnesium Stearate

1.0

1.0

1.0

2.0

3.0

Total

220

220

220

290

370

Procedure:

1. Mix items 1 to 3 in a suitable mixer. Grind in a suitable grinder.

2. Mix with Nos. 4 and 5 and fill the capsule machine.

73

d) Composition of the capsules

No.

Ingredients

mg/capsule

1.

Active ingredient

10.0

20.0

40.0

2.

Lactose

215.0

205, 0

260, 0

3.

Fennel starch

60.0

60.0

80.0

4.

Magnesium stearate

3.0

3.0

4.0

5.

Talc

12.0

12.0

16.0

Total

300

300

400

Procedure:

1. Mix items 1 to 3 in a suitable mixer. Grind in a suitable grinder.

2. Mix with Nos. 4 and 5 and fill the capsule machine.

Example B

6-(2-chlorophenyl)-4H-imidazo[1,5-[1,4]benzodiazepine-3-carboxamide (reduced to a particle size on the order of microns) can be used as an active ingredient in the following compositions:

a) Tablet composition (Direct Compression)

N?

Ingredients

mg/tablet

1.

Active ingredient

0.1

0.5

5.0

10.0

25.0

2.

Lactose

85.4

85.5

81.0

103.0

112.5

3.

Avicel

30.0

30, 0

o o m

45.0

o o

ÏO

4.

Modified starch

8

7.5

7.5

10, 0

15.0

5.

Magnesium stearate

1.5

1.5

1.5

2.0

2.5

Total 125 125 125 170 215

Procedure:

1. Mix ingredients #1 to #4 in a suitable mixer.

74

for 10 to 15 minutes.

2. Add magnesium stearate (No. 5) to the pre-mixed mixture and mix for 4 minutes. Compress in a suitable press.

b) Tablet composition (Direct Compression)

10

15

20

Ingredients No. mg/tablet

1. Active ingredient 10.0 20.0 40.0

2. Lactose 182.0 172.0 216.0

3. Microcrystalline Cellulose 60.0 60.0 80.0

4. Modified starch 15.0 15.0 20.0

5. Corn starch 30.0 30.0 40.0

6. Magnesium Stearate 3.0 3.0 4.0

Total 300 300 400

Procedure:

1. Mix items 1 to 5 in a suitable blender for 1 to 15 minutes.

2. Add: No. 6 and mix for 5 minutes. Compress in a suitable press.

c) Capsule composition

No.

Ingredients

mg/capsule

1.

Active ingredient

0.1

0.5

5,

0

10, 0

25.0

2.

Lactose

183, 9

183.5

179,

0

218.0

257, 0

3.

Starch

30.0

o o m

30,

0

50, 0

o o

4.

Talc

5.0

5.0

5,

0

10.0

15, 0

5.

IVβ-Gnesium Stearate

1.0

1.0

1,

0

2.0

3.0

Total

220

220

220

290

370

75

Procedure:

1. Mix items 1 to 3 in a suitable mixer. Grind in a suitable grinder.

21 Mix with Nos. 4 and 5 and fill the machine with 5 capsules.

d) Cell composition

No.

Ingredients

ma/aélule

1.

Active ingredient

10, 0

20, 0

o o

2.

Lactose

215.0

205, 0

260.0

3.

Corn starch

60, 0

O

o

80.0

4.

Magnesium stearate

3.0

3.0

4.0

5.

Talc

12, 0

12.0

16.0

Total

300

300

400

Procedure:

1. Mix items 1 to 3 in a suitable mixer. Grind in a suitable grinder.

2. Mix with Nos. 4 and 5 and fill the capsule machine.

Example C

9-chloro-6-(2-chlorophenyl)-4H-imidazotl,5-a][1,4]benzodiazepine-3-carboxamide (reduced to a particle size on the order of microns) can be used as an active ingredient in the following compositions:

<=fr

76

a) Tablet composition (Direct Compression)

No.

Ingredients

mg/tablet

1.

Active ingredient

0.1

0.5

5.0

10, 0

25.0

2.

Lactose

85.4

85.5

81.0

103, 0

112.5

3.

Avicel

30.0

30.0

30.0

45.0

60.0

4.

Modified starch

8

7.5

7.5

10.0

15.0

5.

