LT3231B - Methylpiperazinoazepine derivatives, preparation and use tereof - Google Patents

Abstract

Methylpiperazinoazepine derivatives of general formula (I), wherein X, R1, R2, N1 and N2 have various meanings, pharmaceutically acceptable salts thereof, and their preparation and use, are described.

Description

The present invention relates to novel methylpiperazinazepine derivatives and their non-toxic salts, as well as to the synthesis and therapeutic use of these novel compounds.

The novel methylpiperazinazepine derivatives are represented by the general formula I:

in which

X represents an oxygen atom, a sulfur atom, a selenium or a group NH or NR ₃ wherein R ₃ is a "G ₆ " group or a branched or unbranched alkyl group of 1 carbon atom;

up to 4

R _x represents a hydrogen atom, a halogen atom or a branched or unbranched alkyl group of 1 to 4 carbon atoms;

N _x represents a benzene ring and N _{2 a} pyridine ring, or vice versa, provided that R _x and R ₂ are

R ₂ represents a hydrogen atom, a halogen atom or a branched or unbranched alkyl group of 1 to 4 carbon atoms; and hydrogen while X is sulfur, oxygen or NH, N _x is pyridine and N ₂ benzene, and the pyridine nitrogen atom is not in position d ', and both, N _x and N ₂ may be benzene when X is a selenium atom.

Some derivatives of methylpiperazinazepine have already been reported in the literature (see Dupont et al., Act. Crystal., C43, 716-718 (1987) for oxygen derivatives; Hoffmann et al., U.S. Patent No. 4,363,785 (1979) for a sulfur compound; Chakrabarti et al. ., Journal of Medicinal Chemistry, Vol. 32, No. 10, 2375-2381 (1989) for a nitrogen derivative). However, in contrast to the derivatives of the present invention, the methylpiperazine azepines disclosed so far do not show interesting pharmacological activity.

As noted above, the methylpiperazinazepine derivatives of the present invention are represented by the general Formula I. A branched or unbranched alkyl group of 1 to 4 carbon atoms is understood in the above general formula as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. The term halogen means chlorine, fluorine, iodine or bromine.

The most significant classes of compounds of general formula I are, in particular, the class wherein R ₄ is hydrogen, chlorine, fluorine or methyl, and the class wherein R ₂ is hydrogen or chlorine. A particularly important class of these compounds is where R _x is hydrogen, chlorine, fluorine or methyl and at the same time R ₂ is hydrogen or chlorine.

The derivatives of formula I which may be in the form of non-toxic salts are in particular salts of inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates or salts of organic acids such as acetates, citrates, maleates, fumarates and methyl sulfonates.

Examples of derivatives of the present invention are:

11- (4-methylpiperazin-1-yl) -5H-pyrido (4,3-b) benzo-1,5-diazepine;

6- (4-methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,4-thiazepine;

8-Chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,4-thiazepine fumarate;

5- (4-methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,5-oxazepine maleate;

8-chloro-5- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,5-oxazepine fumarate;

5- (4-methylpiperazin-1-yl) -8-methylpyrido (2,3b) benzo-1,5-oxazepine fumarate;

6- (4-methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,4-oxazepine fumarate;

8-chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,4-oxazepine fumarate;

6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3-b) benzo [1,4-diazepine];

8-chloro-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4-diazepine;

6- (4-methylpiperazin-1-yl) -8-methyl-11H-pyrido (2,3b) benzo-1,4-diazepine;

9-chloro-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4-diazepine;

8-fluoro-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4 diazepine;

5-formyl-11- (4-methylpiperazin-1-yl) -5H-pyrido (4,3b) benzo-1,5 diazepine;

11-formyl-5- (4-methylpiperazin-1-yl) -H-pyrido (2,3-b) benzo-1,5 diazepine;

11-trifluoromethylcarbonyl-5- (4-methylpiperazin-1-yl) -HH-pyrido (2,3-b) benzo-1,5-diazepine;

11-formyl-6- (4-methylpiperazin-1-yl) -H-pyrido (2,3-b) benzo-1,4-diazepine;

10- (4-methylpiperazin-1-yl) -pyrido (4,3-b) benzo-1,4-thiazepine;

5- (4-methylpiperazin-1-yl) dibenzo (b, f) 1,4-selenazepine;

6- (4-methylpiperazin-1-yl) dipyrido (2,3-b: 3 ', 2'f) 1,4-thiazepine;

6- (4-methylpiperazin-1-yl) 11-methyl-11H-pyrido (2,3b) benzo-1,4-diazepine.

The novel compounds of the present invention may be synthesized according to the general procedure from known or readily synthesized azepinones of formula II:

where X, R! and R ₂ is as defined herein above, and wherein N _x and N ₂ are a benzene or pyridine ring.

In this regard, a number of azepinones already published in the literature are listed below:

5,11-Dihydro-6H-pyrido (2,3-b) benzo-1,4-diazepin-6one;

6,11-dihydro-5 H -pyrido (2,3-b) benzo-1,5-diazepin-5 one;

5.10-dihydro-11 H -pyrido (4,3-b) benzo-1,5-diazepin-11-one;

5.11-dihydro-11-methyl-6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one;

5H, 6H-pyrido (2,3-b) benzo-1,5-oxazepin-5-one;

5H, 6H-pyrido (2,3-b) benzo-1,4-oxazepin-6-one;

5.11-dihydro-8-methyl-6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one;

9-chloro-5,11-dihydro-6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one;

10H, HH-dibenzo (b, f) 1,4-selenazepin-11-one.

