CA1073454A - Imidazolobenzodiazepines, processes for their preparation and compositions incorporating them - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

1,2-Dihydro-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodia-zepin-1-ones having the general formula:

(I)

Description

iQ~345~1 The present invention relates to imidazolobenzodia-zepines and, more particularly, to certain pharmaceutically active 1,2-dihydro 6-phenyl lH, 4H-imidazo-~1,2a~ ~1,4~ benzo-diazepin-l-ones that may be of use in human or veterinary me-dicine, as well as to a process for-their preparation.
The 1,2-dihydro 6-phenyl lH, 4H-imidazo fl,2a~ fl, ~
benzodiazepin-l-ones with which the invention is concerned are represented by the ge~eral formula :

;C \ R5 N (I) }1,1~'\~

~ R2 wherein:
Rl represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical;
R2, which may be at any appropriate position in the phenyl ring, represents a hydrogen atom or a halogen atom;
R3 represents a hydrogen atom or a methyl radical; and R4 and R5, which are the same of different, each re-presents a hydrogen atom, an alkyl radical containing from 1 to5 carbon atoms, a hydroxyalkyl radical containing from 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl radical ~the LD~

` 1073454 alkyl moieties each containing from 1 to 5 carbon atoms), a phenyl radical or a cycloalkyl radical containing from 3 to 8 carbon atoms, or R4 and R5 represent together with the nitrogen atom to which they are bound a heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-l-yl, 4-alkyl-piperazin-l-yl, 4-hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-l-yl, 4-(l'-phenyl-5'-imidazolyl-4'-one) piperazin-l-yl and R6-piperazin-l-yl radicals, in which R6represents a cycloalkyl--alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a ~-4-dialkylphosphinyl alkyl radical, the alkyl moieties containing from 1 to 5 carbon atoms. Pharmaceutically acceptable acid addition salts of these derivatives are also within the scope of the present invention.
~ Where Rl represents a halogen atom, it may convenient-ly be a fluorine, chlorine or bromine atom, but is preferably a chlorine atom.
Where R represents a halogen atom, it too may con-- 20 veniently be a fluorine, chlorine or bromine atom, but is pre-ferably a fluorine or chlorine atom. Furthermore, the halogen atom R2 is preferably in the ortho-position.
R3 is most preferably a hydrogen atom.
Where either of R4 and R5 represents an alkyl radical, it may conveniently be a methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl radical, but is preferably a methyl, ethyl, n-propyl, n-butyl or t-butyl radical.
Where either of R4 and R5 represents a hydroxyalkyl radical, the alkyl moiety may conveniently be a methyl, ethyl, propyl, butyl or pentyl radical, but is preferably an ethyl radical.
Where either of R4 and R5 represents an aminoalkyl

-2-.

1073~5~

or alkylaminoalkyl radical (which latter term includes both monoalkyl- and dialkylaminoalkyl), each of the alkyl moieties may conveniently be a methyl, ethyl, propyl or butyl radical, but is preferably a methyl or ethyl radical. Preferably R4 and/orR5 represent an aminomethyl, aminoethyl, dimethylaminoethyl or die-thylaminoethyl radical, but may also represent an aminopropyl, aminobutyl, methylaminomethyl, methylaminoethyl or dimethyl-aminopropyl radical.

- . . ~ .............. ........ .

:: - -' : - ': .......... , : . ,,,~
. .. , -; . . : . :

0734 ~
Where either of R4 and R5 represents a cycloalkyl radical, it is conveniently one containing from 3 to 8 carbon atoms, and is preferably a cyclohexyl radical.
R4 and R5 may be the same - they each may be, for example, a methyl group - or different, and when they are different one of them is preferably hydrogen.
Where R4 and R5, together with the conjoining nitrogen atom, form a heterocyclic grouping, this grouping is saturated, may be substituted or unsubstituted, and may optionally contain a second heteroatom. Typical examples of unsubstituted hetero-cyclic groupings are pyrrolidinyl,piper~ino, m~holin~ thiom~rpholino and pipe~azin-l-yl. Preferred substituents for such heterocyclic groupings are alkyl radicals containing from 1 to 5 carbon atoms, such as methyl~ ethyl and propyl; hydroxyalkyl radicals con-taining from 1 to 5 carbon atoms, such as hydroxyethyl; dialkyl-phosphinylalkyl radicals, each alkyl moiety of which contains from 1 to 5 carbon atoms, such as methyl; cycloalkylalkyl radicals containing from 3 to 6 carbon atoms in the cycloalkyl moie$y and from 1 to 5 carbon atoms in the alkyl moiety, such as cyclo-propylmethyl; alkenyl radicals containing from 2 to 5 carbon -atoms, such as allyl; aryl radicals, such as phenyl; and nitrogen heterocyclic radicals, such as l-phenyl-5-imidazolyl-4-one.
~ypical examples of substituted heterocyclic groupings are the 4-a1kyl-piperazin-1-yls and especially 4-methyl , 4-ethyl- and 4-propyl-piperazin-1-yl; the 4-hydroxyalkyl-piperazin-1-yls and especially 4-hydroxyethyl-piperazin-1-yl; the 4-dialkylphosphinyl-alkyl-piperazin-l-yls and especially 4-dimethylphosphinylmethyl-piperazin-l-yl; the 4-cycloalkylalkyl-piperazin-1-yls and especially 4-cyclopropylmethyl-piperazin-1-yl; 4-alkenyl-piperazin-l-yls and especially 4-allyl-piperazin-1-yl; 4-phenyl-piperazin-l-yl; and 4-(1'-phenyl-5'-imidazoyl-4'-one)-piperidin-l-yl .

- 3 -~0~3454 Within the broad area encompassed by general formula I, the following smaller groups of compounds are preferred :
a) the imidazolobenzodiazepine~ of general formula I wherein either R4 and R5, which may be the same or different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyethyl radical, a dimethyl- or diethylaminoethyl radical, a phenyl radical, or a cyclohexyl radical, or R4 and R5 together with the nitrogen atom form a pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-l-yl, 4-alkyl-piperazin-1-yl, 4-hydroxyalkyl-piperazin-1-yl,

4-phenyl-piperazin-1-yl or 4-(1~-phenyl-5~-imidazolyl-4'-one) piperidin-l-yl radical;
b) the imidazolobenzodiazepines of general formula I wherein Rl represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom, a chlorine atom or a fluorine atom, R3 represents a hydrogen atom, and either R4 and R5, which may be the same or different, each represents a hydrogen atom, a straight aIkyl radical containing from 1 to 5 carbon atoms~ a hydroxyethyl radical, a phenyl radical, or a cyclohexyl radical, or R4 and -R5 together with the nitrogen atom form a piperidino, morpholino, piperazin-l-yl, 4-alkyl-piperazin-1-yl or 4-hydroxyethyl-piperazin-l-yl radical;
c) the imidazolobenzodiazepines of general formula I wherein Rl represents a chlorine atom or a nitro radical, R2 represents a hydrogen, chlorine or fluorine atom, R3 represents a hydrogen atom, and either R4 represents a hydrogen atom and R5 represents a methyl, ethyl, propyl or butyl radical, or R4 and R5 together with the nitrogen atom form a piperazin-l-yl, 4-methyl-piperazin-l-yl, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl or 4-hydroxyethyl-piperazin-1-yl radical;
d~ the imidazolobenzodiazepines of general formula I wherein Rl represents a chlorine atom or a nitro radical, R2 represents ~ 4 ~

. , ' : ' ~ .

