FI62090B - PROCEDURE FOR THE FRAMSTATION OF 1,2-DIHYDRO-6-PHENYL-1H, 4H-IMIDAZO (1,2-A) (1,4) BENZODIAZEPIN-1-ONER WITH A NETWORK FOR NERVOUS SYSTEM - Google Patents

Description

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e (45) Patent granted 10 11 1932 Patent sr Melat (51) Kv.lk?/lnt.a.3 C 07 D 4-87 / 04- FINLAND — FINLAND (JM) Patent application — Patent * 6knln | 760347 (22) Htkemltpilvl - AfMttknlnpdtg 12.02.76 ^ ^ (23) Alkuptlvi - Glltl | hMsdt | j2 02 ^ 6 (41) Interpreters for the Public - Ulvlt offemllg Qg vg ^ Board of Examiners and Registers ... .........,, '1 _ * (44) Date of publication of the deliberation | ΛΓΙ

Patents and registries '' Amekan utiagd och uti.skHfun pubticersd 30.07. o2 (32) (33) (31) Pyydattr «uoikrni. — B« | ini priority 15 - 02.73 04.11.75 England-England (GB) 6509/75, 45800/75 (71) Roussel-Uclaf, 35, Boulevard des Invalides, F-75007 Paris, France-

Frankrike (FR) (72) John Bodenham Taylor, no. Cirencester, Gloucestershire, Derek Ralph Harrison, Swindon, Wiltshire, England-England (GB) (74) Oy Ant-Wuorinen Ab (54) Method for the treatment of central nervous system 1,2-dihydro-6-phenyl-1H, 4H-imidazo (l , 2-a) for the preparation of (1,4) benzodiazepin-1-ones - For the preparation of 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepines The onset of the network is central to the nervous system

The invention relates to a process for the preparation of pharmaceutically active 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-ones for human or veterinary use, having the general formula is 3 ^

vN

XLj! _ R2 2 62090 wherein R represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, 2 R which may be in an arbitrary position of the phenyl ring means a hydrogen atom or a halogen atom, R 1 represents a hydrogen atom or a methyl group, and either R 5 and R which may be identical or different, each represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl group in which the alkyl moieties each contain 1 to 5 carbon atoms, a phenyl or naphthyl group or a cycloalkyl group having 3 to 8 carbon atoms R or R together with the nitrogen atom denote morpholine, thiomorpholine, piperidino or piperdino substituted by 4-oxo-1-phenyl-2-imidazolin-5-yl, or piperazin-1-yl or piperazin-1-yl which substituted in the 4-position by an alkyl group, a hydroxyalkyl group having 1 to 5 carbon atoms in the alkyl group, a cycloalkyl group in which the cyclo the alkyl moiety has 3 to 6 carbon atoms and the alkyl moiety has 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a phenyl group or a dialkylphosphinylalkyl group having 1 to 5 carbon atoms in the alkyl moiety, and acid addition salts thereof.

When R represents a halogen atom, it is preferably a chlorine atom.

2

When R represents a halogen atom, it is preferably a fluorine atom or a chlorine atom. In addition, the halogen atom R is preferably in the ortho position.

3 R is preferably a hydrogen atom.

4 5

When either R or R represents an alkyl radical, this is preferably a methyl, ethyl, n-propyl, n-butyl or t-butyl radical.

4 5

When either R and R represents a hydroxyalkyl radical, the alkyl group is preferably an ethyl radical.

4 5

When either R and R represent an aminoalkyl or alkyl and aminoalkyl radical (the latter term meaning both monoalkyl and dialkylaminoalkyl), each alkyl

3 b2U * U

4 5

the group is preferably a methyl or ethyl radical. R and / or R

preferably represents an amonomethyl, aminoethyl, dimethylaminoethyl or diethylaminoethyl radical, but may also mean an aminopropyl, aminobutyl, methylaminomethyl, methylaminoethyl or dimethylaminopropyl radical.

4 5

Of the aryl radicals R and R, the phenyl radical is more preferable.

4 5

When either R and R represents a cycloalkyl radical, this is preferably a cyclohexyl radical.

R 5 and R 5 may be the same, for example methyl groups, or different, and when they are different one of them is preferably hydrogen.

4 5

When R and R together with an adjacent nitrogen atom form a heterocyclic group, typical examples of such groups are 4-alkyl-piperazin-1-yl and especially 4-methyl-, 4-ethyl- and 4-propyl-piperazin-1-yl; 4-hydroxyalkyl-piperazin-1-yl and especially 4-hydroxyethyl-piperazin-1-yl; 4-dialkylphosphinylalkyl-piperazin-1-yls and especially 4-dimethylphosphinylmethyl-piperazin-1-yl; 4-cycloalkylalkyl-piperazin-1-yls and especially 4-cyclopropylmethyl-piperazin-1-yl; 4-alkenyl-piperazin-1-yl and especially 4-allyl-piperazin-1-yl; 4-phenyl-piperazin-1-yl; and 4- (1'-phenyl-5'-imidazoyl-4'-one) -piperidin-1-yl.

Within the scope of general formula I, the following smaller groups of compounds are preferred: a) imidazolobenzodiazepines of general formula I, in which either R and R, which may be identical or different, each denote a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms, a hydroxyethyl radical, a dimethyl or diethylaminoethyl radical, a phenyl radical, or a cyclohexyl radical, or 4 R and R together with the adjacent nitrogen atom form piperidino, morpholine, thiomorpholine, piperazin-1-yl, 4-alkylpiperazin-1-yl hydroxyalkyl-piperazin-1-yl, 4-phenyl-piperazin-1-yl or 4- (1 * -phenyl-5'-imidazolyl-41-one) -piperidin-1-yl; b) imidazolobenzodiazepines of the general formula I in which 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 R, which may be the same or different, each 4 62090 denotes a hydrogen atom, a direct alkyl radical having 1 to 5 carbon atoms, a hydroxyethyl radical, a phenyl radical, a cyclohexyl radical or R and R together with a nitrogen atom form piperidino, morpholino, piperazin-1-yl, 4-alkyl piperazin-1-yl or 4-hydroxyethyl-piperazin-1-yl radical, c) imidazolobenzodiazepines of the general formula I, in which R represents a chlorine atom or a nitro radical, R represents a hydrogen, chlorine or fluorine atom, RJ represents a hydrogen atom , and either R 5 represents a hydrogen atom and R represents a methyl, ethyl, propyl or butyl radical, or R and R together with the nitrogen atom form piperazin-1-yl, 4-methylpiperazin-1-yl the radical 1-, 4-ethyl-piperazin-1-yl, 4-propyl-piperazin-1-yl or 4-hydroxyethyl-1-piperazin-1-yl; d) imidazolobenzodiazepines of the general formula I, in which 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 R and R together with the nitrogen atom form 4-methylpiperazine-1 a yl, 4-ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl radical; e) imidazolobenzodiazepines of the general formula I, of which 1 2