The last mention of azepinone, i.e. 10H, HH-dibenzo (b, f) -1,4-selenazepin-11-one could be synthesized from 2,2'-dibromobenzanilide. Synthesize as follows: Place 150 ml of dry dimethylformamide, 0.015 mol of selenium and 0.06 mol of sodium in a round-bottomed flask. The mixture is heated with stirring at 100 ° C for four hours. When all is dissolved, 0.025 mol of 2,2'-dibromobenzanilide is added and stirred for 20 hours. At 100110 ° C. The solution is poured into a mixture of glacial and hydrochloric acid. The precipitate is filtered off. The resulting product is treated with boiling alcohol and filtered. The derivative is recrystallized from a mixture of dimethylformamide and water. Melting point 275 ° C.

Synthesis of a number of original azepinones not described in the literature is described below.

synthesis

8-Chloro-5H, 6H-pyrido (2,3-b) benzo-1,5-oxazepin-5-one (Formula II: X = O, R _X = C 1 at position b, R ₂ = H, N with N at position d ', N ₂ = benzene).

A solution of 2-chloropyridine-3-carboxylic acid chloro-anhydride (0.1 mol) was added slowly to a solution of 2-amino-4-chlorophenol (0.2 mol) in tetrahydrofuran (150 ml). The mixture is refluxed for one hour. Dilute with one liter of water. The precipitate formed is filtered, washed and dried. The impure product is used at another stage. Oxazepine is synthesized by treating the amide with a theoretical amount of sodium ethylate in absolute ethanol. The sodium salt is isolated by evaporation of the solvent. The desired cyclization is carried out by boiling for 3-4 h. dimethylformamide. The mixture was concentrated by vacuum distillation of DMF and crystallized at 0 ° C in a 3231 B volume. The isolated product is washed with cold methanol and recrystallized from DMF / methanol. Melting point 300 ° C.

synthesis

5H, 6H-8-methylpyrido (2,3-b) benzo-1,5-oxazepin-5-one (Formula II: X = O, R ₁ = CH _{3 at} position b, R ₂ = H, N ₁ = pyridine with N at position d ', N ₂ = benzene)

This material is synthesized according to Synthesis Method 1 using 2-chloropyridine-3-carboxylic acid and 2-amino-4-methylphenol as starting materials. Melting point 203 ° C.

synthesis

8-Chloro-5H, 6H-pyrido (2,3-b) benzo-1,4-oxazepin-6-one (Formula II: X = O, R ₁ H, R ₂ = C 1 at position b ', N _r = benzene, N ₂ = pyridine with N in position d)

The phenyl ester of 5-chlorosalicylic acid is synthesized by boiling 0.1 mol of phenol and 0.1 mol of 5-chlorosalicylic acid in POCl for ₃ , 2 hours. The reagent was distilled off under vacuum. The resulting dough mass is treated with water. The precipitate formed is filtered off and washed with water. Melting point Mp 9 ° C.

The title compound is obtained by heating to 0.05 mol of the above ester with 0.1 mol of 3 amino-2-chloropyridine until the reaction is complete. The mass is treated with 30 ml of ethanol and triturated until a precipitate suitable for filtration is obtained. After isolation, the product is washed with ethanol and recrystallized from dioxane or DMF / methanol. Melting point 280 ° C.

synthesis

5H, 6H-Pyrido (2,3-b) benzo-1,4-thiazepin-6-one (Formula II: X = S, R ₁ = R ₂ = H, N _x = Benzene, N ₂ = Pyridine with N in position d) method:

a) Synthesis of 2- (Phenylthio) pyridine-3-carbonic acid 0.2 mol of thiophenol and 0.2 mol of 50% NaH are dispersed in 50 ml of propylene glycol. To this mixture is added 0.1 mol of 2-chloropyridine-3-carboxylic acid and the mixture is brought to boiling. After the reaction, the solvent is evaporated. The residue is treated with water and the medium is adjusted to pH = 7. The excess thiophenol is extracted with chloroform. The aqueous phase is purified with activated carbon and acidified. The product is a white powder. Melting point 164 ° C.

b) The above compound is converted to the azide by reaction of the above acid with the acid anhydride. Add the acid anhydride to an excess of the cooled sodium azide solution. After stirring, the mixture is stirred for 1/4 hour. and diluted with water. The product is isolated and then dried and used for another reaction. The cyclization of this compound is carried out according to the following procedure. 1 g of crude azide is added slowly with stirring to a solution of AlCl ₃ in ortho-dichlorobenzene at 120 ° C. The temperature is maintained for 1/2 hour. period. The mixture is treated with chloroform and extracted with 0.1 N hydrochloric acid. The acidic phase is reextracted several times with CHC1 ₃ . The chloroform phases are combined, dried and concentrated in vacuo. The residue is taken up in acetone and left for 2 hours. in the fridge. The precipitate is filtered off. Melting point 206-208 ^ū C.

method:

0.01 mol of 3-amino-2-chloropyridine with 0.01 mol of 2-thiosalicylic acid are heated to the melting point until the reaction is complete. After cooling, add 30 ml of ethanol to the residue. Boil for a few minutes and then allow to cool. The precipitate is filtered off, washed with ethanol and dried. Melting point 205-208 ° C.

synthesis

5H, 6H-Pyrido (4,3-b) benzo-1,4-thiazepin-6-one (Formula II: X = S, R ₁ = R ₂ = H, N _{2 -} Benzene, N ₂ = Pyridine with N b)

