IE43791B1 - 1,2-dihydro-4h-imidazo/1,2-a/ /1,4/benzodiazepin-1-ones,prcess for their preparation,and compositions incorporating them - Google Patents

1,2-dihydro-4h-imidazo/1,2-a/ /1,4/benzodiazepin-1-ones,prcess for their preparation,and compositions incorporating them

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IE43791B1
IE43791B1 IE298/76A IE29876A IE43791B1 IE 43791 B1 IE43791 B1 IE 43791B1 IE 298/76 A IE298/76 A IE 298/76A IE 29876 A IE29876 A IE 29876A IE 43791 B1 IE43791 B1 IE 43791B1
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radical
piperazin
dihydro
imidazo
benzodiazepin
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IE43791L (en
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Roussel Uclaf
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Application filed by Roussel Uclaf filed Critical Roussel Uclaf
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Publication of IE43791B1 publication Critical patent/IE43791B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

Cpds. of formula (I) and their acid addition salts are new (where R1 is H, halogen, NO2 or CF3, R2 is H or halogen, R3 is H or CH3, R4 and R5 are each H, 1-5C alkyl, 1-5C hydroxy alkyl, amino-1-5C-alkyl, or 1-5C-alkylamino-1-5C-alkyl, aryl or cycloalkyl, or NR4R5 is a satd. heterocycle, opt. substd. and opt. contg. another heteroatom). Also new are inters. of formula (II) where R is H or lower alkyl except Et. (I) have sedative, hypnotic, anciolytic, tranquillising, anticonvulsant and myorelaxant activities, they are useful for treating agitation, irritability, agression, insomnia, certain psychosomatic syndromes, certain muscular contractions or spasms, certain character disorders, and certain behavioural disorders. Adult doses are e.g. 1-50 mg/day p.p. Admin. may be via the digestive tract or parenterally in conventional forms.

Description

This invention relates to imidazolobenzodiazepines, processes for their preparation, and compositions incorporating them. More particularly, the invention concerns certain pharmaceuticallyactive 1,2-dihydro-6-phenyl-4H-imidazo- 0,2-a] Q,4]benzodiazepin5 1-ones that may be of use in human or veterinary medicine.
In one aspect, therefore, this invention provides the 1,2 - dihydro - 6 - phenyl - 4H - imidazo - [j ,2-jij|j ,4jbenzodiazepin 1-ones of the general formula wherein: R1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical; ? R , which may be at any position in the phenyl (0) ring, represents a hydrogen atom or a halogen atom; R represents a hydrogen atom or a methyl radical; and R and R , which may be the same or different, either 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 alkyl aminoalkyl radical (the alkyl moieties each containing from 1 to 5 carbon atoms), Λ C an aryl radical, or a cycloalkyl radical, or RH and R together with the nitrogen atom represent a saturated, substituted or unsubstituted, heterocycle optionally containing another hetero atom; and acid addition salts thereof. Where R1 represents a halogen atom, it may conveniently be a fluorine, chlorine or bromine atom, but is preferably a chlorine atom. 20 2 Where R represents a halogen atom, it too may conveniently be a fluorine, chlorine or bromine atom, but is preferably a fluorine or chlorine atom. Furthermore, the 2 halogen atom R is preferably in the ortho-position.
R is most preferably a hydrogen atom. Λ 5 Where either of R and R represents an alkyl radical, it may conveniently be a methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or pentyl radical, but is preferably a methyl, ethyl, ji-propyl, ji-butyl or t-butyl radical. Λ c Where either of R and R 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 R and R represents an aminoalkyl or alkyl aminoalkyl radical (which latter term includes both monoalkyl10 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 and/or R® represent an aminomethyl, aminoethyl, dvraethylaminoethyl or diethylaminoethyl radical, but may also represent an aminopropy'i, aminobutyl, methyl ami nomethyl, methyl ami noethyl or dimethyl aminopropyl radical.
When either of R4 and R$ represents an aryl radical this may be mono- or di-nuciear - thus, for example, phenyl or naphthyl. The phenyl radical is preferred. Λ K Where either of R and R 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. 43?0l ι.
Where R and If, together with the conjoining nitrogen atom, form a heterocyclic group, this grouping is saturated, may be substituted or unsubstituted, and may optionally contain a second heteroatom. Typical examples of unsubstituted heterocyclic groupings are pyrrolidinyl, piperidinyl, morpholinyl, thioroorpholinyl and piperazinyl. Preferred substituents for such heterocyclic groupings are alkyl radicals containing from 1 to 5 carbon atoms, such as methyl, ethyl and ji-propyl; hydroxyalkyl radicals containing from 1 to 5 carbon atoms, such as hydroxyethyl; dialkylphosphinylalkyl radicals, each alkyl moiety of which contains from 1 to 5 carbon atoms, such as methyl; cycloalkylalkyl radicals containing from to 6 carbon atoms in the cycloalkyl moiety and from 1 to 5 carbon atoms in the alkyl moiety, such as cyclopropylmethyl; 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-4-oxo-5~imidazolyl. Typical examples of substituted heterocyclic groupings are the 4-alkyl-piperazin-l-yls and especially 4-methyl-, 4-ethyl- and 4-propyl-piperazin-l-yl; the 4-hydroxyalkyl-piperazin-l-yls and especially 4 - β - hydroxyethyl - piperazin - 1 - yl; the 4 - dialkylphosphinylalkyl - piperazin - 1 yls and especially 4 - dimethylphosphinylmethyl - piperazin - 1 yl; the 4 - cycloalkyl alkyl - piperazin - 1 - yls and especially 4 cyclopropylmethy1 - piperazin - 1 - yl, 4 - alkenyl - piperazin - 1 - yls and especially 4 - allyl - piperazin - 1 - yl; - phenyl - piperazin - 1 - yl; and 4 - (T - phenyl - 4‘ - oxo 5' - inridazoyl)-piperidin-l-yl.
Within the broad area encompassed by general formula I, the following smaller groups of compounds, and their acid addition salts, are preferred: a) the imidazolobenzodiazepines of general formula I wherein Λ c either R and R , which may be the same or different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyetbyl radical, a dimethyl- or diethyl aminoethyl radical, a phenyl radical, or a cyclohexyl radical, or R and R together with the nitrogen atom form a pyrrolidinyl, piperidinyl, 1 morpholinyl, thiomorpholinyl, piperazin-l-yl-4 - alkyl - piperazin -1-yl, 4 - hydroxyalkyl - piperazin -1-yl, 4 - phenyl piperazin -1-yl or 4-(11 phenyl - 4' - Oxo - 5’ - imidazolyl) - piperidin -1-yl radical; b) the imidazolobenzodiazepines of general formula I wherein > r' represents a chlorine atom or a nitro radical, R represents a hydrogen atom, a chlorine atom or a fluorine atom, R represents a hydrogen atom, and either R^ and R3 4 5, which may be the same or different, each represents a hydrogen atom, a straight alkyl radical containing from 1 to 5 carbon atoms, a hydroxyethyl radical, a phenyl radical, or a cyclohexyl radical, or 4- ς R and R together with the nitrogen atom form a piperidinyl, morpholinyl, piperazin-l-yl, 4 - alkyl - piperazin -1-yl or - e - hydroxyethyl - piperazin -1-yl radical; c) the imidazolobenzodiazepines of general formula I wherein R^ represents a chlorine atom or a nitro radical, Ο R represents a hydrogen, chlorine or fluorine atom, R represents a hydrogen atom, and either R4 represents a hydrogen atom and R® represents a methyl, ethyl, propyl or butyl radical, or R^ and r5 together with the nitrogen atom form a piperazin-l-yl, 4-methyl-piperazin-1-yl, 4-ethyl - piperazin - 1 - yl, - propyl-piperazin - 1 - yl or 4 - β - hydroxyethyl piperazin-l-yl radical; d) the imidazolobenzodiazepines of general formula I wherein represents a chlorine atom or a nitro radical, o R represents a hydrogen, chlorine or fluorine atom, R 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 η 4 - £ - propyl - piperazin - 1 - yl radical; e) the imidazolobenzodiazepines of general formula I wherein R1 represents a hydrogen atom, a chlorine atom or a nitro radical, o R represents a hydrogen atom, a chlorine atom or a fluorine atom, ο R represents a hydrogen atom and ζ R and R together with the nitrogen atom form a 4 dialkylphosphinylalkyl-piperazin-l-yl radical; and f) the imidazolobenzodiazepines of general formula I wherein r1 represents a hydrogen atom, a chlorine atom or a nitro radical, R2 represents a hydrogen atom or a chlorine atom, ο R represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 4-dimethylphosphinyl methyl - piperazin - 1 - yl radical.
The imidazolobenzodiazepines I may be in the form of 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, formic, benzoic, maleic, fumaric, succinic, . tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic and arylsulphonic acids. Preferred acid addition salts are the tartrates and alkanesulphonates, and the methanesulphonates are especially preferred.
There are further preferred groups of compounds of the invention in the form of acid addition salts. These are as follows:g) acid addition salts of the imidazolobenzodiazepines of general formula I wherein R1 represents a hydrogen atom, a 2 chlorine atom or a nitro radical, R represents a hydrogen atom, o a chlorine atom or a fluorine atom, R represents a hydrogen atom and R4 and R5 together with the nitrogen atom form a 4-alkyl-piperazin-l-yl radical; and h) the tartrates and alkahesulphonates (particularly methanesulphonates) . of the imidazolobenzodiazepines of general formula I wherein R1 represents a chlorine atom or a nitro radical, o R represents a hydrogen atom or a chlorine atom, r3 represents a hydrogen atom and R4 and R® together with the nitrogen atom form a 4-methyl-piperazin-l-yl or a 4-ethyl-piperazin-l-yl radical.
