HK1104288B - 2h or 3h-benzo[e]indazol-1-yle carbamate derivatives, the preparation and therapeutic use thereof - Google Patents

Description

Carbamate derivatives of 2H-or 3H-benzo [ e ] indazol-1-yl, preparation thereof and therapeutic use thereof

The subject of the invention is a compound which exhibits in vitro and in vivo properties towards peripheral benzodiazepines2H-or 3H-benzo [ e ] of receptor (PBR or p site) affinity]Indazol-1-yl carbamate derivative compounds.

A first subject of the invention is a compound corresponding to the following general formula (I).

Another subject of the invention is a process for the preparation of the compounds of general formula (I).

Another subject of the invention is the use of the compounds of general formula (I), in particular in medicaments or pharmaceutical compositions.

The compounds of the invention correspond to the general formula (I):

wherein

W represents an oxygen or sulfur atom;

X₁、X₂、X₃and X₄Each independently of the others represents a hydrogen or halogen atom or a cyano group, C₁～C₆Alkyl radical, C₁～C₆-fluoroalkyl, C₁～C₆-alkoxy, C₁～C₆-a fluoroalkoxy group;

y is at the (N2) or (N3) position;

when Y is at the (N2) position, Y represents C₁～C₆Alkyl radical, C₁～C₆-a fluoroalkyl, aryl or heteroaryl group;

when Y is in the (N3) position, Y represents an aryl or heteroaryl group;

the aryl or heteroaryl group being optionally substituted by 1 or more groups selected from halogen atoms, C₁～C₆Alkyl radical, C₁～C₆-alkoxy, C₁～C₆-alkylthio radical, C₁～C₆alkyl-S (O) -, C₁～C₆alkyl-S (O)₂-or C₁～C₆-an atom or group of a fluoroalkyl group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others, represents aryl, benzyl or C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by 1 or more C₁～C₆-an alkyl or benzyl group.

For the purposes of the present disclosure:

-C_t～C_zwhen t and z can assume values of 1 to 6, this is understood to mean carbon chains which can have from t to z carbon atoms, for example C_1-3A carbon chain having 1 to 3 carbon atoms;

alkyl is understood to mean saturated, linear or branched aliphatic radicals. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like;

-fluoroalkyl is understood to mean an alkyl group whose 1 or more hydrogen atoms have been replaced by fluorine atoms;

alkoxy is understood to mean-O-alkyl, wherein the alkyl radical is as defined above;

fluoroalkoxy is understood as meaning an alkoxy radical whose 1 or more hydrogen atoms have been replaced by fluorine atoms;

alkylthio is understood to mean-S-alkyl in which the alkyl radical is as defined above;

heterocycle is understood to mean a 4-to 7-membered cyclic group comprising a nitrogen atom and optionally further heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Examples of heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and azanylA piperazinyl, or homopiperazinyl (homopiprazinyl) group;

aryl is understood to mean an aromatic cyclic radical comprising from 6 to 10 carbon atoms. Examples of aryl radicals are phenyl orA radical group;

heteroaryl is understood as meaning a 5-to 6-membered aromatic cyclic group containing 1 to 2 heteroatoms, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups, mention may be made of pyridyl, thienyl, furyl, pyrimidinyl, pyrazinyl or pyridazinyl groups;

-element is understood to mean, in a cyclic group, the atoms connecting 2 adjacent atoms of the ring;

halogen atoms are understood to mean fluorine, chlorine, bromine or iodine.

The compounds of formula (I) may contain 1 or more asymmetric carbons. They may exist in enantiomeric or diastereomeric forms. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention.

The compounds of formula (I) may be present as bases or as addition salts with acids. Such addition salts form part of the present invention.

These salts are advantageously prepared from pharmaceutically acceptable acids, but other useful acids, for example, salts of acids for the purification or isolation of compounds of formula (I), also form part of the invention.

The compound of formula (I) may be in the form of a hydrate or solvate, i.e. in association or association with 1 or more water molecules or with a solvent. Such hydrates and solvates also form part of the present invention.

Among the compounds of general formula (I) which are the subject of the present invention, the first subclass of compounds consists of those in which:

w represents an oxygen or sulfur atom; and/or

X₁、X₂And X₃Each independently of the others, represents a hydrogen atom or a halogen atom, more particularly a fluorine, chlorine or bromine atom, or a cyano group, C₁～C₆Alkyl radicals, more particularly methyl radicals, C₁～C₆-alkoxy groups, more particularly methoxy groups; and/or

X₄Represents a hydrogen atom; and/or

Y is at the (N2) or (N3) position;

when Y is at the (N2) position, Y represents C₁～C₆Alkyl radicals, more particularly methyl or ethyl radicals, C₁～C₆-a fluoroalkyl group, more particularly a trifluoroethyl group, an aryl group, more particularly a phenyl group, or a heteroaryl group, more particularly a pyridyl or pyrazinyl group;

when Y is in the (N3) position, Y represents an aryl group, more particularly a phenyl group, or a heteroaryl group, more particularly a pyridyl or pyrimidinyl group;

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups, more particularly by 1 or 2 atoms or groups, selected from halogen atoms, more particularly fluorine, chlorine atoms, C₁～C₆-alkyl radicals, more particularlyA methyl group, and C₁～C₆-alkoxy groups, more particularly methoxy groups; and/or

The bond at the C4-C5 position is a double or single bond; and/or

R₁And R₂Each independently of the other represents an aryl group, more particularly a phenyl group, C₁～C₆-alkyl groups, more particularly methyl, ethyl, n-propyl, tert-butyl, isopropyl groups; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocyclic ring, more particularly pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, optionally substituted by 1 or 2C₁～C₆-alkyl groups, more particularly methyl groups.