0.01 mol of thiosalicylic acid and 0.01 mol of 3-amino-4-chloro-pyridine in the presence of ortho-dichlorobenzene are refluxed for several hours. At the end of the reaction, the solvent is removed. The residue is poured into a small amount of water and the medium is made up to pH = 5-6. The compound is extracted with chloroform. Chl-orof ormic extracts were evaporated. The residue is taken up in aqueous bicarbonate solution and stirred for 1/2 hour. The suspended compound is filtered and rinsed with water. Melting point 244 ° C.

synthesis

8-Chloro-5H, 6H-pyrido (2,3-b) benzo-1,4-thiazepin-6-one (Formula II: X = S, R 1 = H, R ₂ = C , N ₂ = pyridine with N in position d)

The compound is synthesized according to Synthesis 4 Method 1. Melting point 314 ° C.

synthesis

5H, 6H-Dipyrido (2,3-b: 3 ', 2'-f) 1,4-thiazepin-5-one (Formula II: X = S, R ₁ = R ₂ = H, N ₁ = N ₂ = pyridine with N at positions d and d ')

The reaction of 1.575 g of 2-chloropyridine-3-carboxylic acid with thionyl chloride gives the acid anhydride. After evaporation of the excess reagent, add the residue to 20 ml of dioxane and add gradually to a solution of 3.12 g of 3-amino-2-mercaptopyridine in 50 ml of dioxane with vigorous stirring. Shake the mixture for 1/4 hour. and then diluted five times with water. Everything dissolves and the medium is slightly acidic. Optional precipitate is removed. The pH is adjusted to 7 with the aid of bicarbonate and the solution is allowed to crystallize. The product obtained is dried in a ventilated oven and recrystallized from toluene if necessary. Melting point 183 ° C.

0.01 molar amide derivative is added to 0.012 mol Na tert-butylate suspension in 50 ml DMF. The mixture was refluxed for 10-20 h, the DMF was evaporated in vacuo and the residue was taken up in water (50 mL). The precipitate is filtered off, washed with water and dried. After drying, the precipitate is taken up in ether and removed. After filtration and drying, the product can, if necessary, be recrystallized from DMF. Melting point 305 ° C.

synthesis

8-Chloro-5H, 6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one (Formula II: X = NH, R ₁ = C 1 at position b ', R ₂ = H, N ₁ = benzene, N ₂ = pyridine with N in position d)

1) 0.01 mol of 5-chloro-2-nitrobenzoic acid, 20 ml of SOCl ₂ and several drops of DMF are boiled for one hour. Excess SOC1 ₂ is removed and the residue is taken up in 20 mL of dioxane. This solution is gradually added to a solution of 0.015 mol of 3-amino-2-chloropyridine in 20 ml of dioxane. After stirring for one hour, the mixture is diluted five times with water. The precipitate is filtered off and washed with cold water. If necessary, the product is recrystallized from isopropanol. Melting point 190 ° C.

2) Dissolve 0.01 mol of nitro derivative in 25 ml of concentrated HCl. 11 g of SnCl ₂ .2H ₂ O dissolved in 20 ml of concentrated HCl are added gradually to this solution. The solution is then left for one hour in a water bath. After cooling, the precipitate is filtered, treated with 10% NaOH and extracted with chloroform. The chloroform phase is dried and concentrated to low volume in the presence of petroleum ether 100-140. The crystallized product is then filtered off and washed with petroleum ether 40-60. Melting point 173 ° C.

3) Dissolve 0.01 mol of the amino derivative obtained in 2) in 18 ml of diethylene glycol monomethyl ether. 0.2 ml of 5% HCl are added. The mixture is heated to 130 ° C with stirring. After 2-3 hours. heating the resulting suspension. Once the reaction is complete, the mixture is cooled and filtered. The isolated product is washed with cold methanol and recrystallized from dioxane if necessary. Melting point 296 ° C.

synthesis

5,11-Dihydro-8-fluoro-6 H -pyrido (2,3-b) benzo-1,45 diazepin-6-one (Formula II: X = NH, R ₁ = F at position d ', R ₂ = H , N _x = benzene, N ₂ = pyridine with N in position d)

This compound is prepared according to synthesis procedure 8, but starting from 5-fluoro-2-nitrobenzoic acid and 3 amino-2-chloropyridine. Melting point 270 ° C.

The general method of preparing the methylpiperazinazepines represented by Formula I of the present invention from the azepinones represented by Formula II can be accomplished in three ways, the schemes of which are set forth and commented below.

Scheme A:

pyridine (II)

Thionium (III) is synthesized by the action of azepinone (II) on P ₂ S ₅ pyridine. A pure product is isolated which

R '= paranitrobenzylation

R = N-methylpiperazinyl is also used to give the thioether (IV) when potassium tert-butylate and paranitrobenzyl chloride are added. Reaction of the thioether with N-methylpiperazine in glacial acetic acid affords the compound represented by formula (I) (see Hunzicker 1588 (1967)).

Scheme B:

and others, Helv.Chim.Actą, 50,

R = N-methylpiperazinyl

Azepinones (II) are mixed with N-methylpiperazine in the presence of TiCl ₄ solution in anisole. This mixture allows compound (I) to be obtained by stirring and heating (see Chakrabarti JK et al., J.Med.Chem., 23, 878 (1980) and Press J. et al., J. Med.Chem. 22, 725 (1979).

