CH618171A5 - Process for the preparation of new imidazolobenzodiazepines and of their salts - Google Patents

Abstract

The compounds of formula <IMAGE> in which R1 represents hydrogen, a halogen, nitro or trifluoromethyl and R2 represents hydrogen or a halogen, are obtained by reaction of N,N-dimethylacetamide with a corresponding 1,2-dihydro-6-phenyl-1H,4H-imidazo[1,2-a][1,4]benzodiazepin-1-one. A transamination on the dimethylamino group can be carried out by an amine HNR4R5 to form R4R5-amino derivatives, R4 and R5 meaning various hydrocarbon radicals. The compounds and their salts have sedative, hypnotic, anxiolytic, tranquillising, anticonvulsive and myorelaxing properties and can be used in the corresponding therapeutic indications.

Description

The subject of the present invention is a process for the preparation of new imidazolobenzodiazepines, as well as their addition salts with mineral or organic acids, said imidazolobenzodiazepines corresponding to the formula:

2 db)

2. Method according to claim 1, characterized in that the compounds obtained are transformed into their salts, by the action of a mineral or organic acid.

3. Use of the compounds of formula Ib according to claim 1 for the preparation of l, 2-dihydro-6-phenyl-1H, 4H-imidazo- [1,2a] - [1,4] -benzodiazepine-l-ones of formula:

(Formula at the top of the next column)

in which Ri and R2 are defined as above and R4 and Rs, which are identical or different, represent a hydrogen atom, an alkyl radical containing from 2 to 5 carbon atoms, a hydroxyalkyl radical comprising from 1 to 5 carbon atoms, a aminoalkyl radical, mono- or dialkoylamino-

in which R 1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical and R 2 represents a hydrogen atom or a halogen atom.

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From the compounds of formula Ib, one can prepare compounds of formula:

in which Ri and R2 are defined as above and R4 and R5, which are identical or different, represent a hydrogen atom, an alkyl radical containing from 2 to 5 carbon atoms, a hydroxyalkyl radical comprising from 1 to 5 carbon atoms, a aminoalkyl, mono- or dialkoylaminoalkyl radical, in which the alkyl radicals contain from 1 to 5 carbon atoms, an aryl radical or a cycloalkyl radical, or R4 and Rs represent, with the nitrogen atom, a saturated, substituted or unsubstituted,

which may contain another heteroatom, as well as their addition salts with acids.

When R 1 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, and more particularly a chlorine atom.

When R2 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, and more particularly a fluorine or chlorine atom. In addition, when R2 is a halogen atom, it is preferably in the ortho position.

When R4 and Rs represent an alkyl radical, it is preferably an ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl radical, and more particularly an ethyl, n-propyl, n- radical. butyl or tert-butyl.

When R4 and Rs represent a hydroxyalkyl radical, the alkyl radical is preferably a methyl, ethyl, propyl, butyl or pentyl radical, and more particularly an ethyl radical.

When R4 and Rs represent an aminoalkyl or alkylaminoalkyl radical (the latter including the monoalkylaminoalkyl and dialkoylaminoalkyl radicals), the alkyl radicals are preferably methyl, ethyl, propyl or butyl radicals, and more particularly methyl or ethyl radicals. Thus, R4 and Rs preferably represent an aminomethyl, aminoethyl, dimethylaminoethyl or diethylaminoethyl radical or even an aminopropyl, amino-butyl, methylaminomethyl, methylaminoethyl or dimethyl-aminopropyl radical.

When R4 and Rs represent an aryl radical, this can be mono- or dinuclear, such as, for example, phenyl or naphthyl and, preferably, phenyl.

When R4 and Rs represent a cycloalkyl radical, the latter preferably contains from 3 to 8 carbon atoms and represents, more particularly, a cyclohexyl radical.

R4 and Rs may be the same or different, and, in this case, one of them preferably represents a hydrogen atom.

When R4 and Rs represent, with the nitrogen atom, a heterocycle, the latter is saturated, substituted or unsubstituted, and may contain a second heteroatom.