Among the compounds of general formula (I) which are the subject of the present invention, the second subclass of compounds consists of those in which:

w represents an oxygen or sulfur atom; and/or

X₁、X₂And X₃Each independently of the others, represents a hydrogen atom or a halogen atom, more particularly a fluorine, chlorine or bromine atom, C₁～C₆Alkyl radicals, more particularly methyl radicals, C₁～C₆-alkoxy groups, more particularly methoxy groups; and/or

X₄Represents a hydrogen atom; and/or

Y is in the (N2) or (N3) position and represents an aryl group, more particularly a phenyl group, or a heteroaryl group, more particularly a pyridyl, pyrazinyl or pyrimidinyl group;

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups, more particularly by 1 or 2 atoms or groups, selected from halogen atoms, more particularly fluorine, chlorine atoms, C₁～C₆-an alkyl group, more particularly a methyl group, and C₁～C₆Alkoxy radicals, more particularly methoxy radicalsA radical group; and/or

The bond at the C4-C5 position is a double or single bond; and/or

R₁And R₂Each independently of the other represents an aryl group, more particularly a phenyl group, C₁～C₆-alkyl groups, more particularly methyl, ethyl, n-propyl, tert-butyl, isopropyl groups; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle, more particularly pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, optionally substituted by 1 or 2C 1-C₆-alkyl groups, more particularly methyl groups.

Among the compounds of general formula (I) which are the subject of the present invention, the third subclass of compounds consists of those in which:

w represents an oxygen or sulfur atom; and/or

X₁、X₂And X₃Each independently of the others, represents a hydrogen atom or a halogen atom, more particularly a fluorine, chlorine or bromine atom, C₁～C₆Alkyl radicals, more particularly methyl radicals, C₁～C₆-alkoxy groups, more particularly methoxy groups; and/or

X₄Represents a hydrogen atom; and/or

Y is in the (N3) position and represents an aryl group, more particularly a phenyl group, or a heteroaryl group, more particularly a pyridyl or pyrimidinyl group;

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups, more particularly by 1 or 2 atoms or groups, selected from halogen atoms, more particularly fluorine, chlorine atoms, C₁～C₆-an alkyl group, more particularly a methyl group, and C₁～C₆-alkoxy groups, more particularly methoxy groups; and/or

The bond at the C4-C5 position is a double or single bond; and/or

R₁And R₂Each independently of the others, represents an aryl group, more particularly a phenyl group, or C₁～C₆-alkyl groups, more particularly methyl, ethyl, tert-butyl, isopropyl groups; or R₁And R₂Together with the nitrogen atom bearing them forming a heterocyclic ring, more particularly a piperidinyl group, optionally substituted by 1 or 2C₁～C₆-alkyl groups, more particularly methyl groups.

The compounds of formula (I) may be prepared according to the methods described in the schemes below.

According to the first preparation route (scheme 1), compounds of the general formula (II) in which X₁、X₂、X₃And X₄Reaction with methyl carbonate in the presence of a catalytic amount of a base, e.g., sodium methoxide or sodium hydride, as defined in formula (I), affords the ketoester of formula (III). The condensation of the ketoester (III) with hydrazine, for example in a polar solvent such as DMF or acetic acid, allows the isolation of the pyrazole of the formula (IV). The latter are then non-selectively N-substituted by the action of aryl or heteroaryl halides of the formula Y-hal, where Y is as defined in formula (I) and hal is a halogen atom, for example iodine or bromine, in the presence of a base, for example potassium carbonate or cesium carbonate or in the presence of potassium triphosphate, a catalytic amount of copper salt and a diamine (S.l. Buchwald, J.am. chem. Soc. (American society for chemistry, 2001, 123, 7727).

The mixture obtained consists of positional isomers of the general formulae (Va) and (Vb) in which the Y groups are located in the 2-and 3-positions, respectively, of the pyrazole ring, and is subsequently converted into the corresponding compounds by means of the general formula ClC (W) NR₁R₂(wherein W, R₁And R₂The aminomethylcarboxylic acid chloride derivatives as defined in formula (I) are derivatized in the presence of a base, e.g. potassium carbonate, sodium hydride or triethylamine, to give carbamates of formula (Ia) and (Ib) which are at this stage isolated by methods known to those skilled in the art, e.g. chromatography on silica gel columns.

Scheme 1

Alternatively, the second preparation route enables the preparation of compounds of general formula (Ia) (scheme 2)

Scheme 2

Which comprises a ketoester of the formula (III) as defined above and a ketone of the formula Y-NH-NH₂For example, in a polar solvent such as DMF or acetic acid, and enables the isolation of pyrazoles of formula (Va) as defined above. The latter being subsequently obtained by means of the general formula ClC (W) NR as defined above₁R₂By the action of the aminomethylcarbonyl chloride derivative of (a), in the presence of a base such as potassium carbonate, sodium hydride or triethylamine, to obtain a carbamate of the general formula (Ia).

The single bond at the C4-C5 position of the compound of formula (I) may optionally be dehydrogenated to form a double bond according to methods known to those skilled in the art, for example Tetrahedron, 1989, 45, 18, 5791-5804, in analogy to the method described by KozoShido et al. Alternatively, compounds of formula (I) containing a single bond at the C4-C5 position may be dehydrogenated by reaction with a halogenating agent, e.g., N-bromosuccinimide, in the presence of an initiator such as 2, 2' -azobis (2-methylpropanenitrile). Under such conditions, the compound of formula (I) comprising a single bond at the C4-C5 position is first halogenated and then the resulting intermediate undergoes an elimination reaction to yield a compound of formula (I) comprising a double bond at the C4-C5 position.

In schemes 1 and 2, when methods for their preparation are not specified, these reactants are commercially available or described in the literature, or can be prepared according to methods described in the literature or according to those methods well known to those skilled in the art.

The compounds of the general formula (II) are commercially available or can be prepared by methods described in the literature (Sims, J.J. et al, Tetrahedron Lett., 1971, 951).

Another subject of the invention, according to another of its aspects, is the compounds of formulae (Va) and (Vb). These compounds are useful as intermediates in the synthesis of compounds of formula (I).

The chemical structures and physical properties of some of the compounds of general formulae (Va) and (Vb) are given in table 1 below. The melting point of the product is given in the column "PF".

TABLE 1

Numbering	X	X	X	X	Y	PF(℃)
							Va.1	H	H	H	H	2- (4-methylphenyl)	221-222
Vb.1	H	Me	H	H	3- (pyridin-4-yl)	315-316
							Va.2	H	F	H	H	2- (4-fluorophenyl)	220-221
Vb.2	H	Cl	H	H	3- (pyridin-4-yl)	336-342
							Va.3	H	Cl	H	H	2- (pyridin-4-yl)	190-216

The preparation of certain compounds of the invention is described in the following examples. These examples are not intended to be limiting and merely illustrate the invention. Many of the compounds cited as examples refer to those given in tables 1 and 2. The structure of the obtained compound was confirmed by elemental microanalysis, LC-MS (liquid chromatography coupled with mass spectrometry) analysis, and IR and NMR spectroscopy.