`` ` iO~34S4 a hydrogen, chlorine or fluorine atom, R3 represents a hydrogen atom, and R4 and R5 together with the nitrogen atom form a 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-l-yl radical;
e) the imidazolobenzodiazepines of general formula I wherein Rl represents a hydrogen atom, a chlorine atom or a nitro radical, R represents a hydrogen atom, a chlorine atom or a fluorine atom, R3 represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl radical; and f) the ;midazolobenzodiazepines of general formula I wherein Rl represents a hydrogen atom, a chlorine atom or a nitro radical, R2 represents a hydrogen atom or a chlorine atom, R3 represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 4-dimethylphosphinylmethyl-piperazin-1-yl radical.
The imidazolobenzodiazepines ~ may be in the form of pharmaceutically acceptable acid addition salts, and these may be salts with mineral or organic acids. Typical mineral acids ~ --are hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric and phosphoric acids, while typical organic acids are acetic, form c, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic~
glyoxylic, aspartic, alkanesulphonic and arylsulphonic acids.
Preferred acid addition salts are the tartrates and alkane-sulphonates, and the methanesulphonates are especially preferred.
~ here are further preferred groups of compounds of formula I in the form of pharmaceutically acceptable acid addition salts. ~hese are as follows:-g) acid addition salts of the imidazolobenzodiazepines of general formula I wherein Rl represents a hydrogen atom, a chlorine atom or a nitro radical, R2 represents a hydrogen atom9 a chlorine atom or a fluorine atom, R3 represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 0~345~

4-alkyl-piperazin-1-yl radical; and h) the tartrates and alkanesulphonate~ (particularly methane-sulphonates) of the imidazolobenzodiazepines of general formula I
wherein Rl represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom or a chlorine atom~ R3 represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 4-methyl-piperazin-1-yl or a 4-ethyl-piperazin-1-yl radical.
Specifically preferred imidazolobenzodiazepines of general formula I and their pharmaceutically acceptable salts are : .
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2~ benzodiazepin-l-one;
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzodiazepin-l-one tartrate; -~
8-chloro-1,2-dihydro-2-(N-hydroxyethyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,y benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(~-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-lH,4H~imidazo ~ ,2 ~ ~ ,~ benzo-diazepin-l-one;
8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one tartrate;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2-~ ~ ,~ benzodiazepin-l-one;
8-chloro-1,2-dihydro-2-(n-butyl-amino)methylene-6-phenyl-lH~4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one; .-~o 8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-~luorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one .

8-chloro-1,2-dihydro-2-(_-propylamino)methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzo-diazepin-l-one methanesulphonate;
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-fluorophenyl)-~H,4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one;
8-chloro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~1,~ benzodiazepin-l-one;
8-chloro-1,2-dihydro-2-(N-propyl-piperazin-l-yl) methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one;
8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzo-diazepin-l-one;
8-chloro-1,2-dihydro-2-(N-ethyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one;
8-nitro-1,2-dihydro-2-~N-ethyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one;
8-nitro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-lH~4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one;
8-chloro-1,2-dihydro-2-(ethyl~mino)methylene-6-phenyl-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(~-dimethylphosphinylmethyl-lOq3454 piperazin-l-yl)methylene-6-phenyl-IH,4H-imidazo ~ ,2~ ~ ,~
benzodiazepin-l-one;
8-chloro-1~2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-l-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo- ~ ,2 ,~ benzodiazepin-l-one;
1,2-dihydro-2-(~-dimethylphosphinylmethyl-piperazin-1-yl)methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one; and 8-nitro-1,2-dihydro-2-(~-dimethylphosphinylmethyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH~4H-imidazo-,2~ ~ ,~ benzodiazepin-l-one.
Of these specifically preferred compounds, 8-nitro-1,2-dihydro-2-(~-methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one methanesulphonate has shown a particularly remarkable pharmacological activity.
The imidaz~olobenzodiazepines of general formula I may conveniently be prepared starting from corresponding compounds unsubstituted at the 2-position, and these in their turn can be prepared from corresponding 2-alkoxycarbon~l- or 2-carboxy-methyl~ino-benzodiazepinesO These processes are set out in the Reaction Scheme shown in the accompanying drawings, and will now be described. In this description, the Roman numerals refer to the general formulae in the Reaction Scheme, and each substituent group symbol is as first defined.
Thus~ the present invention also provides a process for the preparation of compounds of the aforesaid general for-mula I wherein :
Rl represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical;
R2, which may be at any appropriate position in the phenyl ring, represents a hydrogen atom or a halogen atom;
R3 represents a hydrogen atom or a methyl radical; and . . .

` ~
` 10'~345~

either R4 and R , which may be the same or different, each represents a hydrogen atom, an alkyl radical containing from l to 5 carbon atoms, a hydroxyalkyl radical containing from 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl radical (the alkyl moieties each containing from 1 to 5 carbon atoms), a phenyl radical or a cycloalkyl radical containing from 3 to 8 carbon atoms, or R and R r.epresent together with the nitrogen atom to which they aee bound a heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-l-yl, 4-alkyl-piperazin-1-yl, 4-hydro-xyalkyl-piperazin-l-yl, 4-phenyl-piperazin-1-yl, 4-(1'-phenyl-

5'-imidazolyl-4'-one) piperaz n-l-yl and R6-piperazin-1-yl radicals, in which R6 represents a cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical contain-ing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl alkyl radical, the alkyl moieties containing from l to 5 carbon atoms;
and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula:

~ ~ N

//
Bll~`~ (V) ~30 in which Rl and R2 have the meaning already indicated is reacted, - either with a dimethylformamide acetal of formula :
(AlK-0~2 = CH - N = (CH3)2 (VI) g . ~

10~3~15~

in which AlR represents a lower alkyl radical containing from l to 5 carbon atoms to give the 8-R2-l,2-dihydro-2-(dimethyl-amino)methylene-6-(R2-phenyl)-lH, 4H-imidazo ~l,2a~ ~l,4~ benzo-diazepin-l-one of formula :

~. .. ..... . ... ...

~ i :;: . , . .. : , - . : . . . : . .
: : , iO73~S4 ~ ~ N 3 Rl ~ ~ (Ia) ~R2 in which Rl and R2 have the aforesaid meaning and that, if desired, said compound of formula (Ia) is either salified or transaminated by reaction with a suitable amine of formula ~

H - N \ (YIII) wherein R4 and R5 have the meaning already indicated, except that they do not both represent a methyl radical~ to give the desired compound of formula :