sa R represents a hydrogen atom, a chlorine atom or a nitro radical, R

3.4.5 a hydrogen atom, a chlorine atom or a fluorine atom, R a hydrogen atom and R 3a R together with a nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl radical; and f) imidazolobenzodiazepines of the general formula I, of which 1 2

sa R represents a hydrogen atom, a chlorine atom or a nitro radical, R

3 4 5 represents a hydrogen atom or a chlorine atom, R represents a hydrogen atom and R and R together with the nitrogen atom form a 4-dimethylphosphinylmethyl-piperazin-1-yl radical.

The imidazolobenzodiazepines of the formula I may be in the form of acid addition salts and these may be salts with mineral or organic acids. Typical mineral acids include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids, and typical organic acids include acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic -, glyoxyl, aspartic, alkanesulfonic and arylsulfonic acids. Preferred acid addition salts are tartrates and alkanesulfonates, and in particular methanesulfonates.

Preferred compounds of formula I are their acid addition salts

62090 I

5 are also as follows: g) acid addition salts of imidazolobenzodiazepines of the general formula I / in which R represents a hydrogen atom, 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 R and R together with a nitrogen atom form a 4-alkyl-piperazin-1-yl radical; h) tartrates and alkanesulfonates (especially methanesulfonates) of imidazolobenzodiazepines of the general formula I, in which R represents a chlorine atom or a nitro radical, R represents a hydrogen atom 3 4 5 or a chlorine atom, R represents a hydrogen atom and R and R together with a nitrogen atom form a 4-methyl-piper yl or 4-ethyl-piperazin-1-yl radical.

In particular 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo (1,2-a) (1, 4) Benzodiazepine-1-one methanesulfonate has been shown to have particularly remarkable pharmacological activity.

The imidazolobenzodiazepines of the general formula I can preferably be prepared starting from the corresponding 2-unsubstituted compounds and these in turn can be prepared from the corresponding 2-alkoxycarbonyl or 2-carboxymethylaminobenzodiazepines.

These methods are shown in the reaction schemes of the accompanying drawing, and are explained in the following. In this specification, Roman numerals refer to the general formulas shown in the reaction schemes, and each group of substituents has the same meaning as above.

According to the present invention, compounds of general formula I can be prepared by reacting a compound of formula II / (V) u 1 x __h2 6 62090 1 2 wherein R and R are as defined above with either dimethylformamide acetal of formula ( AlK-O) 2 = CH - N = (CH3) 2 (VI) wherein AlK represents a lower alkyl group having 1 to 5 carbon atoms, 8-R'-1,2-dihydro-2- (dimethylamino) methylene- For the preparation of 6- (R-phenyl) -1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one of the formula ^ CH2-ch. · "

X cti5 \ J

-N- ^, ΧΧ-> fXT, Π ir 12 wherein R and R are as defined above, and the resulting compound of formula (Ia) is optionally salified or transaminated by reaction with a suitable amine of formula .R 4 H - N (VIII) \ r 4 4 5 wherein R and R are as defined above, provided that they do not both represent a methyl group, to prepare the desired compound of formula

II - C -N ^ C

il 7 62090 12 4 5 wherein R, R, R and R are as defined above, provided, however, that R and R do not both represent a methyl group, which compound is optionally converted into a salt, or the above compound of formula (V) is reacted with N- with dimethylacetamide of the formula? H3 / CH3 O = C - N (VII)

Xch3 to form the corresponding compound of formula ^ CH „CH - C - N y 3 11 ^ CH„ ro - '--Ή [^ -jj- R "1 2 wherein R and R are as defined above and the formula (Ib ) is optionally either salified or transaminated by reacting it with a suitable amine of formula .R 1 H - N,. (VIII) ^ R2 5 2 wherein R and R have the same meaning as above, except that both do not represent a methyl group, to give the desired compound of formula 8 w S kj ^ R, i

CIT .. - c. - N

"^ n5, Λ X, /

R1 "Y = -N

r> 2 -I— *

Ax 12 4 5 where R, R, R and R have the same meaning as above, except that 4 5 R and R do not both represent a methyl group, and optionally, 1 2 3

if desired to prepare a compound of formula I wherein R, R and R

4 5 has the same meaning as above and R and R together with the nitrogen atom form an R-piperazin-1-yl group in which R represents a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkyl moiety, or 2- An alkenyl group containing 5 carbon atoms, a compound of formula I in which R 5 and R together with a nitrogen atom form a piperazin-1-yl group is reacted with a suitable halo-R compound in which halo is a g halogen atom of the corresponding R to prepare a piperazin-1-yl compound, and if desired to prepare a compound of formula I wherein R and R together with the nitrogen atom form a 4-dialkylphosphinylalkyl-piperazin-1-yl group having 1-5 alkyl moieties. carbon atom, a suitable compound of formula I wherein R and R together with the nitrogen atom form a piperazin-1-yl group is reacted with the appropriate haloalkyl dialkylphosphine oxide of the corresponding formula I m for the preparation of a 2- (N-dialkylphosphinylalkyl-piperazin-1-yl) compound, and optionally converting the compound obtained in the process into a salt.

The reaction with the acetal VI is suitably carried out in an anhydrous organic solvent, for example arene such as benzene, and in the presence of a base (preferably a nitrogenous base such as an amine, for example triethylamine).

The reaction with acetamide VII is conveniently carried out in an anhydrous organic solvent such as a chlorinated alkane, for example methylene chloride, below room temperature (and preferably 9620 min below 10 ° C), and in the presence of a condensation agent, for example a halogenated derivative such as phosphorus oxychloride.

The reaction with the amine VIII is suitably carried out in an anhydrous organic solvent, for example an arena such as toluene, and at a high temperature which is preferably the boiling point of the reaction mixture. It is clear that when it is desired to prepare a compound of formula I in which R and R are both hydrogen, the compound VIII used in the trans-amination is ammonia itself.