As examples of an unsubstituted heterocyclic radical, mention may be made of the pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazin-1-yl radicals. These heterocycles can be substituted by alkyl radicals containing from 1 to 5 carbon atoms, such as methyl, ethyl and propyl, by hydroxyalkyl radicals containing from 1 to 5 carbon atoms, such as hydroxyethyl, by dialkoylphosphinylalkyl radicals, in in which the alkyl radical contains from 1 to 5 carbon atoms, such as methyl, by cycloalkylalkyl radicals, the cycloalkyl radical comprising from 3 to 6 carbon atoms and the alkyl radical comprising from 1 to 5 carbon atoms, such as cyclopropylmethyl, by alkenyl radicals containing from 2 to 5 carbon atoms, such as allyl, by aryl radicals,

such as phenyl, by nitrogen heterocyclic radicals, such as 1-phenyl 5-imidazolyl-4-one.

As examples of substituted heterocyclic radicals, mention may be made of the 4-alkylpiperazin-1-yl radicals and preferably 4-methyl-, 4-ethyl- and 4-propylpiperazin-1-yl radicals, the 4-hydroxyalkylpiperazin-1-radicals yl and, preferably, 4-hydroxyethyl-piperazin-1-yl, the radicals 4-dialcoylphosphinylalcoylpiperazin-1-yl and, preferably, 4-dimethylphosphinylmethylpiperazin-l-yl, the radicals 4-cycloalcoylalcoylpiperazin preferably 4-cyclopropylmethylpiperazin-1-yl, the radicals 4-alkenylpiperazin-1-yl and, preferably, 4-allylpiperazin-l-yl, the radical 4-phenyl-piperazin-l-yl, the radical 4- ( l-phenyl 5-imidazolyl 4-one) piperidin-1-yl.

In addition, compounds of formula Ib, the following compounds are more particularly retained:

a) imidazolobenzodiazepines of formula Id, in which R4 and Rs, identical or different, represent a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, a hydroxyethyl radical, a dimethylaminoethyl or diethylaminoethyl radical, a phenyl radical or a cyclohexyl radical, or R4 and Rs represent together, with the nitrogen atom, a pyrrolidinyl, piperidino, morpholino, thiomorpholino, pipérazin-l-yl, 4-alcoylpiperazin-l-yl, 4-hydroxyalkoylpiperazin-l- radical yl, 4-phenylpiperazin-1-yl or 4- (1-phenyl 5-imidazolyl 4-one) -piperidin-1-yl;

b) imidazolobenzodiazepines of formula Id, in which Ri represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom, a chlorine atom or a fluorine atom, and R4 and Rs, which are identical or different, represent a hydrogen atom, a linear alkyl radical containing

1 to 5 carbon atoms, a hydroxyethyl radical, a phenyl radical or a cyclohexyl radical, or R4 and Rs represent,

with the nitrogen atom, a piperidino, morpholino, piperazin-1-yl, 4-alkylpiperazin-1-yl or 4-hydroxyethylpiperazin-1-yl radical;

c) imidazolobenzodiazepines of formula Id, in which Ri represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom, a chlorine atom or a fluorine atom, R4 represents a hydrogen atom and Rs represents a ethyl, propyl or butyl radical, or R4 and Rs represent,

with the nitrogen atom, a piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl or 4-hydroxyethylpiperazin-1-yl radical;

d) imidazolobenzodiazepines of formula Id in which Ri represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom, a chlorine atom or a fluorine atom, and R4 and Rs represent, with the atom of nitrogen, a 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl or 4-propylpiperazin-1-yl radical;

e) imidazolobenzodiazepines of formula Id in which Ri represents a hydrogen atom, a chlorine atom or a nitro radical, R2 represents a hydrogen atom, a chlorine atom or a fluorine atom, and R4 and Rs represent, with

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the nitrogen atom, a 4-diaIcoylphosphinylalcoylpiperazin- radical

1-yl;

f) imidazolobenzodiazepines of formula Id in which Ri represents a hydrogen atom, a chlorine atom or a nitro radical, R2 represents a hydrogen atom or a chlorine atom, and R4 and Rs represent, with the atom d 'nitrogen, a 4-dimethylphosphinylmethylpiperazin-1-yl radical.

