FR2722501A1 - New 9H-Imidazo (1,2-A) benzimidazole-3-acetamide derivs. - Google Patents

Abstract

9H-Imidazo (1,2-A) benzimidazole-3-acetamide derivs. of formula (I) and their salts are new. X = H, halo or methyl and Y = OH or methoxy, or X = OH and Y = H; R1 = methyl, and R2, R3 = H or methyl. Also claimed is a compsn. of formula (IV), a necessary intermediate in the prepn. of (I).

Description

The present invention relates to 9H-imidazole derivatives.

  zo [1,2-a] benzimidazole-3-acetamide, their preparation and their

therapeutic application.

  The compounds of the invention correspond to the general formula

(I) R1

R 1

N N X

N (I) Y'O

0

  Wherein R2 is either hydrogen or halogen or methyl and Y is hydroxy or methoxy, X is hydroxy and Y is hydrogen, R1 is methyl; , and R, and R3 are each independently of one another,

  a hydrogen atom or a methyl group.

  The compounds of the invention may be present in the form of

  free bases or addition salts with acids.

  Compounds of the general formula (I) in which Y represents

  A methoxy group is provided by the general formula described in patent application EP-0607076; however

  none of them are specifically described.

  According to the invention, the compounds of general formula (I) can be prepared according to a process illustrated by the scheme

following.

  A 9H-imidazo [1,2a-a] benzimidazole derivative of the general formula (II) (wherein X is hydrogen, halogen or methyl and Y is methoxy) is reacted; either X represents a methoxy group and Y represents a hydrogen atom, and R 1 is as defined above) with N, N-dimethylglyoxamide (which

HO 0E

(AI) N

X _ N N

18g of H

H HD - H

-N (eI) - N

X N N

- O (III) N

X _ N -N

Tu 01 JúH

úHD-N H

O O

(II) - -N ---

X _ N N

l8 T 0agoS

  in situ is prepared using 2,2-diethoxy-N, N-dimethyl-

  acetamide, as described in patent application EP-251859) in a protic solvent such as acetic acid at a

temperature from 20 to 80 C.

  The α-hydroxyacetamide derivative of general formula (III) is then treated with a polyhalide of sulfuric acid or

  phosphoric acid, for example thionyl chloride or oxy-

  phosphorus chloride, or any other equivalent agent, in an inert solvent, for example a chlorinated or ethereal solvent such as dichloromethane or tetrahydrofuran, at a

  temperature of 20 to 80 C to form the α-halogen derivative

  corresponding genoacetamide, then the latter is reacted either with a reducing agent such as a simple or complex alkali metal hydride, for example sodium borohydride or potassium borohydride, in a protic solvent, for example an aliphatic alcohol such as methanol or methyl alcohol. ethanol, or in an inert solvent miscible with water, for example dioxane or tetrahydrofuran, at a temperature of -40 to 40 ° C., or with a reducing agent such as a hyposulphite or a dithionite

  alkaline, for example hyposulphite or dithionite

  dium, or with sodium hydroxymethylsulfoxylate (Rongalite), in an inert solvent, for example a chlorinated solvent such as dichloromethane, optionally in the presence

  an inert cosolvent miscible with water, for example N, N-

  dimethylformamide or N-methylpyrrolidone at a temperature of

from 20 to 40 C.

  This gives a N, N-dimethylacetamide derivative of

  general mule (Ia), which corresponds to the general formula (I) when either X represents a hydrogen or halogen atom or a methyl group and Y represents a methoxy group, or X represents a methoxy group and Y represents an atom of hydrogen, and R2 and R3 each represent a methyl group. If it is desired to prepare a compound of general formula (I) in

  which R2 and R3 do not each represent a group

  thyle, the compound of general formula (Ia) is converted into an acid of general formula (IV) by hydrolysis by means of a strong base, for example sodium hydroxide or potassium hydroxide, in a

  protic solvent, for example ethanol or 2-methoxyetha-

nol, in the presence of water.

  The acid of general formula (IV) is then reacted with N, N'carbonyldiimidazole, in an inert solvent, by

  a chlorinated or ethereal solvent such as dichloromethane

  methane or tetrahydrofuran, at a temperature of 20 to C, to obtain the corresponding imidazolide, and finally the latter is treated with an amine of general formula HNR2R3 (in which R2 and R3 are as defined above) to a

temperature from 0 to 25 C.