The imidazolobenzodiazepines Ie or Id formed may, if desired, be further reacted to convert them to other compounds of general formulas Ie or Id; in particular, compounds in which R and R together with the nitrogen atom represent a heterocycle may be further reacted to introduce various substituents on the heterocyclic ring.

Preferred haloalkyl dialkyl phosphine oxides for use in further reactions of the process are chloroalkyl dialkyl phosphine oxides, and the reaction is preferably carried out in an organic solvent, for example an arene such as toluene.

The starting imidazolobenzodiazepine V can be prepared from a compound of formula R1 '. · /

^ J --- (ID

wherein R and R are as defined above, by reacting it with a compound of the formula C - CH - (III) R "° where R represents a hydrogen atom or an alkyl radical having 1 to 5 carbon atoms, to form a formula of 62090 1 o V- 11 \ a / op li! (TV) ...

Wherein R, R and R are as defined above, which is reacted with a dehydrating agent to form the desired compound of formula V.

The reaction of a compound of formula II with a compound of formula III is preferably carried out in an organic solvent, preferably an alcohol such as ethanol, and at a high temperature, which is preferably the boiling point of the reaction mixture.

The dehydrating agent that reacts with the acid IV is preferably a carbodiimide such as dicyclohexylcarbodiimide, and the reaction is preferably carried out in a chlorinated alkane such as methylene chloride. The pyrolysis of ester IV is preferably carried out in a high-boiling solvent such as arene, for example toluene.

The obtained compounds Ia, Ib, Ie and Id can be converted into salts by conventional methods. The invention also relates to a process for the preparation of acid addition salts of compounds of general formula I, wherein the appropriate compound Ia, Ib, Ie or Id is reacted in a substantially stoichiometric ratio with a suitable mineral or organic acid to form the desired acid addition salt.

The salt formation reaction is preferably carried out in an organic solvent or 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-1-ones of the formula I and their acid addition salts have very interesting pharmacological properties. In particular, they have remarkable sedative, hypnotic, analgesic, sedative, anticonvulsant and muscle relaxant properties, as shown in the following test report: ,, 62090

Experimental Description 1) Anti-Aggressive Activity in Mice (AAM) Groups of 20 arbitrarily selected male mice (weight 25-30 g, Tuck TO strain) were orally administered either vehicle alone (10 ml / kg distilled water) or vehicle and test compound. Thirty minutes after dosing, two mice were placed on a metal grid under an inverted Pyrex dish. The grating was connected to a Palmer square wave stimulator and the paws of mice were electrically stimulated with 90 volt pulses lasting 5 milliseconds at 2 pulses per second for 2 minutes. This procedure elicited combat reactions in control mice (the combat reaction here is an aggressive attack from the front, usually in the bite of one or the other mouse). The total number of attacks in the control group was calculated.

The ED50 of the test compound is the dose that reduces the number of attacks by 50% in the groups of mice receiving the test compound compared to the control group (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 electric shock in mice (AEM)

Groups of ten mice were orally injected with test compound in vehicle using different dosages (control group was given vehicle alone). Thirty minutes after dosing, each group was given electric shocks with auricular electrodes using an electric shock device (Ugo Basile ECT device for small mammals). The pulses had a pulse width of 0.2 milliseconds and a frequency of 100 Hz, and each shock was delivered for 0.2 s using a current of 55 milliamps.

The number of mice in which tonic stretching movements of the hind limbs were observed was determined. The dose that protected 50% of the mice (TED ^ q) compared to the control group was determined, and the results are shown in Table 3 below.

3) Anticonvulsant test against pentylenetetratol in mice (ALM)

Groups of ten mice were orally injected with the test compound in vehicle using varying doses, with the control group given vehicle alone. Thirty minutes after dosing, each mouse was administered subcutaneously 130 mg / kg of pentylenetetrazole stimulant (pentylenetetrazole is a central nervous system stimulant), and the mice were then placed in separate 2,62090 observation boxes. The number of mice in which tonic seizures were observed 30 minutes after administration of the pentylenetetrazole irritant was counted, and the results of the tonic phases were expressed as a percentage decrease in control values. A dose-response curve was constructed evaluating the doses that protected 50% of the mice (TED ^ q) against tone and is shown in Table 3 below.

4) Anticonvulsant test against strychnine in mice (ASM)

Groups of ten mice were orally administered the test compound and vehicle at varying dosages, with the control group receiving vehicle alone. Thirty minutes after dosing, each mouse was given subcutaneously 1 mg / kg of strychnine stimulus (strychnine is a central nervous system stimulant) and the mice were then placed in separate observation boxes. The number of mice in which tonic seizures were observed 15 minutes after strychnine administration was counted, and the results of the tonic phase were expressed as a percentage decrease in control values. A dose-response curve was constructed evaluating the doses that protected 50% of the mice (TED ^ q) against tone and are shown in Table 3 below.

5) Hexobarbital potentiation in mice (PHM)

A group of ten control mice was administered an ED2Q dose of hexobarbital intraperitoneally (150 mg / kg) (hexobarbital is a secular and hypnotic agent) followed orally by either vehicle alone or varying oral doses of vehicle and test compound. The number of mice in which the disappearance of the righting reflex was observed for 30 seconds half an hour after dosing was counted and a dose-response curve was plotted. The amount of test compound that caused the loss of the corrective reflex in 50% of the mice in the group (ED, - ^) was evaluated and the results are shown in Table 3 below.

6) Chlorprothixene potentiation in mice (PXM)

Groups of ten randomly selected CFLF male mice (Carworth Europe) weighing 20–25 g were administered chlorprothixene (12.5 mg / kg) intraperitoneally (chlorprothixene is a sedative and antipsychotic agent); this dose consistently caused a loss of righting reflex in 10% of mice 30 minutes after dosing. At the same time, experimental groups of mice were orally administered either vehicle alone (10 mg / kg distilled water) or a dose of vehicle and test compound. Each mouse was then placed separately in a small observation chamber and the loss of righting reflex was monitored 30 minutes after dosing.

The ED50 of the test compound is the dose that causes the loss of the righting reflex in 50% of the mice in the group in which, in the absence of oral treatment, no loss of the righting reflex would be expected. The results are shown in Table 3 below.