Specifically preferred imidazolobenzodiazepines of general formula I and their salts are: ί 3 70 t - chloro - 1,2 - dihydro -2-(4- methyl piperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo[l,2 - a] 0,4jbenzodiazepin - 1 - one; - chloro - 1,2 - dihydro -2-(4- methylpiperazin - 1 - yl methylene - 6 - phenyl - 4H - imidazo J ,2-aJ J,4]benzodiazepin - 1 one tartrate; - chloro - 1,2 - dihydro -2-(4-8- hydroxyethyl - piperazin - 1 - yl)methylene - 5 - phenyl - 4H - imidazo [l ,2-a] 0 ,4jbenzodiazepi n-1-one; - chloro - 1,2 - dihydro -2-(4- methylpiperazin - 1 yl (methylene - 6 - (o - chlorophenyl) - 4H - imidazofl ,2-a )(1, benzodiazepin-l-one; - chloro - 1,2 - dihydro -2-(4- methylpiperazin - 1 yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo0 ,2-ajQl ,40 benzodiazepin - 1 - one tartrate; - nitro - 1,2 - dihydro -2-(4- methylpiperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo0,2-a)0l ,4) benzodiazepin - 1 - one; - chloro- 1,2 - dihydro - 2 - (jn - butyl ami no )methylene - 6 phenyl - 4H imidazo -Jl ,2-aj[l ,4) benzodiazepin-l-one; - chloro - 1,2 - dihydro -2-(4- methylpiperazin - 1 - yl) methylene - 6 - (o - fluorophenyl) - 4H - imidazo 0,2 - ajQ,4j benzodiazepin - 1 - one; - chloro - 1,2 - dihydro - 2 - (n_ - propyl ami no )methylene - 6 - phenyl - 4H - imidazo0,2-aJ[l ,4jbenzodiazepin-l-one; - nitro - 1,2 - dihydro -2-(4- methylpiperazin - 1 yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazoD»2 - £. J.A benzodiazepin-l-one; - nitro - 1,2 - dihydro -2-(4- methyl piperazin - 1 yl)methylene - 6 - (o - chlorophenyl) - 4H imidazo [l,2-aj[j ,4]benzodiazepin-l-one methanesulphonate; - nitro - 1,2 - dihydro -2-(4- methylpiperazin - 1 yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo 0,2 - a][l,4|benzodiazepin-l-one; - chloro - 1,2 - dihydro -2-(4- ethyl pi perazin - 1 yl)methylene - 6 - phenyl - 4H - imidazo 0,2 - ajjj,4]benzodiazepin - 1 - one; - chloro - 1,2 - dihydro - 2 - (4 - n. - propyl - piperazin - 1 - y1)methylene - 6 - phenyl - 4H - imidazo [l ,2 - ajj_l ,4] benzodiazepin-1-one; - chloro - 1,2 - dihydro -2-(4- ethyl pi perazin - 1 y1)methylene - 6 - (£- chlorophenyl) - 4H - imidazo 0,2 - a] 0,0] benzodiazepin - 1 - one; - chloro - 1,2 - dihydro -2-(4- ethyl pi perazin - 1 yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo 0,2 - aj 0,4J benzodiazepi n-1-one; - nitro - 1,2 - dihydro - 2 - (4 - ethyl piperazin - 1 yl)methylene - 6 - {£ - chlorophenyl) - 4H - imidazo El ,2 - a][j,4jbenzodiazepin-l-one; - nitro - 1,2 - dihydro - 2 - (4 - ethylpiperazin - 1 yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo El,2 - J 0>a1· benzodiazepin-l-one; - chloro - 1,2 - dihydro - 2 - (ethyl ami ηβ/methylene-6 phenyl - 4H - imidazo 01,2-^] 01,4] benzodiazepin-l-one; 3 7 31 - chloro - 1,2 - dihydro -2-(4- dimethylphosphinylmethyl piperazin - 1 - yl) - methylene - 6 - phenyl - 4H - imidazo 0,2 - a] [l,4] benzodiazepin-l-one; - chloro - 1,2 - dihydro -2-(4- dimethylphosphinylmethyl 5 - piperazin - 1 - yl)-methylene -6-(0- chlorophenyl) - 4H imidazo [][j >^] benzodiazepin-l-one; 1,2 - dihydro -2-(4- dimethylphosphinylmethyl - piperazin - 1 - yl )methylene - 6 - phenyl - 4H - imidazo [jl ,2 - aQ [_1,4j benzodiazepin-l-one; and 8 - nitro - 1,2 - dihydro -2-(4- dimethylphosphinylmethyl piperazin - 1 - yl)-methylene -6-(0- chlorophenyl) - 4H imidazo 0 ,2-_a] 01,4]benzodiazepin-l-one.
Of these specifically preferred compounds, - nitro - 1,2 - dihydro -2-(4- methylpiperazin - 1 - yl)methylene - 6 - (a - chlorophenyl) - 4H - imidazo 01,2 - aj Ql ,4jbenzodiazepin -1-one methanesulphonate has shown a particularly remarkable pharmacological activity.
The imidazolobenzodiazepines of general formula I may conveniently be prepared by a process starting from corresponding compounds unsubstituted at the 2-position, and these in their turn can be prepared from corresponding 2-alkoxycarbonyl- or 2-carboxymethylamino-benzodiazepines. These processes, which form another aspect of this invention, 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, unless stated otherwise, as first defi ned.
This invention provides processes for the preparation of 3 compounds of general formula I wherein R represents a hydrogen 4 5 atom and R and R each represent a methyl radical, in which an 8 - Rl - 1,2 - dihydro - 6 - (R2-phenyl) - 4H - imidazo 0,2 - a] 01,4] benzodiazepin-l-one V is reacted with a dimethylformamide acetal VI (wherein alk represents an alkyl radical containing from 1 to 5 carbon atoms) to give the desired 8 - R^ - 1,2 - dihydro - 2 (dimethylamino)methylene - 6 - (R2 - phenyl) - 4H - imidazo 0,2 - a]0,40] - benzodiazepin-l-one U.
The 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, which is preferably a nitrogenous base such as an amine, for instance triethylamine.
This invention also provides processes for the preparation 3 4 5 of compounds of general formula I wherein R , R and R each represent a methyl radical, in which an 8-R1-!,2-dihydro - 6 (R2 - phenyl) - 4H - imidazo - 01,2 - jfjp ,4jbenzodiazepin - 1 - one V is reacted with a N-dimethyl-acetamide VII to give the desired 2 8-R -1,2-dihydro-2-(1'-dimethylamino)ethylidene - 6 - (R - phenyl) 4H - imidazo 01,2 - aj 0,4jbenzodiazepin-l-one IL The reaction with the acetamide VII is conveniently carried out in an anhydrous organic solvent - for example, a chlorinated alkane such as methylene chloride - at a temperature below room temperature (and preferably lower than 10°G), and in the presence of a condensation promotor - for example, a halogenated derivative such as phosphorus oxychloride. 43701 The imidazolobenzodiazepin starting material V may conveniently be prepared by subjecting either a 2-carboxymethylamino1 2 or 2 - alkoxycarbonyimethyiamino - 7 - R - 5 - (R - phenyl) - 3H - 1,4 - benzodiazepin IV (wherein R represents a hydrogen atom or an alkyl radical) respectively to the action of a dehydrating agent or to pyrolysis to give the desired product.
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.
The benzodiazepine starting material IV which is itself a new compound when R is other than an ethyl group, may conveniently be prepared by reacting 7-R^-l,3-dihydro-5(R2-phenyl) - 2H - 1,4 - benzodiazepine-2-thione II with glycine (aminoacetic acid) or an alkyl ester thereof III to give the desired product.
The reaction 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 invention further provides processes for the preparation of compounds of general formula I wherein R^ and R do not both represent methyl radicals in which 2-(dimethyl amino)methylene imidazolobenzodiazepin - 1 - one. Ia or 2-(1’-dimethylamino)ethylidene - imidazolobenzodiazepin - 1 - one lb is transaminated by reaction with an amine VIII (wherein R4 and R5 are as defined hereinbefore, except that they do not both represent a methyl radical) to give the desired 8 - R^ - 1,2 - dihydro - 2 (substituted amino)methylene, -or 8 - R1 - 1,2 - dihydro - 2-(1'-substituted amino)· ethylene-6- ' ..(Rz - phenyl) - 1H,4H - imidazo [J >2 - aj -β ,£jbenzodiazepin - 1 4 5 one Ic or Id, wherein R and R are as just desired.
Naturally, the compound Ia^ or lb is preferably prepared by a process as described and claimed herein.
The reaction with the amine VIII is conveniently carried out in an anhydrous organic solvent - for example, an arene such as toluene - and at a high temperature, which is preferably the boiling temperature of the reaction mixture. 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.
The formed imidazolobenzodiazepines Ic, or Id may if desired, be further reacted to convert them into different compounds of general formula Ic or Id. In particular, compounds wherein R4 and R5 together with the nitrogen atom represent a heterocycle may be further reacted so as to introduce substituents onto the heterocyclic ring.
When it is desired to prepare a compound Ic or M wherein R4 and Rg form with the conjoined nitrogen atom a Rg-piperazin-l-yl radical, wherein Rg represents a cycloalkylalkyl radical, an alkenyl radical ora 4-dial kyl phosphinyl al kyl radical, one may first prepare a compound Ic or Id, wherein R4 and Rg form a piperazin-l-yl radical with the conjoined nitrogen atom, and then react this compound with a halo-Rg compound to form the desired product.
When it is desired to prepare a compound Ic or Id wherein R4 and R5 form, together with the conjoined nitrogen atom, a 4-dialkylphosphinylalkyl-piperazin-l-yl radical, one may first prepare a compound Ic or Id., wherein R4 and R® form, with the nitrogen atom, a piperazin-l-yl radical with the conjoined nitrogen atom, and then react this compound with a haloalkyl-dialkylphosphine oxide to form the desired product.
The preferred haloalkyl-dialkylphosphine oxides for use in such a conversion are the chloroalkyl-dialkylphosphine oxides, and the reaction is preferably carried out in an organic solvent- for example, an arene such as toluene.
The formed compounds Ia, lb, l£ and Id may be salified by normal methods. In another aspect this invention provides processes for the preparation of acid addition salts of compounds of general formula I, in which an imidazolobenzodiazepine I is reacted, in substantially stoichiometric proportions, with a mineral or organic acid to form the desired 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.
