Heterocyclic amines and methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as a drug for the treatment of asthma and inflammation of the respiratory tract. The inventive product - heterocyclic amines of General formula (I):

where X is CH2- group or - S - group, B - group - CO-, -CH2OCO-, -CH2OCS-, -CH2NHCO -, and-CH2NHCS-; D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, and others, is a simple carbon-carbon bond or a group of formula-CH2- CH2and others; And selected from the group comprising carboxyl group, amide, sulfonamide or hydroxyamide and other Reagent I: compound of formula II. Reagent II - compound of formula III. The proposed compound of the formula I a, where A' is A halogen atom. Also proposed pharmaceutical composition having anti-asthma activity and anti-inflammatory effects on the respiratory tract. 5 C. and 4 h.p.

The invention relates to heterocyclic amines, method for their production and pharmaceutical compositions containing them.

The invention relates to heterocyclic amines of formula I:

,

in cotoran2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) alkylmercury, inorganic salts of the formula: -CONRcRd, sulfonamide of the formula: -CONHSO2Rfor hydroxyamide formula: -CNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridi-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases.

The invention relates also to compounds of formula (1a), where "y" represents a group other than C-C bonds, A1represents a halogen atom (Cl, Br or I) as an intermediate product.

Examples of C1-C3C1-C40 or C1-C6-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, n-pentyl, n-hexyl.

Examples of mono-C1-C5-alkylamino are methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, tert-butylamino.

Examples of the mono C3-C6- monoalkyl or monoalkanolamines groups are allylamino, propargylamine.

Examples of di-C1-C6-alkylamino PR is Ino, methyl-n-butylamino.

Examples of optionally substituted benzhydryl groups are: bis/pair-forfinal/-methyl; bis/p-chlorophenyl/-methyl. Examples of optionally substituted phenyl groups are: p-forfinal, p-chlorophenyl.

If Y represents -/CRaRb/-group, Ra- preferably the same group as Rband they represent methyl or taken together with the carbon atom which they are linked, represent cyclopropyl, cyclopentyl or cyclohexyl.

If A represents an ester group, A is preferably methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl.

If A represents a group-CO-NRcRd, Rcis preferably hydrogen and Rdis, preferably, pyridin-2-yl, or Rcand Rdtaken together with the nitrogen atom represent a 4-thiomorpholine - or 4,5-diseaseyou.

Particularly preferred compounds (1) are those compounds in which B represents-CO-, -CH2-O-CO-, -CH2NH CO - or - CH2-NHCS - group; D is a heterocycle selected from the group consisting of [2,6-bis/pyrrolidin-1-yl/-4-pyrimidinyl] , [4,6-bis/pyrrolidin-1-yl/-1,3,5-ing, and Rband represents hydrogen or methyl or, taken together they represent cyclopentyl, or cyclohexyl; A is etoxycarbonyl, toolsllosepainmoney, pyridine-2-yl-aminocarbonyl, N-methyl-hydroxylaminopurine, N-(4,5-diseasein)carbonyl, N-(4,5-diseasein).

The most preferred groups are those in which X represents carbon, other values will be those as defined above.

When in the compound of formula (I) is acidic or basic group, it can be converted into a salt, respectively, with a pharmaceutically acceptable base or acid. Received non-toxic salts, as well as single enantiomers, diastereomers, diastereomeric mixtures and racemates of the compounds (I) are within the scope of the invention. The main group can be converted into a salt with a pharmaceutically acceptable inorganic and organic acids, such as hydrochloric, Hydrobromic, itestosterone, phosphoric, metaphosphoric, nitric, or sulfuric acid, acetic, oxalic, tartaric, citric, benzoic, glycolic, gluconic, glucuronic, succinea, maleic, fumaric acids and the like.

Carboxy pharmaceutically acceptable. Examples of these salts include salts: ammonium, sodium, potassium, calcium, magnesium, aluminum, iron salts, zinc, copper, arginine, lysine, his-tag, melaminovye, ethylamine, dimethylamine, dibenzylamine, formoline, phenylglycine and D-glucosamine.

Prolinamidy with piperazineethanol described as ACE-inhibitors (Sankyo Co., JP 82.91.987; C. A., 97: 198218W, 1982).

N-carbamoylphenoxy N-methylpiperazine known as filaricidal (Indian J. Chem., Sect. B, 1987, 26 B/8/, 748-751).

Compounds of the invention are effective in preventing and/or weakening of the increased reactivity of the respiratory tract and in the elimination of the inflammatory state, which is accompanied by acute and subacute inflammation of the bronchial mucous membrane.

