Derivatives methylpiperazine or pharmaceutically acceptable salts of these derivatives

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds exhibiting activity against Central nervous system. The essence of the invention: derivatives methylpiperazine formula I listed in the description, where X Is O, S, Se, NH, or NR3where R3-, or C1-C4-alkyl; R1, R2- H, halogen, or C1-C4-alkyl, N1is a benzene nucleus and N2is pyridine cycle, or Vice versa, in which the nitrogen atom of the pyridine cycle is in position b, b', d or d', if R1and R2are H, and X Is S, O or NH, N1is pyridine cycle, and N2- benzene nucleus, and a pyridine nitrogen may not be in position d'; or N1and N2both of the benzene nucleus, if X Is Se; or N1and N2both pyridine cycles with nitrogen atom in d and d' position, when X Is S, and R1and R2- H, or their salts. 4 C.p. f-crystals, 1 table.

The present invention relates to new derivatives methylpiperazine and their non-toxic salts, as well as to a method for producing these compounds and their use in therapy.

New methylpiperazine of the invention correspond to the General who SUB> where R3is the group ,

or alkyl with 1-4 carbon atoms, branched or not;

R1is a hydrogen atom, halogen atom or alkyl with 1-4 carbon atoms, branched or not;

R2is a hydrogen atom, halogen atom or alkyl with 1-4 carbon atoms, branched or not; and

N1is a benzene nucleus and N2is a pyridine nucleus or Vice versa if R1and R2are hydrogen and X is sulfur, oxygen or the group NH, and N1is pyridine cycle, and N2-benzene nucleus, and a pyridine nitrogen may not be in position d', and N1and N2in addition, can be both benzene nucleus, if X is an atom of selenium.

Some representatives derivatives methylpiperazine of this type are described in the literature. In this regard, in particular, to mention articles with DuPont al., Acta cryst., S. 43, 716-718, 1987, which describes oxygen-containing derivatives of Hoffmann with TCS. U.S. patent N 4163785 (1979), which describes sulfur-containing derivatives and Chakrabarti with TCS. Journal of Medicinal Chemistry, T. 32, N 10, 2375-2381, 1989, describes nitrogen-containing derivatives. However, in contrast to derived this from the ur, did not possess interesting pharmacological activity.

As mentioned previously, derivatives methylpiperazine of the present invention correspond to the General formula (I). In the above General formula alkyl with 1-4 carbon atoms, branched or not, understand methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert. butyl. The term "halogen" includes chlorine, fluorine, iodine and bromine.

Preferred classes of compounds of formula (I) are, for example, those in which R1is a hydrogen atom, a chlorine atom, a fluorine atom and stands, and those in which R2is a hydrogen atom or a chlorine atom. Particularly preferred class of these compounds are those in which R1is hydrogen, chlorine, fluorine or stands and simultaneously R2is hydrogen or chlorine.

The derivatives of formula (I), which may be in the form non-toxic salts are, in particular, salts of inorganic acids, such as chlorhidrate, bromhidrosis, phosphates, sulfates, or organic acids such as acetates, citrates, maleate, fumarate and methansulfonate.

Examples of the derivatives according to the invention are: 11-/4-methylpiperazin-1-yl/-5H-pyrido/4,3-b-the IDO/2,3-b/benzo-1,4-diazepine,

maleate 5-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo-1,5 - oxazepine, fumarate 8-chloro-5-/4-methylpiperazin-1-yl/pyrido/2,3-b/ benzo-1,5-oxazepine,

fumarate 5-/4-methylpiperazin-1-yl/-8 methylpyridin/2,3-b/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/2,3-b/benzo-1,4-oxazepine,

6-/4-methylpiperazin-1-yl-11H-pyrido/2,3-b/benzo-1,4 - diazepin,

8-chloro-6-(4-methylpiperazin-1-yl)-11H-pyrido/2,3-b/benzo-1,4 - diazepin,

6-/4-methylpiperazin-1-yl/-8-methyl-11H-pyrido/2,3-b/benzo-1,4 - diazepin,

9-chloro-6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,4 - diazepin,

8-fluoro-6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,4 - diazepin,

5-formyl-11-/4-methylpiperazin-1-yl/-5H-pyrido/4,3-b/benzo-1,5 - diazepin,

11-formyl-5-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,5 - diazepin,

11-trifloromethyl-5-/4-methylpiperazin-1-yl/-11H-pyrido- /2,3-b/benzo-1,5-diazepin,

11-formyl-6-/4-methylpiperazin-1-yl/-11H-pyrido-/2,3-b/benzo-1,4 - diazepin,

10-/4-methylpiperazin-1-yl/pyrido/4,3-b/benzo-1,4-diazepin,

5-/4-methylpiperazin-1-yl/dibenzo(b,f) 1,4-selenation,

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

6-/4-methylpiperazin-1-yl/-11-methyl-11H-pyrido/2,3-b/benzo-1,4-diazepin.