This invention extends, of course, to imidazolobenzodiazepinl-ones Ia., Ib^, l£ or W, and acid addition salts thereof, whenever prepared by a process as described and claimed herein.
The imidazolobenzodiazepin-l-ones of the invention possess very interesting pharmacological properties. They are endowed especially with remarkable sedative, hypnotic, anxiolytic, tranquillising, anticonvulsive and myorelaxant properties which may make them of use as medicaments in the treatment of states of agitation or irritability, of agression, of insomnia, of certain psychosomatic syndromes, of certa'in character and behavioural disorders, and of certain spasms or muscular contractions.
However, before any of the compounds of this invention may be used in medicine, they should preferably be formed into pharmaceutical compositions by association with suitable pharmaceutical vehicles.
The 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 pharmaceutical formulations.
Accordingly, in yet another aspect this invention provides pharmaceutical compositions containing one or more imidazolobenzodiazepin-l-ones I, or pharmaceutically-acceptable acid addition salts thereof, in association with a suitable pharmaceutical vehicle. 3701 Preferred pharmaceutical compositions of the invention are those which contain, as active material, one or more compounds selected from the following:a) the imidazolobenzodiazepines of general formula I falling within the preferred groups a) to f) set out hereinbefore, and their acid addition salts; b) 8 - chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - phenyl - 4H - imidazo 0,2 - a ~|5,4] benzodiazepin - 1 - one and its tartrate, 8 - chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - (o - thlorophenyl) - 4H - imidazo 01,2 - aJFl,4] benzodiazepin - 1 - one, - chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl )met.hylene - 6 - (o - fluorophenyl) - 4H - imidazo 01,2 - aj[j ,4J benzodiazepin - 1 - one, - nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 -(o - chlorophenyl) - 4H - imidazo 01,2 - aJ01,40] benzodiazepin - 1 - one and its methone sulphonate, - nitro - 1,2 - dihydro -2-(4- methyl piperazin - 1 20 yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo 01,2 - aJJ ,4j benzodiazepin - 1 - one and - chloro - 1,2 - dihydro -2-(4- dimethylphosphinylmethylpiperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - ^01,4^ benzodiazepin - 1 - one; and 4379 1 c) 8 - nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - (o_ - chlorophenyl - 4H - imidazo 5,2 - a_*]5,4J benzodiazepin - 1 - one.
The compositions of this invention may be administered orally, transcutaneously or rectally, and in respect of these modes the pharmaceutical vehicle is preferably:a) the ingestible excipient of a tablet, such as a coated or sublingual tablet, or of a 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 cj a base material of low melting point capable of releasing the active ingredient to perform its pharmacological function, which base material when appropriately shaped forms a suppository.
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 animal or vegetable oil, a paraffin derivative, or a glycol). It may if desired incorporate wetting, dispersing or emulsifying agents, and preserving agents.
Whilst the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities.
The compositions of this invention 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, Lo a certain degree, depend upon the route by which the compositions are to be administered, nevertheless, by way of general indication, it may be said that useful dose ranges from 1 mg to 50 mg active ingredient per day for an adult, a unit dose containing from 0.5 mg to 20 mg active ingredient.
The following Examples, Formulations and Test Results are now given, though only by way of illustration, to show details of various aspects of the invention.
EXAMPLES Example 1 8-chloro-l ,2-dihydro-2-(dimethylamino)-methy1ene-6-phenyl4H-imidazo- ί1,2-aJf1,4Jbenzodiazepin-l-one (la) Stage A: 2 - carboxymethyl amino - 7 - chloro - 5 - phenyl - 3H 15 1,4 - benzodiazepine (IV) - Chloro - 1,3 - di hydro - 5 - phenyl - 2H - 1,4 benzodiazepine - 2 - thione II (3.5 g), glycine III (5.5 g) and sodium carbonate (5.5 g) were suspended in ethanol (100 ml) and water (30 ml), and were stirred and refluxed for 1 hour. The Z0 suspension was then poured into water to give a clear solution, and this was acidified to pH 4 with 2N HCI, and extracted with CHClg. Some solid precipitated from the extracts, and was filtered off.
The organic layer was dried over MgSO^ and evaporated to give a gum that crystallized on trituration with methanol. This solid, and the solid filterd off above, was crystallized from a large amount of ethanol to give 2-carboxymethylamino-7-chloro5-phenyl-3H-l,4-benzodiazepine, 3.1 g (77%). m.p. = 215°-220°C.
Stage B: 8 - chloro - 1,2 - dihydro - 6 - phenyl - 4H - imidazoLl,2 - al b ,4]benzodiazepin - 1 - one (V) - Carboxymethylami no - 7 - chloro - 5 - phenyl - 3H - 1,4 benzodiazepine IV (2.5 g) was suspended in dry CH2C12 (120 ml), and stirred, and dicyclohexylcarbodiimide (2.1 g) was added.
The suspenion was stirred at room temperature for 3 hours, then filtered, and the filtrate was evaporated to give 8 - chloro - 1,2 - dihydro - 6 - phenyl - 4H - imidazo 0,2 - £]0,4]benzodiazepin - 1 - 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 - (dimethylaminomethylene - 6 - phenyl - 4H - imidazo G,2 - J -tl ,41benzodiazepin-l one (la).
The 8 - chloro - 1,2 - dihydro - 6 - phenyl- 4H imidazo|j,2- a_ j[l ,4jbenzodiazepin - 1 - one V obtained in stage 8 above was dissolved in dry benzene, and dimethylformamide diethyl acetal VI (1.5 g) and triethylamine (1 ml) was added. The 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 - chloro - 1,2 - dihydro - ? - (dimethylamino)methylene - 6 phenyl - imidazo [l ,2 - a Jj 1,4jbenzodiazepin - 1 - one la, 2.7g (97%) m.p. = 264° - 5°C.
Analysis:C20H17C1 N4 0 = 364.9 Calculated a 65.85 HZ 4.66 NZ 15.37 C1Z 9.74 Found: 65.87 4.67 15.37 9.74 I.R. Spectra (KBr disc): C = 0 at 1690 cm 0 C=N at 1621 cm 1 Examples 2 to 6 Ιθ Using a similar method to that used in Example 1, the following compounds IV, V and Ia, were prepared: Example 2: Compound IV: 2 - carboxymethyl ami no - 7 - nitro 5 - phenyl - 3H - 1,4 - benzodiazepine.
Compound V: 8 - nitro - 1,2 - dihydro - 6 - phenyl 15 4H - imidazo - 0,2 - a ]0,4] benzodi azepin - 1 - one.
Compound Ia 8 - nitro - 1,2 - dihydro - 2 (dimethylamino)-methylene - 6 - phenyl - 4H imidazo 01,2 - a] jj ,4jbenzodiazepin - 1 - one.
Example 3: Compound IV: 2 - carboxymethyl ami no - 7 - chloro -- 5 - o - chlorophenyl - 3H - 1,4 - benzodiazepine.
Compound V: 8 - chloro - 1,2 - di hydro - 6 - £ - chlorophenyl 4Himidazo Q,2 - aj β ,4] benzodiazepine - 1 - one.
Compound Ia; 8 - chloro - 1,2 - dihydro - 2 - (dimethylamino) methylene - 6 - £ - chlorophenyT - 4H - imidazo 0,2 5 benzodiazepin - 1 - one. ample 4: Compound IV: 2 - earboxymethylamino - 7 - nitro - 5 - £ chlorophenyl - 3tf - 1,4 - benzodiazepine.
Compound V; 8 - nitro - 1,2 - dihydro - 6 - £ - chlorophenyl - 4H imidazo 0,2 - a~||l»4l benzodiazepin - 1 - one.
Compound Ia: 8 - nitro - 1,2 - dihydro - 2 - (dimethylamino)methylene - 6 £ - chlorophenyl - 4H - imidazo0,2 - aJ0,4]benzodiazepin - 1 - one. unple 5: Compound IV: 2 - earboxymethylamino - 7 - chloro - 5 - £ fluorophenyl - 3H - 1,4 - benzodiazepine.
Compound V: 8 - chloro - 1,2 - dihydro - 6 - £ - fluorophenyl - 4H 15 imidazo 0,2 - aj Q ,4j benzodiazepin - 1 - one.
Compound l£: 8 - chloro - 1,2 - dihydro - 2 - (dimethylamino) methylene 6 - £ - fluorophenyl - 4H - imidazo jj,2 - aj 0,4^ benzodiazepin - 1 - one mple 6 Compound IV: 2 - earboxymethylamino - 7 - nitro - 5 - £ 20 fluorophenyl - 3H - 1,4 - benzodiazepine.
Compound V: 8 - nitro - 1,2 - dihydro - 6 - o - fluorophenyl 4H - imidazo0,2 - aj[j,4j benzodiazepin - 1 - one.
Compound Ia: 8 - nitro - 1,2 - dihydro - 2 - (dimethylamino) methylene - 6 - £ - fluorophenyl - 4H - imidazo 01,2 - ajjl ,4.] benzodiazepin - 1 - one. 22.
In each case the compound III was glycine, the compound VI was dimethylformamide diethyl acetal, the compound V was used without further purification, and the crystallization solvent for the compound l£ was methanol. The data for these compounds (excluding the compounds V) is summarized in Table I below.