Bronchial increased reactivity, which is a clinical symptom of asthma pathology is considered as a direct consequence of the abnormal and hidden contractility and sensitivity of the bronchial mucosa, which may cause an acute crisis of asthma in certain subjects after exercise and/or exposure to external stimuli, such as inhale is cnyh symptoms increased bronchial reactivity can be induced experimental model, consisting in increased inhalation of tobacco smoke (e.g., within 10 min) male Guinea pigs weighing 400-450 g, by artificial respiration during anesthesia by ethylurethane and pancuronium (L. Gallico et al., American Review of Respiratory Disease, 141/4/Suppl. A840 (1990))/

The activity of compounds of the invention considered in pharmacological models proved by normalization of the parameters resulting from changes after intensive inhalation of tobacco smoke, such as sustained increases in pulmonary artery pressure (measured according to the method of Konzett and Rossler, Naun. Schmied. Arch. .. Pathol.Pharmacol: 191, 71(1970); increased number of cells (leukocytes, eosinophils, epithelial cells) in the bronchial-alveolar lavage (BAL); edematous fluid in the bronchial tissues (trachea) Evans Blue, previously introduced intravenously.

Compounds of the invention, is introduced through 2 hours before exposure to tobacco smoke, in doses varying from 2 to 50 mg/kg, showing a protective effect, which lasts for at least 4-6 hours, and the result is the reduction of high blood pressure caused by the inhalation of smoke with a simultaneous normalization of the number of cells in BAL and inhibition of staining edematous fluid.

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Compounds of the invention are also effective in the inhibition of cough caused by contact with the aerosol of citric acid, in doses that vary from 30 to 60 mg/kg (Charlier R., et al., Arch. Int. Pharmacodyn., 134, 306-27, 1961).

It is shown that the compounds according to this invention can be used for human therapy for the treatment of asthma and obstructive conditions of the respiratory tract and treatment of inflammatory processes. For a given therapeutic application of compounds (will be introduced in the form of pharmaceutical compositions, which can be obtained with conventional fillers and conventional technique, such as described in Remington's Pharmaceuticol Sciences Handbook, Mack Pub. Co. , N. Y. USA, 17th edition, 1985, used for intramuscular, intravenous, oral, aerosol and rectal administration.

The daily dose will depend on a number of factors, such as severity of disease and conditions of the patient; usually this dose will be in the region of 1 to 50 mg of the compound of formula I for a patient weighing 70 kg, one or more times a day.

The compounds of formula (I) is produced by interaction of the compounds of formula II.

,

where

X, B and D represent values, as defined above, with a compound of formula III.

,

that is, if A' is a halogen atom, is subjected to the interaction with the amine HNRcRdwhere Rcand Rddefined above, to obtain compounds of General formula (I), where A denotes the group: -NRcRdor, if A' means the ether group, if necessary, converted into the compound of General formula (I), where A denotes the free carboxyl group by hydrolysis with a mineral base, such as hydroxide of alkali metal, and the target product is isolated in free form or in the form of salts with pharmaceutically acceptable acids or bases.

The reaction of the compound (II) with compound (III) is usually carried out in an inert solvent and in the presence of an appropriate base. When the E-CO - represents carboxypropyl (E= OH), the reaction is carried out in an inert solvent and in the presence of condensing agents, such as carbodiimide, isonitrile and the like.

The compounds of formula (II) receive, from the acid of formula IIa.

,

where

R is a suitable protecting the molecule. A suitable protecting group present: tert-butoxycarbonyl, methoxycarbonyl, 9-peroxycarbonates, 2,2,2-trichlorocyanuric, allyloxycarbonyl, benzyloxycarbonyl. The compounds of formula (IIa) may be subject to transformation into a salt and/or separation of the optically-active isomers in the form of salts or diastereomers connection according to conventional methods.

The conversion of compounds of formula (IIa) in such compounds of formula IIb.

,

where

R has the above meanings, can take place using conventional reactions, such as: a) the transformation of carboxypropyl in Succinimidyl, acid chloride, mixed anhydride or other known reactive derivative and subsequent condensation with an amine of the formula IIc.

,

b) restore carboxypropyl or the corresponding mixed anhydride or carboxyamide group derived from a primary alcohol (CH2OH), which, after conversion into the corresponding halide or sulfonate can turn into alkylamine interaction with the amine of formula (IIc); appropriate reducing agents include DIBORANE or borgerding or alkaline earth metal;

c) alcohols obtained in zootecnia in the corresponding halide or sulfonate, interaction with the azide of an alkali metal. The above alkylated can then be transformed to the amine recovery, for example, with trialkyl or Triaryl-phosphines, trialkylphosphine, metal hydrides, alkaline earth metals and the like compounds;

d) halide or sulfonates obtained in accordance with b) can be transformed into the corresponding amines using conventional reactions such as the synthesis of Gabriel or reaction with precursors of the amino group, such as hexamethylenetetramine or triptorelin, which can give the desired amine by hydrolysis under appropriate conditions;

e) alcohols obtained in accordance with b) and amines obtained in accordance with (C), can turn into carbamates, THIOCARBAMATE, urea or thiourea reaction with carbonyl diimidazol or thiocarbonyldiimidazole and then with an amine of the formula (IIc).

The conversion of compounds of formula (IIb) in the compounds of formula (II) can be carried out in accordance with customary methods for specific and selective removal used protecting group, in particular, in the case of RE-derived using triperoxonane acid or trimethylsilylmethyl.