As indicated above, the salts of the compounds obtained by the process of the invention can be formed with mineral or organic acids.

Among the mineral acids, mention may be made of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids; among the organic acids, there may be mentioned acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic and arylsulfonic acids. Among the addition salts with acids, there may be mentioned, preferably, tartrates and alkanesulfonates and, more particularly, methane sulfonates.

Among the addition salts with acids of the compounds obtained by the process of the invention, there may be mentioned more particularly:

a) the addition salts with acids of imidazolobenzodiazepines of formula Ib and Id in which 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, and R4 and Rs represent, with the nitrogen atom, a 4-alkylpiperazin-1-yl radical;

b) tartrates and alkanesulfonates, preferably methanesulfonates, imidazolobenzodiazepines of formulas Ib and Id in which Ri represents a chlorine atom or a nitro radical, R2 represents a hydrogen atom or a chlorine atom, and R4 and Rs represent, with the nitrogen atom, a 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl radical.

Among the compounds obtained by the process of the invention and their salts, there may be mentioned, in particular: 8-chloro-2- [1- (dimethyl-amino) ethylidene] -1,2-dihydro-6-phenyl- 1H, 4H-imidazo- [1,2-a] - [1,4] -benzodiazepine 1-one, and 8-chloro-1,2-dihydro-2- [1- (N-methylpiperazino) ethylidene] - 6-phenyl-1H, 4H-imidazo- [1,2-a] - [1,4] -benzodiazepine 1-one.

The imidazolobenzodiazepines of formula Ib are prepared from the corresponding compounds unsubstituted in position 2, these can be prepared from the corresponding 2-alkyloxycarbonyl- or 2-carboxymethylaminobenzodiazepines.

Thus, the subject of the invention is a process for the preparation of the compounds of formula Ib, in which Ri and R2 have the abovementioned meaning, and of their addition salts with acids, characterized in that a compound is reacted of formula:

in which Ri and R2 are defined as above,

with the N-dimethylacetamide of formula:

çh3

0 = C-N (CH3) 2 (VII)

If desired, the compound obtained can be salified or submitted

to a transamination by action of an amine of formula:

/ *

H-N ^ (VIII)

Rs in which R4 and Rs are defined as above, to obtain the desired compound of formula Id given above.

The reaction with the acetamide of formula VII is preferably carried out in an anhydrous organic solvent, such as a chlorinated alkane, such as methylene chloride, at a temperature below room temperature and, preferably, below 10 ° C, and in the presence of a compound facilitating condensation, such as a halogenated derivative, such as phosphorus oxychloride.

The reaction with the amine of formula VIII is preferably carried out in an anhydrous organic solvent, for example, an arene such as toluene, and preferably at the boiling point of the reaction medium.

It is understood that, when it is desired to make a compound of formula Id in which R4 and Rs represent a hydrogen atom, the compound of formula VIII used is ammonia.

The imidazolobenzodiazepines obtained above of formula Id can, if desired, be transformed into other compounds of formula Id. In particular, the compounds, in which R4 and Rs represent, with the nitrogen atom, a heterocycle, can be transformed to introduce a substituent on said heterocycle.

When we want to prepare a compound of formula Id, in which Ri and R2 are defined as above and R4 and Rs form, with the nitrogen atom, a radical Rô-pipérazin-l-yl, in which rô represents a cycloalkylalkyl radical , an alkenyl radical or a 4-dialkoylphosphinylalkyl radical, a compound of appropriate formula Id is first prepared, in which R4 and Rs form, with the nitrogen atom, a piperazin-1-yl radical, then reacts this compound with a reagent of formula:

hai-rô

in which hai represents a halogen atom, to obtain the corresponding compound comprising the Rô-pipérazin- radical

1-yl of formula Id.