TABLE 1 Example Compound IV r' R2 Compound la Yield % M.p. °C Crystallisation solvent Yield % M.p. UC 2 66 154-5 MeOH no2 H 43 277-8 3 75 136-9 Me0H-Et20 Cl o-Cl 53 288-90 4 83 158-61 Et^O no2 o-Cl 78 253-5 5 69 gum - Cl o-F 63 257-60 6 44 EtgO N02 o-F 80 228-31 Example 7 -chloro - 2 - 1' - (dimethylamino)ethylidene 1,2 - dihydro 6 - phenyl - 4H - imidazo -0,2 a] [l,i]benzodiazepin-l-one (lb) - Chloro - 1,2 - dihydro - 6 - phenyl - 4H - imidazo 5 O’2 - aJ0»4jbenzodiazepin - 1 - one V, prepared as described in Stage B of Example 1, was dissolved in dry methylene chloride (200 ml) with dimethyl acetamide VII (2.0 g). The solution was cooled to 0°C. and phosphorus oxychloride (3.7 g) was added dropwise over 5 minutes with good stirring. The solution was then stirred at room temperature over 20 hours, and poured into saturated NaHCOg solution (500 ml). The mixture was stirred until the evolution of CO^ ceased, the organic layer was removed, and the aqueous layer was extracted with methylene chloride (2 X 100 ml). The combined organic extracts were washed with saturated NaHCOg solution, and water, dried over MgSO^, and evaporated to give a yellow solid. Recrystallization of this solid from chloroform/diethyl ether gave 8 - chloro - 2 - V - (dimethylamino)ethylidene - 1,2 - dihydro - 6 - phenyl - 4H - imidazo 0,2 - aJQl,4/- benzodiazepin - 1 - one IJj, 2.3 g (40?). m.p. = 251-2°C.
Analysis: C21HigCl N40 = 378.9 Calculated: C? 66.58 H? 5.02 N? 14.79 Cl? 9.38 Found: 66.32 4.91 14.77 9.02 I.R. Spectra (KBr disc): C = 0 at 1653 cm'1: C = N at 1610 cm'1 Example 8 - chloro - 1,2 - di hydro -2-(4- methylpiperazin-1-yl)methylene6 - phenyl - 4H - imidazo - [j,2 a]|l,4jbenzodiazepin - 1 -one (Ic), and its tartrate A) 8 - Chloro - 1,2 - dihydro - 2 - (dimethyl aminoImethylene 6 - phenyl - 4H - imidazo fl,2 - aJ0 ,4j benzodiazepin - 1 - one L· (obtained as in Stage C of Example 1) (2.3 g) and N-methyl-piperazine (4.0 g) were stirred under reflux in dry toluene (50 ml) for 24 hours.· One cooling, crystals separated out, and were filtered off. Evaporation of the solvent gave a Dale yellow solid, and this was treated with methanol, and filtered. The two sets of solids were combined and recrystallized from methanol/ethyl acetate to give 8 - chloro - 1,2 - dihvdro -2-((4- methylpiperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo D’2 - benzodiazepin - 1 - one lc 2.3 g (87%). m.p· . = 255-6°C. Analysis:C23H22C1 N5° = 419.9 Calculated: C% 65.80 H% 5.24 N% 16.69 Cl% 8.46 Found: 65.64 5.27 16.63 8.56 I.R. Spectra (KBr disc): C=0 at 1705 cm'1; C=N at 1635 cm1 B) The tartrate salt of 8 - chloro - 1,2 - dihydro - 2 (4 - methylpiperazin - 1 - yl) methylene - 6 - phenyl - 4H imidazo0,2 - a.JQ ,4_Jbenzodiazepin - 1 - one l£ was prepared by adding a stoichiometric amount in methanol of tartaric acid to the 8 - chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo - T,2 - ajj,ϋbenzodiazepine - 1 - one Ic. The formed crude salt was recrystallized from methanol to give the desired product. M,Pt.= 146-150°C.
Analysis: C27H28C1N5°7 = ^θ·1 Calculated: C% 56.89 H% 4.92 M 11.29 CU 6.23 Found: 56,44 4.93 11.79 5.93 I.R. Spectra (KBr disc): OH at 3400 cm1 and 2500cm1; C = 0 at 1730-1 and 1960 cm1; C = N at 1630 cm1; Examples 9 to 46 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-(4- methylpiperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo 0,2 - £^0,4] benzodiazepin 1 - one Ic in Example 8 was used to prepare the following compounds I: Compound I Example 9: 8 - chloro - 1,2 - di hydro -2-(4- morpholinyl)methylene - 6 - phenyl - 4H - imidazo 01,2 - a00,4/benzodiazepin - 1 - one.
Example 10: 8 - Chloro - 1,2 - dihydro - 2 - (4 - p - hydroxyethyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - Example 11: 8 - Chloro - 1,2 - dihydro -2-(4- phenyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - a] 01 ,.47benzodiazepin - 1 - one.
Example 12: 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl) -methylene - 6 - (o- chlorophenyl - 4H - imidazo 01,2 - a~j 0 ,4] benzodiazepin - 1 - one.
Example 12B: 8 - Chloro - 1,2 - dihydro -2-(4- methyl piperazin - 1 - yl)methylene - 6 - (£ - chlorophenyl) - 4H - imidazo 01,2 - £00 ,4j benzodiazepin - 1 - one taftrate.
Method: analogous to Example 8B 5 Example 13: 8 - Nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl)methy1ene - 6 - phenyl - 4H - imidazo -01,2 - £]0>4*j benzodiazepin - 1 - one.
Example 14: 8 - Chloro - 1,2 - dihydro - 2 - (piperazin - 1 - yl) methylene - 6 - phenyl - 4H - imidazo 0,2 - £][l,4] benzodiazepin - 1 - one.
Example 15: 8 - Chloro - 1,2 - dihydro - 2 - (£- butyl - amino) methylene - 6 - phenyl - 4H - imidazo 01,2 - £00,40 benzodiazepin - 1 - one.
Example 16: 8 - Chloro - 1,2 - dihydro - 2 - (amino)methylene - 6 15 phenyl - 4H - imidazo 01,2 - a] 0,4] benzodiazepin - 1 - one.
Method: -Chloro - 1,2 - dihydro - 2 - (dimethylamino)methylene - 6 - phenyl - 4H - imidazo 0,2 - a]0 ,43 benzodi azepin - 1 - one Ia (2.1 g) was suspended in dry methanol (100 ml). The suspension 20 was stirred, cooled in a 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 solid residue was recrystallized from methanol/ ethyl acetate to give 8 - chloro - 1,2 - dihydro - 2 - (amino)-methylene 25 - 6 - phenyl - 4H - imidazo 0,2 - a0 (Ϊ ,40 benzodiazepin - 1 - one Ic, 1.9 g (98%) m.p. = 265°-7°C. 3791 Compound I methylene - 6 - phenyl - 4H - imidazofj,2 - 07 fi Example 17: 8 - Chloro - 1,2 - dihydro -2-(1- piperidinyl) methylene - 6 - phenyl - 4H - imidazo 01,2 - aJ0 ,4]benzodiazepin - 1 - one.
Example 18: 8 - Chloro - 1,2 - dihydro -2-(4- thiomorpholinyl) ,4-Jbenzodiazepin 1 - one.
Example 19: 8 - Chloro - 1,2 - dihydro - 2 - (diethylaminoethylamino)methylene - 6 - phenyl - 4H - imidazo 01,2 - aJ0 ,4j benzodiazepin 1 - one.
Example 20: 8 - Chloro - 1,2 - dihydro - 2 - (N - methyl - N (dimethylamino) -ethylamino)methylene - 6 - phenyl - 4H - imidazo [01,2 - aj 0,4] benzodiazepin - 1 - one.
Example 21: 8 - Chloro - 1,2 - dihydro - 2 - (methylamino)methylene - 6 - phenyl - 4H - imidazo 01,2 - a]jj ,4]benzodiazepin - 1 - one.
Example 22: 8 - Chloro - 1,2 - dihydro - 2 - (cyclohexyl ami no) methylene - 6 - phenyl - 4H - imidazo 01,2 - aj01,4]benzodiazepin - 1 - one.
Example 23: 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl)methylene - 6 (o - fluorophenyl) - 4H - imidazo 0,2 - a]|_l ,41 benzodiazepin - 1 - one.
Example 24: 8 - Chloro - 1,2 - dihydro - 2 - |_4 - (Γ - phenyl -4' - oxo - 5' - imidazolyl)piperidin - 1 - yljmethylene - 6 phenyl - 4H - imidazo 01,2 - a]0I,4j benzodiazepin - 1 - one.
Example 25: 8 - Chloro - 1,2 - dihydro - 2 - (phenylamino)methylene - 6 - phenyl - 4H - imidazo 01,2 - aj 01,4]benzodiazepin - 1 - one.
Example 26: 8 - Chloro - 1,2 - dihydro -2-(1 - 4 - methyl piperazin - 1 - yl) ethylidene - 6 - phenyl - 4H - imidazo 01*2 - a001,4] dibenzodiazepin - 1 - one. 43781 Method: - Chloro - 7 - [l - (dimethylamino)ethylidenej - 1,2 dihydro - 6 - phenyl - 4H - imidazo jl,2 - aj.1,4j benzodiazepin - 1 - one lb (Example 7) (2,3 g) and 5 N - methyl - piperazine VIII (15 ml) were stirred at 120°C under nitrogen for 9 hours. The cooled solution was poured into water, NaCl was added to complete precipitation, and the brown precipitate was filtered off, dissolved in CHClg, washed with water, dried over MgSO^, and evaporated to give a dark red oil.
The oil crystallized on triturating with diethylether/methanol, and was recrystallized from ethyl acetate to give 8 - chloro -2-0 -(4- methyl piperazin - 1 - yl )ethylidenej - 1,2 - dihydro - 6 - phenyl - 4H - imidazo |j,2 - aj |j ,4j benzodiazepin - 1 - one Id, 1.0 g (38%) m.p. = 193°-5° C.
Compound I Example 27: 8 - Chloro - 1,2 - dihydro - 2 - {t - butylamino) methylene - 6 - phenyl - 4H - imidazo 0,2 - aJQ ,0] benzodiazepin - 1 - one.
Example 28: 8 - Chloro - 1,2 - dihydro - 2 - (hydroxyethylamino) methylene - 5 - phenyl - 4H - imidazo [l ,2 - £ i_l ,4] benzodiazepin - 1 - one.
Example 29: 8 - Chloro - 1,2 - dihydro - 2 - (n - propylamino) methylene - 6 - phenyl - 4H - imidazo 0,2 - ajj,4j benzodiazepin - 1 - one.
Example 30: 8 - Nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl)methylene - 6 (o - chlorophenyl). 4H - imidazo01,2 - aJ01,40 benzodiazepin - 1 - one.
Example 31: 8 - Nitro - 1,2 - dihydro - 2 (4 - methyl - piperazin - 1 - yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo 01,2 - aJ01,40 benzodiazepin - 1 - one.