The compounds of formula (IISUB>2) alkyl, Y and A' are the values defined above, in accordance with conventional methods, which are reported in the literature. The compounds of formula (IIIa), in turn, receive the following conventional methods disclosed in the literature.

The compounds of formula (I) of the invention can be also obtained by the interaction of the precursor of formula (IId)

,

where

R" represents a-CO-Y-A', Y and A', as defined above, with an amine of the formula IIc

.

These syntheses can be performed using conventional reactions, such as those reported in a), b), c), d) and e) for the conversion of compounds of formula (IIa) in the compounds of formula (IIb). In particular, the separation of optical isomers may be effected by carrying out the reaction of formation of the salt of the racemic mixtures of compounds of the formula (IId) with optically active amines such as (-) or (+) -henini, the Department received diastereomeric salt crystallization, recrystallization to constant values []Dand, finally, obtaining the free acid and the regeneration of a decomposing agent.

Amines of the formula (IIc) are obtained according to the methods described in PCT WO 87/01706.

In the following examples, the concentrations are expressed in mA is e specified value (+) or (-).

Example 1. A solution of 26.5 g (1 ethoxymethyl)-1,3-thiazolidin-2-carboxylic acid (0,107 mol) and 34.8 g of (-)-quinine (0,107 mol) in acetonitrile (2.5 l) was filtered and stirred for 36 h at room temperature; receive a white precipitate (24,1 g), melting point 156-157oC, which is recrystallized from acetonitrile (560 g) to obtain 21 g of (-)-quinine (+)-thiazolecarboxamide, so pl. 170-172oC []D= -43o, []546= -53,5owith c= 2.3 in chloroform.

The mother liquor from the first solution for crystallization concentrated to dryness and distilled water as azeotrope with methanol and acetone (150 ml). The solid residue is suspended in acetone (400 ml), refluxed for 30 min, then cooled to room temperature. After 2 h stirring the suspended solid is filtered (21 g, so pl. 156-158oC []D= -124o, []546= 151 polyurthaneowith c= 2.3 in chloroform). The crystalline solid is again suspended in acetone (200 ml) and refluxed for 30 min, to obtain 12.1 g of (-)-quinine, so pl. 164-166oC []D= to 143o, []546= -174oc c=1.9 in chloroform.

Replacement optically active base of 2N sulfuric acid and extraction-thiazolidin-2-carboxylic acid, []D= +33o, []546= +37owith c=2.7 V chloroform; /-/-/1 ethoxymethyl/-1,3-tsolidis-2-carboxylic acid []D= -32o, []546= -35owith c=2.2 in chloroform.

Example 2. A solution containing 2.5 g of BOC-L-Proline in anhydrous THF (10 ml) at a temperature of 0oC in an atmosphere of inert gas and with stirring to a solution of 2.9 g of N-hydroxysuccinimide dissolved in 10 ml of tetrahydrofuran (THF). A solution of 2.1 ml of morpholinosydnonimine in 5 ml of THF are added dropwise in the final solution and continue stirring for 2 h at room temperature, then the solution is acidified with 1N hydrochloric acid (litmus paper) and extracted with ethyl acetate (310 ml). The combined organic extracts concentrated in vacuo until then, until crystals of BOC-L-Proline succinimido ether which is separated by filtration to obtain 2.6 g connection so pl. 128-130oC.

1 g of BOC-L-Proline succinimido ester are dissolved at room temperature in an atmosphere of inert gas in acetonitrile (7 ml), and then mixed under stirring with a solution of 0.97 g of N-[4,6-bis/pyrrolidin-1-yl]-1,3,5-triazine-2-yl] piperazine dissolved in acetonitrile (5 ml). After 5 h the mixture was concentrated in vacuo is tracerout with ethyl acetate (3 10 ml), then the combined extracts concentrated in vacuo to a small volume. By adding ethyl ether precipitated 1.5 g of N-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N'-[4,6-bis/ pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine, so pl. 148o(after recrystallization from diisopropyl ether), []D= -20,25o(C = 2,01 in EtOH).

Example 3. The reaction of the combined acetonitrile solution of the BOC-Proline N-hydroxysuccinimide ester with the appropriate N-substituted piperazine according to the method described in example 2 given the following N,N'-disubstituted piperazines:

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- /pyridine-2-yl/piperazine; N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/diethylamine/pyrimidine-4-yl] piperazine; N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/allylamino/pyrimidine-4-yl] piperazine; /-/-N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/pyrrolidin-1-yl/pyrimidinyl-4-yl] piperazine, so pl. 168-17oC []D= -20,7o(c = 2.0 V EtOH); /+/-N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, []D= +20,2o(c = 2.03 in EtOH); N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/pyrrolidin-Il/Pirim the one-4-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/diethylamine/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/diethylamine/-5-acetylpyridine-4-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis-/pyrrolidin-1-yl/-5-acetylpyridine-4-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [4,6-bis-/2-propylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [4,6-bis/diethylamine/-1,3,5-triazine-2-yl]piperazine;