C \ R5 N

(Io~
~ R2 , :

``` 10734S~

in which Rl, R2, R4 and R5 have the meaning already indicated, except that R4 and R5 do not both represent a methyl radical~
which compound is salified if deæired, - or~ ~aid compound of formula (V) is reacted, with a N-dimethyl-acetamide of formula :

0 = C - N . (VII) \ CH~
to give the corresponding compound of formula :

H~C \ / N \
C~H~ .
N

(Ib) Rl ~ = N
, .

~ ~2 in which Rl and R2 have the aforesaid meaning and that, if desired, said compound of formula (Ib) is either salified or transaminated by reaction with a suitable amine cf formula :

H - N < (VIII) wherein R4 and R5 have the meaning already indicated, except that they do not both represent a methyl radical, to give the desired compound of formula :

,. , , ~ .

`~ 10~3454 3 \ / \

N

~ Id) [~ R2 in which Rl, R2, R4 and R5 have the meaning already indicated, except that R4 and R5 do not both represent a methyl radical, which compound is salified if desired.
~he reaction with the acetal VI is conveniently carried out in an anhydrous organic solvent - for example, an arene `
such as benzene - and in the presence of a base (preferably a nitrogenous base such as an amine like triethylamine).
~he reaction with the acetamide VII is conveniently carried out in an anhydrous organic solvant - for example, a chlorinated alkane such as methylenechloride - at a temperature below room temperature (and preferably lower than 10C), and in the presence of a condensation promotor - for example, a halogenated derivative such as phosphorus oxychloride. `
~he reaction with the amine VIII is conveniently carried out in an anhydrous organic solvant - for example, an arene such as toluene - and at a high temperature, which is preferably the boiling temperature of the reaction mixtureO
It will be understood that when it is desired to form a compound I wherein R4 and R5 are both hydrogen the compound VIII used in the transamination will be ammonia itself.

- -- ~ : .............................. .
: , . ~ . , `` ` 10~34S4 The formed imidazolobenzodiazepines Ic or Id, may if desired, be further reacted to ¢onvert them into d~fferent compounds of general formula Ic or Id. In particular, com-pounds wherein R4 and R5 together with the nitrogen atom re-present a heterocycle may be further reacted 80 aB to introduce sub~tituents onto the heterocyclic ring.
When it i8 desired to prepare a compound of formula I in which Rl, R2 and R3 have the meaning already indicated and R4 and R5 form together with the nitrogen atom a R6-piperazin-l-yl radical, in which R6 repre~ent~ a oycloalkylalkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl ~ -alkyl radical in which the alkyl moieties each contain~ from 1 to 5 carbon atom~, an appropriate compound of formula Ic or Id wherein R4 and R5 form together with the nitrogen atom a piperazin-l-yl radical i~ first prepared and i~ then reacted - with an appropriate halo-R6, wherein the halo is an halogen atom, to form the corresponding R6-piperazin-1-yl compound of formula Ic or Id.
When it is desired to prepare a compound Ic or Id wherein R4 and R5 form, with the ~itrogen atom, a 4-dialkyl- -phosphinylalkyl-piperazin-l-yl radical in which the aIkyl moietie~ each contains from 1 to 5 carbon atoms, one may first prepare an appropriate compound Ic or Id wherein R4 and R5 form, with the nitrogen atomj a piperazin-l-yl radical and then react this compound with an appropriate haloalkyl-dialkylphos-phine oxide to form the corresponding 2-(n-dialkylphosphinyl-alkyl-piperazin-l-yl) compound Ic or Id.
The preferred haloalkyl-dialkylphosphine oxides for uæe in such a conversion are the chloroaIk~l- dialkylphosphine oxide~, and the reaction is preferably carried out in an organic solvent - for example, an arene such as toluene.
The imidazolobenzodiazepine starting material (V) may be prepared from a compound of formula:

`~` . lOq3454 ~ N
11 ) Rl ~ ~ N (II) [~ R2 in which Rl and R2 have the meaning already indicated, by reac-tion thereof with a compound of formula : ~ -/ - CH2 (III) R-0 ~H2 in which R represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, to give a compound of formula :
O ~- .

/ ~ I~H ~.

~ ~ (I~) Rl / ~ N

~ R2 in which R, Rl and R2 have the aforesaid me~ning~ which is reacted with a deshydrating agent or subjected to a pyrolysis to give the desired compound of formula (v).
~he reaction of the compound of formula II with the - 14 _ compound of formula III is advantageously carried out in an organic solvent, preferably an alcohol such as ethanol, and at a high temperature, which is conveniently the boiling temperature of the reaction mixture.
The dehydrating agent reacted with the acid IV is conveniently a carbodiimide, such as dicyclohexylcarbodiimide, and the reaction is advantageously performed in a chlorinated alkane such as methylene chloride. The pyrolysis of the ester IV is conveniently carried out in a high boiling point solvent such as an arene like toluene. -;
~ he formed compounds Ia, Ib, Ic- and Id may be salified by nor~al methods. In another aspect, this invention provides processes for the preparation of acid addition salts of compounds of general formula I, in which an appropriate com- -pound Ia, Ib, Ic or Id is reacted, in substantially stoichio-metric proportions,~with a suitable mineral or organic acid to form the desired pharmaceutically acceptable acid addition salt.
The salification reaction is conveniently effected in an organic solvent or a mixture of organic solvents~ such as one or more alkanols - for example, methanol or ethanol - and/or one or more alkyl halides - for example, methylene chloride.
The imidazolobenzodiazepin-l-ones of formula I and their acid addition salts possess very interesting pharmacological properties. ~hey are endowed especially with remarkable sedative, hypnotic, anxiolytic, tranquillising, anticonvulsive and myorelaxant properties which may make the compounds of formula I and their pharmaceutically acceptable acid addition salts of use as medicaments in the treatment of states of agitation or irritability, of aggression, of insomnia, of certain psychosomatic syndromes, of certain character and behavioural disorders, and of certain spasms or muscular contractions.

- .
~ -`~ ioq3454 However, before any of the compounds of formula I and their pharmaceutically acceptable acid addition salts may be used in medicine, they should preferably be formed into phar-maceutical compositions by association with suitable pharma-ceutical vehicles.
~ he term "pharmaceutical" is used herein to exclude any possibility that the nature of the vehicle, considered, of course, in relation to the route by which the composition is intended to be administered, could be harmful rather than beneficial. The choice of a suitable mode of presentation, - together with an appropriate vehicle~ is believed to be within the competence of those accustomed to the preparation of phar-maceutical formulations.
The compounds of formula I may be employed for the preparation of pharmaceutical compositions containing one or more imidazolobenzodiazepin-l-ones I, or pharmaceutically acceptable acid addition salts thereof, in association wi-th a suitable pharmaceutical vehicle.
~hese compositions may be administered orally, transcutaneously or rectally, and in respect of these modes the "pha~maceutical vehicle" is preferably~
a) the ingestible excipient of a tablet, coated tablet, sublin-gual tablet or pill; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of a `
powder; or the ingestible liquid medium of a syrup, solution, suspension, or elixir;
b) a sterile injectable liquid solution or suspension medium;
or c) a base material of low melting point capable of releasing the active ingredient to perform its pharmacological func-tion, which base material when appropriately shaped forms a suppository~

.. . . .
- , . :; :' ,,,' . ~ , - ,, , `` 1073454 The vehicle may, as appropriate, be a solid (such as talc, gum arabic, lactose, starch, an animal or vegetable fat, magnesium stearate, or cocoa butter), or it may be an aqueous or non-aqueous liquid (such as an ànimal or vegetable oil, a paraffin derivative, or a glycol). It may if desired incorporate wetting~ dispersing or emulsifying agents, and preserving agents. -~^
~ 1st the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.
The compounds of formula I and the pharmaceutically acceptable acid addition salts thereof may preferably be administered in the form of tablets, of injectable solutions or suspensions dispensed in single-dose ampoules or multi-dose phials, and of suppositories.
Whilst the dosages of the pharmacologically-active ingredient will, to ~ certain degree, depend upon the route by which the compositions are to be administered, nevertheless, by way of general indication, it may be said the useful dose ranges from l mg to 50 mg active ingredient per day:for an adult~ a unit dose containing from 0.5 mg to 20 mg active ingredientO
The 2-carboxymethylamino-7-Rl-5-(R2-phenyl)-3H-1,4-benzodiazepines IV, and the corresponding 2-aIkoxycarbonyl-methylamino-7-Rl-5-(R2-phenyl)-3H-1,4- benzodiazepines IV wherein the alkyl group R is other than an ethyl group, are new compoundsO
The following ~xamples, ~ormulations and Test Results are now given, though only by way of illustration, to show details of various aspects of the invention.

.. . .. ..... .. - :

~XA~?IES
Example 1: 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-

6-phenyl-lH,4H-imidazo-~ ,2~ ~ ,~ benzodiazepin-l-one (Ia) Stage A: 2-carbox~methvlamino-7-chloro-5-Phen~1-3H-1~4-benzodiazepine (IV)

7-Chloro-1~3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione II (3.5g), glycine III (5.5g) and sodium carbonate (5.5g) were suspended in ethanol (lOOml) and water (30ml), and were stirred and refluxed for 1 hour. The suspension was then poured -; into water to give a clear solution~ and this was acidified to -; -pH 4 with 2~ HCl, and extracted with CHC13. Some solid precipi-tated from the extracts, and was filtered off. ---~he organic layer was dried (on MgS04) and evaporated - ;
to give a gum which crystallized on trituration with methanol. - - -This solid~ and the solid filtered off above, was crystallized from a large amount of ethanol to give 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3.1g (77%).
m.p. = 215-220Co Sta~e B: 8-chloro-1,2-dihydro-6-phenyl-lH,4H-imidazo ~1,2~ -~ ,~ benzodiazepin-l-one (V) 2-Carboxymethylamino-7-chloro-5-phenyl-3H-1~4-benzo-diazepine (IV) (2.5g) was suspended in dry CH2C12 (120ml), and stirred, and dicyclohexylcarbodiimide (2.lg) was added. The suspension was stirred at room temperature for 3 hours, then filtered, and the filtrate was evaporated to give 8-chloro-1,2-dihydro-6-phenyl-lH~4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one V in the form of a colourless oil, which was used as it is in the following stage.

.. . . . . . . . .
.

Stage C: 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-6-phenyl-lH.4H-imidazo /I.2a7 /I,~ benzodiazein-l-one (Ia) The 8-chloro-1,2-dihydro-6-phenyl-lH,4H-imidazo ~ ,2~
,~ benzodiazepin-l-one V obtained in stage B above was - `
dissolved in dry benzene, and dimethylformamide diethyl acetal YI (1.5g) and triethylamine (lml) was added. ~he solution was stirred at room temperature for 1.5 hours, then evaporated to give a brown-yellow residue. Recrystallization from ethylacetate/
methanol gave pale yellow rods of 8-chloro-1~ 2-dihydro-2-(dime-thylamino~methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzo-diazepin-l-one I_, 2.7g (97%). m.p. = 264-5~.
Anal~sis: C20H17Cl N4 0 = 364-9 Calculated: C% 65.85 H% 4.66 N% 15.37 Cl% 9.74 Found: 65.87 4.67 15.37 9.79 I.R. Spectra (KBr diSC) :
.
C-0 at 1690 cm 1; C~N at 1621 cm ExamPles 2 to 6 Using a similar method to that used in Example 1, the ` following compounds IV, V and I_ were prepared :
~xam~le ComPounds 2. Compound IV: 2-carboxymethylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine.
Compound V: 8-nitro-1~2-dihydro-6-phenyl-lH~4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one Compound Ia: 8-nitro-1,2-dihydro-2-(dimethylamino) methylene-6-phenyl-lH,4H-imidazo ~ ,2 ~ ,y benzodiazepin-l-one.
3. Compound IV: 2-carboxymethylamino-7-chloro-5-o-chlorophenyl-3H-1,4-benzodiazepineO
Compound V: 8-chloro-1,2-dihydro-6-o-chlorophenyl-lH~4H-imidazo ~ ,2 ~ ~ ,~ benzodiaze-pine-l-one -0~3454 ~xample Compounds 3. Compound Ia: 8-chloro-1,2-dihydro-2-(dimethylamino) methylene 6-o-chlorophenyl-lH,4H- -imidazo ~ ,2~ ~ ,y benzodiazepin-l-one.
4. Compound IV: 2-carboxymethylamino-7-nitro-5-o-chloro-phenyl 3H-1~4-benzodiazepine.
Compound V: 8-nitro-1,2-dihydro-6-o-chlorophenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-oneO
Compound la: 8-nitro-1,2-dihydro-2-(dimethylamino) ~-methylene 6-o-chlorophenyl-lH,4H-imidazo ~ ,2 ~ ~ ,~ benzodiazepin-l-one.
5. Compound IV: 2-carboxymethylamino-7-chloro-5-o-fluoro-phenyl-3H-1,4-benzodiazepine.
Compound V~: 8-chloro-1,2-dihydro-6-o-fluorophenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one.
Compound Ia: 8-chloro-1,2-dihydro-2-(dimethylamino) methylene 6-o-fluorophenyl-lH,4H-imidazo ~ ,2~ ~ ~ benzodiazepin-l-one 6. Compound IV: 2-carboxymethylamino-7-nitro-5-o-fluoro-phenyl 3H-1,4-benzodiazepine.
Compound V: 8-nitro-1~2-dihydro-6-o-fluorophenyl-lH, -4H-imidazo ~ ,2~ ~ ,~ benzodiazepin--l-one.
Compound Ia: 8-nitro-1~2-dihydro-2-(dimethylamino) methylene 6-o-fluorophenyl-lH,4H-imidazo ,2~ ~ , ~ benzodiazepin-l-one.