Example 32: 8 - Chloro - 1,2 - dihydro -2-(4- ethyl -piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - aJ0i,4] benzodiazepin - 1 - one.
Example 32B: . 8 - Chloro - 1,2 - dihydro -2-(4- ethyl piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - <001,4.1 benzodiazepin - 1 - one tartrate.
Method: analogous to Example 8B Example 33: 8 - Chloro - 1,2 - dihydro - 2 - (4 - £ - propyl piperazin -l-yl) methylene - 6 - phenyl - 4H - imidazo01,2 - a] 01,4] benzodiazepin - 1 - one.
Example 34: 8 - ChToro - 1,2 - dihydro - 2 - f 4 - (n - butyl) piperazin - 1 - y£J methylene - 6 - phenyl - 4H - imidazol20 01,2 - a]fl.,40 benzodiazepin - 1 - one.
Example 35: 8 - Chloro - 1,2 - dihydro - 2 - 04 - (isopropyl) piperazin - 1 - ylj methylene - 6 - phenyl - 4H imidazo 01,2 - aJ01,40 benzodiazepin - 1 one.
Method: - Chloro - 1,2 - dihydro - 2 - (piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - aj[l,4] benzodiazepin - 1 - one (the compound of Example 14, obtained as in Example 8) (1.5 g), isopropyl iodide (2.5 g.) and sodium carbonate (3.0 g.) were stirred at 80°C in acetonitrile (25 ml) and methylene chloride (5 ml.) for 18 hours. The cooled solution was poured into water and extracted with chloroform. The extracts were washed with water, dried over MgSO^, and evaporated to give a pale yellow solid. Recrystallisation of this solid from ethyl acetate gave - chloro - 1,2 - dihydro -2-(4- isopropyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - ja]0I,4*| benzodiazepin - 1 - one Ic, 1.2g. (73?) M.pt. = 146°-8°C.
Compound I Example 36. 8 - Chloro - 1,2 - dihydro - 2 (4 - allyl piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo [_1,2 - aJ0>4j benzodiazepin - 1 - one.
Method: analogous to Example 35.
Example 37: 8 - Chloro - 1,2 - dihydro -2-(4- cyclopropylmethyl 2θ - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo »2 - a]ij,4_, benzodiazepin - 1 - one.
Method: analogous to Example 35.
Example 38: 8 - Chloro - 1,2 - dihydro -2-(4- ethyl piperazin - 1 - yl)methylene - 6 - (o - chlorophenyl) - 4H imidazo 0,2 - ajjj,4j benzodiazepin - 1 - one.
Example 39:. 8 - Chloro - 1,2 - dihydro -2-(4- ethyl piperazin - 1 - yljmethylene - 6 - (£ - fluorophenyl) - 4H imidazo Ql ,2 - a][l ,4jbenzodiazepin - 1 - one.
Example 40; 8 - Nitro - 1,2 - dihydro - 2 (4 - ethyl - piperazin - 1 - yl)methylene - 6 - (o. - chlorophenyl) - 4H - imidazo 0,2 - ajl»4] benzodiazepin - 1 - one.
Example 41: 8 - Nitro - 1,2 - dihydro -2-(4- ethyl piperazin - 1 - yl)methylene - 6 - (o - fluorophenyl) - 4H imidazo [j ,2 - a^[l ,4^ benzodiazepin - 1 - one.
Example 42: 8 - Chloro - 1,2 - dihydro - 2 - (ethylaminoJmethylene - 6 - phenyl .- 4H - imidazo 0,2 - a^[t,4j benzodiazepin - 1 - one.
Example 43: 8 - Chloro - 1,2 - di hydro - 2-(4- dimethylphosphinylmethyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo j2 - a jfi ,4J benzodiazepin - 1 - one.
Method; - Chloro - 1,2 - dihydro - 2 - (piperazin - 1 yl )methylene - 6 - phenyl -4H - imidazo 01,2 - aJ0,4j benzodiazepin - 1 - one (the compound of Example 14, obtained as in Example 8) (2.5 g.), chloromethyldimethylphosphine oxide (1.5 g.), and sodium carbonate (5.0 g.) were stirred under reflux in toluene (80 ml) 379 1 for 3 days. The cooled suspension was distributed between chloroform and water, and the chloroform extract was separated,· dried over MgSO^, and evaporated to give a pale yellow oil which crystallized with methanol. The solid (unrequired by-product) was filtered off. and the filtrate was evaporated to give a pale orange oil. This oil was dissolved in chloroform and chromatographed on Kiesel-gel.60.
Elution with chloroform/methanol (5%) gave a pale yellow solid., which on recrystallization from methylene chioride/diethyl ether gave 8 - chloro - 1,2 - dihydro - 2-(4- dimethylphosphinvlmethvl10 piperazin - 1 - ml)methylene - 6 - phenyl - 4H - imidazo 01,2 - a]01,4j benzodiazepin - 1 - one. Ic (1.25 g.) (41%).
M.Pt. = 261°-2°C.
Compound I Example 44: 8 - Chloro - 1,2 - dihydro - 2 - (4 - n - propyl piperazin - 1 - yl) -methylene -6-(()- chlorophenyl) - 4H imidazo 01,2 - aJ01,4] benzodiazepin - 1 - one.
Example 45: 8 - Chloro - 1,2 - di hydro - 2 - (ethyl amino)methylene - 6 - io - chlorophenyl) - 4H - imidazo 01,2 - a]01,4] benzodiazepin - 1 - one Example. 46: 8 - Chloro - 1,2 - dihydro - 2 - in - propyl ami no'methyl ene - 6 - (o - chlorophenyl) - 4H - imidazo 0,2 - aj0,4] benzodiazepin - 1 - one.
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S- >> U X 1 XT f X 1 X 1 fc £- O r— Φ r-» CL φ ·— P £ P c Ρ E P c >> r-W.CN C Φ u Λ Π5 O >) O O- >) Φ ’f- Φ ·Γ· Φ -i- Φ -r~ JZ a 0 p «3 ·—' £X £ O- 1 ··— 1 I 1 N 1 N 1 N 1 I'd P 1 x: Φ U 1 ·»“ Ρ cl <3- Q-r- «3* CL CLr— *3* rti 3* ro «j· «0 3* fO LU (3* ClE Φ •cf CL 3 I ~co~~ ex X X r— Lu X X O 3 3 0 O Lu ... Cd CJ ex 3 O 1—· r*“ o o 3 O Z z ; 0 D O 3 3 tS) Φ «“* CL ε LO fx. co cn O T—· CJ ro in LO φ CO CO CO co <· *3· M- 1 *3· 3· X LU Example 47 - chioro-1,2-dihydro-2-(4-dimethylphosphinylmethylpiperazin-l-yl)methylene-6-(o-chlorophenyl)-4H-imidazo 01,2-a] [l,4j benzodiazepin-!-one 8 - Chloro - 1,2 - dihydro - 2 - (piperazin - 1 - yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2 - a]01,4j benzodiazepin - 1 - one l£ (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 over 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 methanol/ethyl acetate/ether gave 8 - chloro - 1,2 -dihvdro - 2 (4 - dimethylphosphinylmethyl - piperazin - 1 - yl)methylene -βίο - chi orophenyl 1 - 4H - imidazo [l,2 - aj[l,4] benzodiazepin - 1 one Ic, m.p. = 23l-4°C I.R. Spectra (KBr disc): C = O at 1700 cm1·, C = N at 1630 cm1 Example 48 1,2 - dihydro -2-(4- dimethylphosphinylmethylplpeia2in - 1 - yl)methvlene - 6 -phenvl- 4H - imidazojj j2 ,sfj 01,4j benzodiazepin - I - 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 - 4H - imidazo 01,2 - a~] [l,4] benzodiazepin - 1 - one Io which in turn was prepared by a method analogous to that described in Example 8.
The formed 1,2 - dihydro -2-(4- dimethylphosphinylmethylpiperazin -1-yl) - methylene - 6 - phenyl - 4H - imidazo 0,2-£| fl ,4} benzodiazepin - 1 - one Ic melted at 245-7°C I.R. Spectra (KBr disc) C = 0 at 1695 cm’1; C = N at 1630 cm”1 Example 49 8-nitro-l,2-dihydro-2-(4-dimethylphosphinylmethylpiperazin -1-yl )methy1ene-6~(o-chlorophenyl)4H-imidazo 01,2-a]0 benzodiazepin-l-one This compound was prepared, by a method analogous to that used in Example 47, from 8 - nitro - 1,2 - dihydro 2 - (piperazin - 1 - yl)methylene - 6 - (o - chloroDhenyl) - 4H - imidazo 01,2 - a] 0Mj benzodiazepin - 1 - one Ic - which in turn was prepared by a method analogous to that described in Example 8.
The formed 8 - nitro - 1,2 - dihydro -2-(4- dimethylphosphinylmethyl - piperazin - 1 - yl)methylene - 6 - (o - chlorophenyl)4H I imidazo [l,2 - aj |l ,4j benzodiazepin - 1 - one Ic melted at 245-8°C.
I.R. Spectra (KBr disc) C = 0 at 1700 cm'1; C = N at 1642 cm1 Example 50 - nitro-1,2-dihydro-2-(4-methyl-piperazin-l-yl)methylene -6-(o-chlorophenyl)-4H-imidazo 01,2-aJQ,4j benzodiazepin-l-one methanesulphonate Methanesulphonic acid (1.1 g) was added dropwise to 8-nitro-l,2-dihydro -2-(4-methy1-piperazin-l-yl)methylene- 6 - ((o-chlorophenyl -4Himidazo Q^-aJ0,4j| benzodiazepin - 1 - one (obtained as in Example 30) (4.6 g) in dry methylene chloride (100 ml) and methanol (5 ml). Dry diethyl ether was added slowly until crystals formed on scratching and the solution was allowed to crystallise, further ether being added to complete the crystallisation. The pale yellow solid was filtered off, washed with diethyl ether and recrystallised from methylene chloride-methanol to give 8 - nitro - 1,2 - dihydro - 2, f-(4 - m°th''lpipecaz'in - 1 - yl)15 methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2-4)0,41 benzodiazepin - 1 - one methanesulphonate (5.4 g), m.p. - 205-10°C.