  If it is desired to prepare a compound of the general formula (I) in which X or Y represents a hydroxy group, a compound is treated in the formula (I) of which X or Y represents a methoxy group with an agent such as boron tribromide,

  in an inert solvent such as dichloromethane.

  The compounds of general formulas (III) and (IV) are new

  calves and forms part of the invention as intermediates

  synthesis of the process illustrated by the diagram above.

  The derivatives of general formula (II) may be prepared according to any method described in the literature, for example

  in J. Het. Chem., 2, 287 (1965), Khim. Geterosikl. Soedin.

  133 (1967), J. Med. Chem., 15, 923 (1972).

  The following examples illustrate the preparation of

  some compounds of the invention. The microanalyses elemen-

  the spectra I.R. and R.M.N. confirm the structures

tures of the compounds obtained.

  The numbers given in parentheses in the titles of the examples correspond to those in the 1st column of Table 1

given further.

Example 1 (compound N 7)

  6-Methoxy-N, N, 9-trimethyl-2- (4-methylphenyl) -9H-imidazolyl

  zo [1,2-a] benzimidazole-3-acetamide. 1,1-hydroxy-6-methoxy-N, N, 9-trimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole-3-acetamide. 27.86 g (0.159 mol) of 2,2-diethoxy-N, N-dimethyl are dissolved

  acetamide and 3.5 ml (0.042 mole) of concentrated hydrochloric acid

  in 150 ml of acetic acid and the mixture is stirred at 40 ° C. for one hour. 13.4 g (0.159 mol) of sodium acetate are then added and the mixture is stirred for 15 to 20 minutes, then

  add a suspension of 15.42 g (0.053 mol) of 6-methoxy-9-

  methyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole in ml of acetic acid. The mixture is stirred for 7 hours at 40 ° C., the solvent is evaporated off under reduced pressure at a temperature of 40 ° C., the residue is taken up in 300 ml of ice water and 250 ml of dichloromethane, and basified with sodium hydroxide. the insoluble material is filtered off and washed with dichloromethane. The filtrate is decanted, the organic phase is dried over sodium sulphate. 12.9 g of product are obtained which is used as it is in the next step.

  1.2. 6-Methoxy-N, N, 9-trimethyl-2- (4-methylphenyl) -9H-imidazolyl

  zo [1,2-a] benzimidazole-3-acetamide.

  12.61 g (0.032 mol) of α-hydroxy-6-methoxy-N, N, 9-

  trimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole

  3-acetamide with 40 ml of thionyl chloride and shake the

mix for 5h.

  The excess thionyl chloride is evaporated under reduced pressure, the residue is taken up with toluene and evaporated.

  this last. The residue is dissolved in 300 ml of dichloromethane

  methane, 40 g of Rongalite are added and the mixture is stirred for 48 hours. The insoluble material is removed by filtration, the filtrate is washed with sodium bicarbonate and then with water. We dry

  organic phase over sodium sulfate and then concentrated.

  The residue is purified by gel column chromatography

  of silica eluting with a 96/4 mixture of dichloromethane / -

  methanol. 4.97 g of compound are obtained from which a sample of 2.4 g is taken in order to recrystallize it in methanol. After

  drying, 1.96 g of product is obtained.

Melting point: 183.4-184.6 C.

Example 2 (compound N 8)

  6-hydroxy-N, N, 9-trimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-

a] benzimidazole-3-acetamide.

  To a solution of 1 g (0.00265 mol) of 6-methoxy-N, N, 9-

  trimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole

  3-acetamide in 20 ml of dichloromethane, 9 ml (0.009 mol) of boron tribromide in 1M solution are added at -78 ° C.

in dichloromethane.

  The reaction mixture is stirred for 18 h at 20 ° C. and then poured into a mixture of water and ice. It is neutralized by addition of a solution of sodium bicarbonate, the aqueous phase is extracted with dichloromethane, dried over sodium sulphate and then concentrated. 0.92 g of product is obtained which is purified by chromatography on a gel of

  silica eluting with a 94/4/2 mixture of chloroform / metha-

  n-acetone, and the residue is taken up in pentane. We

gets 0.3 g of product.

Melting point: 268.6-269.9 C.