,

in which

X, R1and R2have the previously indicated meanings, and N1and N2each is a benzene or pyridine nucleus.

In this regard, the following are some azepine already described in the literature:

5,11-dihydro-6H-pyrido/2,3-b/benzo/1,4-diazepin-6-he,

6,11-dihydro-5H-pyrido/2,3-b/benzo-1,5-diazepin-5-he,

5,10-dihydro-1H-pyrido/4,3-b/benzo-1,5-diazepin-11-he,

5,11-dihydro-11-methyl-6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he,

5H,6H-pyrido/2,3-b/benzo-1,5-oxazepan-5-he,

5H,6H-pyrido/2,3-b/benzo-1,4-oxazepan-6-he,

5,11-dihydro-8-methyl-6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he,

9-chloro-5,11-dihydro-6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he, 10H,11H-dibenzo/b,f/1.4-selenation-11-he.

Last azepine, namely, 10H, 11H-dibenzo/b,f/1.4-selenation-11-it can also be obtained from 2,2'-dibromobenzene. To this flask is charged with 150 ml of dimethylformamide, 0.015 mol of selenium 0,050 mol of sodium. The mixture is heated to 100oC under stirring for 4 hours When it's all dissolved, add 0,025 mol of 2,2'-dibromobenzene and left under stirring for 20 h at 100-110oC.

The solution is poured into a mixture solasodine recrystallized from a mixture of dimethylformamide and water. The melting point of 275oC.

Listed below are the syntheses of some original azapirones, not yet described in the literature.

Preparation 1.

8-chloro-5H, 6H-pyrido/2,3-b/benzo-1,5-oxazepan-5-he (formula II: X = O, R1= Cl in position b, R2= H, N1= pyridine with N in position d', N2= benzene).

A solution of 0.1 mol of acid chloride of 2-chloropyridin-3-carboxylic acid was poured slowly into a solution of 0.2 mol of 2-amino-4-chlorophenol in 150 ml of tetrahydrofuran. Leave under stirring and boiling under reflux for 1 h Diluted with 1 l of water. Collect the precipitate, washed and dried. The crude product is used as such for further work. Oxazepan receive treatment amide theoretical amount of ateleta sodium in absolute alcohol. Upon evaporation of the solvent is allocated sodium salt. When boiling the latter with reflux for 3-4 h in dimethylformamide get the desired cyclization. Concentrate the mixture by distillation of DMF under vacuum and left to crystallize at 0oC. the isolated product was washed with cold methanol and crystallized from a mixture of DMF/methanol. The melting point 300oC.

Preparation 2.

5H, 6H-medinas with N in position d', N2= benzene).

This substance get on the method of preparation I, but using as starting compounds 2-chloropyridin-3-carboxylic acid and 2-amino-4-METHYLPHENOL. The melting point 203oC.

Preparation of 3.

8-chloro-5H, 6H-pyrido/2,3-b/benzo-1,4-oxazepan-6-he (formula II: X = O, R1= H, R2= Cl in position b', N1= benzene, N2= pyridine with N in position d).

Prepare complex phenolic ester 5-chlorosalicylic acid, heating at boiling under reflux 0.1 mol of phenol and 0.1 mol of 5-chlorosalicylic acid in the presence of excess OPCl3within 2 hours the Reagent is distilled off in vacuum. The obtained pasty mass is gradually treated water. The formed precipitate is filtered off and washed with water. The melting point 89oC.

Heating in the melt to terminate the reaction, 0.05 mol obtained above complex ether with 0.1 mol of 3-amino-2-chloropyridine, get the target connection. Mass absorb 30 ml of ethanol and triturated to obtain a filterable precipitate. After separation, the product is washed with ethanol and recrystallized from dioxane or from a mixture of DMF/methanol. The melting point 280oC.

Preparation 4.

< / The N at position d).

Method 1.

a) Obtaining 2-/penalty/pyridine-3-carboxylic acid.

Dispersed 0.2 mol thiophenol and 0.2 mol of sodium hydride (50%) in 50 ml of propylene glycol. To this mixture was added 0.1 mol of 2-khlorpirimidinov acid and heated to boiling. Upon completion of the reaction the solvent is evaporated. The remainder absorb water and set pH 7. Extracted excess thiophenol chloroform. The aqueous phase is purified with activated charcoal and acidified with. The product precipitates as a white powder. The melting point 164oC.

b) the above compound is transformed into azide in the interaction obtained above carboxylic acid. The acid chloride of the acid poured into excess cold solution of sodium azide. Upon completion of addition, continue stirring for 1/4 h and diluted with water. The product is isolated and used after drying as such in subsequent reactions. The cyclization of compounds is conducted by the following method. Add gradually 1 g crude azide to a solution of AlCl3in ortho-dichlorobenzene at 120oC and under stirring. Maintain the temperature for 0.5 hours the mixture is Then absorbed chloroform and extracted with 0.1 H hydrochloric acid. Acidic phase re-extracted with n the t acetone and left for 2 h in the cold. The precipitate is collected by filtration. The melting point 206-208oC.