Example 1(Compound 1)

N, N-diethylcarbamate of 7-fluoro-2- (4-fluorophenyl) -4, 5-dihydro-2H-benzo [ e ] indazol-1-yl

1.1 methyl 6-fluoro-2-hydroxy-3, 4-dihydro--1-formic acid ester

12.66g (316mmol) of 60% sodium hydride in oil, 900mL of toluene and 17.69mL (210mmol) of dimethyl carbonate were introduced into a 2L reactor. The reaction mixture was stirred at reflux for 1 h. Followed by the addition of 19g (115mmol) of 6-fluoro-3, 4-dihydro-1H--2-ketone in 350mL of toluene. The reaction mixture was heated at reflux for 24 h. The reaction mixture was then cooled to 0 ℃ and then acidified by the addition of 114mL of acetic acid. 114mL of water was added and the organic phases were separatedSeparated by settling and washed 2 times with 150mL water each time and then with 100mL of saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure, as a result, 26.1g of the product was obtained, which was used directly in the next stage.

1.27-fluoro-2- (4-fluorophenyl) -1-hydroxy-4, 5-dihydro-2H-benzo [ e ] indazole (Va.2)

2g (9mmol) of the product obtained in stage 1.1 and 2.73g (16.8mmol) of 4-fluorophenylhydrazine hydrochloride are introduced into a 100mL reactor. The mixture was dissolved in 100mL of acetic acid and heated at reflux for 4 h. The reaction mixture was subsequently cooled and then concentrated under reduced pressure. The residue was dispersed in 150mL ethyl acetate and 100mL water. The organic phase is separated by settling and washed 2 times with 100mL of water each time and then once with 100mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure, as a result of which 3.5g of the expected compound are obtained.

Melting point: 220-221 DEG C

NMR¹H(DMSO D6)：δ(ppm)：2.72(dxd，2H)，2.95(dxd，2H)，7.01(m，2H)，7.3(m，2H)，7.75(m，3H).

1.37-fluoro-2- (4-fluorophenyl) -4, 5-dihydro-2H-benzo [ e ] -indazol-1-yl (of) N, N-diethylcarbamate (Compound 1)

3.5g (9mmol) of the product obtained in stage 1.2, 3, 48g (25mmol) of potassium carbonate and 2.66g (21mmol) of N, N-diethylcarbamoyl chloride are introduced into a 500mL reactor. The reaction mixture was heated at reflux for 24h and subsequently concentrated under reduced pressure. The product obtained was dispersed in 100mL of ethyl acetate. The organic phase was washed 2 times with 100mL of water each time, followed by 1 time with 100mL of saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure, resulting in 5.96g of a crude product. The mixture was purified by chromatography on a silica gel column, wherein elution was carried out with a mixture of cyclohexane and ethyl acetate. 2.2g of the expected product are subsequently isolated and recrystallized from isopropanol to yield 1.5g (3.77mmol) of the final product.

Melting point: 141-142 DEG C

NMR¹H(CDCl₃)：δ(ppm)：1.95(t，3H)，2.6(t，3H)，2.97(t，2H)，3.98(t，2H)，3.4(q，2H)，3.52(q，2H)，7.00(m，2H)，7.2(m，2H)，7.32(m，1H)，7.56(m，2H).

Example 2(Compound 2)

N, N-diethylcarbamate of 7-fluoro-2- (4-fluorophenyl) -2H-benzo [ e ] indazol-1-yl

A solution of 0.7g (1.76mmol) of the N, N-diethylcarbamate of 7-fluoro-2- (4-fluorophenyl) -4, 5-dihydro-2H-benzo [ e ] indazol-1-yl obtained in stage 1.3 of example 1 and 1.2g (5.2mmol) of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone in 25mL of toluene was stirred at reflux for 2H and then cooled. The mixture was poured into 100mL of ethyl acetate. The organic phase is washed 2 times with 100mL each of saturated aqueous sodium bicarbonate solution, with 100mL of water and then with 100mL of saturated aqueous sodium chloride solution. The organic phase is separated off by settling, then dried over magnesium sulfate and concentrated under reduced pressure. After purification by chromatography on a silica gel column (eluent: mixture of dichloromethane and ethyl acetate) and recrystallization from isopropanol, 500mg (1.26mmol) of the expected product are obtained.

Melting point: 159-160 ℃ C

NMR¹H(DMSO)：δ(ppm)：1.04(t，3H)，1.21(t，3H)，3.28(q，2H)，3.55(q，2H)，7.45(m，3H)，7.7(m，5H)，7.9(dxd，1H).

Example 3(Compounds 3 and 4)

N, N-diethyl carbamate hydrochloride of 7-chloro-2- (pyridin-4-yl) -4, 5-dihydro-2H-benzo [ e ] -indazol-1-yl (Compound 3) and N, N-diethyl carbamate hydrochloride of 7-chloro-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] -indazol-1-yl (Compound 4)

3.1 methyl 6-chloro-2-hydroxy-3, 4-dihydro--1-formic acid ester

10.1g (252mmol) of 60% sodium hydride in oil, 621mL of toluene and 14.18mL (163mmol) of dimethyl carbonate were introduced into a 2L reactor. The reaction mixture was stirred at reflux for 1 h. Followed by addition of 15.2g (84mmol) of 6-fluoro-3, 4-dihydro-1H-naphthalene-2-ketone in 268mL toluene. The reaction mixture was heated at reflux for 24 h. It was then cooled to 0 ℃ and then acidified by addition of 92mL of acetic acid. 114mL of water are added and the separated organic phases are separated by settling and washed 2 times with 150mL of water each time and then with 100mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (elution was carried out with a mixture of cyclohexane and dichloromethane) and 12.8g (53.6mmol) of the expected product were obtained, which was used directly in the next stage.