FORMULATIONS Formulation 1 : Tablets Tablets were prepared having the following per tablet: - chloro - 1,2 - dihydro -2-(4methylpiperazin - 1 - yl)methylene - 6 phenyl - 4H - imidazo 01,2-a] 01,4] benzodiazepin - 1 - one Excipient (q.s. for a tablet up to The excipient was lactose, starch, talc constituents mg 100 mg and magnesium stearate.
Formulation 2: Capsules The ingredients for gelatin capsules were prepared to have the following constituents per capsule: - chloro - 1,2 - dihydro -2-(2- methylpiperazin 5 - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - £10,4j benzodiazepin - 1 - one tartrate 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: - chloro - 1,2 - dihydro -2-(4- methylniperazin 1 - yl)methvlene - 6 - phenyl - 4H - imidazo 01,2 - a~|0,4j benzodiazepin - 1 - one tartrate 10 mg aqueous solvent q.s.v. 2 ml Formulation 4: Tablets Tablets were orenared having the following constituents per tablet: - chloro - 1,2 - dihydro -2-(4- meth/lpiperazin 20 - 1 - yl)methvlene - 6 - (o - chlorophenyl 1 - 4H imidazo 01,2 - aT]01,4] - benzodiazepin - 1 - one 5 mg ExciDient (a.s. for a tablet) up to 100 mg The excipient was lactose, s+arch, talc and magnesium stearate, Formulation 6: Tablets Tablets were prepared having the following constituents per tablet: - nitro - 1,2 - dihydro -2-(4methylpiperazin - 1 - yl) - methylene - 6 (o - chlorophenyT) - 4H - imidazo 01,2-aJ[l,4]benzodiazepin - 1 - one 5 mg Excipient (q.s. for a tablet) up to 100 mcf The excipient was lactose, starch, talc and magnesium stearate.
Formulation 7: Tablets Tablets were prepared having fhe following constituents Der tablet: - nitro - 1,2 - dihydro -2-(4- methvl - piperazin - 1 ->1) - methylene - βίο - chlorophenyT) - 4H - imidaz n 01,2 - aT]|j,401 benzodiazepin - 1 - one toethanesulphonate 5 mg Excipient (q.s- for a tablet)up to 100 mg The excipient was lactose, starch, talc and magnesium stearate.
Formulation ..8: Tablets Tablets were prepared having the following constituente per tablet: - chloro - 1,2 - dihydro -2-(4- methyl piperazin - 1 - yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2-aj01,4]benzodiazepin — 1 - one tartrate 5 mg Excipient (q.s. for a tablet) up to 1Q0 mg The excipient was lactose, starch, talc and magnesium stearate PHARMACOLOGICAL ACTIVITY 1) Antiaggressive activity in mice (AAM) Groups of 20 randomly selected male mice (25-30 g 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 minutes after dosing, pairs of mice were placed under an inverted 1 litre pyrex beaker on a metal grid. The grid was connected to a Palmer square wave stimulator, and the feet of the mice were electrically stimulated with 90 volt pulses of milli-second duration at a frequency of 2 pulses per second for a period of 2 minutes. This 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). The total number of fights in the control group was calculated.
The ED of a test compound is that dose which causes a 50% reduction in the number of fights of the batch of mice given that compound as compared with the control batch (Tedeschi. R. E. et al (1959) J. PHARM. Exptl. Ther 125.28-34).
The results are shown in Table 3 below. 2) Anticonvulsant test against 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 was then shocked via auricular electrodes using electroshock apparatus (Ugo Basile ECT apparatus for small mammals). The shocks had a pulse width of 0.2 miHi-seconds, 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 noted. The dose protecting 50% of the mice (ΤΕ05θ), as compared with the control group, was noted, and the results are shown in Table 3 below. 3) Anticonvulsant test against pentylenetetrazone in mice (ALM) 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 mg/kg pentylenetetrazole challenge (pentylenetetrazole is a central nervous system stimulant), 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 reduction of the control levels. From a constructed dose response curve, the doses protecting 50% of the mice (TEDgg) against tonus were estimated, and are shown in Table 3 below. 4) Anticonvulsant test against strychnine in mice (ASM) 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 1 mg/kg strychnine challenge (strychnine is a central nervous system . stimulant), and the mice were then housed individually in observation boxes. The number of mice exhibiting tonic convulsions within 15 minutes of the strychnine challenge was noted, and the results for the tonic phase expressed as a percentage reduction of the control value.
From a constructed dose response line, the doses protecting 50% of the mice (TEDgQ) against tonus were estimated, and are shown in Table 3 below.
) Potentiation of hexobarbital in mice (PHM) A group of ten control mice received an EDgO 11056 hexobarbital intraperitoneally (150 mg/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 (EDgQ), and the results are shown in Table 3 below. 6) Potentiation of chlorprothixene in mice (PXM) Groups of ten randomly selected male CFLP mice (Carworth Europe), weighting 20-25 g each, were given chlorprothixene (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 ml/kg), or a dose of vehicle plus test compound. Each mouse was then placed individually in a small observation chamber, and tested for loss of righting reflex 30 minutes after dosing. 3 7 91 The EDg0 value of a test compound is the dose which causes loss of 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 reflex. The results are shown in Table 3 below. 7) Rotating 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 were placed on a 30 cm diameter rotating drum revolving at 1 revolution/minute. The mice were placed on the drum against its direction of movement, and the number of micefalling off within a 2 minute test period was noted. From the results obtained a dose response line was constructed, and the dose causing 50% of the mice to fall of the drum (EDg0) was estimated. The results are shown in Table 3 below. 8) Mouse Acute Toxicity Test (ATM) Acute toxicity tests by oral and intraperitoneal routes were conducted using groups of ten mice at various dose levels. The groups were assessed for mortality at 24 hours, and the results are shown in Table 3 below, given in mg/kg. o o o o o o o o 1 o o o o A Λ Λ -A_ r--. d LO CO LO CM CO CM <3· Τ'TABLE 3 I O U Φ ex c s~ ai o x x Ξ Σ x υ -p a.
S >» LO S Φ C Φ Φ rr— O _ >» N X -P Φ _J C t< Φ -P CL Φ o $ -P Φ u X Φ O UJ ·—· J= C Φ w I ΙΛ •Γ» v) P Φ c s(o cn —- cn _EL Φ O r— O. Oe e ο φ u X UJ Φ . σ> «3* LfJ LO CM co LO LO CM CO CO o d co co CM d co o o to to cn ΟΟ o co Ο ΓCO r— r— o CM O CM cn d LO LO i— CO i— CM CO o «3* O CM CM co CM CM CO CO 437 ο SQ. Φ S- C Ο Φ γ- X S3 ·γυ χ: Ο *f“ X XJ Φ U JZ to *-*xi 4-> I φ C Φ φ <— r— Ο >» Ν +-> fO c iφ +J α. Φ •χ-'.ρ t Ο S-—+J -X u υ φ ο r— Φ (Λ •γ- φ •Ρ S. C ο φ cn KO σ> in in r-x CM m © co τ— o o111 © CO © r— in σι CM CM co σ» r-χ IO IO 1— co CM οt r— d in r— - CM Ό r-x 10 10 in COt · 00 r-x © CM O o co CM CM ό d d © o 1“ in r*“ «3· co tO co ΙΟ - CM111 1— in in o CM CM Λ CM V rx in co in CO cy» co Λ σ 1 co O o 1 1 Α o © © o © in 10 r-x CM in in o r> CM CM r*·.11 co co o d r— co A CO co «Φ m *d- io CM co m *3* o (O CO (O O mt- sf - o 0 o o d d -- CM d CL ο ε α. to ε X Ο Ltl υ 4φ ο 3 7 9! The results obtained show that the compounds of the invention possess a very important activity on the central nervous system as anticonvulsant, anti-anxiety and hypnotic sedatives, and that they have a very low 5 toxicity.
The references in the following claims to general formulae are, unless stated otherwise, reference tn those formulae shown in +he Reaction Scheme of the accompanying drawings. The substituent group symbols employed are, unless stated otherwise, as first defined.

Claims (13)

1. A 1,2 - dihydro - 6 - phenyl - 4H - imidazo 0,2 - ij 0,40 benzodiazepine of the general formula wherein: R 1 represents a hydrogen atom, a halogen atom, a nitro radical or a tri fluoromethyl radical; o R , which may be at any position in the phenyl (0) ring, 5 represents a hydrogen atom or a halogen atom; ο R represents a hydrogen atom or a methyl radical; and either R^ and R 5 , which may be the same or different, each represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyalkyl radical containing from 10 1 to 5 carbon atoms, an aminoalkyl or alkyl aminoalkyl radical (the alkyl moieties each containing from 1 to 5 carbon atoms), and aryl radical, or a cycloalkyl radical. 4 5 or R and R together with the nitrogen atom represent a saturated, substituted or unsubstituted heterocyclic optionally 15 containing another hetero atom; and acid addition salts thereof.
2. A compound as claimed in claim 1, wherein R 1 represents a chlorine atom.
3. A compound as claimed in either of the preceding claims, 20 wherein R represents a halogen atom in the ortho-position.
4. A compound as claimed in any of the preceding claims, ? wherein R represents a fluorine or chlorine atom.
5. A compound as claimed in any of the preceding claims, wherein R represents a hydrogen atom.
6. A compound as claimed in any of the preceding claims, wherein either of R 21 and R 5 represents a methyl, ethyl, n-propyl, 5 π-butyl or t-butyl radical.
7. A compound as claimed in any of claims 1 to 5, wherein where either R 4 or R 5 represents a hydroxyalkyl radical, the alkyl moiety is an ethyl radical.
8. A comDound as clainpd in an v of claims 1 to 5, wherein 10 where either R or R represents an aminoalkyl or alkylaminoalkyl radical each of the alkyl moieties is a methyl or ethyl radical.