7) "Rotating knot" * - test in mice (RDM)

Groups of ten mice were orally injected with vehicle and test compound in varying doses while the control group was given vehicle alone. Thirty minutes after dosing, each group of mice was placed on a 30 cm diameter rotating drum rotating at 1 rpm. Mice were placed on the drum in the opposite direction to this direction of rotation, and mice dropped from the drum during the 2-minute experimental period were counted. From the results obtained, a dose-response curve was constructed and the dose that caused 50% of the mice to fall out of the drum (ED ^ q) was evaluated. The results are shown in Table 3 below.

8) Acute toxicity in mice (ATM)

Acute toxicity when administered orally and intraperitoneally was determined using groups of ten mice and varying dose levels. Mortality in the groups was determined after 24 hours and the results are shown in Table 3 below, expressed in mg / kg.

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The results show that the compounds according to the invention have a very significant activity on the central nervous system as anticonvulsants, analgesics and hypnotic sedatives and that they have a very low toxicity.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments for acceleration! to treat conditions of irritation, aggression, insomnia, certain psychosomatic syndromes, certain disorders of character and behavior, and certain convulsions or muscle contractions.

However, before the compounds of formula I and their pharmaceutically acceptable acid addition salts are used in medicaments, they should preferably be formulated into pharmaceutical compositions by combining them with suitable pharmaceutical carriers.

This phrase "pharmaceutical" used precludes the possibility that the carrier composition, given the dosage, could be more harmful than beneficial. Suitable dosage forms, together with suitable carriers, will be apparent to those skilled in the art.

The compounds of formula I may be used in the preparation of pharmaceutical compositions containing one or more imidazolobenzodiazepin-1-ones I, or a pharmaceutically acceptable acid addition salt thereof, in association with a suitable pharmaceutical carrier.

62090 1 6 These compositions may be administered orally, transcutaneously or rectally, and the pharmaceutical carrier is preferably: a) an edible carrier for a tablet, coated tablet, sublingual tablet or pill; capsule edible shell; powdered solid carrier edible powder component; or an edible liquid medium of a syrup, solution, suspension or elixir.

b) a sterile injectable liquid solution or suspension medium; or c) a low melting point matrix from which the active ingredient is released to perform its pharmacological function, which base material, suitably shaped, forms a suppository.

The carrier may be a solid (such as talc, acacia, lactose, starch, animal or vegetable fat, magnesium stearate or cocoa butter) if necessary, or it may be an aqueous anhydrous liquid (such as animal or vegetable oil, paraffin derivative or glycol). ). S. = may, if desired, contain wetting, dispersing or emulsifying agents and preservatives.

Although the uses listed above are the most likely, they do not take advantage of all possibilities.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are preferably administered in the form of tablets, injectable solutions or suspensions in unit ampoules or multidose vials, and in the form of a suppository.

Although the dose of the pharmaceutically active ingredient depends to some extent on the mode of administration of the composition, it is generally mentioned that a useful dose is 1 mg to 50 mg of active ingredient per day for an adult, with a unit dose containing 0.5 to 20 mg of active ingredient.

1/2-Carboxymethylamino-7-R -5- (R '-phenyl) -311-1,4-benzodiazazine II and the corresponding 2-alkoxycarbonylmethylamino-7-R'-5-yl ~ -phenyl) -3II-1,1-benzodiazepines IV in which the alkyl group P is other than an ethyl group are novel compounds.

The following examples, compositions and test results illustrate the invention.

Example 1: 8-Chloro-1,2-dihydro-2- (dimethylamino) -methyl-6-phenyl-3H-1H-iridazo [1,2-47] -1,3-benzodiazepine-1 -one (Ia)

Step A: 2-Carboxyl methylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (IV).

17 62090 7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-L-thione II (3.5 g), glycine III (3.3 g) and sodium carbonate (5.5 g) was suspended in ethanol (100 ml) and water (30 ml) and quenched and refluxed for 1 hour. The suspension was then poured into water to form a clear solution, which was oxidized with 2N hydrochloric acid to pH and extracted with chloroform. Slightly solids separated from the extracts, which were filtered off.

The organic layer was dried (magnesium sulfate) and evaporated to give a gum which crystallized on trituration with methanol. This solid, as well as the above-mentioned filtered solid, was crystallized from a large amount of ethanol to give 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3.1 g (77%), m.p. p. 215-220 ° C.

Step B: 8-Chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-f] 7 / 1,4,7-benzodiazepin-1-one (V) 2-carboxymethylamino -7-Chloro-5-phenyl-3H-1,4-benzodiazepine IV (2.3 g) was suspended in dry dichloromethane (120 ml), stirred and dicyclohexylcarbodiimide (2.1 g) was added. The suspension was stirred at room temperature for 3 hours, filtered and the filtrate evaporated to give 8-chloro-1,2-dihydro-6-phenyl-11,4H-imidazo [1,4] benzodiazepin-1-one V as a colorless oil. in the form used as such in the following step:

Step <3: 8-Chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4] benzodiazepin-1-one (Ia)

The 8-chloro-1,2-dihydro-6-phenyl-1H, 411-imidazo [1,2-a] 1,4 / 4-benzodep sepin-1-one V obtained from Step B above was dissolved in dry benzene and dimethylformamide-diethylacetal VI (1.5 g) and triethylamine (1 ml) were added. The solution was stirred at room temperature for 1.5 hours and then evaporated to a brownish-yellow residue. Recrystallization from ethyl acetate / m ethanol gave pale yellow rod-like crystals of 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidate. m.p., 2-q // 1,4-benzodiazepin-1-one Ia, 2.7 g (97%), m.p. 264-5 ° C. Analysis: CH 2 Cl 2 / N (O = 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 »Spectrum (KBr plate): C = O 169 cm-1; C = N 1621 cm -1.

18 62090

Examples 2-6: Using the same procedure as in Example 1, the following compounds IV, V and Ia were prepared:

Example Compounds 2. Compound IV: 2-Carboxymethylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine.

Compound V: 8-Nitro-1,2-dihydro-6-phenyl-1H, 1H-imidazo [1,2-a] [1,7] benzodiazepin-1-one

Compound Ia: 8-Nitro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-c] benzodiazepin-1-one.

3. Compound IV: 2-carboxymethylamino-7-chloro-5-o-chlorophenyl-3H-1,4-benzodiazepine.

Compound V: 8-Chloro-1,2-dihydro-6-o-chlorophenyl-1H, imidazo [1,2- a] [1,1'-benzodiazepin-1-one

Compound Ia: 8-Chloro-1,2-dihydro-2- (dimethylamino) -methylene-6-o-chlorophenyl-1H, 4H-imidazo [1,2- b] 1H, benzodiazepine-1- one.