Magnesium stearate

1.5

1.5

1.5

2.0

2.5

Total 125 125 125 170 215

Procedure:

1. Mix items 1 to 4 in a suitable blender for 10 to 15 minutes.

2. Add magnesium stearate (No. 5) to the pre-mixed mixture and mix for 4 minutes. Compress in a suitable press.

b) Tablet composition (Direct Compression)

N" Ingredients mg/tablet

1. Active ingredient 10.0 20.0 40.0

2. Lactose 182.0 172.0 216.0

3. Microcrystalline cellulose 60.0 60.0 80.0

4. Modified starch 15.0 15.0 20.0

5. Corn starch 30.0 30.0 40.0

6. Stearate of .

magnesium 3.0 3.0 4.0

Total 300 300 400

Procedure:

1. Mix items 1 to 5 in a suitable blender for 1 to 15 minutes.

2. Add #6 and mix for 5 minutes.

77

sea in a suitable press.

c) Composition of ailule

No.

Ingredients mg/capsule

1.

Active ingredient 0.1

0.5

5.0

10.0

25.0

2.

Lactose 183.9

183.5

179, 0

218.0

257.0

3.

Starch 30.0

30.0

30.0

50.0

70.0

4.

Talc 5.0

5.0

5.0

10.0

15.0

5.

Magnesium stearate 1.0

1.0

1.0

2, 0

3.0

Total 220

220

220

290

370

Procedure:

1. Mix ingredients 1 to 3 in a suitable mixer. Grind in a suitable grinder.

2. Mix with Nos. 4 and 5 and fill the capsule machine.

d) Capsule composition

No.

Ingredients

mg/capsule

1.

Active ingredient

10.0

20.0

40,

0

2.

Lactose

215.0

205, 0

260,

0

3.

Corn starch

O

o vo

60.0

80,

0

4.

Magnesium stearate

3.0

3.0

4,

0

5.

Talc

12.0

12.0

16,

0

Total

300

300

400

Procedure:

1. Mix items 1 to 3 in a suitable mixer. Grind in a suitable grinder.

2. Mix with Nos. 4 and 5 and fill the capsule machine.

78

DEMANDS

i >

1. Process for manufacturing imidazobenzodiazepine derivatives corresponding to the general formula:

^N^ /CONHR2

R5 • 4—1 H

Y y v

/R4

i II

in which R"*" represents a hydrogen atom or a lower dialkyl(inf)-aminoalkyl radical or

2

lower alkyl, R represents a hydrogen atom or a lower alkanoyl radical or lower alkyl 3

R represents a hydrogen atom or a radical

[lower 4 alkanoyloxy|_or hydroxy, R represents a chlorine, bromine or fluorine atom or a trifluoromethyl radical and R^ represents a hydrogen, fluorine or

3

chlorine, under the conditions that a) R cannot represent-

2

to smell a hydroxy radical when R is a radical

3

lower alkanoyl and b) R represents a hydrogen atom when R is a lower dialkyl(inf)aminoalkyl radical,

and their pharmaceutically acceptable salts, characterized in that it consists of:

a) to submit a compound of general formula

79

< A./coor r5 'J H

W \ / X //

i II x-/ XII

% A x

■9=N4 H

X/R

I II

\y'

in which R represents an alkyl radical inf-14 5

rieur and R, R and R have the same meanings as above,

21

has an aminolysis with an amino compound of formula H„NR

21 >

in which R represents a hydrogen atom or a lower alkyl radical, or b) to submit a compound of general formula

/cocl

R5 • it H

W \ / v y

II XVI

V=H/ XH

R4 I II

V/'

14 5

in which R, R and R have the same meanings as above,

21

to an aminolysis with an amino compound of formula H„NR.

21

in which R is as defined above, or c) to treat a compound of general formula

80

10

15

R\ /conhr21

r5 .. i >3 H

K\/ \./N X XH

I II

N<?—

y'\ /R4

XVII

1 21 4 5

in which R, R, R and R have the same meanings as above,

with a carboxylic acid anhydride in or d) to treat a compound of general formula

Rj .N, .CONHR21

\m/

R5. À_'js OCOR'

i il).( Ib'

20 XÇ===N/ XH

• R4

S \7

I II

"

in which R' represents a C alkyl radical.