Scheme C:

R = N-methylpiperazinyl

This scheme begins with azepinone (II), which is treated with POCl ₃ and DMF, and yields the corresponding iminochloride (V) which, without further isolation, reacts with N-methylpiperazine in toluene to form compound (I). .Chim.Acta, 49 (5), 1933 (1966)).

Of course, the compounds of the present invention can be synthesized without the use of azepinone (II) as starting materials or intermediates, as will be shown below, referring to the synthesis of Example 21 methylpiperazinazepine starting from orthohalogenitritropyridine represented by Formula V:

wherein Hal represents a reaction product of a halogen atom, such as Cl, F, J or Br, and benzenecarboxylic acid represented by formula (VI).

(VI) wherein X is as previously defined.

The salts of the methylpiperazinazepines represented by the formula (I) may be prepared by methods well known in the art. In general, these salts may be prepared by reacting methylpiperazinazepine with an equimolecular acid in an appropriate solvent such as alcohol, followed by precipitating the salt by adding another solvent which is miscible with the former and in which the salt is insoluble, such as ether, or further neutralizing the ethereal solution of the acid or acids, phosphorus Organic acids with a base or acid. Preferred inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and the like.

are either carboxylic or sulfuric acids such as acetic, citric, maleic, fumaric, propane, glycolic, lactic, ascorbic, pamoic, amber, tartaric, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, methanesulfonic, glucuronic acids and so on

Detailed examples of some syntheses of the methylpiperazinazepines of the present invention are provided below.

example

11- (4-Methylpiperazin-1-yl) -5 H -pyrido (4,3-b) benzo-1,5-diazepine (Formula I: X = NH, R ₁ = R ₂ = H, N ₁ = Pyridine with N) b ', N ₂ = benzene).

Method A:

1) 0.01 mol of 5,10-dihydro-11 H -pyrido (4,3) benzo-1,5-diazepin-11-one is treated with an excess of P ₂ S ₅ in boiling pyridine. After heating for several hours, remove excess solvent and reagent. The residue is carefully treated with ice. The resulting precipitate is isolated and used in the next step.

2) 5.2 g of thiolactam are added to a suspension of potassium tert-butylate in 80 ml of dioxane (obtained as follows: 1.64 g of potassium is dissolved in 40 ml of tert-butanol, the solvent is removed at the end of gas evolution and 80 ml of dioxane is added). The mixture is boiled for one hour. Thereafter, 4.1 g of paranitrobenzyl chloride were added. All boil for four hours. The solvent is removed. The residue is taken up in chloroform and washed with an alkaline solution. The chloroform phase is dried and evaporated to dryness. The residue is recrystallized from petroleum ether / acetone. Melting point 127 ° C.

3) 4.3 g of the thioether obtained in 2) is refluxed in the presence of N-methylpiperazine (10 ml) and 0.1 ml of glacial acetic acid for 24 hours. After evaporation to dryness, the residue is taken up in dilute acetic acid. The resulting precipitate is filtered off.

decolorization, activated by treatment, the base is precipitated by the addition of concentrated filtrate, rinsed with water and the product can be recrystallized from

Filtrate carbon. of ammonia, dried.

dichloromethane / hexane mixture. Melting point 216 ° C,

Method B:

0.01 mol of 5,10-dihydro-11 H -pyrido (4,3-b) benzo-1,5-diazepin-11-one is mixed with 10 ml of N-methylpiperazine. With stirring, 1.2 ml of TiCl ₄ solution in 5 ml of anisole are carefully added to the diazepinone suspension. The reaction was carried out with stirring at 120 ° C for 2-3 hours. The mixture is cooled and treated with ice water. The pH of the solution should be alkaline. The product is then extracted with dichloromethane. After evaporation of the solvent, the residue is purified on a silica gel column (elution phase: acetone / petroleum ether 40-60: 9/1). After removal of the eluent, the product is recrystallized from hexane. Melting point 216 ° C.

example

6- (4-Methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,4-thiazepine (Formula I: X = S, R ₁ = R ₂ = H, N ₁ = Benzene, N ₂ = Pyridine At N (d) g of 5H, 6H-pyrido (2,3-b) benzo-1,4-thiazepin-6-one was boiled for 20 hours with excess phosphorus oxychloride and drops of N, N-dimethylaniline. Add anhydrous toluene to the solution and evaporate to dryness. The residue is taken up in 5 ml of anhydrous toluene and an excess of N-methylpiperazine is added. The mixture is then refluxed for 2-4 hours. As soon as the reaction is complete, the solvent is removed. The colored mass is filled with chloroform and washed twice with water. The chloroform phase is decolorized with carbon and dried. When concentrated to a low volume, the mixture is passed through a silica gel column (Woelm Act. III). Elution with acetone. After separation, the different phases containing the above product are evaporated to dryness. The residue is recrystallized from petroleum ether 100/140. Melting point 134 ° C.

Example 3

8-Chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3-b) benzo1,4-thiazepine fumarate (Formula I: X = S, R 1 = H, R ₂ = C 1 at position b '

N ₂ = pyridine with N at position d ').