9. A compound as claimed in claim 8, wherein either R^ or R 5 represents an aminomethyl, aminoethyl, 15 dimethyl ami noethyl or diethylaminoethyl radical.
10. A compound as claimed in any of claims 1 to 5, wherein 4 5 either R or R represents a phenyl radical.
11. A compound as claimed in any of claims 1 to 5, wherein either R 4 or R 5 represents a cycloalkyl radical containing from 20 3 to 8 carbon atoms.
12. A compound as claimed in claim 11, wherein either 4 5 R or R represents a cyclohexyl radical.
13. A compound as claimed in any of the preceding claims, 4 5 wherein one of R and R represents hydrogen. 4379 j 14. A compound as claimed in any of claims 1 to 5, wherein where 4 5 R and R , together with the conjoining nitrogen atom, form an unsubstituted heterocyclic grouping, this grouping is a pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or 5 piperazin-l-yl grouping. 15. A compound as claimed in any of claims 1 to 5, wherein, where R 4 and R 5 , together with the conjoining nitrogen atom, form a substituted heterocyclic grouping, the substituent is an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyalkyl radical 10 containing from 1 to 5 carbon atoms, an aryl radical or a nitrogen containing heterocyclic radical. 16. A compound as claimed in any of claims 1 to 5, wherein R 4 and R 5 , together with the conjoining nitrogen atom, form a substituted heterocyclic grouping which is a 15 4 - methyl-, 4 - ethyl or 4 - propyl - piperazin -1-yl group, or a 4 - β - hydroxyethyl - piperazin -1-yl, 4 - dimethylphosphinylmethyl - piperazin -1-yl, 4 - cyclopropyl methyl - piperazin -1-yl, 4 allyl - piperazin -1-yl, 4 - phenyl - piperazin -1-yl, or 4 - (1' - phenyl - 4' - oxo - 5' - imidazolyl)piperidin -1-yl group. 20 17. A compound as claimed in claim 1, wherein either R 4 and R 5 , 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 25 R 4 and P0 together with the nitrogen atom form a pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazin - 1 - yl, 4 - alkyl - piperazin -l-yl, 4 - hydroxyalkyl - piperazin - I - yl, 4 - phenyl - piperazin - 1 yl or 4 (T phenyl - 4' - oxo - 5' - imidazolylj piperidin -l-yl radical. 18. A compound as claimed in claim 1, wherein R 1 represents a chlorine atom or a nitro radical, R represents a hydrogen atom, a chlorine atom or a fluorine atom, R represents a hydrogen atom, and either R 4 and R 5 , which may be the same or different, each represent a hydrogen atom, a straight alkyl radical containing from 1 to 5 carbon atoms, a hydroxyethyl radical, a phenyl radical, or a cyclohexyl radical, or 4 5 R and R together with the nitrogen atom form a piperidinyl, morpholinyl, piperazin-l-yl, 4 - alkyl - piperazin -l-yl or 4 - β - hydroxyethyl - piperazin - l -yl radical. 19. A compound as claimed in claim 1, wherein R 1 represents a chlorine atom or a nitro radical, R represents a hydrogen, chlorine or fluorine atom, 3 4 R represents a hydrogen atom, and either R represents a hydrogen atom and R 5 represents a methyl, ethyl, propyl or Λ 5 butyl· radical, or R and R· together with the nitrogen atom form a piperazin -l-yl, 4 - methyl - piperazin - l-yl, 4 - ethyl - piperazin -l-yl, 4 - propyl - piperazin - 1 - yl or 4 - β - hydroxyethyl - piperazin -l-yl radical. 20. □1 A compound as claimed in claim 1, wherein R represents a chlorine atom or a nitro radical, R 2 represents a hydrogen, chlorine or fluorine atom, R represents a hydrogen atom, and, η K R and R together with the nitrogen atom form a 4 - methyl - piperazin - 1 - yl, 4 - ethyl - piperazin -1-yl or 4 - £ - propyl - piperazin -1-yl radical. 21. A compound as claimed in claim 1, wherein R 1 represents a hydrogen atom, a chlorine atom or a nitro radical, R 2 represents a hydrogen atom, a chlorine atom or a fluorine atom, R 3 represents a hydrogen atom and R and R together with the nitrogen atom form a 4 - dialkylphosphinylalkyl - piperazin -1-yl radical. R represents a hydrogen atom or a chlorine atom, n 3 R represents a hydrogen atom and Λ 5 R and R together with the nitrogen atom form a 4 - dimethyl - phosphinylmethyl - piperazin -1-yl radical. 4379 1 22. 23. An acid addition salt as claimed in any of the preceding claims, which is formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric or phosphoric acid, or with acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, an alkanesulphonic or an arylsulphonic acid. 23. 24. An acid addition salt, as claimed in claim 23, which is formed with methanesulphonic acid. 24. 25. ,1 An acid addition salt as claimed in claim 1, wherein R represents a hydrogen atom, a chlorine atom or a nitro radical, p R represents a hydrogen atom, a chlorine atom or a fluorine atom, q R represents a hydrogen atom and R 4 and R$ together with the nitrogen atom form a 4 - alkyl - piperazin -1-yl radical. 25. 26. An acid addition salt as claimed in claim 1, which is a tartrate or an alkanesulphonate wherein »1 represents a chlorine atom or a nitro radical, represents a hydrogen atom or a chlorine atom, R J represents a hydrogen atom and 4 5 R and R together with the nitrogen atom form a 4 - methyl - piperazin -1-yl or a 4 - ethyl - piperazin -1-yl radical 26. 27. An acid addition salt as claimed in claim 26 which is a methanesulphonate. 27. 28. 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - phenyl - 4H - imidazo 0,2 - £j fl ,4] benzodiazepin - 1 - one. 28. 29. 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 0»2-aJQ ,4] benzodiazepin - 1 - one tartrate. 29. 30. 8 - Nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 5 yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - £]0.,4] benzodiazepin - 1 - one. 30. 31. 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2-a0 [l ,4] benzodiazepin - 1 - one. 10 31. 32. 8 - Chloro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - (o - fluorophenyl) - 4H - imidazo01,2 - aj(j,4]benzodiazepin - 1 - one. 32. 33. 8 - Nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2 - ij 0 ,40 15 benzodiazepin - 1 - one. 33. 34. 8 - Nitro - 1,2 - dihydro -2-(4- methyl - piperazin - 1 yl)methy1ene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2 - aj01,4] benzodiazepin - 1 - one methanesulphonate. 34. 35. 8 - Chloro - 1,2 - dihydro - 2 - (4 - methyl - piperazin 20 - 1 - yl)methylene -6-(0.- chlorophenyl) - 4H - imidazo 01,2 - aj 0,40 benzodiazepin - 1 - one tartrate. 35. 36. 8 - Nitro - 1,2 - dihydro - 2 - (4 - methyl - piperazin - 1 - yl)methy1ene - 6 - (o- fluorophenyl) - 4H - imidazo 01,2 - 0,40 benzodiazepin - 1 - one. ; 36. 37. 8 - Chloro - 1,2 - dihydro -2-(4- ethyl - piperazin - 1 - ylmethylene - 6 - phenyl - 4H - imidazo 01,2 - a][l ,4] benzodiazepin - 1 - one. 37. 38.- 8 - Chloro - 1,2 - dihydro - 2 - (4 -£ - propyl - piperazin 1 - yl)methylene - 6 - phenyl - 4H - imidazo01,2 - a] 0,4] benzodiazepin - 1 - one. 38. 39. 8 - Chloro - 1, - di hydro - 2 - (jn - butyl - amino)methylene 5 - 6 - phenyl - 4H - imidazo 01,2 - ij 0,4] benzodiazepin - 1 - one. 39. 40. 8 - Chloro - 1,2 - dihydro - 2 - (4 - β - hydroxyethyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - aj0,0]benzodiazepin - 1 - one. 40. 41. 8 - Chloro - 1,2 - dihydro - 2 - (n - propylamino)methylene 10 - 6 - phenyl - 4H - imidazo 01,2 - aj0,4] benzodiazepin - 1 - one. 41. 42. 8 - Chloro - 1,2 - dihydro -2-(4- ethyl - piperazin - 1 - yljmethylene -6-(0- chlorophenyl) - 4H - imidazo 01,2 - aj [1,4j benzodiazepin - 1 - one. 42. 43. 8 - Chloro - 1,2 - dihydro -2-(4- ethyl - piperazin 15 1 - yl)methylene -6-(0- fluorophenyl) - 4H - imidazo Π,2 - £j 01,4j benzodiazepin - 1 - one. 43. 44. 8 - Nitro - 1,2 - dihydro -2-(4- ethyl - piperazin - 1 yl)methylene -6-(0- chlorophenyl) - 4H - imidazo 01,2 - aj[l,4] benzodiazepin - 1 - one. 20 45. 8 - Nitro - 1,2 - dihydro -2-(4- ethyl - piperazin 1 - yl)methylene - 6 - (£ - fluorophenyl) - 4H - imidazo 01,2 - aJ 01,4j- benzodiazepin - 1 - one. 46. 8 - Chloro - 1,2 - dihydro - 2 - (ethylamino)methylene 6 - phenyl - 4H - imidazo 01,2 - aj01,4j benzodiazepin - 1 - one. 25 47. - 8 - Chloro - 1,2 - dihydro -2-(4- dimethylphosphinylmethyl - piperazin - 1 - yl)methylene - 6 - phenyl - 4H - imidazo 01,2 - aj 01,4j benzodiazepin - 1 - one. 48. 8 - Chloro - 1,2 - dihydro -2-(4- dimethylpliosphinylmettiyl - piperazin - 1 - yl)methylene - 6 - (£ - chlorophenyl) - 4H - 49. 1,2 - Dihydro - 2 (4 dimethylphosphinylmethyl - piperazin - 1 - one. 50. 8 - Nitro - 1,2 - dihydro -2-(4- dimethylenephosphinylmethyl - piperazin - 1 - yl)methylene - 6 - (o - chlorophenyl) - 4H - imidazo 01,2 - i] 0,40 benzodiazepin - 1 - one. 51. A process for the preparation of a compound of general formula I wherein R represents a hydrogen atom and R 4 and R 5 each represent a methyl radical, in which an 8 - R 1 - 1,2 - dihydro - 6 - (R 2 - phenyl)- 4H - imidazo 0,2 - eQ0,4·]benzodiazepin - 1 - one V is reacted with a dimethylformamide acetal VI (wherein alk represents an alkyl radical containing from 1 to 5 carbon atoms) from 1 to 5 carbon atoms) to give the desired 8 - R - 1,2 2 dihydro - 2 - (dimethylamino)methy1ene - 6 - (R - phenyl) - 4H imidazo 01,2 - aj 01,4] benzodiazepin - 1 - one Ija. 52. A process as claimed in claim 51, in which the reaction with the acetal VI is carried out in an anhydrous organic solvent. 