* 1. Compound IV: 2-Carboxymethylamino-7-nitro-5-o-chlorophenyl-3H-1H-benzodiazepine.

Compound V: 8-Nitro-1,2-dihydro-6-o-chlorophenyl-1H, 4H-imidazo [b, f] benzodiazepin-1-one.

Compound Ia: 8-Nitro-1,2-dihydro-2- (dimethylamino) methylene-e-o-chlorophenyl-1H-H-imidazo [1,2-a] -1,17 benzodiazepin-1-one.

3. Compound IV: 2-Carboxymethylamino-7-chloro-5-o-fluorophenyl-1H-3β-1,4-benzodiazepine.

Compound V: 8-Chloro-1,2-dihydro-6-o-fluorophenyl-1H, 4H-imidazo [1,2- a] 73, benzyl azepin-1-one.

Compound Ia: 8-Chloro-1,2-dihydro-2- (dimethylamino) methyl- [8-O-fluorophenyl-1H, 4H-imidazo [2,3-b] benzodiazepin-1-one.

6. Compound IV: 2-Carboxymethylamino-7-nitro-5-o-fluorophenyl-3H-1,1-benzodiazepine.

Compound V: 8-Nitro-1,2-dihydro-6-o-fluorophenyl-1H, thiol imidazo [1,2- b] -1H-benzodiazepin-1-one.

Compound Ia: 8-nitro-1,2-dihydro-2- (dimethylamino) methylene

ni-6-o-fluorophenyl-1H, midazo [1,2-a] E X

benzodiazepin-l-one.

19 62090

In each case, compound UI was glycine, compound VI. dimethylphenyldiethylacetal, compound V was used without further purification and the solvent of compound Ia was methyln-1i. The characteristics of these compounds (excluding compounds V) are summarized in the following table.

Table 1

Compound IV Compound Ia —NR R 2 is a dimethylamino symbol Yield1; sul.pV ^ C Crystallization solvents in R1 "] R2 Yield1;! sul.p.i

__L ___________ ° c I

2 66 15't-5 MeOH NOo H h3 277-8 [3 75 136-9 MeOH-Et2O Cl o-Cl 73 l83-v) j 83 I58-6I Et2O NCb od? 8: 2 5 3-- j 5 69 rubber - Cl oF 63 257-60 6 V i - Et 2 O NOo o-F 80 2 2 8-51 |

Example 7: 8-Chloro - (dimethylamino) -ethylene / 1,2-dihydro-6-phenyl-1H, 1H-imidazo [1,2-a] [1,7] benzodiazepin-1-one (Ib) 8-Chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,1 '] benzodiazepin-1-one V, prepared as described in Example 1, Step B, was dissolved in dry methylene chloride (200 mL). ) together with dimethylacetamide VII (2.0 g). The solution was cooled to 0 ° C and phosphorus oxychloride (3 x 7 g) was added dropwise over 5 minutes while stirring thoroughly. The solution was then stirred at room temperature for over 20 hours and poured into saturated sodium carbonate solution (500 mL). The mixture was stirred until the formation of carbon dioxide 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 sodium bicarbonate solution and water, dried (magnesium sulfate), and evaporated to a yellow solid. Crystallization of this solid from chloroform / ether gave 8-chloro-2/1 '- (dimethylamino) ethylene-1,2-dihydro-6-phenyl-β, 1,2H-imidazo [1,2-a] [1,2'] benzodiazepine. -1-one Ib, 2.3 g ('; 0%), m.p. 251-2 ° C.

20 6 2 0 9 0

Annjyy.si: c:> ini9Cl N / (O = 578.9

Calculated: C% 66.58 H% 5.02 N% 14.79 Cl 2 (, 9.58

Found: 66.32 4.91 14.77 9.02 l.R, Spectrum (Kbr plate): CL O 1653 cm-1; Example 16: 8-Chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] * 4 / benzodiazepin-1-one (Ic), and its tartrate 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-b] [1,4] benzodiazepin-1-one Ia (obtained as in Example 1, Step C) (2.3 g) and N-methylpiperazine (4.0 g) were stirred under reflux in dry toluene (90 ml) for 24 hours. Upon cooling, crystals separated which were filtered. Evaporation of the solvent gave a pale yellow solid which was treated with methanol and filtered. Both batches of solids were combined and recrystallized from methanol / ethyl acetate to give 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) -motylene-6-phenyl-ΙΗ, 4H -im.idat so / ΐ, 2-a7 / l, 47'-benzodiazepin-1-one-B Ic 2.3 K (δ75 Å), m.p. 255-6 ° C.

Analysis: c2 HOJJCl N2O = 419.9

Calculated: C% 65.80 K% 5.24 N% 16.69 Cl% 8.46

Found: 65.64 5.27 16.63 8.56 l.R. Spectrum (Kbr plate): OO 1705 cm-1 ·, CN I635 cm-1B) 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) -methylene-6-phenyl The 1H-tartrate salt of 1H-4H-imidazo [1,2-b] f] -4 / benzodiazepin-1-one was prepared by adding a stoichiometrino amount of tartaric acid in methanol to 8-chloro-1,2-dihydro-2- (N-methylpiperazine). -i-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2- a] [3,47] benzodiazepin-1-one in Ic. The crude salt formed was crystallized from methanol to give the desired product, m.p. 146-150 ° C.

Analysis: C 12 H 12 ClCl 3 / O = - * 70.1

Calculated: C% 56.89 H * 4.92 N ° / o 11.29 Cl% 6.23

Found: 56.44 4.93 11.79 5.93 l.R. Spectrum (Kbr plate): OH 5400 cm-1 and 2500 cm-1; C = 0 1730 cm-1 and 1690 cm-1; C \ I63O cm J.

Examples 9-4 2/3213: In these examples, unless otherwise stated, the 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) -21,62090 methylene-6-phenyl-1H-Example 8 was prepared. 4H-imidazo [1,2-b] 1,4] benzodiazepin-1-one The corresponding compounds of the formula I, respectively:

Example Compound I

9. 8-Chloro-1,2-dihydro-2- (morpholine) -methylene-6-phenyl-1H, 4H-imidazo [1,2- b] 1,4] benzodiazepin-1-one, 1 () , 8-chloro-1,2-dihydro-2- (N-hydroxyethylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepine -1-one * 11. 8-Chloro-1,2-dihydro-2- (N-phenyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] // l, 4 / benzodiazepin-1-one.