3.27-chloro-1-hydroxy-4, 5-dihydro-2H-benzo [ e ] indazole

28g (117mmol) of the product obtained in stage 3.1 and 28.6mL (586.6mmol) of hydrazine monohydrate were introduced into a 2 liter reactor. The mixture was dissolved in 782mL of acetic acid and heated at reflux for 4 h. The reaction mixture was subsequently cooled and then concentrated under reduced pressure. The resulting product was dispersed in 300mL ethyl acetate and 300mL water. The organic phase is separated by settling and washed 2 times with 200mL of water each time and then once with 200mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. The residue obtained is triturated from 200mL of ethyl ether and subsequently filtered off, so as to yield 25g (113.3mol) of the expected product.

Melting point: 232-233 DEG C

3.37-chloro-1-hydroxy-2- (pyridin-4-yl) -4, 5-dihydro-2H-benzo [ e ] indazole and 7-chloro-1-hydroxy-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] indazole

15.2g (68.8mmol) of the product obtained in stage 3.2, 16.95g (82.66mmol) of 4-iodopyridine, 4.14mL (34.44mmol) of trans-1, 2-diaminocyclohexane, 1.31g (6.89mmol) of copper iodide and 36.55g (172.2mmol) of potassium phosphate are introduced into a 2L reactor under an inert atmosphere. The reaction mixture was suspended in 690mL dioxane, heated at reflux for 24h, and then cooled. The mixture was concentrated under reduced pressure and then dispersed in 200mL of water. The aqueous phase was acidified to pH5 by the sequential addition of acetic acid. The suspension is stirred for 30min, and the precipitate obtained is subsequently filtered off, washed with water and then dried under reduced pressure to give 16.6g (55.7mmol) of the expected N-arylated product as a mixture of isomers.

LC-MS: 2 peaks at 60.4% and 38%, corresponding to [ MH ]]⁺＝298。

N, N-diethyl carbamate hydrochloride of 47-chloro-2- (pyridin-4-yl) -4, 5-dihydro-2H-benzo [ e ] -indazol-1-yl (Compound 3) and N, N-diethyl carbamate hydrochloride of 7-chloro-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] -indazol-1-yl (Compound 4)

13g (43.66mmol) of the isomer mixture obtained in stage 3.3, 18.1g (131mmol) of finely ground potassium carbonate and 11.07mL (87.32mmol) of N, N-diethylcarbamoyl chloride are introduced under inert atmosphere into a 2L reactor. The reaction mixture was suspended in 1L of acetonitrile, heated at reflux for 24h and subsequently cooled. The reaction mixture was concentrated under reduced pressure. The product obtained was dispersed in 300mL of ethyl acetate and 300mL of water. The organic phase is separated off by settling and washed 2 times with 200mL of water each time and 1 time with 200mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and subsequently concentrated under reduced pressure. The product obtained contained 2 positional isomers (compounds 3 and 4). The latter is separated by column chromatography (300g Merck 15-40 μm silica, eluent: a mixture of heptane and ethyl acetate).

N, N-diethyl carbamate hydrochloride of 7-chloro-2- (pyridin-4-yl) -4, 5-dihydro-2H-benzo [ e ] -indazol-1-yl (Compound 3)

The product 3 thus isolated was converted to the hydrochloride as follows: dissolved in a 0.1N solution of hydrochloric acid in isopropanol. The solution was concentrated to dryness under reduced pressure. After trituration from ethyl ether, filtration and drying under reduced pressure, 2.3g (5.79mmol) of the final product are obtained.

Melting point: 250 to 251 DEG C

NMR¹H(DMSO)：δ(ppm)：1.08(t，3H)，1.31(t，3H)，2.98(m，4H)，3.3(q，2H)，3.68(q，3H)，7.27(d，1H)，7.38(dxd，1H)，7.46(dxd，1H)，7.92(d，2H)，8.87(d，2H).

N, N-diethyl carbamate hydrochloride of 7-chloro-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] -indazol-1-yl (Compound 4)

The product thus isolated was converted to the hydrochloride salt as follows: dissolved in a 0.1N solution of hydrochloric acid in isopropanol. The solution was concentrated to dryness under reduced pressure. After trituration from ethyl ether, filtration and drying under reduced pressure, 6.2g (15.62mmol) of the final product are obtained.

Melting point: 224-226 ℃ C

NMR¹H(DMSO)：δ(ppm)：1.18(t，3H)，1.29(t，3H)，3.02(t，2H)，3.31(m，4H)，3.51(q，2H)，7.20(d，1H)，7.32(dxd，1H)，7.45(d，1H)，8.08(d，2H)，8.98(d，2H).

Example 4(Compound 5)

N, N-diethyl carbamate hydrochloride of 8-methoxy-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] -indazol-1-yl

4.1 methyl 6-methoxy-2-hydroxy-3, 4-dihydro--1-formic acid ester

3.4g (85.12mmol) of 60% sodium hydride in oil, 180mL of toluene and 4.78mL (56.75mmol) of dimethyl carbonate were introduced into a 1L reactor. The reaction mixture was stirred at reflux for 1 h. Followed by addition of 5g (28.37mmol) of 7-methoxy-3, 4-dihydro-1H--2-ketone in 100mL of toluene. The reaction mixture was heated at reflux for 24 h. The reaction mixture was then cooled to 0 ℃ and then acidified by the addition of 30mL of acetic acid. 30mL of water are added and the separated organic phases are separated off by settling and washed 2 times with 50mL of water each time and then with 50mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. Purification by chromatography on a column of silica gel (eluent: mixture of dichloromethane and heptane) gave 3.9g (16.64mmol) of the expected product, which was used directly in the next stage.

4.21-hydroxy-8-methoxy-4, 5-dihydro-2H-benzo [ e ] indazole

3.9g (16.65mmol) of the product obtained in stage 4.1 and 4.06mL (83.24mmol) of hydrazine monohydrate were introduced into a 0.5L reactor. The mixture was dissolved in 166mL of acetic acid and heated at reflux for 4 h. The reaction mixture was subsequently cooled and then concentrated under reduced pressure. The resulting product was dispersed in 100mL ethyl acetate and 100mL water. The organic phase is separated by settling and washed 2 times with 100mL of water each time and then once with 100mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. The residue obtained is triturated from 50mL of ethyl ether and subsequently filtered off, thus obtaining 2.4g (11.1mmol) of the expected product.