Example 3 (compound N 5)

  6-Methoxy-N, 9-dimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] -

benzimidazole-3-acetamide.

  3.1. 6-Methoxy-9-methyl-2- (4-methylphenyl) -9H-imidazoic acid

zo [1,2-a] benzimidazole-3-acetic acid.

  3.5 g (0.01 mol) of 6-methoxy-N, N, 9-trimethyl-2-

  (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole-3-acetamide in 80 ml of 2-methoxymethanol, 10 g of hydroxide

of potassium and 20 ml of water.

  The reaction mixture is stirred for 4 hours under reflux, the solvent is evaporated off under reduced pressure. The residue is taken up with water and with acetic acid (pH = 5), and an

  precipitated which is dried under reduced pressure.

  2.93 g of product are obtained which is used as such in

the next step.

  Melting point: 134 C (decomposition).

  3.2. 6-Methoxy-N, 9-dimethyl-2- (4-methylphenyl) -9H-imidazolyl

  zo [1,2-a] benzimidazole-3-acetamide. A suspension of 2.85 g (0.008 mol) of acid is prepared

  6-methoxy-9-methyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benz

  imidazole-3-acetic acid in 100 ml of dry tetrahydrofuran, 3 g of N, N-carbonyldiimidazole are added and the mixture is stirred at 20 ° C.

for 24h.

  The solution obtained is treated with an excess of methylamine

  dry gaseous and stirred for 8h.

  The solvent is evaporated under reduced pressure, the residue is treated with water and the insoluble material is filtered off.

wash it with water and then dry it.

  The residue is purified by chromatography on silica gel, eluting with a 91/9 mixture of dichloromethane / methanol. The eluent is evaporated under reduced pressure and the residue is rinsed off.

with pentane.

0.82 g of solid is obtained.

Melting point: 243.6-245 C.

EXAMPLE 4 (Compound N 6)

  6-Hydroxy-N, 9-dimethyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] -

benzimidazole-3-acetamide.

  To a solution of 1.6 g (0.003 moles) of 6-methoxy-N, 9-dimethyl

  thyl-2- (4-methylphenyl) -9H-imidazo [1,2-a] benzimidazole-3

  acetamide in 60 ml of dichloromethane, 12 ml (0.012 mol) of boron tribromide in 1M solution are added at -78 ° C. in

dichloromethane.

  The reaction mixture is stirred at 20 ° C. for 8 h and then poured into a mixture of water and ice. Acidified (pH = 6) with acetic acid. Evaporated under reduced pressure, dissolved in a 50/50 mixture of chloroform / methanol

then add water.

  The organic phase is dried over sodium sulphate, evaporated

  pore under reduced pressure, and the residue is purified on

  column of silica gel eluting with a 93/7 mixture of dichloromethane / methanol, and the residue is recrystallized from ethanol. 0.8 g of product are obtained.

Melting point: 271.2-272.3 C.

  Table 1 which follows illustrates the chemical structures and the physical properties of some compounds of formula

General (I).

  In the "Salt" column, "-" denotes a compound in the base state. In the column "F (C)", "(d)" means a temperature of

fusion with decomposition.

  9uZ-ZUZ- _ úHD H 'HD H HO ~ 6 LO 6'69Z-9'89Z _HD HD' HD HO-9 'HD-t 8 N 9' t8T- 'Ü8T _ 9HD' HZ) 'HZ)' HOO-9 'HD-t L ú' ZLZ-Z 'TZH-9' HO-9 'HO-9' HD-9 'HD-9' HD-t '( p) bSZ-Z - úHD 'HD' tHD HO-9 H tb L 8I-S '581-tHD HHD HD' HDO-9 H ú oa '<P) o8Z <-' HD H IHD HO- 9 H 8 ' 90SBZE <Z'SZ t H3 H tHO H3O-9 HI 8 '9 -zg' 9EHD H 'HD fHDO-9 HI (Do), IaS' I d AX oN NN

X '-, N N

  Table 2 below illustrates the chemical structures and physical properties of some compounds of the formula

  general (IV), intermediates in the preparation process.

  All compounds are in the form of bases.

Table 2

Ri

N N X

N (IV)

Y y _ OH

NO X Y RI F (OC)

1 H 6 -OCH 3 CH 3 150

2 'CH3 6-OCH3 CH3 134 (d)

  In the column "F (oC)", "(d)" means a temperature

  melting with decomposition.