/-/-N'-[/pyrrolidin-1-trituratsionnye-2-yl/carbonyl] -N- [3,6-bis/diethylamine/pyridine-2-yl] piperazine, []D= -19,3o(c = 2,07 in EtOH, (+)-N'-[/pyrrolidin-1-tert-butoxycarbonyl-2 - yl/carbonyl] -N-[3,6-bis/diethylamine/pyridine-2-yl] piperazine, []D= +19,8o(c = 2,01 in EtOH, N'-[/pyrrolidin-1-tert - butoxycarbonyl-2-yl/carbonyl]-N-[3,6-bis/pyrrolidine-1-Il/ pyridine-2-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- [3,6-bis/Allina/pyridine-2-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- /3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N- //3-hydroxy-2-pyridinyl/methyl/piperazine.

Example 4. of 2.54 ml triperoxonane acid is added under stirring in an inert gas atmosphere to a solution of 1.4 g of N'-[/pyrrolidin-1-tert-butoxycarbonyl-2-yl/carbonyl] -N'- [4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine in 10 ml of methylene chloride. After 3 h reaction at room temperature to the reaction mixture is added 1N NaOH to the main reaction and then the reaction mixture is extracted with methylene chloride and washed again with water.

The organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The crude product is crystallized from ethyl ether to obtain 950 mg of N-[/pyrrolidin-2-yl/carbonyl]-N'-[4,6-bis/pyrrolidin-1-yl/-1,3,5 - triazine-2-yl] piperazine, so pl. 143oC []D= 65,75o(c = 0,23 in EtOH)

Example 5. The interaction of N, N'-disubstituted piperazines described in example 3, in accordance with the method described in example 4 given the following N'-substituted N-[/pyrrolidin-2-yl/carbonyl]piperazines:

N'-[/pyrrolidin-2-yl/carbonyl]-N-/pyridine-2-yl/piperaz rbony] -N-[2,6-bis/allylamino/ pyrimidine-4-yl/piperazine;

/-/-N'-[/pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/pyrrolidin-1 - yl/pyrimidine-4-yl] piperazine, so pl. 172-174oC []D= 56,6o(c = 1,88 in EtOH), /+/ N'-[/pyrrolidin-2-yl/carbonyl]-N-[2,6 - bis/pyrrolidin-1-yl/pyrimidine-4-yl/piperazine, so pl. 148-151oC []D= +53,5o(c = 2,02 in EtOH);

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/ pyrimidine-4-yl/piperazine, so pl. 137oC;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/diamino/ pyrimidine-4-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/diethylamine/-5 - benzoylpiperidine-4-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/diethylamine/-5 - acetylpyridine-4-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/-5 - acetylpyridine-4-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/-5 - benzoylpiperidine-4-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/allylamino-1,3,5 - triazine-2-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/2-propylamino/-1,3,5 - triazine-2-yl/piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/diethylamine/-1,3,5 - triazine-2-yl/piperazine;

/-/-N'-[/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/diethylamine/- pyridin-2-yl]piperazine, oil, []D= -43,3o(c = 2,56 in EtOH);

/+/-N'-[/pyrrolidin-2-yl/carbonyl]-N-[33,6 bis/pyrrolidin-1-Il/ pyridine-2-yl] piperazine;

N'-[/pyrrolidin-2-yl/carbonyl]-N-[3,6-bis/allylamino/ pyridine-2-yl]piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/propargylamine/- pyridin-2-yl]piperazine;

N'-[/pyrrolidin-2-yl/carbonyl] -N-[3,6-bis/N-ethyl-N-allylamino/ pyridine-2-yl]piperazine;

N'-[/pyrrolidin-2-yl/carbonyl]-N-//3-hydroxy-2-pyridinyl/ methyl/piperazine.

Example 6. 0.8 g of N'-[/pyrrolidin-2-yl/carbonyl]-N'-[4,8-bis/ pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine dissolved in 20 ml of acetonitrile and added dropwise at 0oC and under stirring to 0.22 g of potassium bicarbonate and a solution of 0.28 ml ethylmaleimide in 5 ml of acetonitrile. After 4 h reaction at room temperature and under stirring to the reaction mixture are added water (50 ml) and extracted again with ethyl acetate (320 ml). The organic extracts are dried over sodium sulfate and remove the solvent under reduced pressure. The residue (0,86 g) clean chromatography on silica gel (eluent 1:1 hexane/ethyl acetate) to give N-[/1-ethoxypyrrolidine-2-yl/carbonyl]-N'- [4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl] piperazine, so pl. 95oC []D= -23,95o(c = 0.2 in EtOH).

Example 7. In accordance with the method described in example 6, based on N, N'-disubstituted piperazines described in example 5, and neo is their piperazines:

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-/pyridine-2-yl/ piperazine, oil:

Found,%: C, In Comparison With 60.87; H 6,91; N 14,88.

Calculated,%: C 60,96; H 6,95; N 14,97.