4.31-hydroxy-8-methoxy-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] indazole

1.2g (5.55mmol) of the product obtained in stage 4.2, 1.36g (6.66mmol) of 4-iodopyridine, 0.33mL (2.77mmol) of trans-1, 2-diaminocyclohexane, 0.105g (0.55mmol) of copper iodide and 2.94g (13.87mmol) of potassium phosphate are introduced into a 0.1L reactor under an inert atmosphere. The reaction mixture was suspended in 55mL dioxane, heated at reflux for 24h, and then cooled. The mixture was then dispersed in a 1L1/1 mixture of water and ethyl acetate. The organic phase was separated by settling and then washed with water (50 mL). The aqueous phase was acidified to pH5 by the sequential addition of acetic acid. The precipitate obtained is filtered off, washed with water and subsequently dried under reduced pressure to give 0.2g (0.68mmol) of the expected N-arylated product. The organic phase is dried over magnesium sulfate and subsequently concentrated under reduced pressure. The product obtained is purified by chromatography on a silica gel column (eluent: mixture of dichloromethane and methanol) to yield a further 0.57g (1.94mmol) of the expected N-arylated product.

NMR¹H(DMSO D6)：δ(ppm)：2.89(dxd，2H)，3.09(dxd，2H)，3.73(s，3H)，6.2(dxd，1H)，7.1(m，2H)，7.48(m，2H)，8.6(m，2H).

N, N-diethylcarbamate of 48-methoxy-3- (pyridin-4-yl) -4, 5-dihydro-3H-benzo [ e ] indazol-1-yl (Compound 5)

0.77g (2.63mmol) of the product obtained in stage 4.3, 1.09g (7.88mmol) of finely ground potassium carbonate and 0.67mL (5.25mmol) of N, N-diethylcarbamyl chloride are introduced under inert atmosphere into a 0.1L reactor. The reaction mixture was suspended in 30mL of acetonitrile, heated at reflux for 24h and subsequently cooled. The reaction mixture was concentrated under reduced pressure. The product obtained was dispersed in 100mL of ethyl acetate and 100mL of water. The organic phase is separated off by settling and washed 2 times with 50mL of water each time and 1 time with 50mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and subsequently concentrated under reduced pressure. The product obtained is purified by column chromatography (90g Merck 15-40 μm silica, eluent: a mixture of heptane and ethyl acetate). The compound thus isolated is recrystallized from isopropanol and subsequently redissolved in a 0.1N solution of hydrochloric acid in isopropanol. The solution was concentrated to dryness under reduced pressure. After trituration from ethyl ether, filtration and drying under reduced pressure, 234mg (0.59mmol) of the expected compound are obtained.

Melting point: 225-227 DEG C

NMR¹H(DMSO)：δ(ppm)：1.15(t，3H)，1.3(t，3H)，2.92(t，2H)，3.2-3.4(m，4H)，3.51(q，2H)，3.71(s，3H)，6.8(m，2H)，7.2(d，1H)，7.98(d，2H)，8.82(d，2H).

Example 5(Compound 82)

N, N-diisopropylcarbamate hydrochloride of 7-chloro-4, 5-dihydro-3- (pyridin-4-yl) -3H-benzo [ e ] indazol-1-yl

In a 1L reactor, a solution of 2.3g (7.72mmol) of the mixture of isomers obtained in stage 3.3 of example 3 in 30mL of dimethylformamide is added dropwise under an inert atmosphere and at 0 ℃ to a suspension of sodium hydride in 17mL of dimethylformamide. After stirring for 1h at ambient temperature, a solution of 1.39g (8.5mmol) of N, N-diisopropylcarbamoyl chloride in 30mL of dimethylformamide is added dropwise. The reaction mixture was stirred at ambient temperature for 18h, then concentrated under reduced pressure. The product obtained was dispersed in 300mL of ethyl acetate and 300mL of water. The aqueous phase was adjusted to pH5 by the addition of acetic acid. The organic phase is separated by settling and washed 2 times with 200mL of water each time and then 1 time with 200mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. The product obtained is purified by column chromatography (300g Merck 15-40 μm silica, eluent: mixture of dichloromethane and ethyl acetate).

The compound thus isolated is converted to the hydrochloride by dissolution in a solution of 0.1N hydrochloric acid in isopropanol. The solution was concentrated to dryness under reduced pressure. After trituration from ethyl ether, filtration and drying under reduced pressure, 1.2g (2.6mmol) of the final product are obtained.

Melting point: 237 to 269 DEG C

NMR¹H(DMSO)：δ(ppm)：1.29(m，12H)，3.02(m，2H)，3.19(m，2H)，3.91(m，1H)，4.2(m，1H)，7.2(d，1H)，7.35(dxd，1H)，7.42(s，1H)，7.6(d，2H)，8.7(d，2H).

Example 6(Compound 84)

N, N-diisopropylcarbamate hydrochloride of 7-chloro-3- (pyridin-4-yl) -3H-benzo [ e ] indazol-1-yl

1.65g (3.38mmol) of N, N-diisopropylcarbamate of 7-chloro-4, 5-dihydro-3- (pyridin-4-yl) -3H-benzo [ e ] indazol-1-yl, prepared according to the method described in example 5, 1.105g (6.21mmol) of N-bromosuccinimide and 0.127g (0.78mmol) of 2, 2' -azobis (2-methylpropionitrile) were charged to a 100mL reactor. The mixture was dissolved in 40mL of carbon tetrachloride, stirred under reflux for 24h, and then concentrated under reduced pressure. The product obtained was dispersed in 300mL of dichloromethane and 2mL of concentrated ammonia. The organic phase was separated off and washed with 200mL of water and then with 200mL of saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of alumina (eluent: mixture of dichloromethane and methanol) and then on a column of silica (eluent: mixture of dichloromethane and ethyl acetate).

The product thus isolated is converted to the hydrochloride by dissolution in a solution of 0.1N hydrochloric acid in isopropanol. The solution was concentrated to dryness under reduced pressure. After trituration from ethyl ether, filtration and drying under reduced pressure, 1.2g (2.6mmol) of the final product are obtained.

Melting point: 234-248 DEG C

NMR¹H(DMSO)：δ(ppm)：1.42(m，12H)，4.02(m，1H)，4.41(m，1H)，7.6(dxd，1H)，7.8(m，3H)，7.92(d，2H)，8.15(d，1H)，8.79(d，2H).

The chemical structures and physical properties of several compounds of general formula (I) of the present invention are shown in table 2 below.