Ni = benzene,

Starting with 5H, 6H-pyrido (2,3-b) benzo-1,4-thiazepin-6-one, the above methylpiperazinazepine base is obtained according to Method 2 of Example 2. After evaporation, chloroform dissolves in a minimum boiling Add equimolecular amount of fumaric acid previously dissolved in hot alcohol. Cool the solution. If the product does not crystallize, the ether is added to aid in crystallization. It is left standing and the fractions obtained are left in the alcohol content.

the white precipitate is isolated and washed with ether. Melting point 198 ^U C.

example

5- (4-Methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,5-oxazepine maleate (Formula I: X = O, R ₁ = R ₂ = H, N ₁ = Pyridine with N at position d ' , N ₂ = benzene)

Product obtained from 5H, 6H-pyrido (2,3-b) benzo-1,5-oxazepin-2-one according to the procedure of Example 2. The chloroform fractions are then evaporated to dryness. The residue is taken up in methyl ethyl ketone. An equimolar amount of maleic acid dissolved in methylethylketone was added followed by anhydrous ether. The product crystallizes. It is isolated and rinsed with ether. Melting point 206 ° C.

example

8-Chloro-5- (4-methylpiperazin-l-yl) pyrido (2,3-b) benzo1,5-oxazepine fumarate (Formula I: X = 0, R @ ₁ = C1 in position b, R ₂ = H, N ₁ = pyridine with position d ', N ₂ = benzene)

Starting with the oxazepine described in Synthesis 1 and using the method of Example 2, the compound is isolated in the form of fumarate in the same manner as in Example 3. Melting point 260 ° C.

example

5- (4-Methylpiperazin-1-yl) 8-methylpyrido (2,3-b) benzo-1,5-oxazepine Fumarate (Formula I: X = O, R g = CH _{3 at} position b, R ₂ = H, N ₂ -Pyridine with N at position d ', N ₂ = benzene)

Starting with the oxazepine described in Synthesis 2 and using the method of Example 2, the compound is isolated in the form of fumarate in the same manner as in Example 3. Melting point 235 ° C.

example

6- (4-Methylpiperazin-1-yl) pyrido (2,3-b) benzo-1,4-oxazepine fumarate (Formula I: X = O, R ₁ = R ₂ = H, Ng = Benzene, N ₂ = Pyridine with N in position d)

Starting with 5H, 6H-pyrido (2,3-b) benzo-1,4-oxazepin-6-one and following the procedure of Example 2, the compound is isolated in the form of fumarate. Melting point 183 ° C.

example

8-Chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3-b) benzo1,4-oxazepine fumarate (Formula I: X = 0, R = H, R = C1 at position b ', N = benzene, N = pyridine with N in position d)

Starting from the synthesis of 8-chloro-5H, 6H-pyrido (2,3-b) benzo-1,4-oxazepin-6-one, the compound is obtained according to the procedure described in Example 2. The compound is isolated in the form of fumarate in the same manner as in Example 3. Melting point 250 ° C.

example

6- (4-Methylpiperazin-1-yl) -IIH-pyrido (2,3-b) benzo-1,4-diazepine (Formula I: X = NH, R 1 = R ₂ = H, N _x = Benzene, N ₂ = pyridine with N in position d)

Starting with 5,11-dihydro-6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one, condensation is carried out according to Example 1, Process B. Melting point 141 ^U C.

example

8-Chloro-6- (4-methylpiperazin-1-yl) -1H-pyrido (2,3b) benzo-1,4-diazepine (Formula I: X = NH, R ₁ = C 1 at position b ', R ₂ = H, N ₁ = benzene, N ₂ = pyridine with N in position d)

Starting with diazepinone 8 synthesis, the above product is obtained according to the procedure described in Example 1, Method B. Lyd.t. 180 ° C.

example

6- (4-methylpiperazin-1-yl) -8-methyl-11 H -pyrido (2,3b) benzo-1,4-diazepine (Formula I: X = NH, R ₁ = CH _{3 at} position b ', R ₂ = H, N _x = benzene, N ₂ = pyridine with N in position d)

Starting with 5,11-dihydro-8-methyl-6H-pyrido (2,3-b) benzo [1,4-diazepin-6-one], the above compound is obtained according to the method of Example 1, B. Lyd.t. 157 ° C.

example

9-Chloro-6- (4-methylpiperazin-1-yl) -H-pyrido (2,3b) benzo-1,4-diazepine (Formula I: X = NH, R ₁ = Cl, in position c ', R ₂ = H, N ₁ = benzene, N ₂ = pyridine with N in position d)

Starting with 9-chloro-5,11-dihydro-6H-pyrido (2,3-b) benzo-1,4-diazepin-6-one, the above product is obtained according to the method of Example 1, B. Melting point. 186 ° C.

example

8-Fluoro-6- (4-methylpiperazin-1-yl) -H-pyrido (2,3b) benzo-1,4-diazepine (Formula I: X = NH, R ₄ = F at position b ', R ₂ = H, N ₁ = benzene,

N ₂ = pyridine with N in position d)

Starting with diazepinone 9 synthesis, the above compound is obtained according to the method of Example 1, B. Lyd.t. 188 ° C.

example

5-Formyl-11- (4-methylpiperazin-1-yl) -5H-pyrido (4,3b) benzo-1,5-diazepine

O // (Formula I: X = NC, R ₁ = R ₂ = H, N ₁ = Pyridine with N at H b ', N ₂ = Benzene)

This example begins with the compound of Example 1. 15 cm ^{3 of} acetic anhydride are cooled and 7 cm ^{3 of} 99% formic acid is added slowly with stirring. The mixture is kept for 15 minutes. 50 ° C and then cooled in an ice bath. 0.01 mol of the compound of Example 1 is added and the mixture is stirred overnight. The mixture is treated with ice, basified and extracted with dichloromethane. Dry and concentrate in vacuo and recrystallize from hexane. Melting point 19β ^υ ϋ.