Method 2.

Heated in the melt 0.01 mol of 3-amino-2-chloropyridine to terminate the reaction with 0.01 mol of 2-thiosalicylic acid. After cooling, the precipitate absorb 30 ml of ethanol. Boil a few minutes, then allow to cool. The precipitate is filtered off, washed with ethanol and dried. The melting point 205-208oC.

Preparation 5.

5H,6H-pyrido/4,3-b/benzo-1,4-diazepin-6-he (formula II: X = S, R1= R2= H, N1= benzene, N2= pyridine with N in position b).

Heated to boiling under reflux for several hours 0.01 mol thiosalicylic acid and 0.01 mol of 3-amino-4-chloropyridine in the presence of ortho-dichlorobenzene. Upon completion of the reaction remove the solvent. The remainder absorb a small amount of water and set the pH to 5-6. The compound is extracted with chloroform. Evaporate the chloroform extracts. The remainder absorb bicarbonate water and stirred for 0.5 hours Filtered suspension connection and washed with water. The melting point of 244oC.

Preparation of 6.

8-chloro-5H,6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he (formula II: X = S, R1= H, R2= Cl in position b', N1= betonline 4, method 1. The melting point of 314oC.

Preparation 7.

5H, 6H-dihydro/2,3-b: 3',2'-f/1.4-diazepin-5-he (formula II: X = S, R1= R2= H, N1= N2= pyridine with N in position d and d'/.

Get the acid chloride of the acid of 1,575 g 2-chloropyridin-3-carboxylic acid when interacting with thionyl chloride. After evaporation of the excess reagent, the residue is treated with 200 ml of dioxane and slowly poured into a solution of 3.12 g of 3-amino-2-mercaptopyridine in 50 ml of dioxane with good stirring. Continue mixing 1/4 h, then diluted 5 times with water. Everything goes into solution and the medium is slightly acidic, in some cases remove the precipitate. Set bicarbonate pH 7 and allowed to crystallize. The product is dried in a drying Cabinet and recrystallized from toluene, if necessary. The melting point 183oC.

Add 0.01 mol amide derivative to suspension of 0.012 mol of tert. the butyl sodium in 50 ml of DMF. Refluxed for 10-20 h, the DMF is evaporated under vacuum and absorb the residue 50 ml of water. The precipitate is filtered off, washed with water and dried. After drying, it is treated with ether and triturated. After filtering and drying the product, if necessary, the PR-5H, 6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he (formula II: X = NH, R1= Cl in position b', R2= H, N1= benzene, N2= pyridine with N in position d).

1) Treated with 0.01 mol of 5-chloro-2-nitrobenzoic acid 20 ml OCl2and a few drops of DMF while boiling under reflux for 1 h Distilled off excess OCl2the residue is absorbed in 20 ml of dioxane. This solution is slowly added to a solution of 0.015 mole of 3-amino-2-chloropyridine in 20 ml of dioxane. After an hour of mixing, the mixture is diluted with five volumes of water. The precipitate is filtered off, washed with cold water. If necessary, the product is recrystallized from isopropanol. The melting point 190oC.

2) Dissolve in 0.01 mol nitro-derivatives in 25 ml of concentrated HCl. To this solution was added little by little 11 g SrCl22H2O, dissolved in 20 ml of concentrated HCl. Then the solution was incubated for one hour in a water bath. After cooling, the precipitate is filtered off, absorb 10% NaOH and extracted with chloroform. The chloroform phase is dried and concentrated to small volume in the presence of petroleum ether 100-140. The crystalline product is filtered and washed with petroleum ether 40-60. The melting point 173oC.

oC under stirring. After 2-3 h of heating get a suspension. Upon completion of the reaction the mixture is cooled and filtered. The isolated product was washed with cold methanol and recrystallized from dioxane, if necessary. The melting point of 296oC.

Preparation of 9.

5,11-dihydro-8-fluoro-6H-pyrido/2,3-b/benzo-1,4-diazepin-6-he (formula II: X = NH, R1= F in d', R2= H, N1= benzene, N2= pyridine with N in position d).

This compound is prepared as in preparation method 8, but starting from 5-fluoro-2-nitrobenzoic acid and 3-amino-2-chloropyridine. The melting point 270oC.