In the column of "salts" of the table, "HCl" represents the hydrochloride and "-" represents the compound in the base state. The molar ratio of acid to base is the opposite. The column "PF" gives the melting point of the product and the amorphous compound is characterized by its Mass Spectrometry (MS) analysis.

TABLE 2

^＊[MH]⁺

Pharmacological tests have been carried out on the compounds of the invention, demonstrating their advantages as having a therapeutically active substance.

The compounds of the present invention also exhibit water-soluble characteristics that cause them to exhibit good activity in vivo.

[3H]Ro5-4864 on peripheral benzodiazepines Investigation of binding of receptor (PBR or p site) Is especially suitable for the treatment of diabetes

The compound of the present invention was assayed for PBR or p site (peripheral-type p-benzodiazepine)Binding site of (d) of a protein.

The p-site receptor can be selectively labeled in the renal membrane of a rat (rat) cultured in the presence of [3H ] Ro 5-4864. The affinity of the compounds of the invention for these receptors was studied in vitro.

The animals used were male Sprague-Dawley mice (Iffa Credo) weighing 180-300 g. After removing the head, the kidney was removed and the tissue was processed at 4 ℃ using Polytron^TMHomogenizer 50mM Na in 35 volumes₂HPO₄In phosphate buffer, its pH is Na₂HPO₄Adjusted to 7.5 and homogenized for 2min below a maximum speed of 6/10. The membrane homogenate was filtered through gauze and diluted 10-fold with buffer.

[3H] Ro5-4864 (specific activity: 70-90 Ci/mmol; New England Nuclear), at a concentration of 0.5nM, was incubated in a final volume of 1mL buffer containing the test compound in the presence of 100. mu.L membrane homogenate.

After 3h incubation at 0 ℃, the membranes were recovered by filtration through Whatman GF/BTM filters washed 2 times with 4.5mL cold (0 ℃) incubation buffer each time. The radioactivity retained by the filter was determined by liquid scintillation mapping.

For each concentration of the compound investigated, [3H ] was determined]Percent inhibition of binding of Ro5-4864, then IC was determined₅₀The concentration, i.e., the concentration that inhibits 50% of the specific binding.

IC of most active Compounds of the invention₅₀Values ranged from 0.5nM to 300 nM. In particular, compounds 14, 20 and 56 in Table 2 exhibited IC's of 1.6nM, 2.8nM and 1.4nM, respectively₅₀Numerical values.

The compounds of the invention are thus compounds having a para-peripheral benzodiazepineA ligand for the affinity of the receptor.

Study of neuroprotective Activity

Survival test of motor neurons in 4-day-old mice after facial nerve amputation

Following facial nerve injury in immature mice, the motor neurons of the facial nucleus undergo a neuronal death process due to an apoptose action. Neuronal survival was assessed using neuronal counting and histology.

4-day immature mice were anesthetized with pentobarbital (3mg/kg via the i.p. route). The right nerve is exposed and severed from the exit of the styloid mastoid cavity. After waking up, the pups were returned to their mother rats and treated by oral or intraperitoneal route at a dose of between 1-10 mg/kg for 7 days by 1 or 2 daily administrations.

7 days after injury, animals were decapitated and brains were frozen in isopentane at-40 ℃. The entire surface of the nerve was cut into 10 μm wide pieces with the aid of a cryostat. Motor neurons were stained with cresyl violet and with Histo^TMSoftware (Biocom)^TM) Counting is performed.

In this mode, the compounds of the invention increase neuronal survival by 38-78%. The results of the motor neuron survival assay for compounds 14, 20 and 56 are shown in Table 3 below.

TABLE 3

Numbering	14	20	56
				Increase in neuronal survival% (10mg/kg po)	38％	59％	74％

The test results show that the highest active compounds of the invention can promote neuroprotective effect.

The compounds of the invention are therefore useful for the preparation of medicaments, in particular for the preparation of medicaments intended for the prevention and treatment of diseases involving peripheral benzodiazepinesA medicament for a disease of a receptor.

Thus, according to another of its aspects, the subject of the invention is a medicament comprising a compound of general formula (I), or an addition salt of the latter with a pharmaceutically acceptable acid, or a hydrate or solvate.

These medicaments are used for the treatment, in particular for the prophylaxis and/or treatment, of various types of neuropathies, such as traumatic and ischemic neuropathies, infections, alcoholism, diabetic, pharmacological or genetic neuropathies, and motor neuron symptoms, such as spinal muscular atrophy and amyotrophic lateral sclerosis. These drugs will also find application in the treatment of neurodegenerative diseases of the central nervous system, including acute, e.g., stroke and cranial and bone marrow trauma, or chronic, e.g., autoimmune diseases (multiple sclerosis), Alzheimer's disease, parkinson's disease, and any other disease where the administration of neuroprotective/neurotrophic factors should be therapeutically effective.

The compounds of the invention can also be used for the preparation of medicaments intended for the prevention and/or treatment of anxiety, for example, epileptic and sleep disorder-induced. This is because ligands at the PBR or p site stimulate the production of neurosteroids, e.g., pregnenolone (pregnenolone), dehydroepiandrosterone, and 3 α -hydroxy-5 α -pregn-20-one, by facilitating the transfer of cholesterol from the outside of the mitochondrial membrane to the inside. These neurosteroids modulate GABA_A-the activity of chloride channel macromolecular complexes, thus giving anxiolytic, anticonvulsant and sedative activity.

The compounds of the invention can also be used for the treatment of acute or chronic renal insufficiency, glomerulonephritis, diabetic nephropathy, myocardial ischemia and cardiac insufficiency, myocardial infarction, lower limb ischemia, coronary vasospasm, angina pectoris (angiode poitrine), diseases associated with heart valves, inflammatory heart diseases, side effects due to cardiotoxic drugs or to cardiac surgery, atherosclerosis and its thromboembolic complications, restenosis (restenosis), graft rejection or symptoms associated with incorrect proliferation or incorrect migration of smooth muscle cells.

In addition, recent data in the literature indicate that peripheral benzodiazepinesReceptors may play a fundamental role in the regulation of cell proliferation and the process of cancer. In general and in comparison with normal tissues, peripheral benzodiazepines are observed in various types of tumors and cancersAn increase in receptor density.