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis/ diethylamine/pyrimidine-4-yl/piperazine, so pl. 156-159oC;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis/ allylamino/pyrimidine-4-yl/piperazine, so pl. 147-148oC;

/-/-N'-[/1-ethoxypyrrolidine-2-yl/carbonyl]-N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl/piperazine, so pl. 170-172oC []D= 26,5o(c = 2,19 in EtOH);

/+/-N'-[/1-ethoxypyrrolidine-2-yl/carbonyl]-N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl/piperazine, so pl. 133-135oC []D= +26,5o(c = 2,14 in EtOH);

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-/pyrimidine-4-yl/piperazine, so pl. 127-129oC,

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[2,6-bis/ diamino-pyrimidine-4-yl]piperazine, so pl. 160-164oC;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[2,6-bis/ diethylamine/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[2,6-bis/ diethylamine/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[2,6-bis/ pyrrolidin-1-yl/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[4,6-bis/ allylamino/-1,3,5-triazine-2-yl/piperazine, so pl. 188-190oC;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[4,6-bis/ 2-propylamino/-1,3,5-triazine-2-yl/piperazine, so pl. 179-181oC;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[4,6-bis/ diethylamine/-1,3,5-triazine-2-yl/piperazine, so pl. 200-201oC;

/-/-N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[3,6-bis/ diethylamine/pyridine-2-yl] piperazine, so pl. hydrochloride 80-85oC []D= -20,6o(free base, c = 2.09 EtOH);

/+/-N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[3,6-bis/ diethylamine/pyridine-2-yl]piperazine, []D= +20,1o(c = 2,01 in EtOH);

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl/-N-[3,6-bis/ pyrrolidin-1-yl/piperazine, so pl. 64-67oC;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3,6-bis/ allylamino/pyridine-2-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3,6-bis/ propargylamine/pyridine-2-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3,6-bis/ N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/carbonyl] -N-[3 - hydroxy-2-pyridinylmethyl]piperazine;

N'-[/2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl]-N - pyridin-2/iltil/ethoxymethyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/diethylamine/pyrimidine-4-yl]piperazine, so pl. 175-177oC;

N'-[/2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/allylamino/pyrimidine-4-yl]piperazine, so pl. 171-173oC;

/-/-N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/ carbonyl]-N- [2,6-bis/pyrrolidin-1-/pyrimidine-4-yl] piperazine, so pl. 139-140oC: []D= -15,3o(c = 0.2 in EtOH);

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/ carbonyl] -N- [2,6-bis/diamino/pyrimidine-4-yl]piperazine, so pl. 148-150oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/ carbonyl] -N- [2,6-bis/diethylamine/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl)pyrrolidin-2-yl/carbonyl] - N-[2,6-bis/diethylamine/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl)pyrrolidin-2-yl/carbonyl] - N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl)pyrrolidin-2-yl/carbonyl] - N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/1-//2', 2'-/ethoxymethyl)pyrrolidin-2-yl/carbonyl] - N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine, so pl. 190-194oC;

N'-[/1-//2', 2'-/ethoxymethyl)pyrrolidin-2-yl/carbonyl] - N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine, so pl. 190-194oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/ka is the IMT/pyrrolidin-2-yl/carbonyl] - N-[4,6-bis/2-propylamino/-1,3,5-triazine-2-yl]piperazine, so pl. 181-185-oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[4,6-bis/diethylamine/-1,3,5-triazine-2-yl]piperazine, so pl. 177-178-oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, oil element. analysis:

Found,%: C 64,06; H 8,87; N 15,50.

Calculated,%: C 63,97; H 8,82; N 15,44.

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine, so pl. 71-74oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/allylamino/pyridine-2-yl]piperazine, so pl. 80-83oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/propargylamine/pyridine-2-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl]piperazine, oil:

Found,%: C 65,44; H 8,43; N OF 14.76

Calculated,%: C 65,49; H 8,45; N 14,79

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/carbonyl] - N-[3-hydroxy-2-pyridinylmethyl/piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidin-2 - yl] -N-/pyridine-2-yl/piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolyl the cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/allylamino/pyrimidine-4-yl]piperazine;

/-/-N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/ pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/pyrrolidin/pyrimidine-4-yl] piperazine hydrochloride, T. pl. 189-190oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/ pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/diamino/pyrimidine-4-yl] piperazine, so pl. 130-133oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/ pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/diethylamine/-5-benzoyl - pyrimidine-4-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/diethylamine/-5-acetylpyridine-4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine-4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine-4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl] -N-[4,6-bis/allylamino/1,3,5-triazine-2-yl] piperazine, so pl. 155-157oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl]piperazine, so pl. 162 to 165 of theoC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl] -N-[4,6-bis/2-p is irreligion-2 - yl/carbonyl] -N-[4,6-bis/diethylamine/-1,3,5-triazine-2-yl] piperazine, so pl. 150-151oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, oil:

Found,%: C 65,23; H 8,76; N 14,74

Calculated,%: C 65,26; H 8,77; N 14,74

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/propargylamine/pyridine-2-yl]piperazine, oil:

Found,%: C 65,20; H 7,15; N 15,70

Calculated,%: C age of 65.17; H 7,12; N 15,73

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/N-ethyl-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3-hydroxy-2-pyridinyl-methyl/piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-/pyridine-2-yl/piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl] -N-[2,6-bis/diethylamine/pyrimidine-4-yl] piperazine, so pl. 110-113oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine-2 - yl/ka is ntan-1'-carbonyl/ pyrrolidine-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, so pl. 192-193oC []D= -19,6o(c = 02 in EtOH),

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/ pyrrolidine-2-yl/carbonyl]-N-[2,6-bis/diamino/pyrimidine-4-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/diethylamine/-5-benzoylpiperidine-4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[2,6-bis/diethylamine/-5-acetylpyridine-4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl] -N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl] piperazine, so pl. 212-214oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl]piperazine, so pl. 230-231oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[4,6-bis/2-propylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl] -N-[4,6-bis/diethylamine/-1,3,5-triazine-2-yl] piperazine, so PL 204-207oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/peraboni]-N-[3,6-bis/allylamino/pyridine-2-yl]piperazine so pl. 99-100oC;

N'-[/1-/1'-/etoxycarbonyl/CYCLOBUTANE-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/propargylamine/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopropane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-[3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopropane-1'-carbonyl/pyrrolidine-2 - yl/carbonyl]-N-/3-hydroxy-2-pyridinylmethyl/piperazine;

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-/pyridine - 2-yl/piperazine, so pl. 159-160oC;

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/ diethylamine/pyrimidine-4-yl]piperazine, so pl. 188-190oC;

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/ allylamino/pyrimidine-4-yl]piperazine;

/-/-N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine so pl. 198-199oC []D= 8,4o(c = 0,19 in DMF);

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis-/diethylamine/-5-benzopyrene-4-yl]piperazine;

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis-/diethylamine/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-cyanomethylene/pyrrolidin-2-yl/carbonyl]-N- [2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-/cyan is N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[4,6-bis/ pyrrolidin-1-yl/-1,3,5-triazine-2-yl]piperazine so pl. 260-263oC;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[4,6-bis/ 2-propylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[4,6-bis/ diethylamine/-1,3,5-triazine-2-yl]piperazine, so pl. 209-212oC;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[3,6 - bis-/diethylamine/pyridine-2-yl]piperazine, so pl. 147-150oC;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[3,6 - bis-/pyrrolidin-1-Il/pyridine-2-yl]piperazine, so pl. 162 to 165 of theoC;

N'-[/1-/ciancarini/pyrrolidin-2-yl/carbonyl]-N-[3,6 - bis-/allylamino/pyridine-2-yl]piperazine;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[3,6 - bis-/propargylamine/pyridine-2-yl]piperazine;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[3,6 - bis-N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] -N-[3 - hydroxy-2-pyridylmethyl/piperazine;

N'-[/1-/methoxyphenylpiperazine-2-yl/carbonyl] -N'-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 151-153oC;

N-[/1-tert-butoxyaniline-2-yl/carboxyl]-N'-[3,6-bis-/ diethylamine/pyridine-2-yl]piperazine, so pl. 183-184oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/ pyrrolidine-2-yl/carbonyl]-N-[2,6-bis (pin-2-yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5 - benzoylpiperidine-4-yl]piperazine;

N'[/1-/cyanomethylene/pyrrolidin-2-yl/carbonyl] - N-[2,6-bis-/pyrrolidin-1-yl/-5-benzoylpiperidine-4-yl]piperazine.

Example 8. 0,023 ml of concentrated sulfuric acid is carefully added to a solution of 4 g of 2,2-dimethylmaleic acid in 30 ml of a mixture of 1:2 absolute ethanol/toluene. The reaction mixture is refluxed, distilled azeotropic mixture of water/toluene, and each time add a mixture of ethanol/toluene. After 3 hours the reaction to the reaction mixture 50 ml of water and extracted with ethyl acetate (315 ml). The combined organic extracts dried over sodium sulfate and remove the solvent under reduced pressure. The residue is cleaned chromatography on silica gel (eluent 2:1 hexane-ethyl acetate). Get 3.3 grams diethyl ether 2,2-dimethylmaleic acid.

3 g of the obtained diapir dissolved in 20 ml of a mixture of 1:1 ethanol/water and add to 0.89 g of powdered potassium hydroxide under stirring. After 3 hours reaction at 60-70oC the ethanol is distilled off under reduced pressure and then the reaction mixture are added 20 ml of water and extracted with methylene chloride (210 ml). The aqueous phase is acidified with 1N hydrochloric acid and again extracted with methylene chloride (410 ml). The second extracts are combined, dried over sodium sulfate and UDA is koplatadze solid (so pl. 25-30oC).

Example 9. to 5.4 g of trimethylphenylammonium and a solution of 4 g of diethylmalonate and 4.3 g of 1,4-dibromobutane in 30 ml of toluene is added to 50 ml of a 50% aqueous solution of sodium hydroxide in water at 40oC and under stirring.