``` 10~34S4 In each case the compound III was glycine, the com-pound ~I was dimethylformamide ethyl acetal, the compound V was used without further purification, and the crystallization solvent for the compound Ia was methanol. The data for these compounds (excluding the compounds Y) is summarized in Table I
below.
TA~IE 1 Example Compound IV ¦ amino Crystalli-Yield% Mop~Csation Rl R2 YieldYo MopoC
.. .
2 66 154-5 MeOH N02 H 43 227-8 3 75 136-9 MeOH-Et20 Cl o-Cl 53 288-90 4 83 158-61 Et20 P02 _-Cl 78 253-5 .
69 gum _ Cl o-F 63 257-60 _ 6 44 I ~ Et20 ~02 o-P 80 228-31 Example 7: 8-chloro-2-/I'-(dimethylamino)et~ylidene~-1,2-dihydro-6-Phenyl-lH.4H-imidazo/I,2a7~i~47benzodia- ~`
ze~in-l-one (Ib)

8-Chloro-1~2-dihydro-6-phenyl-lH,4H-imidazo~ ~2~7 ~ ~47benzodiazepin-1-one V, prepared as described in Stage B of Example 1, was dissolved in dry methylene chloride (200ml) with dimethylacetamide VII (2.0g). The solution was cooled to 0C, and phosphorus oxychloride (3.7g) was added dropwise over 5 minutes with good stirring. The solution was then stirred at room temperature over 20 hours, and poured into saturated NaHC03 solution (500ml). The mixture was stirred until the evolution f o02 ceased~ the org~n;c layer was removed, and the aqueous layer was extracted with methylene chloride (2xlOOml). ~he combined organic extracts were washed with saturated ~aHC03 ;' ' ` ' ~ ' "' ' " ''" ` ` '' " ''' ' " ~0~3454 solution, and water, dried (on MgS04)~ and evaporated to give a yellow solid. Recrystallization of this solid from chlorofo ~
ether gave 8-chloro-2-~ ~-(dimethylamino)ethyliden~ -1~2-dihydro-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ib, 203g (40%). m.p. = 251-2C
Analysis: C21HlgC1 ~4 0 = 378-9 Calculated: C% 66058 H% 5002 N~o 14.79 Cl% 9038 ~ound: 66.32 4091 14.77 9.02 I.R. Sectra (Kbr disc): ~ -C=O at 1653 cm 1; C=N at 1610 cm 1 Example 8. 8-chloro-1.2-dih~dro-2-(~-meth~lPiperazin-l-Yl) meth,ylene-6-Phenrl-lH,4H-imidazo/~i.2a7/~i,47 -benzodiazePin-l-one (Ic), and its tartrate A) 8-Chloro-1,2-dihydro-2-(dimethylamino)methylene-6-phenyl~
lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ia (obtained as in Stage C of ~xample ~) (203g) and ~-methyl-piperazine (4.0g) were stirred under reflux in dry toluene (50ml) for 24 hours.- On cooling, crystals separated out, and were filtered off. Evapo-ration of the solvent gave a pale yellow solid, and this was treated with methanol, and filtered. The two sets of solids -were combined and recrystalIized from methano ~ ethyl acetate to give 8-chloro-1~2-dihydro-2-(N-methylpiperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one Ic 2.3g (87%). m.p. = 255-6C.
Anal~sis C23H22C1 ~5= 419-9 Calculated: C% 65.80H% 5.24 ~% 16.69 Cl% 8.46 ~ound: 65.64 5.27 16.63 8.56 _~R. Spectra (Kbr disc):
C=O at 1705 cm~l; C=~ at 1635 cm~l B) ~he tartrate salt of 3-chloro-1,2-dihydro-2-(~-methyl-piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic was prepared by adding a stoichiometric .

10~3454 amount in methanol of tartaric acid to the 8-chloro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)methylene-6-phenyl-lH~4H-imidazo ,~ benzodiazepine-l-one Ico ~he formed crude salt was recrystallized from methanol to give the desired product.
M.Pt. = 146-150C.
Analysis: C2 ~28ClN ~ 570.1 Calculated: C~O 56089H% 4092 N% 11.29 Cl~o 6023 ~ound: 56044 4093 11.79 5-93 I.R. SPectra (Kbr disc):
OH at 3400 cm 1 and 2500 cm 1, C=O at 1730cm 1 and 1690cm 1;
C=N at 1630 cm 1.
Exam~les 9 to 46/32B
In these Examples, except where it is stated otherwise, a method analogous to that used in the preparation of 8-chloro-1,2-dihydro-2-(N-methylpiperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ be~nzodiazepin-l-one Ic in Example 8 was used to prepare the foll~wing compounds I :
Example Com~ound I

9. 8-Chloro-1,2-dihydro-2-(morpholino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.