When it is desired to prepare a compound of formula Id, in which R "and Rs form, with the nitrogen atom, a 4-dialkoylphosphinylalkyllipiperazin-1-yl radical, one can first prepare an appropriate compound of formula Id, in which R4 and Rs form, with the nitrogen atom, a piperazin-1-yl radical, then react this compound with a haloalkyl-dialkoylphosphine oxide, to obtain the corresponding compound

2- (N-dialkoylphosphinylalcoylpiperazin-1-yl) of formula Id.

The preferred haloalkylcoylphosphine oxides are the chloroalkoyldialcoylphosphine oxides, and the reaction is preferably carried out in an organic solvent, for example, an arene such as toluene.

The imidazolobenzodiazepine of formula V used at the start of the process can be prepared by a process, characterized in that a 7-Ri-1,3-dihydro-5- (R2-phenyl) -2H-1 is reacted, 4-benzodiazepine-2-thione of formula II:

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in which Ri and R2 are defined as above, with a compound of formula III:

O

RO NH2 (III)

in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, to obtain a compound of formula IV:

RO

R

in which R, Ri and R2 are defined as above, which is reacted with a dehydrating agent or which is subjected to a pyrolysis when R represents an alkyl radical, to obtain the compound of formula V.

The reaction of the compound of formula II with the compound of formula III is preferably carried out in an organic solvent, such as an alcohol such as ethanol, and preferably at the boiling point of the medium. reactive.

The dehydrating agent which is reacted with the acid of formula 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 the ester of formula IV is carried out, preferably in a solvent with a high boiling point, such as an arene such as toluene.

The salification of the compounds of formula Ib is preferably carried out with a stoichiometric amount of a mineral or organic acid in an organic solvent or a mixture of organic solvents, such as alcohols, for example methanol or ethanol, halides d alkyl, for example methylene chloride.

The imidazolobenzodiazepine-1-ones obtained according to the process of the invention have very interesting pharmacological properties. They are endowed in particular with a remarkable sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsant and muscle relaxant activity.

The properties of the products obtained by the process of the invention justify their use in therapy.

Thus, these products can be used as medicaments, in particular in the treatment of states of agitation or irritability, aggressiveness, insomnia, certain psychosomatic syndromes, certain character disorders, certain behavioral disorders, certain muscle spasms or contractions.

The usual dose varies depending on the condition in question, the product used, the subject treated and the route of administration. It can be, for example, from 1 to 50 mg / d, in adults.

The compounds of formula I, as well as their addition salts with pharmaceutically acceptable acids, can be

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used to prepare pharmaceutical compositions which contain, as active principle, at least one of the products defined above.

These compositions are produced so that they can be administered by the digestive or parenteral route. They can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, solutions or injectable suspensions or suppositories; they are prepared according to the usual methods.

The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The 2-carboxymethylamino-7-Ri-5- (R2-phenyl) -3H-1,4-benzodiazepines of formula IV, and the 2-alkyloxycarbonyl-methylamino-7-Ri-5- (R2-phenyl) -3H- 1,4-benzodiazepines of formula IV in which R represents an alkyl radical different from the ethyl radical, are new compounds.

The following examples illustrate the invention.

Example 1:

8-Chloro-2- [l- (dimethylamino) ethylidene] -1,2-dihydro-6-phenyl-1H, 4H-imidazo- [1,2-a] - [1,4] -benzodiazepine 1-one

Stage A: 2-Carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (IV):

3.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4, benzodiazepine-2-thione (II) are suspended in 100 cm3 of ethanol and 30 cm3 of water. 5.5 g of glycine (III) and 5.5 g of sodium carbonate. The mixture is brought to reflux with stirring for 1 h. The suspension obtained is poured into water, acidified to pH 4 with 2N hydrochloric acid and extracted with chloroform. The organic phase is filtered, dried and evaporated to dryness. The residue obtained is crystallized from methanol. It is joined to the solid previously filtered, recrystallized from ethanol and obtained 3.1 g of 2-carboxy-methylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine. M = 215-220 ° C.

