Derivatives of aryl(or heteroaryl)- piperazinylmethyl, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Usage: as pharmaceutical compositions. The inventive product - derivatives of aryl (or heteroaryl) piperazinylmethyl formula

< / BR>
,

R3is hydrogen, halogen, carboxyl, carboxamide, phenyl; Z1- nitrogen, C - R1; Z2- nitrogen, C - R2; Z4-nitrogen; C - R4; Z5- nitrogen, carbon; Ar is phenyl which can be substituted by chlorine, methoxy or represents 2-N-methyl imidazole, 3-(1,2-benzothiazole) and so on. 3 S. p. f-crystals, 8 PL.

The invention relates to the field of synthesis of new biologically active compounds. In particular, the invention relates to new derivatives 1-{4-/4-(2-aryl (or heteroaryl)-1-piperazinil/-alkyl}-1H-azole, method of production thereof and to their use in farbkomposition.

Already known 1-{4-/4-(aryl (or heteroaryl))-1-piperazinil/-alkyl}-N-heterocyclization, for example:

Wu, Y. H., and others J. Med. Chem. 1969, 12, 876; Wu Y. H., and others J. Med. Chem. 1972, 15, 477; Temple, D. L. and others, U.S. Patent N 4456756; J. P. Yevich and other J. Med. Chem. 1983, 26, 194; on the other hand, the azoles are described in the French patent A. Colombo and other FR 2642759).

Currently, the applicant has discovered that new derivatives 1-{4-/4-(2-aryl (or heteroaryl))-1-Pipistrello nervous system, in particular, they exert anxiolytic and sedative, and antidepressant effect in the inhibition of the withdrawal syndrome and cerebral disorders associated with senile dementia, memory loss, as well as on the cardiovascular system, in particular, antihypertensive activity.

Compounds according to the invention correspond to General formula 1:

< / BR>
where Ar is phenyl which can be substituted by chlorine, methoxy or represents 2-N-Mei, 3-/1,2-benzothiazol/ or represents a group of the formula:

< / BR>
R3hydrogen, halogen, carboxyl, carboxamide, phenyl;

Z1the nitrogen or the group C-R1;

Z2the nitrogen or the group C-R2;

Z4nitrogen, a group C-R4;

Z5nitrogen or CH;

Z6Aza or a methylene group;

R1hydrogen, halogen, lower alkyl, phenyl;

R2hydrogen, lower alkyl or

R1and R2together form a radical-CH=CH-CH=CH-;

R2and R3together form a radical-CH=CH-CH=CH-;

R4hydrogen, phenyl, trifluoromethyl, halogen,

R3and R4together form a radical-CH=CH-C/C1/=CH-, -CH=C(C1)-CH=CH-, -CH= C(CH3)-C(CH3)=CH-;

and provided that Z5means nitrogen, ZUB>, Z5together form a benzimidazole, which may be substituted with halogen or salt of citric acid, except when:

Ar is phenyl which can be substituted by chlorine, methoxy group, Z2and Z5are each a nitrogen atom, Z1- represents the group C-R1and Z4represents C-R4and R3and R4together form-CH=CH-C(C1)= CH-, -CH=C(C1)-CH=CH-, -CH=C(CH3)-C(CH3)=CH - and with the exception of compounds in which Z1, Z2, Z4, Z5or Z1, Z2, Z4, Z6all represent a nitrogen atom.

The invention relates also to a method for producing derivatives of arylpiperazines of alkylation formula II:

< / BR>
where Ar' represents a group

< / BR>
or 3-(1,2-benzothiazole) or phenyl which may be substituted by methoxy, halogena;

Z1represents nitrogen or , where hydrogen, phenyl, lower alkyl;

Z2represents nitrogen or C-R2where R2is hydrogen, lower alkyl, or R2together form-CH=CH-CH=CH-,

Z4represents N or C-R4where R4represents hydrogen, phenyl, trifluoromethyl, halogen;

R3hydrogen, phenyl, carboxamide, >represents nitrogen;

Z6-CH2-; n is 1-3.