A common way to obtain methylpiperazine formula (I) of the invention from azapirones formula (II) can be carried out in accordance with the three variants of implementation of the scheme are given and commented on below.

Scheme A.

< / BR>
R' = pair-nitrobenzyl; R = N-methylpiperazine.

Of azaperone (II) synthesize the corresponding tion (III) under the action of P2S5in pyridine. Produce the crude product, use it as such and added tert. butyl potassium and para-nitrobenzylidene to obtain tiefer (IV). The compound of formula (I) PE with TCS. , Helv. Chim. Acta, 50, 1588, 1967).

Scheme B.

.

R = N-methylpiperazine.

Mix azepine (II) with N-methylpiperazine in the presence of a solution of TiCl4in anisole. This mix allows you to get under stirring and heating compound (I) of the invention (see Chakrabarti with al., J. Med. Chem. 23, 876, 1980 and Press J. with al., J. Med. Chem. 22, 725, 1979).

.

R = N-methylpiperazine.

Azepine (II) process OPCl3and DMF, to obtain the corresponding imidocloprid (V) that no selection enter into the reaction, and subsequent condensation with N-methylpiperazine in toluene, to obtain the compound (I) (see Hunsicker with al., Helv. Chim. Acta 49(5), 1933, 1966).

You can also synthesize compounds of the invention without the use of azaperone (II) as a source or an intermediate product, as will be shown in the framework of the synthesis methylpiperidine of example 21, from the reaction product of ortho-galoidirovaniya formula (V)

,

in which

Hal is a halogen atom such as Cl, F, I or Br, and benzolkarbonovyh acid of formula (VI):

,

in which

X has the previously indicated meaning.

Salt of methylpiperazine formula (I) can be obtained by well Izvestia methylpiperazine acid in an appropriate solvent, as, for example, in alcohol, and then, if necessary, the deposition of salt, add another solvent miscible with the first, and in which the salt is insoluble, for example, a simple ester, or neutralize the ethereal solution of the acid or base by base or acid. Used or acids are organic acids or inorganic acids. As the inorganic acids used preferably hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc., Organic acids are, or carboxylic acids or sulfonic acids, such as acetic, citric, maleic, fumaric, propionic, glycolic, lactic, ascorbic, succinic, tartaric, phenylacetic, benzoic, p-aminobenzoic, Anthranilic, p-oksibenzoynoy, salicylic, methanesulfonic, econsultancy, glucuronic, etc.

The following are detailed examples of the preparation of some derivatives of methylpiperazine according to the invention.

Example 1.

11-/4-methylpiperazin-1-yl)-5H-pyrido/4,3-b/benzo-1,5-diazepin (formula I: X = NH, R1= R2= H, N1= pyridine with N in position b', N2= benzene).

Method A.

1) About which aceii under reflux. After several hours of heating to remove excess reagents and solvent. The resulting residue is carefully treated with ice. Allocate the sediment and used as such for further work.

2) was Added to 5.2 g thiolactam to a suspension of tert.-the butyl potassium in 80 ml of dioxane (prepared as follows: 1.64 g of potassium are dissolved in 40 ml of tert.-butanol, after the flue gas to remove solvent and the residue absorb 80 ml of dioxane). A mixture of 1 h refluxed. Then added 4.1 g of para-nitrobenzaldehyde. Refluxed 4 h to Remove the solvent. The residue is absorbed chloroform and washed with alkali. The chloroform phase is dried and evaporated to dryness. The residue is recrystallized from a mixture of petroleum ether/acetone. The melting point 127oC.

3) is refluxed 4.3 g of tiefer obtained in 2), within 24 h in the presence of 10 ml of N-methylpiperazine and 0.1 ml of glacial acetic acid. After evaporation to dryness the residue absorb the diluted acetic acid. If necessary, filter the precipitate. The filtrate discolor treatment activated carbon. Precipitated base by the addition of concentrated hydroxide ammonium, f is Lavinia 216oC.

Method B.

Mix 0.01 mol 5,10-dihydro-11H-pyrido/4,3-b/benzo-1,5-diazepin-11-she's in 10 ml of N-methylpiperazine. Under stirring carefully added to a suspension of diazepinone a solution of 1.2 ml of TiCl4in 5 ml of anisole. The reaction mixture was kept under stirring at 120oC for 2-3 hours the Mixture is cooled and absorb ice water. the pH of the solution should be alkaline. Then the product is extracted with dichloromethane. After evaporation of the solvent purify the residue on a column of diatomaceous earth (eluent: acetone/petroleum ether 40-60: 9(1)). After removal of the solvent is recrystallized product from hexane. The melting point 216oC.