Example 1111-Formyl-5- (4-methylpiperazin-1-yl) -IIH-pyrido (2,3b) benzo-1,5-diazepine

O // (Formula I: X = NC, R ₁ = R ₂ ^: = H, Nn = Pyridine with N in position \

H d ', N ₂ = benzene)

This compound starts with the compound described in Chekrabarti et al., J.Med.Chem. 32, No 10, 23752381 (1989), which is formylated according to the procedure of Example 14. Melting point 194 ° C.

Example 11 11-Trifluoromethylcarbonyl-5- (4-methylpiperazin-1-yl) -11H-pyrido (2,3-b) benzo-1,5-diazepine (Formula I: X = N-CO-CF ₃ , R 1 = R ₂ = H, N ^ pyridine with N at position d ', N ₂ = benzene)

This example begins with the compound described in the article mentioned in Example 15. 0.02 mol of this compound is mixed with 15 ml of trifluoroacetic anhydride and a few drops of N, N-dimethylaniline under reflux, followed by boiling for 5 minutes and stirring overnight. The mixture is poured onto ice, basified and extracted with chloroform. Purify on a silica gel column and concentrate. Recrystallization from hexane. Melting point 183 ° C.

Example 11 11-Formyl-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4-diazepine

O // (Formula I: X = NC, R ₁ = R ₂ = H, N, = Benzene, N ₂ = Pyridine H with N in D)

This example begins with the compound of Example 9, which is formylated according to the procedure of Example 14. Melting point Mp 202 ° C.

example

10- (4-Methylpiperazin-1-yl) pyrido (4,3-b) benzo-1,4-thiazepine (Formula I: X = S, R ₁ = R ₂ = H, N ₂ - Benzene, N ₂ = Pyridine with N in position b)

Starting with the thiazepinone described in Synthesis 5, the above compound is obtained using the procedure of Example 2. Melting point 143-144 ° C.

example

5- (4-Methylpiperazin-1-yl) dibenzo (b, f) 1,4-selenazepine (Formula I: X = Se, R ₁ = R ₂ = H, N ₁ = N ₂ = Benzene)

Starting with 10H, HH-dibenzo (b, f) 1,4-selenazepin-11-one, the above compound is obtained using the procedure of Example 2. Melting point Mp 107 ° C.

example

6- (4-Methylpiperazin-1-yl) dipyrido (2,3-b: 3 ', 2'-f) 1,4-thiazepine (Formula I: X = S, R ₁ = R ₂ = H, N ₁ = N ₂ = pyridine with N at positions d and d ')

This product is prepared starting from the compound described in Synthesis 7 and using the procedure of Example 2. Melting point 170 ° C.

example

6- (4-Methylpiperazin-1-yl) -11-methyl-11 H -pyrido (2,3b) benzo-1,4-diazepine (Formula I: X = N-CH ₃ , R ₁ = R ₂ = H, N ^ benzene, N ₂ = pyridine with N in position d)

0.02 mol of 2-chloro-3-nitropyridine, 0.01 mol of N-methylanthranilic acid, 5 g of anhydrous K ₂ CO ₃ and 50 ml of dry isopropanol are refluxed for 24 hours. After evaporation of the solvent, the residue is taken up in water and boiled in the presence of activated carbon. After cooling, the solution is acidified to pH about 3. The product settles as a yellow powder and is filtered, washed with water and dried. Melting point 174 ° C.

0.005 mol of the resulting acid is suspended in anhydrous ether. The compound is esterified with diazomethane, which is prepared starting with 4 g of nitrosomethylurea, the latter being decomposed by soda in ether. The diazomethane ethereal solution is gradually added to the ethereal solution of nitric acid. As soon as the reaction is complete, the solvent is evaporated. The residue is treated with NaHCO ₃ solution and extracted twice with CHCl ₃ . The chloroform solution was dried and concentrated in the presence of 100-140 petroleum ether. The crystallized product is then filtered off and washed with petroleum ether 40-60. Melting point 71 ° C.

0.01 mol of a nitroester derivative (dissolved in 150 ml of ethanol) is catalytically hydrogenated with palladium on carbon (Pd / C 10%; 1 g) in a low pressure hydrogen generator. After 2 or. the reaction is complete and the solvent is evaporated. Transfer the residue (amino ester) into 50 ml of anisole and transfer to a round-bottomed flask. 20 ml of N-methylpiperazine are added. The mixture is heated with stirring at 120 ° C. Carefully pour 5 ml of TiCl ₄ solution into 10 ml of anisole. The reaction contents were refluxed for 12 hours. The mixture is then cooled and treated with 10 ml of isopropanol, 10 ml of concentrated ammonia and 2 g of silica gel. The mixture is filtered and the collected precipitate is carefully washed with chloroform. The filtrate is washed once with water and then extracted with 2N HCl. This solution is decolorized with activated carbon and basified with ammonia. The resulting precipitate is extracted with chloroform. Chloroform fractions were collected and concentrated to low volume. The resulting residue was purified on a silica gel column using acetone / petroleum ether 40-60 9/1 as eluent. Except, the product is recrystallized from a mixture of dichloromethane and hexane. Melting point 146 ° C.

The compounds of the present invention were tested by pharmacological tests used to determine effects on the central and peripheral nervous system. The following results from Examples 1, 10, 11, 17, 18 and 19 confirm the hypotheses and thus the antidepressant, antipsychotic, anxiolytic, neuroleptic and sedative activity of the compounds of this invention.