12. 8-Chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chloro-phenyl) -1H, 4H-imidazo [1,2- α / 1,4-benzodiar-sepin-1-one.

12B 8-Chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-4] !, 47bentsodiat-SEPI-l-one-tartrate.

Method: According to Example 8B, 2 3. 8-Nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [2,2] -a7 / l, 4 / Bent sodiat sepin-1-one.

14. 8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methylene-6-phenyl-1,4H-imidazo-1,2-47 / 1,4 / benzodiazepin-1-one.

13. 8-Chloro-1,2-dihydro-2- (n-butylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-b] [1,4] benzodiazepine-1-yl one.

16. 8-Chloro-1,2-dihydro-2- (piperidino) -methylene-6-phenyl-1,4,4H-imidazo [1,2-4] [1,47b] tothia sepin-1-one .

17. 8-Chloro-1,2-dihydro-2- (thiomorpholine) -methylene-6-phenyl-11,4H-imidazo [1,2- b] 1,4] benzodiazepin-1-one.

18. 8-Chloro-1,2-dihydro-2- (diethylaminoethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2- b] 1,1-benzodiazepin-1-one.

19. 8-chloro-1,2-dihydro-2- (N-methyl-N- (dimethylamino) ethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-47] 1, / (7-benzodiazepin-1-one.

20. 8-Chloro-1,2-dihydro-2- (methylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one.

21. 8-Chloro-1,2-dihydro-2- (cyclohexylamino) -methylene-6-phenyl-1,4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one.

22. 8-Chloro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H, 4H-imidazo [1,2-a] / l, /] 7bent sodiat sepin-1-one.

22 6 2 0 9 0 8-Chloro-1,2-dihydro-2- (1'-phenyl-51-imidazol-4'-one) -piperidin-1-yl} -methylene-6-phenyl-1H, 4H-imidazo {2, 2-o7 / 3 i 'i / bonzodiazepin-1-one.

24. 8-Chloro-1,2-dihydro-2- (phenylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-b] [1,4] benzodiazepin-1-one, 25. 8 -Chloro-1,2-dihydro-2- (t-butylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] [X,4] benzodiazepin-1-one, 26. 8-chloro-1 , 2-Dihydro-2- (hydroxyethylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,2- b] -1H-benzodiazepin-1-one.

2 7. 8-Clone-1,2-dihydro-2- (n-propylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,1'-Bent sodiat sepin-1-one.

28. G-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -3H, 4H-imidazo [1,2-a] [1] , (i) benzodiazepine-1-one.

29. 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H, 4H-imidazo [1,2-a] [1], 27-benzodiazepin-1-one.

50. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -methylene-G-phenyl-1H-1H-imidazol-1 H -benzodiazepine-1- oni.

30B 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -1H-ethylene-G-phenyl-1H, 4H-imidazo2lt2-a7 / 1,47benzodiazepin-3-one -tartrate.

Method: Example 8b, respectively 31. 31. 8-Chloro-1,2-dihydro-2- (N-propyl-piperazin-1-yl) -N-ethylene-6-phenyl-1H, 4H-imidazo [2,2-a] 2H ybent.sodiazepin-1-one.

32. 8-Chloro-N, N-dihydro-2H-N- (n-butyl) -piperazin-1-yl

n.ethylene - (> - phenyl-1H, 4H-imidazole, 2-α7Z1,4-benzodiazepin-1-one.

3 3. 8-Chloro-1,2-dihydro-2- (N-allyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] [1,47] benzodiazepine -L-one.

Method: Corresponding to Example 45 34. 8-Chloro-1,2-dihydro-2- (N-cyclopropylmethyl-piperazin-1-yl) -methyl] -6-phenyl-111,4H-imidate -J, 4 / benzodiazepin-1-one.

23 62090

Method: According to Example 45 55. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1], 2-7% X% benzodiazepin-1-one.

36. 8-Chloro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H-4H-imidazo [1,2-a] i, hj benzodiazepin-1-one.

37. 8-Nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] , hj benzodiazepin-1-one.

38. 8-Nitro-1,2-dihydro-2- (N-ethyl-piperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H, 1H-imidazo [1,1] α7 / l, J and benzodiazepin-1-one.

39. 8-Chloro-1,2-dihydro-2- (ethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2- b] 4,7-benzodiazepin-1-one.

40. 8-Chloro-1,2-dihydro-2- (N-propyl-piperazin-1-yl) -methylene-6-o-chlorophenyl-1H, 4H-imidazole, 2-yl benzodiazepin-l-one.

h 1. 8-Chloro-1,2-dihydro-2- (ethylamino) -methylene-6-O-chlorophenyl-1H, 4H-imidazo [1,2- b] 771,47 benzodiazepin-1-one.

h 2. 8-chloro-1,2-dihydro-2- (n-propylamino) methylene-6-O-chlorophenyl-1H / 1H-imidazo [1,2-a] 1,4-benzodiazepin-1-one, 6 2 0 9 0 __24___

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Example 43: 8-Chloro-1,2-dihydro-2- (amino) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one.

8-Chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (Ί,4) benzodiazepin-1-one Ia (2.1 g ) was suspended in dry methanol (100 ml). The suspension was stirred, cooled in a dry ice / acetone bath and then bubbled with ammonia gas VIII for 15 minutes. The suspension was then warmed to room temperature and stirred for a further 2 days and the solvent was evaporated off. The solid residue was recrystallized from methanol / ethyl acetate to give 8-chloro-1,2-dihydro-2- (amino) methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1.4 ) benzodiazepin-1-one Ie, 1.9 g (98%), m.p. 265-7 ° C.

Analysis: C 19 H 19 Cl 2 N 2 O = 336.8

Calculated: C% 64.19 H% 3.86 N% 16.64 Cl% 10.54 Found 64.22 3.92 16.68 10.53 I.R. Spectrum (KBr plate): NH 3320, 3180 cm -1; C = O 1690, 1665 cm -1; C = N 1640, 1625 cm-Example 44: 8-Chloro-1,2-dihydro-2- (1- (N-methyl-piperazine) -ethylene) -6-phenyl-1H, 4H-imidazo (1,2 -a) (1,4) benzodiazepin-1-one.