In human astrocytomas, peripheral benzodiazepinesThe expression level of the receptor correlates with the malignancy of the tumor, the proliferative index, and the survival rate of the patient. In human brain tumors, peripheral benzodiazepinesThe increase in the number of receptors is used as a diagnostic index in medical imaging and as a therapeutic target for treatment with peripheral benzodiazepinesA ligand for a receptor and a cytostatic drug. High density peripheral benzodiazepinesReceptors have also been observed in ovarian and breast cancers. With regard to the latter, it has now been demonstrated that peripheral benzodiazepinesThe expression level of the receptor correlates with the invasive potential of the tumor; furthermore, peripheral benzodiazepinesThe presence of the receptor agonist stimulates a mammalian cancer line.

The above combined results indicate that the peripheral benzodiazepine is presentThe receptor has a detrimental effect on the cancerization process, constituting a study on the peripheral benzodiazepines capable of blocking their actionReceptors have a relevant basis for the specific synthetic ligands.

Thus, these compounds are used to treat tumors and cancers.

Peripheral benzodiazepinesReceptors are also present in the skin, in which respect the compounds that can be used according to the invention can be used for the prevention or treatment of skin stress.

The term "skin stress" is understood to mean any kind of irritation which can cause damage, in particular to the epidermis, whatever the agent which can cause such stress. Such agents may be in vivo and/or in vitro, e.g., chemical or free radical, or external, e.g., ultraviolet radiation.

Thus, the compounds which can be used according to the invention can prevent and treat skin irritation, dry spots, erythema, dysbestehsique sensations, burning sensations, itching of the skin and/or mucous membranes, or ageing, and can also be used for skin diseases, such as psoriasis, les maladies prurigineuses, herpes, photodermatosis, atopic dermatitis, contact dermatitis, lichen, pruritus, insect bites, disorders in fibrogenesis and other collagen maturation, immunological diseases or dermatological disorders, such as eczema.

The compounds of the invention are also useful in the prevention and treatment of chronic inflammatory diseases, particularly rheumatoid arthritis, and pulmonary inflammatory diseases.

According to another of its aspects, the present invention relates to a pharmaceutical composition comprising the compound of the present invention as a main active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate, or solvate of said compound, and at least one pharmaceutically acceptable excipient. The excipients are selected from the common excipients known to those skilled in the art, according to the desired pharmaceutical form and method of administration.

In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the main active ingredient of the above general formula (I), or an optional salt, solvate or hydrate thereof, may be administered in unit administration form, in a mixture with conventional pharmaceutical excipients, to animals or humans, in order to prevent or treat the above diseases or disorders.

Suitable unit-dosage administration forms include oral forms, for example, tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, as well as forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration and forms and implants for rectal administration. For topical application, the compounds of the invention may be used in the form of creams, gels, ointments or lotions.

By way of example, a tablet of a compound of the invention for single dose administration may comprise the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl-methylcellulose 2.25mg

Magnesium stearate 3.0mg

The single dosage form comprises a daily dosage of administration of 0.001-20 mg of the main active ingredient per kilogram of body weight, depending on the pharmaceutical form.

There may be special cases where higher or lower doses are appropriate; such dosages are also within the scope of the present invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

According to another aspect of the present invention there is also provided a method of treating a disease state as indicated above, comprising administering to a patient an effective amount of one of a compound of the present invention, a pharmaceutically acceptable salt thereof, a solvate of such a compound or a hydrate of such a compound.

Claims (12)

1. A compound corresponding to the general formula (I):

wherein

W represents an oxygen or sulfur atom;

X₁、X₂、X₃and X₄Each independently of the others represents a hydrogen or halogen atom or a cyano group, C₁～C₆Alkyl radical, C₁～C₆-fluoroalkyl, C₁～C₆-alkoxy, C₁～C₆-a fluoroalkoxy group;

y is at the (N2) or (N3) position;

when Y is at the (N2) position, Y represents C₁～C₆Alkyl radical, C₁～C₆-a fluoroalkyl group, an aryl group comprising 6 to 10 carbon atoms or a 5-6 membered heteroaryl group comprising 1 and 2 heteroatoms;

when Y is in the (N3) position, Y represents an aryl group containing 6 to 10 carbon atoms or a 5-6 membered heteroaryl group containing 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more groups selected from halogen atoms, C₁～C₆Alkyl radical, C₁～C₆-alkoxy, C₁～C₆-alkylthio radical, C₁～C₆alkyl-S (O) -, C₁～C₆alkyl-S (O)₂-、C₁～C₆-an atom or group of a fluoroalkyl group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others, represents an aryl group containing 6 to 10 carbon atoms, a benzyl group or C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by 1 or more C₁～C₆-an alkyl or benzyl group;

said compounds being in the form of a base or of an addition salt with an acid.

2. A compound of the general formula (I) according to claim 1,

w represents an oxygen or sulfur atom;

X₁、X₂and X₃Each independently of the others represents a hydrogen atom or a halogen atom or a cyano group, C₁～C₆-alkyl radical or C₁～C₆-an alkoxy group;

X₄represents a hydrogen atom;

y is at the (N2) or (N3) position;

when Y is at the (N2) position, Y represents C₁～C₆-alkyl radical, C₁～C₆-a fluoroalkyl group, an aryl group comprising 6 to 10 carbon atoms or a 5-6 membered heteroaryl group comprising 1 and 2 heteroatoms;

when Y is in the (N3) position, Y represents an aryl group containing 6 to 10 carbon atoms or a 5-6 membered heteroaryl group containing 1 and 2 heteroatoms,

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups selected from halogen atoms, C₁～C₆-alkyl radicals and C₁～C₆-an alkoxy group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others represents an aryl radical containing 6 to 10 carbon atoms or C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by 1 or 2C₁～C₆-an alkyl group;

said compounds being in the form of a base or of an addition salt with an acid.

3. A compound of the general formula (I) according to claim 1 or 2,

w represents an oxygen or sulfur atom; and/or

X₁、X₂And X₃Each independently of the others represents a hydrogen atom or a halogen atom or C₁～C₆-alkyl radical, C₁～C₆-an alkoxy group;

X₄represents a hydrogen atom;

y is in the (N2) or (N3) position and represents an aryl group containing 6 to 10 carbon atoms or a 5-6 membered heteroaryl group containing 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups selected from halogen atoms, C₁～C₆-alkyl radicals and C₁～C₆-alkanesAn oxy group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others represents an aryl radical containing 6 to 10 carbon atoms or C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by 1 or 2C₁～C₆-an alkyl group;

said compounds being in the form of a base or of an addition salt with an acid.