Tn in vitro: Affinity assays for D ₂ dopaminergic and muscarinic receptors

The code Inhibition,% ('Hspiperone Binding) Inhibition,% ( ³ H QNB binding) Clozapine Clothiapine Haloperidol Example I Example 10 Example II Example 17 Example 18 Example 19 57.3 94, 6 100 56, 2 31.5 24, 8 22.8 50.2 26, 7 80.35 38.05 0 4.48 62, 08 67.3 43.38 57.61 78, 31

D ₂ Dopaminergic receptors:

Characterization by (H) spiperone replacement test

Preparation of membranes:

Male Wistar rats (200-250 g) are removed from the brain. The gutter is rapidly cut and homogenized in 20 ml buffer (50 nM Tris / HCl, pH = 7.4, 25 ° C) using a Teflon homogenizer. Homogenate centri10 for two minutes

The final is centrifuged at 4 ° C for 10,000 G, the concentrate is washed with ice buffer and the recentrifugation concentrate is suspended in ice buffer (50 nM Tris / HCl, pH 7.4) containing 5 nM magnesium sulfate, 0.5 nM EDTA. After rehomogenization, the suspension is brought to 1 mg of protein per ml. Protein content was determined by Lowry et al. (J. Biol. Chem. 193, 265-275 (1951)) using bovine serum albumin as the standard.

Binding test:

Is used by Tecott et al. proposed method (Biol. Psvchiatry 21, 1114-1122 (1986). ( ³ H) -Spiperone Binding Estimated with the following mixture: 200μ1 membrane preparation (0.1-0.2 mg protein), 100 μΐ (10 ~ ⁶ M) of test substance and 600 μΐ buffer to a final volume of 1 ml. Control tubes, which are taken as non-specific binding standards, also have

1 μΜ (ι) butaclamol. The samples (triplicate) were then incubated with 0.5 nM ( ³ H) spiperone at 25 ° C for 60 minutes. This step is stopped by rapid vacuum filtration of the suspension through a glass texture filter GF / C. Wash the filter three times with 5 ml of ice-buffer. Radioactivity is measured on a liquid scintillation spectrometer (LKB Rack Beta 1219). Results are expressed as percentage difference between control (1µΜ (1) butaclamol) and test substance.

Characterization of muscarinic receptors

Receptor binding:

The method is inspired by the technique described by Yamamura and

Snyder (Proc.Natl.Sci.USA 71, 1725 (1974)). Following rapid removal of CFY, the rat brain (130-180 g) is incised to remove the cerebellum. Other tissues were homogenized with Potter in 0.32 M sucrose and 50 nM ^m ris / HCl buffer pH 7.5. Protein concentration is determined by the Peterson method iAnai.Biochem. 83, 346

977)).

the passage test is performed Iris times at 25 ° C. . The incubation medium (1 ml) consisted of 60

3 ^r NaCl, Tris / HCl buffer with pH 7.5 and 1.5 riM ( ³ H) QNB

•) w England Nuclear, specific act: 1.18 TBq / mol). the action with the homogenate containing 250-400 µg of protein is maintained for 60 minutes. Non-specific binding is accomplished by 10 ' ⁵ M atropine. The operation is stopped by rapid filtration on a Whatman glass filter GF / C. The free ligand is removed in this manner. Each sample is washed with 2x10 ml cold buffer. The filters are dried, placed in a toluene solution for scintillation and placed in a scintillation counter (Packard Tricarb liquid scintillation counter) for one day. Receptor binding is directly proportional to a protein concentration of up to 700 µg protein per milliliter.

In vivo: Apomorphine antagonism assay.

Many compounds at 20 mg / kg decrease the motility of animals and have a sedative effect, in most cases the compounds show activity between the activity of clozapine (20 mg / kg) and haloperidol (0.63 mg / kg). In to in). The following sample results are given.

An example 1 An example 5 An example 7th An example 8th An example 10th An example 11th An example 12th An example 13th An example 19th

The Catalepsy Test

See also: GRAY W.D. OSTARBERG A.C., RAUH C.E.,

Arch.Int.Pharmacodyn. 134, 198, 1961 and Costall B.,

Olley J.E. Neuropharmacology 10, 297, 1971.

This test is characterized by the extrapyramidal effects that many neuroleptics have (undesirable secondary effect). The compounds of the present invention induce very low catalepsy and thus do not exhibit this undesirable secondary effect. However, some products showed slight catalepsy.

- Examples 1 and 3: catalepsy at doses above 40 mg / kg

- Example 4: weak cataleptic effect starting at 20 mg / kg

- Clozapine: weak cataleptic effect at doses of 20 mg / kg.

The present invention also relates to pharmaceutical compositions comprising, as active ingredients, one or more compounds represented by the formula (I) or one or other active substances with similar or different effects in admixture with a suitable pharmaceutical excipient.

These pharmaceutical compositions may be solid, such as monolayer or multilayer uncoated or coated tablets, capsules, films, dispersible or soluble powders, suppositories or liquids, such as solutions, colloids, suspensions, emulsions, syrups, formulations for parenteral use, e.g. , in the form of aerosols.

Solid compositions for oral use may be prepared by mixing one or more substances according to the present invention, for example, with milk sugar, sugar powder, starch, talc, products for retention or prolonging effect, such as cellulose acetophthalate, glyceryl stearates, ionic.

The suppositories may be prepared by the incorporation of one or more substances according to the present invention, for example, into cocoa butter or any other suitable material such as mono-, di- and triglycerides of saturated fatty acids.