  The compounds of the invention have been subjected to pharmacological tests which have highlighted their interest as

  substances with therapeutic activities.

  Study of the membrane bonds with respect to the W1 (benzodiazepine type 1) and the (benzodiazepine) receptors

type 2).

  The affinity of the compounds for the cerebellar and spinal cord receptors 1 was determined according to a variant of the method described by S. Z. Langer and S. Arbilla in Fund. Clin. Pharmacol., 2, 159-170 (1988), with use

  3H-flumazenil instead of 3H-diazepam as radioligand.

  The tissue of the cerebellum or spinal cord is homogenized for 60 seconds in 120 or 30 volumes, respectively, of ice-cold buffer (50 mM Tris / HCl, pH 7.4, 120 mM NaCl, 5 mM KCl) and then, after dilution with 1/3, the suspension is incubated with 3H-flumazenil (specific activity 78 Ci / mmol, New England Nuclear) at a concentration of 1 nM and with the compounds of the invention at different concentrations, in a final volume of 525. 4l. After 30 minutes of incubation at 0 ° C, the samples were filtered under vacuum on Whatman GF / B filters and washed immediately with ice-cold buffer. The specific binding of 3H-flumazenil is determined in the presence of unlabelled 1M diazepam. The data are analyzed according to

  usual methods and the IC50 concentration, concentration

  which inhibits the binding of 3H-flumazenil by 50%.

  The IC50s of the compounds of the invention are, in these

tests, between 20 and 2000 nM.

Study of hypnotic activity.

  The sedative or hypnotic activity of the compounds was determined

  born out of the observation of their action on electrocortico-

  gram of the rat, according to the method described by H. Depoortere, Rev. E.E.G. Neurophysiol., 10, 3, 207-214 (1980) and by H. Depoortere and M. Decobert, J. Pharmacol. (Paris), 14, 2,

265 (1983).

  The products to be studied were administered intraperitoneally

  ritoneal in increasing doses. They induce traces of

  sleep at doses ranging from 0.1 to 30 mg / kg.

Study of anxiolytic activity.

  The anxiolytic activity is evaluated in the rat in the drink intake conflict test, according to the method described by J. R. Vogel, B. Beer and D. E. Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971). After a 48h water diet, the rat is placed in a chamber isolated from noise and equipped with a water pipette connected to an anxiometer delivering a slight electric shock every 20 licks. The number of shocks received is automatically counted for 3 minutes, and makes it possible to evaluate the anxiolytic activity of the compounds tested. The results are expressed as the minimum effective dose (DEM), a dose that produces a significant increase in the number of shocks received, compared to the number observed in animals.

witnesses.

  The DEM of the compounds of the invention are, in this test, between 1 and 50 mg / kg by the intraperitoneal or oral route.

  Study of anticonvulsant activity.

  Activity against maximal convulsions induced in

  mice by electroshock or pentetrazol injection.

  The protocol for this trial is described by E. A. Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, New

York, 111-126 (1982).

  minutes after intraperitoneal administration of the compound

  test, we note the number of mice with convulsions

  (immediately after applying an electric current (0.4s, 60mA, 50Hz) using transcorneal electrodes, or during

  30 minutes after the subcutaneous injection of

  trazol (125 mg / kg). The results are expressed by the DA50, a dose which protects 50% of the animals, calculated according to the method of JT Lichtfield and F. Wilcoxon (J. Pharm Exp Ther., 96, 99-113 (1949)) from 3 or 4 doses administered each

to a group of 8 to 10 mice.

  The DA50s of the compounds of the invention are, in this

  test, between 1 and 100 mg / kg by the intraperitoneal route.

  Study of anticonvulsant activity.

  Activity against convulsions induced in mice

by isoniazid.

  The intrinsic activity of the compounds is determined by the latent period of onset of convulsions induced by

  subcutaneous administration of isoniazid (800 mg / kg) simul-

  with the test compound, injected intraperitoneally

  ritoneal, according to the protocol described by G. Perrault, E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988). The results are expressed by DAm, a dose that produces 50% of the maximal effect, compared to

  control animals, determined from 3 or 4 doses administered

  each to a group of 8 to 10 mice.

  The DAs0 of the compounds of the invention are, in this test, between 1 and 50 mg / kg by the intraperitoneal route and,

  depending on the compounds, the maximum effect can be up to 350%.