8-Chloro-2- (1- (dimethylamino) ethylene) -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-a] (1,4) benzodiazepin-1-one Ib ( 2.3 g) and N-methylpiperazine VIII (15 ml) were stirred at 120 ° C under nitrogen for 9 hours. The cooled solution was then poured into water, sodium chloride was added to complete the precipitation and the brown precipitate was filtered, dissolved in chloroform, washed with water, dried (magnesium sulphate) and evaporated to give a dark red oil. the oil was crystallized by trituration with ether / methanol, and recrystallized from ethyl acetate to give 8-chloro-2- (1 '- (N-methylpiperazin-1-yl) -ethylene] -1,2-dihydro-6-phenyl- 1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one Id, 1.0 g (38%), mp 193-5 ° C.

Analysis: C24H24ClNgO = 434.0

Calculated: C% 66.43 H% 5.54 N% 16.14 Cl% 8.38 Found: 66.32 5.50 15.98 8.11 I.R. Spectrum (KBr plate): C = 0 1660 cm C = N 1615 cm 1.

29 62090

Example 45: 8-Chloro-1,2-dihydro-2- (N- (isopropyl) -piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) ( 1,4) benzodiazepin-1-one.

8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (Ί,2-a) (1,4) benzodiazepin-1-one (Example Compound 14 prepared as in Example 8) (1.5 g), isopropyl iodide (2.5 g) and sodium carbonate (2.0 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 (magnesium sulphate) and evaporated to a pale yellow solid. Reuse of this solid from ethyl acetate gave 8-chloro-1,2-dihydro-2- (N-isopropyl-piperazin-1-yl) -methylene-β-phenyl-1H-1H-imidazo-1,2-a) ( 1.4) benzodiazepin-1-one Ie, 1.2 g (73%), m.p. 146-8 ° C. Analysis: ^ 5 ^ 6 ^ 1 ^^ = 448.0

Calculated: C% 67.05 H% 5.89 N% 15.62 Cl% 8.14 Found: 66.71 5.94 15.90 7.92 IRS spectrum (KBr plate): δ = 0 1698 cm -1 1? C = N 1630 cm-1.

Example 46: 8-Chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzo-diazepin-1-one.

8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one ( the compound of Example 14 prepared as in Example 8) (2.5 g), chloromethylphosphine oxide (1.5 g) and sodium carbonate (5.0 g) was stirred at reflux in toluene (80 ml) for 3 days. The cooled suspension was partitioned between chloroform and water, the chloroform extract separated, dried (magnesium sulphate) and evaporated to a pale yellow oil which was crystallized from methanol. The solid (unnecessary by-product) was filtered off and the filtrate was evaporated to a light orange oil. This oil was dissolved in chloroform and chromatographed on Kiselgel 60. Elution with chloroform / methanol (5%) gave a pale yellow solid which was recrystallized from methylene chloride / ether to give 8-chloro-1,2-30 6 2 0 9 0 dihydro. 2- (N-Dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one Ic (1.25 g (41%), mp 261-2 ° C.

Analysis: C25H27ClN5PO2 = 496.1

Calculated: C% 60.54 H% 5.45 N% 7.16 Cl% 14.13 I.R. Spectrum (KBr plate): C = 0 1692 cm -1; C = N 1630 cm -1.

Example 47: 8-Chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo- (1,2- a) (1,4) benzodiazepin-1-one.

8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidaiso (1,2-a) (1,4) benzodiazepin-1 -one Ic (obtained according to the procedure described in Example 8) (850 mg), chloromethyldimethylphosphine oxide (1.0 g), sodium iodide (1.0 g) and sodium carbonate (2.0 g) were stirred while refluxing under dry cooling. in 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 a gummy solid. This was chlorographed on silica gel and eluted with chloroform to give a solid which was crystallized from methanol / ethyl acetate / ether to give 8-chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6- (o). -chlorophenyl) -1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one Ic, m.p. 231-4 ° C. I.R. Spectrum (KBr plate): C = 0 1700 cm -1; C = N 1630 cm -1.

Example 48: 1,2-Dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (Ί,4) benzodiazepin-1-yl one.

This compound was prepared according to the procedure used in Example 47 for 1,2-dihydro-2- (piperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepine-1 from Ic, which in turn was prepared according to the method described in Example 8.

Formed 1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-yl On 1 mp 245-7 ° C.

I.R. Spectrum (KBr plate): C = 0 1695 c, 11; C = N 1630 cm -1.

31 62090

Example 49: 8-Nitro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-piperazin-1-yl) -methylene-6- (ο-chlorophenyl) -1H, 4H-imidazo (1,2-a) ( Ί, 4) -benzodiazepin-1-one.

This compound was prepared according to the procedure used in Example 47 8-nitro-1,2-dihydro-2- (piperazin-1-yl) methylene-6- (o-chlorophenyl) -1H, 4H-imidazo (1,2-a) ) (1,4) benzodiazepin-1-one Ie, which in turn was prepared according to the procedure described in Example 8.

Formed 8-nitro-1,2-dihydro-2- (N-dimethylphosphinyl-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo- (1,2- a) (1,4) Benzodiazepin-1-one Ie melted at 245-8 ° C.

I.R. Spectrum (KBr plate): C = 0 1700 cm -1; C = N 1642 cm-1.

Example 50: 8-Nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo (1,2-a) (1,4) Benzodiazepin-1-one methanesulfonate

Methanesulfonic acid (1.1 g) was added dropwise to 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo (1 , 2-a) (1,4) benzodiazepin-1-one (obtained as in Example 30) (4.6 g) in dry methylene chloride (100 ml) and methanol (5 ml). Dry ether was slowly added until crystallized by scraping and the solution was allowed to crystallize and more ether was added to complete the crystallization. The pale yellow solid was filtered off, washed with ether and recrystallized from methylene chloride-methanol to give 8-nitro-1,2-dihydro-2- (N-methyl-piperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one methanesulfonate (5.4 g), m.p. 205-10 ° C.