10. 8-Chloro-1,2-dihydro-2-(N-hydroxyethyl-piperazin-l-yl) methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzo-diazepin-l-one.

11. 8-Chloro-1,2-dihydro-2-(~-phenyl-piperazin_l-yl) methylene-6-phenyl-lH,4H~imidazo ~ ,2~ ~ ,~ benzodla-zepin-l-one.

12. 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-IH,4H-imidazol~ ,2 ~ ,~ benzodiazepin-l-one~
3 12B 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(Q-chlorophenyl)-lH,4H-imidazo~ ,'2 benzodiazepin-l-one tartrate.
Method: analogou~ to Example 8B

3~54 ~xample ComPound I
13O 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~benzodia-zepin-1-one.
14. 8-Chloro-1,2-dihydro-2-(piperazin-1-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
15. 8-Chloro-1,2-dihydro-2-(n-butyl-amino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-l-oneO ~-16. 8-Chloro-1,2-dihydro-2-(amino)methylene-6-phenyl-lH,4H-imidazo~ ,2~7 ~ ,9;7benzodiazepin-1-oneO
Method: -8-Chloro-1,2-dihydro-2-(dimethyl~ino~ -methylene-6-phenyl-lH,4H-imidazo~i~2,~ ~ ,~7benzodia-zepin-l-one Ia (2.1g) was suspended in dry methanol (lOOml)0 The suspension ~as stirred, cooled in dry-ice/acetone bath~ and ammonia gas VIII was bubbled through for 15 minutes. The suspension was then warmed to room temperature, stirred for a further two days, and the solvent was evaporated. The solia residue was recrystallized from methanol/ethyl acetate to give 8-chloro-1,2-dihydro-2-(amino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-l-one Ic, l.9g (98%)o m.pO = 26~-7C.
~xamPle Compound I
17. 8-Chloro-1,2-dihydro-2-(piperidino)methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~benzodiazepin-l-one.
18. 8-Chloro-1,2-dihydro-2-(thiomorpholino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ ~ benzodiazepin-l-one.
19. 8-Chloro-1~2-dihydro-2-(diethylaminoethylam no) methylene-6-phenyl-lH,4H-imidazo ~ 92~ benzO_ diazepin-l-one.

.

`` 10~3454 20. 8-Chloro-1,2-dihydro-2-(N-methyl-N-(dimethylamino) ethylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
21. 8-Chloro-1,2-dihydro-2-(methylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
22. 8-Chloro-1,2-dihydro-2-(cyclohexylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
23. 8-Chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methy-lene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-oneO
24. 8-Chloro-1,2-dihydro-2-~ -(1'-phenyl-5'-imidazolyl- - --4'-one)piperidin-1-y~ methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
25. 8-Chloro-1,2-dihydro-2-(phenyl~mino)methylene-6- -phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
26. 8-Chloro-1~2-dihydro-2-~ ~(N-methyl-piperazino)ethyli-den~ -6-phenyl-IH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
Method:
8-Chloro-2-~ '-(dimethylamino)ethyliden~ -1~2-dihydro-6_phenyl-lH,4H-imidazo~ ,2~ ~ ,~benzo-diazepin-l-one Ib (example 7) (2.3g) and ~-methyl- - -piperazine VIII (15 ml) were stirred at 120C under nitrogen for 9 hours. The cooled solution was poured into water, ~aCl was added to complete precipitation, and the brown precipitate was filtered off, dissolved in CHC13, washed with water, dried (on MgS04), and evaporated to give a dark red oil. The oil crystallized on triturating with ether/methanol, and was recrys-tallized from ethyl acetate to give 8-chloro-2-~-N-methylpiperazin-l-yl~ethyliden~ -1,2-dihydro-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Id, l.Og (38%). m.p. = 193-5QC. ~ --; .. .. I .,.. ,. -- -, - - ,, : :, , - - .
, . .... . ~ . .

0~3~45~
~xample Compound I
27. 8-Chloro-1~2-dihydro-2-(t-butylamino)methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
28. 8-Chloro-1,2-dihydro-2-(hydroxyethylamino)methylene-6-phenyl-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
29. 8-Chloro-1,2-dihydro-2-(n-propylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-oneO
30. 8-Nitro-1,2-dihydro-2-(~-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-lH~4H-imidazo~ ,2~ ~ ,~
benzodiazepin-1-one.
31. 8-~itro-1,2-dihydro-2-(~-methyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ `
benzodiazepin-l-one.
32. 8-Chloro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodiazepin-. l-oneO ~-32~ 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodia~
zepin-l-one tartrate.
Method: analogous to Example 8~
33. 8-Chloro-1,2-dihydro-2-(M-propyl-piperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiaze-pin-l-one.
34. 8-Chloro-1,2-dihydro-2-~ -(_-butyl)-piperazin-l-y~
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiaze-pin-l-one.
35. 8-Chloro-1,2-dihydro-2-@ -(isopropyl)-piperazin-l-y~
methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ~ benzodia-zepin-l-oneO
Method:
8-Chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-lH,4H-imidazo~ ~2~ ~ ,~ benzodiaze-0~3454 pin-l-one ( the compound of Example 14, obtained as in ~xample 8) (1.5g.), isopropyl iodide (205go) and sodium carbonate (3~0g~) were stirred at 80C in acetonitrile (25 ml) and methylene chloride (5ml.) for 18 hours. The cooled solution was poured into water and extracted with chloroform. The extracts were washed with water~ dried (on MgS04), and evaporated to give a pale yellow solid. Recrystalli-zation of this solid from ethyl acetate gave 8-chloro-1~2-dihydro-2-(N-isopropyl-piperazin-l-yl)methylene- -6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ic, 1.2g. (73%). M. pt. - 146-8C.
Example Compound I
36. 8-Chloro-1,2-dihydro-2-(N-allyl-piperazin-l-yl) methylene-6-phenyl-lH~4H-imidazo ~ 92~ ~ ,~ benzodia-zepin-l-on~e.
Method: analogous to Example 35~
37~ 8-Chloro-1,2-dihydro-2-(~-cyclopropylmethyl-piperazin-l-yl)methylene-6-phenyl-lH~4H~imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
Method: analogous to Example 35. -~
380 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl) ; methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ , benzodiazepin-l-one.
39~ 8-Chloro-1,2-dihydro-2-(N-ethyl-piperazin-l-yl) methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.
40. 8-~itro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
` benzodiazepin-l-oneO
41. 8-Nitro-1,2-dihydro-2-(~-ethyl-piperazin-1-yl) methylene-6-(o-fluorophenyl)-lH,4H-imidazo~ 7 2~ ~ ,~

- 27 _ , .. . . ..

`` lOq3454 benzodiazepin-l-one.
420 8-Chloro-1~2-dihydro-2-(ethylamino)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.
43. 8-Chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2 ~ ,~ benzodiazepin-l-one.
Method:
8-Chloro-1,2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodia-zepin-l-one (the compound of Example 14, obtained as in ~ample 8) (2.5g.), chloromethyldimethylphosphine oxide (1.5g.) and sodium carbonate (5.0g.) were stirred under reflux in toluene (80 ml) for 3 days.
~he cooled suspension was distributed between chloro-form and water, and the chloroform extract was separated~ dried (on MgS04)~ and evaporated to give a pale yellow oil which crystallized with methanol;
~he solid (unrequired by-product) was filtered off, and the filtrate was evaporated to give a pale orange oil. ~his oil was dissolved in chloroform and chromatographed on Kieselgel 60. Elution with chloroform/methanol (5%) gave a pale yellow solid, hich on recrystallization from methylene chloride/
ether gave 8-chloro-1,2-dihydro-2-(N-dimethylphosphinyl-methyl-piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one. Ic (1.25 g.) (41~). M.Pt. = 261-2C.
~xam~le Compound I
44. 8-Chloro-l,~-dihydro-2-(N-propyl-piperazin-l-yl) methylene-6-o-chlorophenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one.