Except when:

Z2and Z5are each a nitrogen atom,

Z1represents a group

where above and Z4group C-R4where R4above, and R3and R4together form-CH=CH-CH=CH - or-CH=C(CH3)-C(CH3)=CH - and with the exception of compounds in which Z1, Z2, Z4, Z5all represent nitrogen, which consists in the fact that carry out the reaction of compounds of General formula III:

< / BR>
where Ar' above, X represents halogen, with a compound of General formula IV:

< / BR>
where Z1-Z4have the above meaning.

The reaction is carried out in the presence of an appropriate solvent, such as dimethyl sulfoxide, dimethylformamide, alcohol, aromatic or non-aromatic hydrocarbon, a simple ether, such as dioxane or diphenyl ether, or mixtures of these solvents. This reaction is mainly carried out in the presence of a base, such as hydroxides, carbonates or bicarbonates of alkali metals, or mixtures of these compounds.

The most suitable temperatures vary between room temperature leads to the formation of mixtures of isomers, by the end of the reaction carry out the separation of components by physical methods such as distillation, crystallization or conventional chromatographic methods.

The invention relates also to pharmaceutical compositions possessing anxiolytic, calming, antidepressant and antihypertensive activity, containing as the active channel derived aryl- (or heteroaryl) piperazinil-alkyl-azole in a therapeutically effective amount and a pharmaceutically acceptable additive.

To illustrate the applicant sends the examples of herbal formulations based on the compounds according to the invention as active principle:

Example formulations for tablets, mg:

The active principle 5

Lactose 60

Microcrystalline cellulose 25

Povidone 5

Pre gelatinizing starch 3

Colloidal silicon dioxide 1

Magnesium stearate 1

Weight tablets 100

An example recipe for gelatin capsules, mg:

The active principle 10

Polyoxyethylenated the glycerides 135

Beginat glycerin 5

Indifferent matter: soft gelatin to sum up the number - 150

One example of a suspension of 10 m is benzoat 0,08

Water Up to 10 ml

In the following examples indicate the receipt of new derivatives in accordance with the invention. Also described some applications.

Example 16

Getting 1-{ 4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-benzimidazole.

Heated to education phlegmy for 14 h the mixture consisting of 6 g (20 mmol) 2-/4-(4-bromobutyl)-1-piperazinil/-pyrimidine, a 2.36 g (20 mmol) of benzimidazole and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide. Evaporated under vacuum, add chloroform, washed with water, dried on sodium sulfate, evaporated under vacuum and obtain 4.8 g 1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-benzimidazole, which can be recrystallized in ethyl ether, with a melting point of 85-88oC.

Compounds identified by examples 2-16, 20, 23, 25-31, 36-41, 43 and 44, obtained by the same procedure, and the data for their identification are given in tables I, II and III.

Examples 17 and 18

Getting 1-{ 4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -3H-imidazol-/5,4-b/-pyridine and 1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-1H-imidazo-/4,5-b/pyridine.

Follow method A, but using 1H-imidazo-/4,5-b/-pyridine as starting reagent.

Paul is anyone pressure.

Compounds identified by examples 17-19, 21, 22 and 24, obtained using a similar method, and the data for their identification are given in table. 1.

Example 35

Getting 4-chloro-1-/4-(4-phenyl-1-piperazinil)-butyl/-1H/-pyrazole.

Heated to education phlegmy within 24 h the mixture of 3.56 g (15 mmol) of N-(4-bromobutyl)-4-chloropyrazole, 2,43 (15 mmol) of 1-phenylpiperazine and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide. Evaporated under vacuum, add chloroform, washed with water, dried on sodium sulfate, evaporated under vacuum and obtain 3.1 g of 4-chloro-1-/4-(4-phenyl-1-piperazinil)-butyl/-1H-pyrazole, which can be recrystallized in ethyl ether, with a melting point 58-61oC.