Claims (3)

A process for the preparation of 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one having the general formula 3 --κ4 yk xo R y = -N where R represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, 2 R which may be in any position on the phenyl ring represents a hydrogen atom or a halogen atom, R represents a hydrogen atom or a methyl group, and either 4 R and R, which may be the same or different, denotes 33 62090 each of a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an aminoalkyl or alkylaminoalkyl group in which the alkyl moieties each contain 1 to 5 carbon atoms, a phenyl or naphthyl group or 3 Cycloalkyl group having 8 carbon atoms or 4 R or R together with the nitrogen atom denote morpholino, thiomorpholino, piperidino or piperidino substituted by 4-oxo-1-phenyl-2-yl midazolin-5-yl, or piperazin-1-yl or piperazin-1-yl substituted in the 4-position by an alkyl group, a hydroxyalkyl group having 1 to 5 carbon atoms in the alkyl group, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and an alkyl moiety having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a phenyl group or a dialkylphosphinylalkyl group having 1 to 5 carbon atoms in the alkyl moiety, and acid addition salts thereof, characterized in that the compound of formula ff> (V, 2 H-R 1 2 R wherein R and R are as defined above, is reacted with either dimethylformamide acetal of the formula (alk-o) 2 = ch - n = (ch3) 2 (VI) wherein AlK represents a lower alkyl group having 1 to 5 carbon atoms, 2 8-R'-1,2-Dihydro-2- (dimethylamino) methylene-6- (R-phenyl) -1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one of the formula 34 620 90 ^ CH_ ch-n · * ΓΙ ^ ch5 \ \ JI (2a) * -f— "V 1 2 wherein R and R have the same meaning as above, and the compound of formula (Ia) obtained is optionally is converted to a salt or transaminated by reacting it with a suitable amine of formula / * 1H - N (VIII) ^ R5 4 5 wherein R and R are as defined above, provided that both do not represent a methyl group, to give the desired compound of formula "-Jj-N-n5 (Ic) -I --- R2 12 4 5 wherein R, R, R and R have the same meaning as above, provided that R and R do not both represent a methyl group, which compound may be converted into a salt, or the above compound of formula (V) 5 2 35 62090 is reacted with N-dimethylacetamide of the formula ob3 / Ch3 O = C - N (VII) Xch3 to give the corresponding compound of the formula CH "Γ H - * C - · N (Ib) 11> -I- r2 1 2 wherein R and R are as defined above and the compound of formula (Ib) obtained is optionally either converted into a salt or transaminated reacting it with a suitable amine of the formula / R 4 H - N (VIII) ^ R 5 5 5 wherein R and R are as defined above, except that both do not represent a methyl group, to give the desired compound of formula c "; - c - N ^ n5 j> (Id) '~> r \ _f_ir 36 62090 1 2 4 5 4 wherein R, R, R and R have the same meaning as above, except that R and R5 do not both represent a methyl group, and optionally, if desired, to prepare a compound of formula I wherein R, R and R are as defined above and R and R together with the nitrogen atom form an R 1 -piperazin-1-yl group in which R® represents a cycloalkylalkyl group, having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkyl moiety, or an alkenyl group having 2 to 5 carbon atoms, a suitable compound of formula I is obtained in which R and R together with the nitrogen atom form a piperazin-1-yl group , reacting with a suitable halo-R compound in which halo is a halogen atom to give the corresponding R 1 -piperazin-1-yl compound of formula I, and, if desired, preparing a compound of formula I wherein R 5 and R 4 together form with a nitrogen atom 4-dialkylphosphinylalkylpiperazine an n-1-yl group having 1 to 5 carbon atoms in the alkyl moiety is reacted with a suitable haloalkyl dialkylphosphine oxide to give the appropriate compound of formula I wherein R and R together with the nitrogen atom form a piperazin-1-yl group. to prepare the corresponding 2- (N-dialkylphosphinylalkyl-piperazin-1-yl) compound of formula I, and optionally converting the compound obtained in the process into a salt. For the preparation of 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-one with a central nervous system and a lower alloy formeln ^ 5 R ^ 'N. N (0 O __ft "37 6 2 0 9 0 i are selected from the group consisting of hydrogen, halogen, nitro or trifluoromethyl, 2 R is a substituent or a methyl group and an antigen is 4 5 R and R is a residue or an alkyl group, an alkyl group having 1-5 cholatomers, a hydroxyalkyl group having 1-5 chol atomers, an aminoalkyl group alkylaminoalkyl group having an alkyldehyde group and in which 1-5 cholate groups, phenyl or naphthyl group or cycloalkyl group having 3-8 cholatomers or a ring moiety 4 5 R and R columns having a quaternary substituent morpholino, thiomorpholine, piperidino or piperidine with 4-oxo-1-phenyl-2-imidazolin-5-yl, piperazin-1-yl or piperazin-1-yl substituted with 4-alkyl groups, hydroxyalkyl, and a single alkyl group having 1-5 cholaters , cycloalkylalkyl groups of 3-6 cholatomers and cycloalkyls and 1-5 alkyl atom in alkyl, alkenyl group in 2-5 cholatom, phenyl group or dialkylphosphinylalkyl in group 1-5 alkyl atom in alkyl, and in the case of a compound of the present invention, the parent compound is used to give a compound of formula (V) 1, in which R and R are selected from the group consisting of reagents with the antigen and dimethylformamide acetal in the form of (AlK-O) 2 = CH - N = (CH3) 2 (VI) and in which the alkyl is selected from the group consisting of 1-5 colaters for 2-position 8-R'-1,2-dihydro-2- (dimethylamino) methylene-6- (R-phenyl) -1H, 4H-imidazo (1,2-a) (1,4) benzodiazepine -1-on with formula 38 62090 ^ CW „CH - N ^ I ^ CH_ 'N __ ^ A ^ i 2 i vilken R and R betecknar decamma som ovan, och optionuellt salt-bildar föreningen med formula (la) eller transaminerar densamma genom in the case of a reactant with a solid Amine with the formula Ar4 H - N (VIII) \ r5 4 5 i is selected from the group consisting of R and R in the form of a group of the same group as the group of the methyl group these self-adhesive formulations etc) I "i— R 12 4 5 i vilken R, R, R and R betecknar decamma som ovan, med undantag 4 5 av att R och R icke bäda betecknar en methylylupp, och eventuellt saltbildar denna förening , or a bicycle with a formulation of (V) 39 62090 of a reagent with N-dimethylacetamide with a formulation of CH, / CH- 0. - C - N the reactant is heated to the amine form / r4 H - N (VIII) XR5 4 5 and then R and R are selected from the group consisting of the same group of methyl groups as the form of the original form of the formulation ^ nl CII .. - C - N XX)