After 5 hours the reaction mixture was cooled to 0oC a mixture of water/ice and add 1N hydrochloric acid until acidic pH of the solution, then extracted with ethyl acetate (425 ml). The combined organic extracts washed again (320 ml), saturated aqueous sodium bicarbonate. Finally, remove the solvent in vacuo under reduced pressure to obtain 3.4 g of diethyl ether 1,1-cyclopentanecarbonyl acid.

3 g of the obtained diapir dissolved in 30 ml of a mixture of 1:1 ethanol/water and add to 0.78 g of powder of potassium hydroxide. The reaction mixture is heated to 60oC for 2 hours under stirring, then distilled ethanol under reduced pressure. The reaction mixture is washed with ethyl acetate (210 ml), then add 1N hydrochloric acid to slightly acid pH and extracted with ethyl acetate (415 ml). The latter organic extracts are combined and dried over sodium sulfate, the solvent is removed under reduced pressure. Receive 2 g of monoethylene ether 1,1-Dicyclopentadiene is ulanishlarga in 5 ml of acetonitrile is added dropwise to the solution, containing 3 g of 2-aminopyridine, 4.4 g of potassium carbonate and 2.17 g triethylmethylammonium in 25 ml of acetonitrile at room temperature and under stirring. After one hour the reaction mixture is diluted with 70 ml of water and re-extracted (320 ml). The combined organic extracts dried over sodium sulfate and then remove the solvent under reduced pressure.

The residue (7 g) clean chromatography on silica gel (eluent 2:1 hexane/ethyl acetate) to obtain 4.4 g of N-/ethoxymethyl/-2-aminopyridine.

A solution of 3.7 g of N-/ethoxymethyl/--2-aminopyridine in 25 ml of acetonitrile cooled to 0oC with a mixture of ice/water and add 1.6 ml of a 35% aqueous solution of sodium hydroxide in water under stirring. After heating to room temperature the reaction mixture is left under stirring over 15 min and then filtering allocate 3.5 g of sodium salt of N-/carboximetilkrahmal/-2-aminopyridine, so pl. 195oC.

Example 11. The solution to 2.79 ml ethylmaleimide in 10 ml of acetonitrile is slowly added dropwise with stirring in an atmosphere of inert gas in a solution containing 2.55 g para-toluensulfonate, 1.35 g of potassium carbonate and 2.25 g of benzyltriethylammonium in 50 ml of acetonitrile, heated to 40oand reduced pressure.

The residue is dissolved in 60 ml of ethyl acetate and the organic solution washed first with saturated aqueous sodium bicarbonate (215 ml) and then water (315 ml). Then the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure.

Get 2,19 g N/ethoxymethyl/para-toluensulfonate.

13,2 ml of 1N aqueous solution of sodium hydroxide are added to a solution of 1.9 g of N-/ethoxymethyl/para-toluensulfonate in 20 ml of acetonitrile at room temperature and under stirring. The reaction mixture is heated to 60oC for one hour, then remove the solvent under reduced pressure and the residue is dissolved in 30 ml of water and again washed with ethyl acetate (35 ml). The aqueous phase is acidified with 1N hydrochloric acid and extracted with ethyl acetate (310 ml). The combined organic extracts dried over sodium sulfate and the solvent is removed under reduced pressure to obtain 1.6 g N/carboximetilkrahmal/para-toluensulfonate, so pl. 80oC.

Example 12. To a solution of 0.4 g of sodium salt of N-/carboximetilkrahmal/-2-aminopyridine in 20 ml of anhydrous DMF, 70 µl of hydrochloric acid - ether solution (of 2.9 mol/l), and 0.37 g of 1-ethyl-3-/3-dimethylaminopropyl/carbodiimide DMF added sequentially in the atmosphere of inert gas. After 3 h the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate (320 ml). The combined organic extracts washed again with water (310 ml) and dried over sodium sulfate. The organic solution concentrated under reduced pressure and the residue (0.65 g) clean chromatographic column on silica gel (eluent to 95.5 : 0.5 methylene chloride/MeOH). Obtain 0.5 g of N'-[1-///pyridine-2-yl/aminocarbonylmethyl/pyrrolidin-2-yl/ carbonyl-N-[2,6-bis/pyrimidine-4-yl]piperazine, so pl. 182oC.

Example 13. Following the method described in example 12, on the basis of N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1/ pyrimidine-4-yl] piperazine and related maleimido obtained according to example 10 are given the following N, N-disubstituted piperazines:

N'-[/1-/N-methylhydroxyethylcellulose/pyrrolidin-2 - yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

N'-[/1-aminocarbonylmethyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 133-136oCoC;

N'[/1-/benzylaminocarbonyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

N'[/1-dimethylaminocarbonylmethyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/R-[/1-/1-piperidinecarbonitrile/pyrrolidin-2-yl/carbonyl] - N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 178-180oC;

N'-[/1-/N-morpholinobenzenediazonium/pyrrolidin-2-yl/carbonyl] - N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 205-206oC;

N'[/1-/N-/4-thiomorpholine/carbonylation/pyrrolidin-2-yl/ carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 215-220oC;

N'[/1-/N-/4,5-diazepino/carbonylation/pyrrolidin-2-yl/ carbonyl]-N - [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine.