53. A process as claimed in claim 52, in which the solvent is benzene. 54. A process as claimed in any of claims 51 to 53, in which the reaction with the acetal VI is carried out in the presence of a base. 55. A process as claimed in claim 54, in which the base is triethylamine. 56. A process for the preparation of a compound of general formula I wherein R^, and R^ each represent a methyl radical, in which an 8 - R - 1,2 - dihydro - 6 - (R - phenyl) - 4H - imidazo 0,2 - 4]0,4] benzodiazepin - 1 - one V is reacted with an N-dimethyl-acetamide VII to give the desired 8 - R 1 - 1,2 - dihydro - 2 - (V - dimethyl amino/ethylidene - 6 (r2 - phenyl) - 4H - imidazo 01,2 - jTJ01,^benzodiazepin - 1 one lb. 57. A process as claimed in claim 56, in which the reaction with the acetamide VII is carried out in an anhydrous organic solvent. 58. A process as claimed in claim 57, in which the solvent is methylene chloride. 59. A process as claimed in any of claims 56 to 58, in which the reaction with the acetamide VII is effected at a temperature below 10°C. 60. A process as claimed in any of claims 56 to 59, in which the reaction with the acetamide VII is effected in the presence of a condensation promotor. 61. A process as claimed in claim 60, in which the condensation promotor is phosphorus oxychloride. 62. A process as claimed in any of claims 51 to 61, in which the imidazo!obenzodiazepine starting material V is prepared by reacting a corresponding 2-carboxy methylamino- or 1 2 2 - alkoxy - carbonylmethylamino - 7 - R -5-(R - phenyl) 3H - 1,4 - benzodiazepine IV (wherein R represents a hydrogen atom or an alkyl radical) with a dehydrating agent to give the desired product. 63. A process as claimed in claim 62, in which the dehydrating agent is a carbodiimide. 64. A process as claimed in claim 63, in which the carbodiimide is dicyclohexylcarbodiimide. 65. A process as claimed in any of claims 62 to 64, in whichthe reaction is performed in methylene chloride. 66. A process as claimed in any of claims 62 to 65, in which the benzodiazepine starting material IV is prepared by reacting a 7 - R^ - 1,3 - dihydro - 5 - (R 2 - phenyl) - 2H 1,4 - benzodiazepin - 2 - thione II with glycine or an alkyl ester thereof III to give the desired product. 67. A process as claimed in claim 66, in which the reaction is carried out in an organic solvent. 68. A process as claimed in claim 67, in which the solvent is ethanol. 69. A process as claimed in any of claims 66 to 68, in which the reaction is effected at the boiling temperature of the reaction mixture. 70. A process for the preparation of a compound of general 44. 4 5 formula I wherein R and R are as defined in claim 1 except that they do not both represent a methyl radical, in which a 2 - (dimethylamino)methylene - imidazolobenzodiazepin - 1 - one Ia_ or a 2 - 0Γ - dimethylaminojethylidene - imidazolobenzodiazepin - 1 - one lb is transaminated, by reaction with an amine VIII 4 5 (wherein R and R are as defined in claim 1 except that they 5 do not both represent a methyl radical) to give the desired 8 -. R 1 - 1,2 - dihydro - 2 - (substituted amino)methy1ene- or 8-R 1 - 1,2 - dihydro - 2 - (1 1 - substituted ami no) ethyl i dene 6 - (R 2 1 phenyl) - 1H,4H - imidazo - 0,2 - aj[l,4j benzodiazepin - 1 one l£ or Id, wherein R 4 and R 5 are just as desired. 10 71. A process as claimed in claim 70, in which the reaction with the amine VIII is carried out in an anhydrous organic solvent. 72. A process as claimed in claim 71, in which the solvent is toluene. 73. A process as claimed in any of claims 70 to 72, in which 15 the reaction is effected at the boiling temperature of the reaction mixture. 74. A process as claimed in any of claims 70 to 73, in which the imidazolobenzodiazepihe starting material la or IJo is prepared by a process as claimed in any of claims 52 to 69. 20 75. A process for the preparation of a compound l£ or M wherein and Rg form with the conjoined nitrogen atom a Rg - piperazin-l-yl radical, wherein Rg represents a cycloalkylalkyl radical, an alkenyl radical or a 4-dialkylphosphinylalkyl radical, in which a compound Ic or Id wherein and Rg form a 25 piperazin -1-yl radical with the conjoined nitrogen atom, is reacted with a halo-Rg compound to form the desired product. 76. A process for the preparation of a compound Ic or Id 4 5 wherein R and R form, together with the conjoined nitrogen atom, a 4 - di alkylphosphinylalkylpiperazin - 1 - yl radical, in which a 4 5 compound Ic or Id, wherein R and R form a piperazin - 1 - yl radical with the conjoined nitrogen atom, is reacted with a haloalkyldialkylphosphine oxide to form the desired product. 77. A process as claimed in claim 76, in which the haloalkyldialkylphosphine oxide used is a chloroalkyldialkylphosphine oxide. 78. A process as claimed in claim 76 or claim 77, in which the reaction is carried out in an organic solvent. 79. A process as claimed in claim 78, in which the organic solvent is toluene. 80. A process as claimed in any of claims 75 to 79, in which the starting material of general formula Ic or hl wherein R 4 and R 5 form, with the nitrogen atom, a piperazin - 1 - yl radical is prepared by a process as claimed in any of claims 70 to 74. 81. A process for the preparation of an acid addition salt of an imidazolobenzodiazepine of general formula I, in which an imidazolobenzodiazepine I is reacted, in substantially stoichiometric proportions, with a mineral or organic acid to form the desired acid addition salt. 82. A process as claimed in claim 81, in which the reaction is effected in an organic solvent or a mixture of organic solvents. 83. A process as claimed in claim 82, in which the reaction is effected in methanol, ethanol or methylene chloride. if84. A process as claimed in any of claims 81 to 83, in which the imidazolobenzodiazepine I is prepared by a process as claimed in any of claims 51 to 80. 85. A process as claimed in any of claims 51 to 84 and substantially as described hereinbefore, with reference to the Examples. 86. An imidazolobenzodiazepin - 1 - one I, or an acid addition salt thereof, whenever prepared by a process as claimed in any of claims 51 to 85. 87. A pharmaceutical composition containing one or more imidazolobenzodiazepin - 1 - one I, or a pharmaceutically-acceptable acid addition salt thereof, as claimed in any of claims 1 to 50 and 86, in association with a suitable pharmaceutical vehicle. 88. A pharmaceutical composition containing one or more imidazolobenzodiazepin - 1 - one I, or a pharmaceutical-acceptable acid addition salt thereof, as claimed in any of claims 17 to 22, in association with a suitable pharmaceutical vehicle. 89. A pharmaceutical composition containing one or more imidazolobenzodiazepin - 1 - one I, or a pharmaceutically-acceptable acid addition salt thereof, as claimed in any of claims 28, 29, 31 to 34, 36 and 47, in association with a suitable pharmaceutical vehicle. 90. A pharmaceutical composition containing 8 - nitro - 1,2 - dihydro 2-(4- methylpiperazin - 1 - yl)methylene - 6 - (o - chlorophenyl) 4H - imidazo£l,2 - j00,4] benzodiazepin - 1 - one methanesulphonate, in association with a suitable pharmaceutical vehicle. 91. A composition as claimed in any of claims 87 to 90, wherein the pharmaceutical vehicle is:64 a) the ingestible excipient of a 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 5 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 function, which base material when appropriately shaped forms a suppository. 92. A composition as claimed in claim 91, wherein the vehicle is talc, gum arabic, lactose, starch, an animal or vegetable fat, magnesium stearate, or cocoa butter, or water, an animal or vegetable oil, a paraffin derivative, or a glycol. 93. A composition as claimed in any of claims 87 to 92, which is in unit dose form and contains from 0.5 to 20 mg active ingredient. 94. A composition as claimed in any of claims 87 to 93, and substantially as described hereinbefore, with reference to the Formulations.
IE298/76A 1975-02-15 1976-02-13 1,2-dihydro-4h-imidazo/1,2-a/ /1,4/benzodiazepin-1-ones,prcess for their preparation,and compositions incorporating them IE43791B1 (en)

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NZ179990A (en) 1978-06-02
FI62090C (en) 1982-11-10
CH613706A5 (en) 1979-10-15
YU42471B (en) 1988-10-31
LU74341A1 (en) 1976-12-31
IE43791L (en) 1976-08-15
NO760468L (en) 1976-08-17
CA1073454A (en) 1980-03-11
NO146201C (en) 1982-08-18
MX3327E (en) 1980-09-29
NL171585B (en) 1982-11-16
AU1113776A (en) 1977-08-25
IL48888A (en) 1979-03-12
IL48888A0 (en) 1976-03-31
PH14669A (en) 1981-10-30
PT64796A (en) 1976-03-01
DK141250B (en) 1980-02-11
DE2605652C2 (en) 1987-08-20
YU34576A (en) 1984-12-31
PH16286A (en) 1983-09-02
PT64796B (en) 1978-02-06
CH618171A5 (en) 1980-07-15
FR2300569A1 (en) 1976-09-10
EG12462A (en) 1979-06-30
FR2300569B1 (en) 1979-09-21
DK141250C (en) 1980-08-04
ES445188A1 (en) 1977-09-16
FI760347A (en) 1976-08-16
DK58776A (en) 1976-08-16

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