Example 2.

6-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo-1,4-diazepine (formula I: X = S, R1= R2= H, N1= benzene, N2= pyridine with N in position d).

Treated with 3 g of 5H,6H-pyrido/2,3-b/benzo-1,4-diazepin-6-it is the excess of phosphorus oxychloride and 5 drops of N,N-dimethylaniline by boiling under reflux for 20 hours, the Solution is treated with anhydrous toluene and evaporated to dryness. The remainder absorb 50 ml of anhydrous toluene and added an excess of N-methylpiperazine. Then the mixture is refluxed for 2-4 hours direct PDAs. The chloroform phase discolor coal and dried. After concentration to a small volume of the mixture is passed through a column of silicon oxide (Woelm act III).

Elute with acetone. Immediately after separation of the various phases containing the target product is evaporated to dryness. The residue is recrystallized from petroleum ether 100-140. The melting point 134oC.

Example 3.

Fumarate 8-chloro-6-/(4-methylpiperazin-1-yl)pyrido/2,3-b/benzo-1,4 - diazepine (formula I: X = S, R1= H, R2= Cl in b', N1= benzene, N2= pyridine with N in position d').

On the basis of 5H,6H-pyrido/2,3-b/benzo-1,4-oxazepan-6-it, get methylpiperazine the basis specified in the title, according to the method of example 2. After evaporation of the chloroform fractions dissolve the residue in a minimum amount of boiling alcohol. Add equimolecular amount of fumaric acid, previously dissolved in hot alcohol. The solution is cooled. If the product does not crystallize upon standing, add ether for crystallization. After settling receive a white powder, which is separated and washed with ether. The melting point 198oC.

Example 4.

Maleate 5-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo-1,5-oxazepa is obtained from 5H,6H-pyrido/2,3-b/benzo-1,5-oxazepine-5-it and by the method of example 2. Chloroform fraction is then evaporated to dryness. The remainder absorb the methyl ethyl ketone. Add equimolecular amount of maleic acid dissolved in methyl ethyl ketone, then simple anhydrous ether. The product crystallizes. It is isolated and washed with ether. The melting point 206oC.

Example 5.

Fumarate 7-chloro-5-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo-1,5 - oxazepine (formula I: X = 0, R1= Cl in position b, R2= H, N1= pyridine with N in position d', N = benzene).

Of oxazepine described in preparation 1, using the method of example 2, highlight the connection fumarata the same way as in example 3. The melting point 260oC.

Example 6.

Fumarate 5-/4-methylpiperazin-1-yl/-8 methylpyridin/2,3-b/benzo-1,5 - oxazepine (formula I: X = 0, R1= CH3in b1, R2= H, N1= pyridine with N in position d', N2= benzene).

Of oxazepine described in preparation 2, using the method of example 2, highlight the connection fumarata the same way as in example 3. The melting point of 235oC.

Example 7.

Fumarate 6-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo-1,4 - oxazepine (formula I: X = O, R1= R2= H, N1= benzene, N2= p is 2, allocate connection fumarata. The melting point 183oC.

Example 8.

Fumarate 8-chloro-6-/4-methylpiperazin-1-yl/pyrido/2,3-b/benzo - 1,4-oxazepine (formula I: X = O, R1= H, R2= Cl in position b', N1= benzene, N2= pyridine with N in position d).

On the basis of 8-chloro-5H,6H-pyrido/2,3-b/benzo-1,4-oxazepan-6-it is the preparation of 3, get the connection according to the method of example 2. The compound is isolated in the form of fumarata the same way as in example 3. The melting point 250oC.

Example 9.

6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,4-diazepine (formula I: X = NH, R1= R2= H, N1= benzene, N2= pyridine with N in position d).

On the basis of 5,11-dihydro-6H-pyrido/2,3-b/benzo-1,4-diazepin-6 - it will perform the condensation according to method B of example 1. The melting point 142oC.

Example 10.

8-chloro-6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,4 - diazepine (formula I: X = NH, R1= Cl in b', R2= H, N1= benzene, N2= pyridine with N in d).

Based on diazepinone preparation 8, get the target product according to the conditions described in example 1, method B. the melting Point 180oC.

Example 11.

6-/4-methylpiperazin-1-yl/-8-methyl-11H-pin N in d/.

On the basis of 5,11-dihydro-8-methyl-6H-pyrido/2,3-b/benzo-1,4 - diazepin-6-it, get the connection specified in the title, according to the method of example 1, method B. the melting Point of 157oC.

Example 12.

9-chloro-6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo-1,4 - diazepine (formula I: X = NH, R1= Cl c', R2= H, N1= benzene, N2= pyridine with N in d/.