Stage B: 8-Chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo- [1,2-a] - [1,4] -benzodiazepine 1-one (V):

2.5 g of the product obtained in Stage A are suspended in 120 cm3 of methylene chloride. 2.1 g of dicyclohexylcarbodiimide are added with stirring. The mixture is stirred for 3 h at room temperature, filtered, the filtrate is evaporated and the expected product is obtained in the form of a colorless oil used as it is for the following stage.

Stage C: 8-Chloro-2- [l- (dimethylamino) ethylidene] -1,2-dihydro-6-phenyl-1H, 4H-imidazo-f l, 2-a] - [1,4] -benzodiazepine 1 -one (Ib):

The product obtained in Stage B is dissolved in 200 cm 3 of methylene chloride, 2 g of dimethylacetamide are added, the solution is cooled to 0 ° C. and 3.7 g of oxychloride are added dropwise over 5 min. phosphorus. The mixture is stirred at ambient temperature for 20 h and poured into 500 cm 3 of a saturated sodium bicarbonate solution. The mixture is stirred until carbon dioxide is released. Decanted, extracted with methylene chloride, washed the combined organic phases with a sodium bicarbonate solution, then with water, dried and evaporated to dryness. The residue is recrystallized from a chloroform / ether mixture and 2.3 g of the expected compound (Ib) are obtained. Mp 251-252 ° C.

Analysis: C2iHi9ClN40 = 378.9

Calculated: C 66.58 H 5.02 N 14.79 Cl 9.38%

Found: C 66.32 H 4.91 N 14.77 Cl 9.02%

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IR spectrum

C = O at 1653 cm- ', C = N at 1610 cm-1.

Example 2:

8-Chloro-1,2-dihydro-2- [I- (N-methylpiperazino) ethylidene] -6-phenyl-1H, 4H-imidazo- [1,2-a] - [1,4] -benzodiazepine 1- one

A mixture of 2.3 g of 8-chloro-2- [1- (dimethylamino) ethylidene] -1,2-dihydro-6-phenyl-1H, 4H-imidazo- [1 is stirred at 120 ° C. for 9 h. , 2-a] - [1,4] -benzodiazepine 1-one (Ib) and 15 cm3 of N-methylpiperazine (VIII). The solution is cooled, poured into water, sodium chloride is added and the precipitate obtained is filtered. It is dissolved in chloroform, washed with water, dried and evaporated to dryness. The residue obtained is crystallized from an ether / me-thanol mixture and recrystallized from ethyl acetate. 1 g of expected product is obtained (Id). Mp 193-195 ° C.

Analysis: c24h24cin5o = 434.0

Calculated: C 66.43 H 5.54 N 16.14 Cl 8.38%

Found: C 66.32 H 5.50 N 15.98 Cl 8.11%

Kl

IR spectrum

C = 0 to 1660 cm-1, C = N to 1615 cm-1.

R

Claims (2)

618,171 2 I. Process for the preparation of new 1,2-dihydro-6-phenyl-1H, 4H-imidazo- [1,2a] - [1,4] -benzodiazepine-1 -ones of formula: ÏH3 2 m in which R 1 represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical and R 2 represents a hydrogen atom or a halogen atom, as well as their addition salts with the acids, characterized in that a compound of formula: (V) in which Ri and R2 are defined as above, with the N-dimethylacetamide of formula: ÇH3 0 = C-N (CH3) 2 (VII) (Id) alkyl, in which the alkyl radicals contain from 1 to 25 carbon atoms, an aryl radical or a cycloalkyl radical, or R4 and R5 represent, with the nitrogen atom, a saturated heterocycle, substituted or unsubstituted, which may contain another heteroatom, as well as their addition salts with acids, characterized in that said compounds of formula Ib are subjected to transamination by the action of an amine of formula: HN / \ R4 (VIII) 35 Rs in which R4 and Rs are defined as above. 40 45