.
.~; -, ... .

lOq3454 Example Compound I
45. 8-Chloro-1,2-dihydro-2-(ethyl~m~no)methylene-6-o-chlorophenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-1-oneO
46. 8-Chloro-1,2-dihydro-2-(n-propylamino)methylene-6-o-chloro-phenyl-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one.

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10~345~

- ~xample 47: 8-chloro-1.2-dihydro-2-(N-dimeth~lPho~phinylmeth~l- piPerazin-l-yl)methylene-6-(o-chlorophen~ H~4H
imidazo/I,2a7/I,47benzodiazePin-l-one 8-Chloro-1~2-dihydro-2-(piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ic (obtained by a method analogous to that described in Example 8) (850 mg)~ chloromethyl-dimethylphosphine oxide (1.0 g), sodium iodide (1.0 g) and sodium carbonate (2.0 g) were stirred under reflux in dry toluene (50 ml) for 24 hours. The cooled solution was partitioned between chloroform and water, the chloroform extract separated, dried on magnesium sulphate and evaporated to give a gummy solid. This was chromatographed on silica eluting with chloroform to give a solid which on crystallisation from methano~ ethyl acetate/ether gave 8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-l-yl)methylene-6-(o-chlorophenyl)-lH~4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one Ic, mOp. ~ 231-4DC.
I.R. SPectra (KBr disc):
C=0 at 1700 cm 1; C=N at 1630 cm 1 ExamPle 48: 1~2-dih~dro-2-(N-dimethvlPhos~hin~lmeth~ iPerazin-1-vl)meth~lene-6-phen~l-lH 4H-imidazo/~.2a7/~47 benzodiazepin-l-one ~ -This compound was prepared, by a method analogous to that used in Example 47, from 1,2-dihydro-2-(piperazin-1-yl)-methylene-6-phenyl-lH,4H--imidazo ~ ,2~ ~ ,~ benzodiazepin-l-one Ic - ~vhich in turn was prepared by a method analogous to that described in ~xample 8.
~he formed 1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-l-yl)methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic melted at 245-7Co I.R. Spectra (KBr disc) C=0 at 1695 cm 1; C~N at 1630 cm 1 _ 35 _ 10~3454 ~xample 49: 8-nitro-1~?-dih,~dro-2-(N-dimethylphosphinylmethyl-piPerazin-l-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo/i,2~/i,47benzodiazepin-1-one ~his compound was prepared, by a method analogous to that used in Example 47, from 8-nitro-1,2-dihydro-2-(piperazin- -l-yl)methylene-6-(o-chlorophenyl)-IH,4H-imidazo~ ,2~ ~ ,~
benzodiazepin-l-one Ic - which in turn was prepared by a method analogous to that described in Example 8.
~he formed 8-nitro-1,2-dihydro-2-(N-dimethylphosph;nyl- -methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-lH,4H_imidazo ,2 ~ ~ ,~ benzodiazepin-l-one Ic melted at 245-8C.
I.R. Spectra (KBr disc) C=0 at 1700 cm 1; C=~ at 1642 cm 1 ~xamPle 50: 8-nitro-1.2-dihydro-2-(N-meth~l-piPerazin-l-yl)- ;~s meth~lene-6-(o-chlorophen~ lH,4H-imidazo/I,2a7 ~1~47benzodiazePin-l-one methanesulphonate Methanesulphonic acid (1.1 g) was added dropwise to 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methylene-6-(o-chlorophenyl)-lH~4H-imidazo~ ~2~ ~ benzodiazepin-1-one (obtained as in Example 30) (4.6 g) in dry methylene chloride (100 ml) and methanol (5 ml). Dry ether was added slowly until crystals formed on scratching and the solution was allowed to crystallise, further ether being added to complete the crystal-lisation. The pale yellow solid was filtered off, washed with ether and recrystallised from methylene chloride-methanol either to give 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-l-yl)methylene-6-~o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~ benzodiazepin-l-one methanesulphonate (5.4 g), m.p. - 205-lO~C.
.

10~3~54 ~OR~ TIONS
~ormulation 1: ~ablets .
Tablets were prepared having the following constituents per tablet:
8-chloro-1,2-dihydro-2-(N-methylpiperazine-l-yl) methylene-6-phenyl-lH,4H-imidazo~ ,2~ ~ ,~
benzodiazepine-l-oneOOOO.. O.O..O.O.OOO............. 5 mg Excipient (qOs. for a tablet) up to...~..O..O.O 100 mg The excipient was lactose, starch, talc and mag~esium stearate.
~ormulation 2: Capsules The ingredients for gelatin capsules were prepared to have the following constituents per capsule:
8-chloro-1~2-dihydro-2-(N-methylpiperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~ benzodia-zepine-l-o~e tartrate..... O.OO.O.O.. O.... O......... 5 mg Excipient (q.s. for a gelatin capsule) up to... 100 mg The excipient was talc, starch and magnesium stearate. --Formulation 3-: Injectable ampoules Injectable ampoules were prepared containing a solution having the following constituents: ~ - -8-chloro-1,2-dihydro-2-(N-methylpiperazin-l-yl) methylene-6-phenyl-lH,4H-imidazo ~ ,2~ ~ ,~benzodia-zepine-l-one tartrate............................. 10 mg aqueous solvent--.O~---O-.--OO-O----O---Oq.s.v- 2 ml ~ormulation 4: Tablets Tablets were prepared having the following constituents per tablet:
8-chloro-1,2-dihydro-2-(N-methylpiperazin-l-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~
~ ,~ benzodiazepine-l-oneO......................... 5 mg Excipient (q.s. for a tablet) up to.............. 100 mg ~ 37 -07 ~ 54 ~ he excipient was lactose, starch, talc and magnesium stearateO
Formulation 5: Tablets Tablets were prepared having the following constituents per tablet:
8-chloro-1,2-dihydro-2-(~-methylpiperazin-1-yl) methylene-6-(o-fluorophenyl)-lH,4H-imddazo~ ,2 ~ ~ ,~
benzodiazepin-l-one--O-~------.O--O.-.O--.-OO~ 5 mg Excipient (qOsO for a tablet) up to~OOOO.OO... 100 mg ~he excipient was lactose, starch, talc and magnesium stearate.
Formulation 6: ~ablets ~ ablets were prepared having the following constituents per tablet:
8-nitro-1,2-dihydro-2-(~-methylpiperazin-1-yl) ~ methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ,~
; benzodiazepin-l-one.................................... 5 mg -~
Excipient (q.s. for a tablet) up to.................. 100 mg ~he excipient was lactose, starch, talc and magnesium ~20 stearateO
Formulation 7: ~ablets -~ Tablets were prepared having the following constituents per tablet:
8-nitro-1~2-dihydro-2-(N-methyl-piperazin-l-yl)-methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ .~
benzodiazepin-l-one methanesulphonate.................. 5 mg Excipient (~.s. for a tablet) up to.................. 100 mg ~ he excipient was lactose, starch, talc and magnesium stearateO
~ormulation 8: ~ablets ~ ablets were prepared having the following constituents per tablet:

- ~8 -iO~3~54 8-chloro-1,2-dihydro-2-(N-methyl-piperazin-l-yl) methylene-6-(o-chlorophenyl)-lH,4H-imidazo~ ,2~ ~ ~
benzodiazepin-l-one tartrate....................... 5 mg Excipient (q.s. for a tablet) up toOO...... O.OO. 100 mg The excipient was lactose, starch, talc and magnesium stearate.