On the basis of 9-chloro-5,11-dihydro-6H-pyrido(2,3-b)benzo-1,4 - diazepin-6-it, get the product that is listed in the title, by the method of example 1, method B. the melting Point 186oC.

Example 13.

8-fluoro-6-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo - 1,4-diazepine (formula I : X = NH, R1= F in b', R2= H, N1= benzene, N2= pyridine with N in d/.

Based on diazepinone preparation 9, get the connection specified in the title, by the method of example 1, method B. the melting Point 188oC.

Example 14.

5-formyl-11/4-methylpiperazin-1-yl/-5H-pyrido/4,3-b/benzo - 1,5-diazepin (formula I : X = , R1= R2= H, N1= pyridine with N in b', N2= benzene).

Originate from a compound of example 1. Cool 15 ml of acetic anhydride and add there little by little while mixing 7 ml of 99% formic acid. The mixture is heated in ECRI stirring overnight. The mixture is treated with ice, alkalinized and extracted with dichloromethane. Dried and concentrated in vacuo, and recrystallized from hexane. The melting point of 196oC.

Example 15.

11-formyl-5-/4-methylpiperazin-1-yl/-11H-pyrido/2,3-b/benzo - 1,5-diazepin (formula I : X = , R1= R2= H, N1= pyridine with N in d', N2= benzene).

On the basis of the connection described in the article by Chakrabarti with TCS. j. Med. Chem., 32, N 10, 2375-2381, 1989, provide formirovanie by the method of example 14. The melting point of 194oC.

Example 16.

11-trifloromethyl-5-/4-methylpiperazin-1-yl/-11H - pyrido-/2,3-b/benzo-1,5-diazepin (formula I: X = N-CO-CF3, R1= R2= H, N1= pyridine with N in d', N2= benzene).

Proceed from compounds described in the article mentioned in example 15. Mix of 0.02 mol of compound with 15 ml of anhydride triperoxonane acid and a few drops of N,N-dimethylaniline with good cooling, then refluxed for 5 min and left under stirring overnight. Poured on ice, alkalinized, extracted with chloroform. Purified on a column of silica and concentrated. Recrystallized from hexane. The melting point 183oC.

Originate from a compound of example 9 and spend formirovanie by the method of example 14. The melting point 202oC.

Example 18.

10-/4-methylpiperazin-1-yl/pyrido/4,3-b/benzo-1,4-diazepine (formula I: X = S, R1= R2= H, N1= benzene, N2= pyridine with N in b).

Come from diazepinone preparation 5, get the connection specified in the title, using the method of example 2. The melting point of 143-144oC.

Example 19.

5-/4-methylpiperazin-1-yl/dibenzo(b, f)1,4-selenation (formula I: X = Se, R1= R2= H, N1= N2= benzene).

Come from 10H, 11H-dibenzo/b, f/1.4-selenation-11-it and get the connection specified in the title, using the method of example 2. The melting point 107oC.

Example 20.

6-/4-methylpiperazin-1-yl/pyrido/2,3-b/3',2'-f/1.4-diazepin (formula I: X = S1, R1= R2= H, N1= N2= pyridine with N in d and d'/.

The product is obtained from the compound of preparation 7, using the method of example 2. The melting point 170oC.

Example 21.

6-/4-methylpiperazin-1-yl/-11-methyl-11H-pyrido/2,3-b/benzo-1,4 - diazepine (formula I: X = N-CH3, R1= R22CO3and 50 ml of dry isopropanol. After evaporation of the solvent the residue absorb water and bring to the boil in the presence of activated charcoal. After cooling, the solution is acidified to pH 3. The product precipitates as a yellow powder, it is filtered off, washed with water and dried.

The melting point of 174oC.

Suspended in anhydrous ether of 0.005 mol of the obtained acid. Connection etherification with diazomethane, which is obtained from 4 g of nitrosodiethylamine decomposition his caustic soda in the presence of ether. The ether solution diazomethane gradually poured to ethereal solution microcolony. Immediately upon termination of the reaction the solvent is evaporated. The remainder of the absorbed solution and extracted two times with CHCl3. The chloroform solution is dried and concentrated in the presence of petroleum ether 100-140. Then the crystalline product is filtered off and washed with petroleum ether 40-60. The melting point 71oC.