4. A compound of the general formula (I) according to claim 1 or 2,

w represents an oxygen or sulfur atom;

X₁、X₂and X₃Each independently of the others represents a hydrogen atom or a halogen atom or C₁～C₆-alkyl radical, C₁～C₆-an alkoxy group;

X₄represents a hydrogen atom;

y is in the (N3) position and represents an aryl group containing 6 to 10 carbon atoms or a 5-6 membered heteroaryl group containing 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more atoms or groups selected from halogen atoms, C₁～C₆-alkyl radicals and C₁～C₆-an alkoxy group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others represents an aryl radical containing 6 to 10 carbon atoms, C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by 1 or 2C₁～C₆-an alkyl group;

said compounds being in the form of a base or of an addition salt with an acid.

5. A process for the preparation of compounds of the general formula (I) according to any of claims 1 to 4, characterized in that,

a mixture of positional isomers of the general formulae (Va) and (Vb),

wherein, X₁、X₂、X₃、X₄And Y is as defined in formula (I) according to any one of claims 1 to 4, and wherein the Y groups are located at the (N2) and (N3) positions, respectively, of the pyrazole ring,

and the general formula ClC (W) NR₁R₂In the presence of a base, wherein W, R₁And R₂As defined in general formula (I) according to any one of claims 1 to 4,

after separation, compounds of the general formulae (Ia) and (Ib) are obtained,

the single bond at the C4-C5 position is then optionally dehydrogenated to form a double bond.

6. A process for the preparation of a compound of formula (Ia),

wherein

W represents an oxygen or sulfur atom;

X₁、X₂、X₃and X₄Each independently of the others represents hydrogen, a halogen atom or a cyano group, C₁～C₆Alkyl radical, C₁～C₆-fluoroalkyl, C₁～C₆-alkoxy, C₁～C₆-a fluoroalkoxy group;

y is in the (N2) position and represents C₁～C₆Alkyl radical, C₁～C₆-a fluoroalkyl group, an aryl group comprising 6 to 10 carbon atoms or a 5-6 membered heteroaryl group comprising 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more groups selected from halogen atoms, C₁～C₆Alkyl radical, C₁～C₆-alkoxy, C₁～C₆-alkylthio radical, C₁～C₆alkyl-S (O) -, C₁～C₆alkyl-S (O)₂-、C₁～C₆-an atom or group of a fluoroalkyl group;

the bond at the C4-C5 position is a double or single bond;

R₁and R₂Each independently of the others, represents an aryl group containing 6 to 10 carbon atoms, a benzyl group or C₁～C₆-an alkyl group; or R₁And R₂Together with the nitrogen atom bearing them, form a heterocycle which is optionally substituted by C₁～C₆-an alkyl or benzyl group;

characterized in that a compound of the general formula (Va)

Wherein X₁、X₂、X₃、X₄And Y is as defined above for formula (Ia),

and the general formula ClC (W) NR₁R₂In the presence of a base, wherein W, R₁And R₂As defined in formula (I) above,

the single bond at the C4-C5 position is then optionally dehydrogenated to form a double bond.

7. A compound of the formula (Va)

Wherein

X₁、X₂、X₃And X₄Each independently of the others represents a hydrogen or halogen atom or a cyano group, C₁～C₆Alkyl radical, C₁～C₆-fluoroalkyl, C₁～C₆-alkoxy, C₁～C₆-a fluoroalkoxy group;

y represents C₁～C₆Alkyl radical, C₁～C₆-a fluoroalkyl group, an aryl group comprising 6 to 10 carbon atoms or a 5-6 membered heteroaryl group comprising 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more groups selected from halogen atoms, C₁～C₆Alkyl radical, C₁～C₆-alkoxy, C₁～C₆-alkylthio radical, C₁～C₆alkyl-S (O) -, C₁～C₆alkyl-S (O)₂-、C₁～C₆-an atom or group of a fluoroalkyl group.

8. A compound of the formula (Vb)

Wherein

X₁、X₂、X₃And X₄Each independently of the others represents a hydrogen or halogen atom or a cyano group, C₁～C₆Alkyl radical, C₁～C₆-fluoroalkyl, C₁～C₆-alkoxy or C₁～C₆-a fluoroalkoxy group;

y represents an aryl group comprising 6 to 10 carbon atoms or a 5-6 membered heteroaryl group comprising 1 and 2 heteroatoms;

the aryl or heteroaryl group being optionally substituted by 1 or more groups selected from halogen atoms, C₁～C₆Alkyl radical, C₁～C₆-alkoxy, C₁～C₆-alkylthio radical, C₁～C₆alkyl-S (O) -, C₁～C₆alkyl-S (O)₂-、C₁～C₆-an atom or group of a fluoroalkyl group.

9. Pharmaceutical composition, characterized in that it comprises a compound of general formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt of said compound, and at least one pharmaceutically acceptable excipient.

10. Use of a compound of general formula (I) according to any one of claims 1 to 4 for the preparation of a medicament intended for the prevention or treatment of diseases involving peripheral benzodiazepinesA disease of the receptor.

11. Use of a compound of general formula (I) according to claim 10 for the preparation of a medicament intended for the prevention or treatment of: peripheral neuropathy, motor neuron disorders, neurodegenerative disorders of the central nervous system, anxiety, epilepsy, sleep disorders, acute or chronic renal insufficiency, glomerulonephritis, diabetic nephropathy, myocardial ischemia and cardiac insufficiency, myocardial infarction, lower limb ischemia, coronary vasospasm, angina pectoris, diseases associated with heart valves, inflammatory heart diseases, side effects due to cardiotoxic drugs or due to cardiac surgery, atherosclerosis and its thromboembolic complications, restenosis, graft rejection, symptoms associated with incorrect proliferation or incorrect migration of smooth muscle cells, tumors and cancers, skin stress, chronic inflammatory diseases, and inflammatory diseases of the lung.

12. The use of claim 11, wherein the chronic inflammatory disease is rheumatoid arthritis.