PHARMACO~OGICA~ AC~IVITY
1) Antiag~ressive activit~ in mice (AAM) Groups of 20 randomly selected male mice (25-30g body weight; Tuck T.O. strain) were given oral doses of either vehicle alone (10 ml per kg distilled water) or vehicle plus test compound. 30 minutes after dosing~ pairs of mice were placed under an inverted 1 litre pyrex beaker on a metal grid.
~he grid was connected to a Palmer square wave stimulator, and the feet of the mice were electrically stimulated wqth 90 volt pulses of 5 milli-second duration at a frequency of 2 pulses per second for a period of 2 minutes. ~his procedure provoked fighting in the control mice (a fight being defined as a frontal aggressive attack, usually biting, by either mouse on the other one). ~he total number of fights in the control group was calculated.
~he ~D50 of a test compound is that dose which causes -a 50~0 reduction in the number of fights of the batch of mice given that compound as compared with the control batch.
(~edeschi. R.E. et al (1959) JO PHARM. ~xptl. ~her. 125.28-34).
~he results are shown in ~able 3 belowO
2) Anticonvulsant test a~ainst maximal electroshock in mice-~AEM~
Groups of ten mice were injected orally with the test compound in a vehicle at various dose levels (a control group receiving the vehicle alone). 30 minutes after dosing each group ~ 39 ~
. ~

0~3454 was then shocked via auricular electrodes using electroshock apparatus (Ugo ~asile ECT apparatus for small mammals). The shocks has a pulse width of 0.2 milliseconds, and a frequency of 100 Hz, and each shock was given for 0.2 seconds at a current of 55 milliamps.
The number of mice which underwent tonic extension of their hind limbs was notedO ~he dose protecting 50% of the mice (~ED50), as compared with the control group, was noted, and the r results are shown in Table 3 below.
103) Anticonvulsant test against Pent~lenetetrazole in mice (AIM) Groups of ten mice were injected orally with the test compound in a vehicle at various dose levels, with a control group receiving the vehicle alone. 30 minutes after dosing each mouse received a sub-cutaneous 130 m~/kg pentylenetetrazole challenge (pentylenetetrazole is a central nervous system sti~ulant), and the mice were then individually housed in observation boxes. The number of mice showing tonic convulsions within 30 minutes of the pentylenetetrazole challenge was noted, and the results for the tonic phase were expressed as a percentage 20reduction of the control levels. From a constructed dose response curve, the doses protecting 50% of the mice (TED50) against tonus were estimated, and are shown in Table 3 below.
4) ~nticonvulsant test a~ainst str~chnine in mice (A~) Groups of ten mice received the test compound and vehicle orally at various dose levels, with a control group receiving the vehicle alone. 30 minutes after dosing, each mouse received a sub-cutaneous lmg/kg strychnine challenge (strychnine is a central nervous system stimulant), and the mice were then housed individually in observation boxes. The 30number of mice exhibiting tonic convulsions within 15 minu~es of the strychnine challenge was noted, and the results for the tonic phase expressed as a percentage reduction of the control ~73454 v~lue. ~rom a constructed dose response line~ the doses protecting 50% of the mice (TED50) against tonus were esti-- mated, and are shown in Table 3 below.
5) Potentiation of hexobarbital in mice (PHM) A group of ten control mice received an ED20 dose of hexobarbital intraperitoneally (150 m~/kg) (hexobarbital is a sedative and hypnotic), followed by an oral dose of either a vehicle alone or various oral doses of the vehicle and a test compound. The number of mice which exhibited loss of the righting reflex for 30 seconds half-an-hour after dosing was noted, and a dose response curve was constructed; the dose of --test compound which caused 50% of the mice in a group to lose the righting reflex was estimated (ED50), and the results are -~
shown in ~able 3 below.
6) Potentiation of chlorprothixene in mice (P~) Groups of ~ten randomly selected male C~P mice (Carworth Europe)~ weighing 20-25g each, were given chlorprothi-xene (12.5 mg/kg) intraperitoneally (chlorprothixene is a tranquillizer and antipsychotic); this dose consistently caused 10~ of mice to lose their righting reflex 30 minutes after dosing. At the same time the test groups of mice were given - orally either vehicle alone (distilled water, 10 m~/kg)~ or a -dose of vehicle plus test compound. Each mouse was then placed individually in a small observation ch~mber, and tested for loss of righting reflex 30 minutes after dosing.
The ED50 value of a test compound is the dose which causes loss Qf the righting reflex in 50% of the number of mice in a group which~ in the absence of oral treatment, would not be expected to lose their righting re~lex. The re~ults are shown in ~able 3 belowO
7) Rotatin~ drum test in mice (RDM) Groups of ten mice were injected orally with vehicle plus the test compound at various dose levels~ with a control group receiving the vehicle alone. 30 minutes after dosing~ -each group of mice ~as placed on a 30 cm diameter rotating drum revolving at 1 revolutio~ minuteO The mice were placed on the drum against its direction of movement~ and the number of mice falling off within a 2 minute test period was r.oted. ~rom the results obtained a dose response line was constructed, and the dose causing 50~0 of the mice to fall off the drum (ED50) was estimatedO ~he results are shown in Table 3 below.
8) Mouse Acute ~oxicity Test (ATM) Acute toxicity tests by oral and intraperitoneal routes were conducted using groups of ten mice at various dose levels.
~he groups were assessed for mortality at 24 hours, and the results are shown in ~able 3 below, given in ~ kg.

.. . .

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iO73454 ~ he results obtained show that the compounds of the invention possessa very important activity on the central nervous system as anticonvulsantj anti-anxiety and hypnotic æedatives, ~nd that they have a very low toxioity.

'~
: :~ '', ; -:

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, ioq:~5 ~EACTION SCHEME

H S C -- CH2R o NH
R~ 1011~2 ,~

O~<\N ( IV ) R~

- CH3 1~3 R
O = C --N(CH3)2 ~ / (V) \ ~ (Alk-0)2CH - N(CH3)2 , (VII) / \ (VI) 3 / c~
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(Ib) / (Ia) \Rs -N/ 5 ( Id) ( Ic)

Claims (19)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of 1,2-dihydro-6-phenyl-1H,4H-imidazo[1,2a] [1,4] benzodiazepin-1-ones having the general formula :

(I) wherein:
R1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical ;
R2, which may be at any position in the phenyl ring, represents a hydrogen or halogen atom;
R3 represents a hydrogen atom or a methyl radical, and R4 and R5, which are the same of different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyalkyl radical containing from 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, a phenyl radical or a cycloalkyl radical containing from 3 to 8 carbon atoms, or R4 and R5 represent together with the nitrogen atom the which they are bound a heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, 4-hydroxyalkyl-piperazin-yl, 4-phenyl-piperazin-1-yl, 4-(1'-phenyl-5'-imidazolyl-4'-one) piperazin-1-yl and R6-piperazin-1-yl radicals, in which R6 represents a cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl alkyl radical, the alkyl moieties containing from 1 to 5 carbon atoms, and of their pharmaceutically acceptable acid addition salts, which process comprises :
a) reacting a compound of the general formula (V) :

(V) wherein R1 and R2 have the aforesaid meanings, with a dimethyl-formamide acetal of formula (VI) or a N-dimethyl-acetamide of formula (VII) :
(Alk-O)2CH - N (CH3)2 (VI) , (VII) wherein Alk represents a lower alkyl radical containing from 1 to 5 carbon atoms, to obtain a compound of the formulae (Ia) or (Ib), respectively:

(Ia) (lb) wherein R1 and R2 have the aforesaid meanings, and b) where a pharmaceutically acceptable salt of the compound thus obtained is desired, reacting said compound of formula (Ia) or (Ib) with a mineral or organic acid to provide an acid addition salt thereof, or c) where a compound of formula (I) is desired in which R4 and R5 have the aforesaid meanings, except that they do not both represent a methyl radical, subjecting said compound of formula (Ia) or (Ib) to transamination by reaction with an amine of the formula (VIII) :

(VIII) wherein R4 and R5 have the meaning just indicated, to provide a compound of the formulae (Ic) or (Id), respectively :

wherein R1, R2, R4 and R5 have the aforesaid meanings, except that R4 and R5 do not both represent a methyl radical, and d) where a pharmaceutically acceptable salt of the compound thus obtained is desired, reacting said compound of formula (Ic) or (Id) with a mineral or organic acid to provide an acid addition salt thereof.