Catalytically restore 0.01 mol derived nitroethene (dissolved in 150 ml of ethanol) per 1 g of 10% palladium on coal Pd/C) in hydrogenator low pressure. After 2 h the reaction ends and rest the Razin. The mixture is heated with stirring to 120oC. Carefully poured to a mixture solution of 5 ml of TiCl4in 10 ml of anisole. The reaction mixture for 12 h refluxed. The mixture is then cooled and treated with 10 ml of isopropanol, 10 ml of concentrated hydroxide ammonium and 2 g of silicon oxide. The mixture is filtered and the collected precipitate is washed thoroughly with chloroform. The filtrate is washed once with water, then extracted with 2n HCl. This solution will discolor activated carbon and alkalinized by hydroxide ammonium. The precipitate is extracted with chloroform. Chloroform fractions are combined and concentrated to a small volume. The obtained residue is purified on a column of diatomaceous earth, elwira a 9/1 mixture of acetone and petroleum ether 40-60. Immediately after the selection is recrystallized product from a mixture of dichloromethane and hexane. The melting point 146oC.

Compounds of the invention were studied in the relevant pharmacological tests to show the activity level of the Central or peripheral nervous system. The following results were obtained on the substances of examples 1, 10, 11, 17, 18 and 19, they confirm the antidepressant, antipsychotic, anxiolytic, neuroleptic or Seda Prov./P> Characterization tests for substitution (3H) spiperone.

Preparation of membranes.

Remove the brain of male Wistar rats (200-250 g). Striped body quickly excised and homogenized in 20 ml of ice-cold buffer (50 nm Tris) HCl, pH 7, 4, 25oC) using a Teflon homogenizer. The homogenate was centrifuged at 4oC and 10,000 g for 10 min, the bottom part twice washed with ice-cold buffer and re-centrifuged. End of bottom part suspended in ice-cold buffer (50 nm/HCl, pH 7,4) containing 5 nm MgSO4, 0.5 nm, EDTA. After re-homogenization, the suspension is set at 1 mg protein/ml Determine the amount of protein by the method of Lowry with TCS. /J. Biol. Chem. 193, 265-275 (1951)), using as a standard bovine serum albumin.

Experience in linking.

Use a method developed by Thecotton with TCS. (Biol. Psychiatry 21, 1114-1122 (1986)). Assess the binding of (3H)-spiropyran the following mixture: 200 μl of membrane preparation (0.1-0.2 mg protein) 100 ál (10-6M) of the test substance and 600 MLK buffer to a final volume of 1 ml of the Control tube, taken to control for nonspecific binding, also contain 1 μm (+)-butaclamol. Contents (three repetitions) and then incubated with 0.5 nm (3H) spiropyran PR is Bologna (CF/C). The filter is washed three times with 5 ml ice-cold buffer. Measure the radioactivity spectrometer with liquid scintillating (ZKB Rack Beta 1219). The results are shown as percentage difference between the control ( IM ) + (butaclamol) and the test substance.

Characterization of muscarinic receptors

Communications receptors

The method is based on the methodology described Yamamura and Snaidero (Proc. Natl. Sci. USA, 71, 1725 (1974)). After a quick withdrawal of the rat brain SGU (130-180 g) dissected for removal of the cerebellum. Other tissues homogenized with a Potter in a solution of 0.32 M sucrose, 50 mm Tris buffer(HCl), pH 7.5. The protein concentration determined by the method of Peterson (Anal. Biochem. 83, 346 (1977)).

Experience in linking was performed three times at 25oC. the incubation Medium (1 ml) consists of 60 mm NaCl, buffer Tris(HCl), pH 7.5 and 1.5 nm (3H) QNB (new England nuclear, Def. activity: 1,18 TBq (mol). The reaction mixture was incubated with the homogenate for 60 min, homogen contains 250-400 µg of protein. The nonspecific binding is 10-5M atropine. Termination of manipulation carried out by rapid filtration through a glass filter (Whatman CF/C. Free ligand also removed. Each sample was washed with 2 x 10 ml of cold buffer. The filters are dried, transferred to toluene of rest the HB. Communication with the receptor is directly proportional to protein concentration up to 700 µg protein/ml

In vivo: a test of antagonism to apomorphine.

At 20 mg/kg, most compounds reduces the mobility of the animals and has a sedative effect. In most cases, the compounds have activity, the intensity of which is located between the activity of clozapine (20 mg/kg) (+) and activity of haloperidol (0,63 mg/kg (+++++). The following results are given as an example.

Example 1 - ++

Example 5 - +

Example 7 - +

Example 8 - +++

Example 10 - +++

Example 11 - +++

Example 12 - +

Example 13 - +

Example 19 - ++

Test for catalepsy.

(See for example, gray U. D., österberg, A. H., Rauch H. E. Arch. Int. Pharmacodyn. 134, 198, 1961, and Costall Century, Olley J., E, Neuropharmacology 10, 297, 1971).

This test shows the level of extrapyramidal effects, which are available with many neuroleptics (unwanted side effects). Compounds of the invention provoke very low catalepsy and, therefore, seem to lack this side of undesirable actions. However, some products have a weak catalepsy:

examples 1 and 3: catalepsy at doses above 40 mg/kg;

- example 4; weak catalg.