Spectroscopic data for the identification of this product are listed in the table.2.

Example 1

Getting 1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-pyrrole.

Heated to education phlegmy for 1 h in a mixture consisting of 4 g (17 mmol) of 2-/4-(4-aminobutyl)-1 - piperazinil/-pyrimidine and 3.3 g of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid. Poured to cold water, neutralized using 10% sodium hydroxide, extracted with chloroform, dried, evaporated and get 2,th procedure.

Spectroscopic data for the identification of these products are given in table.1 and 2.

Example 6

Getting 4-carboxy-1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-1H-pyrazole.

Heated to education phlegmy for 4 h in a mixture of 4.4 g (12.2 mmol) of 4-carboxylate ethyl-1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-pyrazole in 50 ml of 2n HCl. Cooled using an ice bath, neutralized by ammonia and extracted with chloroform. Get that image of 3.4 g of 4-carboxy-1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-1H-pyrazole with a melting point 104-105oC.

Spectroscopic data for the identification of this product are listed in the table.1.

Example 5

Getting 4-carboxamido-1-{ 4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-pyrazole.

Slowly added to 1.1 g (10.3 mmol) of ethylchloride to chilled to a temperature of 0oC the solution containing 3,4 g (10.3 mmol) of 4-carboxy-1-{ 4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-pyrazole (example 6) and 1.04 g (10.3 mmol) of triethylamine in 90 ml of dimethylformamide. After 30 min miss a stream of dry ammonia, left under stirring for 1 h at a temperature of 0oC, left at room temperature in Checheno-1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-1H-pyrazole, which can be recrystallized in acetone, melting point 124oC.

Spectroscopic data for the identification of this product are listed in the table.1.

Method H

Example 45

Obtain 1,3-dimethyl-5-{3-/4-(2- methoxyphenyl)-1-piperazinil/-propylamino}-1H-pyrazole.

Prepare a slurry consisting of 0.5 g (13 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran and added drop by drop over 30 minutes a solution containing 3.9 g (11 mmol) of 1,3-dimethyl-5-{3-/4-(2-methoxyphenyl)-1-piperazinil/-propionamido}-1H-pyrazole in 50 ml of tetrahydrofuran. Maintain at room temperature during the addition, and then heated to education phlegmy within 3 hours Destroy excess lithium aluminum hydride, filtered off the insoluble mineral fraction, remove the tetrahydrofuran, diluted with chloroform, washed with water, dried using anhydrous sodium sulfate, evaporated to dryness and receive 3 g (81%) of 1,3-dimethyl 5-{ 3-/4-(2-methoxyphenyl)-1-piperazinil/-propylamino}-1H-pyrazole.

Spectroscopic data for the identification of this product are listed in the table.3.

Example 42

Getting citrate 4,5-dichloro-2-methyl-1-{4-/4-(2-pyrimidinyl)-1 - piperazinil/-butyl}-1H-which measures 11) in 50 ml of ethanol and added to the solution, containing 3.15 g of citric acid monohydrate in 20 ml of ethanol. Stirred for 1 h and left to crystallize at room temperature. Gain of 7.1 g of crystals with a melting point 137-138oC, which correspond to the citrate 4,5-dichloro-2-methyl-1-{4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl}-1H-imidazole.

Spectroscopic data for the identification of this product are listed in the table.3.

Biological activity

Anxiolytic and/or calming effect

For connections of several examples show the effect on the Central nervous system and, in particular, their anxiolytic and sedative effect using test conditional responsible reaction aversion by the method of J. S. New et cols. (J. S. New J. Yevich P, M. S. Eison, D. P. Taylor, L. A. Riblet, C. P. Vander Maelen, D. L. Templ, J. Med. Chem 1986, 29, 1476).

In this test using male Wistar rats weighing 200 g, trained to overcome the barrier in the cell deviation and output (Shuttle box) (Letica, standard LI 910 and LI 2700) after 30 s after their introduction into the cell.