P c 1 21 4 5 -

and R, R, R and R have the same meanings as above,

with an alkali metal hydroxide, or e) to submit a compound of general formula

30 <>wC00R

R\.^\ >—'"'v /0C0R'

I II /-x XVIII

x./ V==N/ XH

A R4 / \ /

ï H

'V/'

35

81

15

20

in which R represents a hydrogen atom

4 5

or a lower alkyl radical and R, R', R and R

have the same meaning as above,

21

has an aminolysis with an amino compound of formula H0NR

2i ^

in which R has the same meaning as above, f) to treat a compound of general formula y^ONHR21

I _ A

Ib'

R4

^ \ / i il 'V/'

11214 5

in which R, R, R and R have the same meanings as above,

with a chloride or anhydride of carboxylic acid in or g) to treat a compound of general formula

R\^N\/C0NH2

R\ TO *\ /OCOR'

î • \ /

I II

25 ^ Ni

At X

II

V/'

THE'

11 4 5

30 in which R', R', R' and R' have the same meanings as above,

with a chloride or anhydride of carboxylic acid in and h) possibly, to convert a compound of formula I 35 thus obtained into a pharmaceutically acceptable salt.

Yes

82

2. A method according to claim 1, characterized in that Rl represents a hydrogen atom.

3. A method according to claim 1 or 2, characterized in that R^ represents a hydrogen atom or an ethyl radical.

4. A method according to claim 1, 2 or 3, characterized in that R^ represents a chlorine or fluorine atom.

5. A method according to any one of claims 1 to 4, characterized in that R represents a hydrogen atom

6. Process according to claim 1, characterized in that 9-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide is prepared.

7. Process according to claim 1, characterized in that 6-(2-chlorophenyl)-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxamide is prepared.

8. Process according to claim 1, characterized in that 6-(2-chlorophenyl)-l-methyl-4H-imidazo[1,5 a][1,4]benzodiazepine-3-carboxamide is prepared.

9. Process according to claim 1, characterized in that 6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide is prepared.

10. Process according to claim 1, characterized in that N-acetyl-6-(2-chlorophenyl)-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxamide is prepared.

11. A method for manufacturing a medicinal product, in particular intended to serve as an anxiolytic, characterized in that one or more compounds of formula I (claim 1) or one or more pharmaceutically acceptable salts thereof and optionally one or more other therapeutically effective products are combined with one or more therapeutically inert excipients in the form of galenic dosages.

* * *

JOSÉ CURAU

IN PROPERTY CONSULTANT* APPROVED BY LB aouvirnsMlnt PHtHCiBR

CONSULTATIONS • PROCEDURES

STUDIES AND RESEARCH TRADEMARK FILING - PATENTS DESIGNS AND MODELS

BOJTC POSTACH IO » MONTS-CAHtO AORBSSB TCLCOR, < PR1NOU3 (MONACO) OFFICE TEL. « 30.82.3Û TELEX 400477

C.C.P. MARSEILLE 700-07

MONTE CARLO. AUGUST 27, 1 9 B4

2 0»t», PRINCESS-CHARLOTTE BOULEVARD

Mr. Director of the Industrial Property Service

V/N Ref:

RAN 4008/331 Vpt RPM/P

MONACO - CITY

Object :

Submission of priority documents

Title :

Ve,/iivo.&

d ' imidazo bmzodLa.zo.pln2.

Holder :

F. HOFFMANN LA ROCHE é Cl E S.A.

Deposit :

Monaco, £3.8 P.V. n° 1721

Mr. Director,

As of

21 iq?i ■ we have filed the Patent Application cited in reference, with claim of priority.

In order to regularize this matter, we are enclosing the official documents required by law to justify our claim of priority, namely:

FOR REVENUE VICTIM U.S.A. No. 526 194 of August 25, 1983

- copy. o^ideULo, of. bn&v&t

- translation dej> sievmdicationà

- c2A&ion can IzM inve.nt&u/iï to HOFFMANN LA ROCHE U.S.A.

" can HOFFMANN LA ROCHE USA to HOFFMANN LA ROCHE BALE

- tn.aducJU.on dz6 a.ct&> de. dU&ioYi

We would be very grateful if you would acknowledge receipt of our shipment by returning a copy of this letter, bearing your acknowledgement of receipt.

Thank you in advance.

And please accept, Mr. Director, the expression of our distinguished sentiments.

Documents submitted on August 27, 1984

1 S&utU

v José CURAU