The object of the present invention are also pharmaceutical compositions containing as active constituent one or more compounds of the formula (I), alone or with other active substances such or other actions, and a mixture with pharmaceutically acceptable eccipienti.

These pharmaceutical compositions can be solids, such as tablets, coated and without him, the coating can be in one or more layers, wafers, capsules, dispersible or soluble powders, suppositories, or liquid, such as solutions, suspensions, emulsions, syrups, preparations for parenteral administration, for example, in aerosol form.

Solid compositions for oral administration can be prepared by mixing one or more substances according to the invention, for example, with milk sugar, sugar powder, starch, talc, with products designed to slow down or rollover effects, for example, acatitla cellulose, glycerol stearates, ion-exchange resins.

Suppositories can be prepared by introduction of one or more substances according to the invention in cocoa butter, for example, or in any other suitable to be cooked, for example, when dissolved, suspendirovanie or transferred to the emulsion at the time of cooking or just before the introduction of one or more substances according to the invention and, in addition, any other product, the presence of which is desired or required, for example preservatives, such as methyl-p-oxybenzoates and propyl-n-oxybenzoates, thickeners and emulsifiers, for example cellulose derivatives and esters of polyoxyethylenesorbitan, food and flavouring additives, such as sugar, saccharin, sorbitol, natural or synthetic essences, isotonicity, for example sodium chloride, or buffers such as sodium phosphate, in distilled water, in other acceptable hydroxyl-containing liquids, such as ethanol, glycerol, some glycols, mixtures of these solvents or in pharmaceutically acceptable oils.

1. Derivatives methylpiperazine General formula I

< / BR>
where X is oxygen, sulfur, selenium or the group NH or NR3where R3group

< / BR>
or alkyl with 1 to 4 carbon atoms, branched or unbranched;

R1is hydrogen, halogen or alkyl with 1 to 4 carbon atoms, branched or unbranched;

R2- hydrogen, - pyridine cycle or Vice versa, in which the nitrogen atom of the pyridine cycle is in position b, b', d or d', if R1and R2is hydrogen and X is sulfur, oxygen or the group NH, N1 - pyridine cycle, and N2 - benzene nucleus, and a pyridine nitrogen may not be in position d'; or N1 and N2 both are benzene nuclei, if X is selenium; or N1 and N2 both pyridine cycles with nitrogen atom in d and d' position, when X is sulfur, and R1and R2is hydrogen,

or pharmaceutically acceptable salts of these derivatives.

2. Connection on p. 1, in which R1is hydrogen, chlorine, fluorine or methyl.

3. Connection PP. 1 and 2, in which R2is hydrogen or chlorine.

4. Connection PP.1 to 3, which are a salt selected from clorhidrato, brotherton, sulfates, phosphates, acetates, citrates, malatov, fumarates and methansulfonate.

5. Connection PP.1 - 4, representing one of the following compounds: 11-(4-methylpiperazin-1-yl)-5H-pyrido(4,3-b)benzo-1,5-diazepin; 6-(4-methylpiperazin-1-yl)pyrido(2,3-b)benzo-1,4-diazepin; fumarate 8-chloro-6-(4-methylpiperazin-1-yl)pyrido(2,3-b)benzo-1,4-diazepine; fumarate 8-chloro-5-(4-methylpiperazin-1-yl)pyrido(2,3-b)benzo-1,5-oxazepine; fumarate 5-(4-methylpiperazin-1-yl)-8-methylpurine(2,3-b)benzo-1 is l)pyrido(2,3-b)benzo-1,4-oxazepine; 6-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,4-diazepin; 8-chloro-6-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,4-diazepin; 6-(4-methylpiperazin-1-yl)-8-methyl-11H-pyrido(2,3-b)benzo-1,4-diazepin; 9-chloro-6-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,4-diazepin; 8-fluoro-6-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,4-diazepin; 5-formyl-11-(4-methylpiperazin-1-yl)-5H-pyrido(4,3-b)benzo-1,5-diazepin; 11-formyl-5-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,5-diazepin; 11-trifloromethyl-5-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,5-diazepin; 11-formyl-6-(4-methylpiperazin-1-yl)-11H-pyrido(2,3-b)benzo-1,4-diazepin; 5-(4-methylpiperazin-1-yl)dibenzo(b, f) 1,4-selenation; 6-(4-methylpiperazin-1-yl)-11-methyl-11H-pyrido(2,3-b)benzo-1,4-diazepin; 6-(4-methylpiperazin-1-yl)-dipyrido(2,3-b: 3',2' - f)-(1,4-diazepin.

 

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The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

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R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

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(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

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where R1- C1-C6-alkoxy or phenylaminopropyl,

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The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

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< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

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