Compounds with anxiolytic or sedative effect eliminate conditional response aversion.

Training: the first day of the 11 experiments with an interval of 3 minutes Electroshock is Miu exact performances of the first day (except the first experience) > 14).

Day of test: group selected rats. Introduction compounds or solvent is carried out orally 45 minutes before the start of the study.

In table.4 summarizes the results obtained for several compounds.

Given their pharmacodynamic properties, derivatives 1{-4-/4-(2-aryl (or heteroaryl))-1-piperazinil/-butyl}-1H-azoles according to the invention can satisfactorily be used for the treatment of humans and animals, in particular, in the treatment of disorders of the Central nervous system, and especially for the treatment of anxiety or as tranquilizers.

In the treatment of people enter the dose, of course, depends on the severity of the disease. Usually it is between about 5 and about 100 mg/day. Derivatives according to the invention can be administered, for example, in the form of tablets, solutions or suspensions or gelatin capsules.

Inhibition (slow) withdrawal syndrome

Use a test mailbox on the light /darkness, described B. Cos-tall et al. (J. Phar. Pharmasol, 1988, 40, 494-500). Put the mouse in the bright area of the box is divided into two spaces: one well-lit (mailbox on the light), and the other poorly lit (the box in the dark).

1. Consider, SK is P> 2. The activity in each space is determined by counting the number of intersections of the squares is divided into each space (see column 2 in table. 5).

3. Determine the time spent in a dark box for 5 min counting (see column 3 in table.5).

4. Determine the initial latent (hidden) period, i.e. the time elapsed from the moment when the animal is placed in a lighted box at the beginning of the test before it in a dark box (see column 4 in table.5).

Determine the anxiolytic and anxiogenic the behavior of mice during different periods of processing, comparing it all the time behavior of the control group animals, not subjected to any processing.

The treatments and experimental scheme:

1. The effect of a certain treatment (diazepam, cocaine, alcohol or nicotine) through daily introduction during the period from 7 to 14 days. This processing causes anxiolytic response (activity and presence in the illuminated box increase).

Dosage:

diazepam: 10 mg/kg by intraperitoneal 2 times a day for 7 days;

cocaine: 1 mg/kg by intraperitoneal within 14 days;

alcohol: in the times a day for 7 days

2. A break in the processing for 24 h causes a withdrawal syndrome, which manifests as exigences response (increases the activity and being in a dark box).

3. Various other groups, in addition to diazepam, cocaine, alcohol or nicotine, are treated, including compounds that are the subject of the present invention, and as a comparison treatment with buspirone or ipsapirone. In these groups also take into account the processing of diazepam, cocaine, alcohol or nicotine, and see also the response after 24 hours

We studied the connection and tested doses were as follows:

4,5-dichloro-2-methyl-1-{ 4-/4-(2-pyrimidinyl)-1-piperazinil/-butyl} -1H-imidazolium (approximately 42) with a dose of 1 mg/kg by mouth 2 times a day.

The observed results are collected in table.5, below.

The response obtained by using compounds that are the subject of the present invention, were as follows:

Derived from example 42 inhibits withdrawal syndrome, which manifests as a response exigences reaction caused by diazepam, cocaine, alcohol and nicotine, and, in addition, it supports a significant anksioliticheskim withdrawal syndrome, which manifests itself in the form anxiogenic response and which is called diazepam and cocaine. However, when interrupt processing using alcohol and nicotine, withdrawal syndrome, i.e. anxiogenic, no longer exists. Buspirone significantly inhibits only a few parameters anxiogenic response after termination of the treatment with alcohol.

Ipsapirone supports abstinence syndrome, which manifests itself in the form anxiogenic response and which is called diazepam, cocaine and nicotine. Ipsapirone inhibits withdrawal syndrome, which manifests itself in the form anxiogenic response and which is called by the action of alcohol.