  The results of the tests carried out on the compounds of the

  vention show that, in vitro, they shift 3H-flumazenil from its specific binding sites in the cerebellum and spinal cord; therefore they have an affinity for the sites w, and, 2 (benzodiazepine type 1 and type 2) located within the macromolecular complex

GABAA-sites-chloride channel.

  In vivo they behave as complete agonists or

  partial, vis-à-vis these receptors.

  They possess hypnotic, anxiolytic and anticonvulsant properties and, therefore, can be used for the treatment of disorders related to GABAergic transmission disorders, such as anxiety,

  sleep, epilepsy, spasticity, muscular contractures

  mental disorders, cognitive disorders, weaning disorders

  alcoholism, etc. Finally, they can be used in premedication and as general anesthetics for

  induction and / or maintenance of anesthesia, or as anesthesia

  local theses, possibly associated with other anesthetics.

  and / or muscle relaxants and / or analgesics.

  For this purpose they can be presented in any form

  galenic agents, together with appropriate excipients, for ad-

  enteral or parenteral administration, for example in the form of tablets, dragees, capsules, capsules, oral or injectable solutions or suspensions, suppositories, etc., dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (6)

claims   1. Compound corresponding to general formula (I) R1 N N X N (I) N-_ R3   wherein R2 is X is hydrogen, halogen or methyl and Y is hydroxy or methoxy, X is hydroxy and Y is hydrogen, R1 is methyl, and R2 and R3 are each, independently of one another, a hydrogen atom or a methyl group,   in the base state or addition salt.   2. Compound according to claim 1, characterized in that either X represents a hydrogen or halogen atom or a methyl group and Y represents a hydroxyl group, or X represents a hydroxyl group and Y represents a hydrogen atom. 3. Process for the preparation of compounds according to claim   1, characterized in that a 9H-imidazole derivative is reacted   zo [1,2-a] benzimidazole of general formula (II) R1 N N X N __ (II)   (wherein X is hydrogen, halogen or methyl and Y is methoxy, X is methoxy and Y is   a hydrogen atom, and RI is as defined in the   1) with N, N-dimethylglyoxamide, in a protic solvent, at a temperature of 20 to 80 ° C., and then treating the thus obtained ahydroxyacetamide derivative of general formula (III) R N N X N (III) Y .. OH N -CH3   H3C with a polyhalide of sulfuric or phosphoric acid, in an inert solvent, at a temperature of 20 to 80 C, to form the corresponding derivative of a-haloacetamide, then reacting the latter with a reducing agent such as a alkaline hydride, simple or complex, in a protic solvent, or in an inert solvent miscible with water, at a temperature of -40 to 40 ° C., or with a reducing agent such as a hyposulphite or an alkaline dithionite, or with sodium hydroxymethylsulfoxylate, in an inert solvent, optionally in the presence of an inert water-miscible cosolvent, at a temperature of 20 to 40 ° C., to obtain an N, N-dimethylacetamide derivative of general formula (Ia) R1 N N X   Wherein X is hydrogen, halogen or methyl, and Y is methoxy, X is methoxy and Y is hydrogen atom, and R2 and R3 each represent a methyl group, and then, if it is desired to prepare a compound of general formula (I) in   which R2 and R3 do not each represent a group   thyle, the compound of general formula (Ia) is converted into an acid of general formula (IV) R1 N N X N _ (IV)   by hydrolysis by means of a strong base, in a protic solvent, in the presence of water, then the acid of general formula (IV) is reacted with N, N'-carbonyldiimidazole, in an inert solvent, to one   temperature of 20 to 50 C, to obtain the corresponding imidazolide   and the latter is treated with an amine of the general formula HNR 2 R 3 (wherein R 2 and R 3 are as defined in claim 1) at a temperature of 0 to 25 C, and finally, if it is desired to prepare a compound of wherein X or Y represents a hydroxy group, a compound is treated in the formula (I) of which X or Y represents a methoxy group, with the tribromide of boron.   4. Drug characterized in that it consists of a compound according to claim 1 or 2.   5. A pharmaceutical composition characterized in that it   holds a compound according to claim 1 or 2, associated with an excipient. 6. Compound of general formula (IV) as defined in claim 2, as a necessary intermediate in the process according to claim 2.