Liquid compositions may be prepared, for example, by reconstitution, suspension or emulsification at the time of preparation or immediately prior to use of one or more substances, respectively, of the present invention, and, in addition, any product considered to be desirable or necessary such as methyl or propyl p-hydroxybenzoates, thickeners and emulsifiers such as cellulose derivatives and polyoxyethylene esters of sorbitol, sweetening and flavoring agents such as sugar, saccharin, sorbitol, natural or synthetic alcohols, isotonic agents such as sodium chloride, or buffers such as such as sodium phosphates in distilled water, other acceptable hydroxylic liquids such as ethanol, glycerol, some glycols, mixtures of these solvents, or pharmaceutically acceptable oils.

Claims (9)

DEFINITION OF INVENTION 1. Methipiperazine azepine derivative of general formula I: CH ₅ i where: X is an oxygen atom, a sulfur atom, a selenium atom or a group NH or NR ₃ wherein R ₃ is -C, -C Ή 'CK group, or a straight or branched alkyl group containing from 1 to 4 carbon atoms; R _x is a hydrogen atom, a halogen atom, or a branched or unbranched alkyl group containing from 1 to 4 carbon atoms; R ₂ is a hydrogen atom, a halogen atom, or a branched or unbranched alkyl group containing from 1 to 4 carbon atoms; and N _x is a benzene ring and N _{2 is a} pyridine ring, or vice versa, provided that when R _x and R ₂ are hydrogen and X is sulfur, oxygen or NH, N _x is pyridine and N _{2 is} benzene and pyridine nitrogen is not at position d ', both of N _x and N ₂ may be benzene when X is a selenium atom; or pharmaceutically acceptable salts. 2. A derivative according to claim 1, wherein in formula I, R _x is a hydrogen atom or a methyl group. 3. A derivative according to claim 1 or 2, wherein in formula I, R ₂ is a hydrogen atom or a chlorine atom. 4. A derivative according to any one of claims 1 to 3 which is obtained in the form of a salt selected from the group consisting of hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, maleates, fumarates and methanesulfonates. A derivative according to any one of claims 1 to 4, wherein it is selected from the group consisting of: 11- (4-methylpiperazin-1-yl) -5H-pyrido (4,3-b) benzo-1,5-diazepine; 6- (4-methylpiperazin-1-yl) -pyrido (2,3-b) benzo-1,4-thiazepine; 8-Chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,4-thiazepine fumarate; 5- (4-methylpiperazin-1-yl) -pyrido (2,3-b) benzo-1,5-oxazepine maleate; 8-chloro-5- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,5-oxazepine fumarate; 5- (4-methylpiperazin-1-yl) -8-methylpyrido (2,3b) benzo-1,5-oxazepine fumarate; 6- (4-methylpiperazin-1-yl) -pyrido (2,3-b) benzo-1,4-oxazepine fumarate; 8- (chloro-6- (4-methylpiperazin-1-yl) pyrido (2,3b) benzo-1,4-oxazepine fumarate; 6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3-b) benzo-1,4-diazepine; 8-chloro-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4-diazepine; 6- (4-methylpiperazin-1-yl) -8-methyl-11H-pyrido (2,3b) benzo-1,4-diazepine; 9-chloro-6- (4-methylpiperazin-1-yl) -HH-pyrido (2,3b) benzo-1,4-diazepine; 8-fluoro-6- (4-methylpiperazin-1-yl) -H-pyrido (2,3b) benzo-1,4-diazepine; 5-formyl-11- (4-methylpiperazin-1-yl) -5H-pyrido (4,3b) benzo-1,5-diazepine; 11-formyl-5- (4-methylpiperazin-1-yl) -HH-pyrido (2,3-b) benzo-1,5-diazepine; 11-trifluoromethylcarbonyl-5- (4-methylpiperazin-1-yl) -1H-pyrido (2,3-b) benzo-1,5-diazepine; 11 ^: ormyl-6- (4-methylpiperazin-1-yl) -IIH-pyrido (-b) benzo-1,4-diazepine; 10- (4-methylpiperazin-1-yl) pyrido (4,3-b) benzo-1,4-thiophene; 5- (4-methylpiperazin-1-yl) dibenzo (b, f) -1,4-selenazepine; 6- (4-methylpiperazin-1-yl) dipyrido (2,3-b: 3 ', 2'-f) 1,4-thiazepine; 6- (4-methylpiperazin-1-yl) -11-methyl-11H-pyrido (2,3b) benzo-1,4-diazepine. Metilpiperazinazepino sixth derivatives of general Formula I in which X, R _lr R _2, N ₄ and N ₂ have the above-stated values, the method characterized in that the derivative obtained by a compound corresponding to formula II: wherein X, R _x and R ₂ are as defined above and wherein N _x and N _{2 are} each a benzene ring or a pyridine ring. 7. Metilpiperazinazepino derivatives of general Formula I in which X, R ₂ R _o, N _x and N ₂ have the above-stated meaning, said method characterized in that these derivatives receives from ortohalogennitropiridino corresponding to formula V: v wherein Hal is a halogen atom such as Cl, F, J or Br and benzoic acid of formula VI: wherein X is as previously defined in the reaction product. 8. A pharmaceutical composition comprising a derivative as defined in any one of claims 1 to 5 in admixture with a pharmaceutically acceptable excipient or optionally another therapeutic agent. Use of a derivative according to any one of claims 1 to 5 for the manufacture of a preparation having a central or peripheral nervous system action, such as antidepressant, antipsychotic, anxiolytic, neuroleptic or sedative.