2. Process according to claim 1, wherein the compound of formula (V) in which R1 and R2 have the aforesaid meanings is obtained starting from a compound of the formula (II) :

(II) wherein R1 and R2 have the aforesaid meanings, by reaction thereof with a compound of the formula (III) :

(III) wherein R represents a hydrogen atom or an alkyl radical having from 1 to 5 carbon atoms, to give a compound of the formula (IV):

(IV) wherein R, R1 and R2 have the aforesaid meanings, which is then reacted with a deshydrating agent or subjected to a pyrolysis.

3. Process according to claim 1, wherein the compound of formula (Ia) or (Ib) in which R1 and R2 have the aforesaid meanings is reacted with an amine of formula (VIII) in which R4 and R5 form together with the nitrogen-atom a piperazin-1-yl radical, and the resulting product is reacted with a halo-R6 in which the halo is a halogen atom and R6 represents a cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphos-phinyl alkyl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, to form a compound of formula (I) in which R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a R6-piperazin-1-yl radical, R6 having the aforesaid meaning.

4. Process according to claim 2, wherein the compound of formula (Ia) or (Ib) in which R1 and R2 have the aforesaid meanings is reacted with an amine of formula (VIII) in which R4 and R5 form together with the nitrogen atom a piperazin-1-yl radical, and the resulting product is reacted with a halo-R6 in which the halo is a halogen atom and R6 represents a cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphos-phinyl alkyl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, to form a compound of formula (I) in which R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a R6-piperazin-1-yl radical, R6 having the aforesaid meaning.

5. Process according to claim 1, wherein the compound of formula (Ia) or (Ib) in which R1 and R2 have the aforesaid meanings is reacted with an amine of formula (VIII) in which R4 and R5 form together with the nitrogen atom a piperazin-1-yl radical and the resulting product is reacted with a haloalkyl-dialkylphosphine oxide in which the alkyl moieties each con-tains from 1 to 5 carbon atoms, to form a compound of formula (I) in which R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a N-dialkylphos-phinylalkyl-piperazin-1-yl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms.

6. Process according to claim 2, wherein the compound of formula (Ia) or (Ib) in which R1 and R2 have the aforesaid meanings is reacted with an amine of formula (VIII) in which R4 and R5 form together with the nitrogen atom a piperazin-l-yl radical and the resulting product is reacted with a haloalkyl-dialkylphosphine oxide in which the alkyl moieties each contains from 1 to 5 carbon atoms, to form a compound of formula (I) in which R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a N-dialkylphosphinylalkyl-piperazin-1-yl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms.

7. Process according to claim 1, wherein 8-nitro-1,2-dihydro-6-o-chlorophenyl-1H,4H-imidazo[1,2a] [1,4]benzodiazepin-1-one is reacted with dimethylformamide diethyl acetal to form 8-nitro-1,2-dihydro-2-(dimethylamino)methylene-6-o-chlorophenyl-1H,4H-imidazo[1,2a] [1,4]benzodiazepin-1-one, which is then reac-ted with N-methyl-piperazine to obtain 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a] [1,4]benzodiazepin-1-one.

8. Process according to claim 2, wherein 7-nitro-1,3-dihydro-5-o-chlorophenyl-2H-1,4-benzodiazepin-2-thione is reacted with glycine to form 2-carboxymethylamino-7-nitro-5-o chlorophenyl-3H-1,4-benzodiazepine, which is deshydrated to give 8-nitro-1,2-dihydro-6-o-chlorophenyl-1H,4H-imidazo[1,2a]

[1,4]benzodiazepin-1-one, and the latter is reacted with dime-thylformamide diethyl acetal to form 8-nitro-1,2-dihydro-2-(dimethylamino)methylene-6-o-chlorophenyl-1H,4H-imidazo[1,2a]
[1,4]benzodiazepin-1-one, which is in turn reacted with N-methyl-piperazine to obtain 8-nitro-1,2-dihydro-2-(N-methyl-piperazine-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a]
[1,4]benzodiazepin-1-one.

9. Process according to claim 7, wherein the 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one thus obtained is further reacted with methanesulphonic acid to provide 8-nitro-1,2-dihydro-2-(N-methyl-[piperazin-1-yl)methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one methanesulphonate.

10. Process according to claim 8, wherein the 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)methylene-6-(o-chloro-phenyl)-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one thus ob-tained is further reacted with methanesulphonic acid to provide 8-nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl)methylene-6-(o-chlorophenyl)-H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one methanesulphonate.

11. Process according to claim 5, wherein 8-chloro-1,2-dihydro-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one is reacted with dimethylformamide diethyl acetal to form 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one, and the latter is reacted with piperazine to give 8-chloro-1;2-dihydro-2-(piperazin-1-yl) methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one, which is in turn reacted with chloromethyldimethylphosphine oxide to obtain 8-chloro-1,2-dihydro-2-(N-dimethylphosphinyl-methyl-piperazin-1-yl)methylene-6-phenyl-1H,4H-imidzao[1,2a]

[1,4]benzodiazepin-1-one.

12. Process according to claim 6, wherein 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thione is reacted with glycine to form 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, which is deshydrated to give 8-chloro-1,2-dihydro-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one, which is in turn reacted with dimethylformamide diethyl acetal to form 8-chloro-1,2-dihydro-2-(dimethylamino)methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one, and the latter is reacted with piperazine to give 8-chloro-1,2-dihydro-2-(piperazin-1-yl)methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]
benzodiazepin-l-one, which i8 then reaoted with chloromethyl-dimethylphosphine oxide to obtain 8-chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl)methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one.

13. 1,2-Dihydro-6-phenyl-1H,4H-imidazo[1,2a][1,4]
benzodiazepin-1-ones having the general formula:
(I) wherein:
R1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical;

R2, which may be at any position in the phenyl ring, represents a hydrogen or halogen atom;
R3 represents a hydrogen atom or a methyl radical, and R4 and R5, which are the same or different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydrocyalkyl radical containing from 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, a phenyl radical or a cycloalkyl radical containing from 3 to 8 carbon atons, or R4 and R5 represent together with the nitrogen atom to which they are bound a heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidino, morpholino, thiomorpholino, piperazin-1-yl, 4-alkyl-piperazin-1-yl, 4-hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-1-yl, 4-(1'-phenyl-5'-imidazolyl-4'-one) piperazin-1-yl and R6-piperazin-1-yl radicals, in which R6 represents a cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl alkyl radical, the alkyl moieties containing from 1 to 5 carbon atoms, and their pharmaceutically acceptable acid addition salts, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.

14. The compounds of formula (I) as defined in claim 13 and their pharmaceutically acceptable acid addition salts, whenever obtained by a process according to claim 2 or its ob-vious chemical equivalents.

15. The compounds of formula (I) as defined in claim 13 and their pharmaceutically acceptable acid addition salts, wherein R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a R6-piperazin-1-yl radical in which R6 represents a cycloalkylalkyl radical containing from 3 to 8 carbon atoms, an alkenyl radical containing from 2 to 5 carbon atoms or a 4-dialkylphosphinyl alkyl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, whenever obtained by a process according to claims 3 or 4, or their obvious chemical equivalents.

16. The compounds of formula (I) as defined in claim 13 and their pharmaceutically acceptable acid addition salts, wherein R1, R2 and R3 have the aforesaid meanings and R4 and R5 form together with the nitrogen atom a N-dialkylphosphinyl-alkyl-piperazin-1-yl radical in which the alkyl moieties each contains from 1 to 5 carbon atoms, whenever obtained by a pro-cess according to claims 5 or 6, or their obvious chemical equivalents.

17. 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a][1,4]benzo-diazepin-1-one, whenever obtained by a process according to claims 7 or 8, or their obvious chemical equivalents.

18. 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-1-yl) methylene-6-(o-chlorophenyl)-1H,4H-imidazo[1,2a][1,4]benzo-diazepin-1-one methanesulphonate, whenever obtained by a pro-cess according to claims 9 or 10, or their obvious chemical equivalents.

19. 8-Chloro-1,2-dihydro-2-(N-dimethylphosphinylmethyl-piperazin-1-yl)methylene-6-phenyl-1H,4H-imidazo[1,2a][1,4]benzo-diazepin-1-one, whenever obtained by a process according to claims 11 or 12, or their obvious chemical equivalents.