Thus, the derivatives with the General formula 1 in accordance with the invention are useful as active substances of medicinal products intended for the treatment of disorders associated with withdrawal syndrome, which is manifested, in particular, in the form of anxiogenic response and which is called abrupt cessation of prolonged treatment with benzodiazepines, such as diazepam, cocaine, alcohol and/or nicotine.

In the treatment of people dose Wed mg/day.

Antihypertensive activity

For connections of several examples show the effect on the cardiovascular system, in particular, their antihypertensive activity. This activity manifests itself in the form of protection of animals from death caused by the intravenous injection of norepinephrine, which creates a hypertensive crisis in rats.

Test for antagonism to norepinephrine in rats:

Identify antihypertensive activity using the test described by P. A. J. Janssen et cols (P. A. J. Janssen, C. J. E. Niemegeers, K. H. L. Schellehens, F. J. Verbruggen et J. M. Van Nueten, Arzneim, Forsch, 1963, 13, 205).

In this test using male Wistar rats weighing 200 g of the target compound is administered by intraperitoneal, and after 2 h injected by 1.25 mg/kg of norepinephrine. This processing causes death in control animals.

The initial dose of injection in these studies is 40 mg/kg by intraperitoneal.

Define DE-50 for the most active compounds and summarize the results in table.6.

Action to improve recognition

For connection example 42 identify action to improve recognition.

Study the influence of this compound on the process of habituation of mice on a test mailbox on the light/is here habituation), on the other hand, the ability of the block opposite effects caused by scopolamine.

Put the mouse in the bright area of the box is divided into two spaces: one, well-lit (mailbox on the light), and the other, dimly lit (the box in the dark).

1. Consider how many times the mouse stands on his hind legs in each space for 5 min (see column 1 in table.7).

2. The activity in each space is determined by counting the number of intersections of the squares is divided into each space (see column 2 in table.7).

3. Determine the time spent in a dark box for 5 min counting (see column 3 in table.7).

4. Determine the initial latent period, i.e. the time elapsed from the moment when the animal is placed in a lighted box at the beginning of the test before it in a dark box (see column 4 in table.7).

Animal-witnesses spend two processing solvent in the day. Animals treated with compounds according to example 42, administered two doses per day value 0,00001 ng/kg of this compound through the mouth. The same operation is repeated daily for 5 days.

Animals are trained to stay more time in a dark box and Bistrita this treatment animals from a group of witnesses "forget" about learned behavior, which is to stay more time in a dark box.

On the seventh day they restore learned habit.

Treatment using the compounds, which improves recognition leads to the fact that:

1. Learned behavior is improving, learning is faster and the time spent in this box increases.

2. The appeal of learning caused by scopolamine completely locked.

The results obtained are summarized in table.7. They show that the compound according to example 42 has the effect of improving the recognition, because this compound improves the learning process and blocks the effects caused by scopolamine.

Piracetam used in the same conditions, show no activity.

Antidepressant effect

For connection example 42 reveal antidepressant effect. Use test hopeless behavior in mice, described by R. D. Porsolt et cols (Arch. Int. Pharmacodyn. 1977, 229, 327-336).

Animals are placed for 6 min in a cylinder containing water, from which they cannot escape. Measured in groups of 10 mice, compiled by the test dose, the duration of immobility between 2-nd and 5-th minute the ability of animals to the fact, she called their state of depression, which is caused by the presence of the face of opposition and the unresolved situation in a hostile environment, such as water.

Antidepressants reduce this stillness.

In our test using imipramine (30 mg/kg by intraperitoneal) as a compound for comparison.

The results show that the connection 42 has an antidepressant effect, which significantly reduces the immobility time compared with a group of witness.

The results are shown in table.8.

The applicant has compared one of his connections with the active connection from French application N 2642759, which corresponds to French patent N 623734. In particular, the applicant has chosen connection 2-{4-[4-(4-chloro-1-pyrazolyl)-butyl] -1-piperazinil} -pyrimidine (E-4424) and compared it with the compound of example 42 (E-4804) of this application. The results of the comparative tests are presented below.

Anxiolytic activity (in accordance with the tests described Costall, etc. and used in this application, S. 43).

1. Investigation of the reaction light/dark on mice.

Connection Minimum dose with a calming effect

E-44>Connection Minimum dose with a calming effect

E-4424 0.001 mg/kg/b

E-4804 0,00001 mg/kg/b

Inhibition of the abstinence syndrome (occurrence of an alarm condition after the termination of the processing of cocaine, alcohol, diazepam and nicotine).

Connection Active dose

E-4424 0.5 mg/kg, in/b

E-4804 0.001 mg/kg/b

Activity towards improving cognitive abilities

Compound Doses that improves the learning and suppress the influence of scopolamine

E-4424 1 ng/kg, orally

E-4804 0,00001 ng/kg, orally

It is obvious that a new connection E-4804 (example 42) has a higher activity than the compound E-4424 (example 52 cited patent). Moreover, the compounds of the present invention exhibit physiological activity, the presence of which is not expected in the case of compounds known in the above-mentioned patent. In particular, the compounds of the invention and their physiologically acceptable salts also have antihypertensive activity.

1. Derivatives of aryl(or heteroaryl)-piperazinylmethyl General formula

< / BR>
where Ar is phenyl which can be substituted by chlorine, methoxy or represents 2-N-Mei, 3-(1,2-benzothiazole) or is the or group C R1;

Z2the nitrogen or the group C R2;

Z4the nitrogen or the group C R4;

Z5nitrogen or CH;

Z6nitrogen or a methylene group;

R1hydrogen, halogen, lower alkyl, phenyl;

R2hydrogen, lower alkyl, or R1and R2together form-CH CH CH CH-; R2and R3place form a radical-CH CH CH CH-;

R4hydrogen, phenyl, trifluoromethyl, halogen, R3and R4together form a radical-CH CH C (Cl) CH-, -CH C(Cl) CH CH-, -CH C(CH3) C(CH3) CH-;

provided that Z5nitrogen, Z6the group of methylene, n is 1 to 3, and if the Ar group

Z1, Z2, Z4, Z5together form a benzimidazole, which may be substituted with halogen,

or salt of citric acid, except when Ar is phenyl which may be substituted by chlorine, methoxy group, Z2, Z5each nitrogen atom, Z1group C R1and Z4C R4and R3and R4together form-CH CH C(Cl) CH-, -CH C(Cl) CH CH-, -CH C(CH3) C(CH3) CH-, and with the exception of compounds in which Z1, Z2, Z4, Z5or Z1, Z2, Z4, Z6all the nitrogen atom.

2. The method of obtaining derivatives arylpiperazine-alkylation formula II

< / BR>
where Ar<
Z1nitrogen or where hydrogen, phenyl, lower alkyl;

Z2nitrogen or C-R2where R2hydrogen, lower alkyl, or R2together form-CH CH CH CH-;

Z4nitrogen or C-R4where R4hydrogen, phenyl, tripometer, halogen;

R3hydrogen, phenyl, carboxamide, COOH, halogen, or R3and R4together form a group-CH CH CH CH - or-CH C(CH3) - C(CH3) CH-;

Z5nitrogen;

Z6CH2;

n 1-3

except when Z2and Z5each nitrogen atom, Z1the group has the above meaning and Z4group C R4where R4has the above significance, and R3and R4together form-CH CH CH CH - or-CH C(CH3)

C(CH3) CH-,

and with the exception of compounds in which Z1, Z2, Z4, Z5all nitrogen,

characterized in that carry out the reaction of compounds of General formula III

< / BR>
where Arhas the specified values;

X is halogen,

with a compound of General formula IV

< / BR>
where Z1Z4, R3have the specified values.

3. Pharmaceutical composition having anxiolytic, calming, antidepressant and antihypertensive activity, piticescu effective amount and a pharmaceutically acceptable additive.

 

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