Example 14. 165 g of methyl 2-CHLOROACETATE added dropwise into a solution of 152 g of N-methylpiperazine and 212 ml of triethylamine in 1.5 l of toluene under stirring and in an atmosphere of inert gas, and then the reaction mixture is heated to 70oC for 4 h then the reaction mixture is cooled to room temperature, the precipitate is filtered off and washed on the filter with 100 ml of toluene. The resulting organic solution is extracted with water (I ml) and the combined organic extracts refluxed for 20 h, then the water is distilled off under reduced pressure. The residue is crystallized from isopropanol to obtain 168 g 2-/N-methylpiperazine/acetic acid, with so pl. 160-161oC.

Example 15. Following the method described stuudy 2-substituted acetic acids, receive according to the method described in example 14, the following connections:

N'-[/1-/benzylaminocarbonyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 186-187oC;

N'-[/1-/diethylaminoethylamine/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

N'-[/1-/1-piperidinylcarbonyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

Found,%: C 64,20; H 8,61; N 20,64

Calculated,%: C 64,09; H 8,45; N 21,36

N'[/1-/N-morpholinomethyl/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 213-214oC;

/-/-N[/1-/N-/4-thiomorpholine/methylcarbamyl-2-yl/carbonyl] -N-[2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, so pl. 225-226oC []D= -16o(C = 0.2 in DMF),

N'[/1-/N-/4,5-diseasein/methylcarbamyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

/-/-N[/1-/N-/4-thiomorpholine/methylcarbamyl/pyrrolidin-2-yl/carbonyl] -N- [3,6-bis/diethylamine/pyrimidine-2-yl]piperazine, hydrochloride, T. pl. 173-175oC;

/-/-N[/1-/N-/4-thiomorpholine/methylcarbamyl/pyrrolidin-2-yl/carbonyl] -N- [2,6-bis/pyrimidine-1-yl]-1,3,4-triazine-4-yl]piperazine,so pl. 205-207oC;

Example 16. A solution of 1 g N-/peremeshivanii to 0.97 g of 1-ethyl-/3-dimethylaminopropyl/carbodiimide hydrochloride and 1.56 g /-/-N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine in this sequence. After 3 h the reaction mixture was diluted with 70 ml of water and extracted with ethyl acetate (320 ml). The combined organic extracts washed with water (3x10 ml) and dried over sodium sulfate and remove the solvent under reduced pressure. The residue (1.5 g) clean chromatographic silica gel (eluent to 9.5:0.5 Asa/MeOH), to obtain 0.95 g /-/-N'-[/1-/paratoluenesulfonyl-methylcarbamyl/pyrrolidin-2-yl/ carbonyl]-N-[2,6-pyrrolidin-1-yl/pyrimidine-2-yl]piperazine, so pl. 170oC []D= 26,9o(=to 2.06 in OH Et).

Example 17. A solution of 0.6 g of potassium bicarbonate in 5 ml of water are added to a solution of 2 g /-/-N[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine in 25 ml of ethyl acetate. The reaction mixture was cooled to 0oC, then dropwise it added a solution of 0.4 ml of acetonitrile, 2 ml of ethyl acetate under stirring in an atmosphere of inert gas. After 30 min of reaction at 0oC, the reaction mixture was left to warm to room temperature to obtain a precipitate, melting at 40oC. After 15 min to separate the aqueous phase, while maintaining the temperature at 40oC, and the organic phase washed with water (2x5 ml), dried over sodium sulfate, and remove the solvent under reduced pressure to a small volume. From this rastut.sq. 229-231oC []D= -17o(C = 1 in EtOH).

Example 18. A solution of 2 g /-/-N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6 - bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine in 20 ml of anhydrous benzene is added 0.56 g actinophage anhydride and 0.05 g of N, N-dimethylaminopyridine, then the reaction mixture is refluxed for 2 hours then remove the solvent under reduced pressure to obtain 3 g /-/-N'-[/1-/carboxyethylgermanium/pyrrolidin-2-yl/carbonyl] -N-[2,6-/ pyrrolidin-1-yl/pyrimidine-4-yl]piperazine.

The obtained crude product is again dissolved in 25 ml of anhydrous ethanol and add 0.3 ml of concentrated sulfuric acid. The reaction mixture was refluxed for 1 h, then diluted with 50 ml saturated aqueous sodium bicarbonate solution. The ethanol is distilled off under reduced pressure, then the resulting aqueous phase is extracted with ethyl acetate (315 ml). The combined organic extracts washed with saturated aqueous sodium chloride (35 ml), dried over sodium sulfate and the solvent is removed under reduced pressure. The residue (3 g) clean chromatography on silica gel (eluent changing AcOEt-Ac OEt/MeOH10:1) to obtain 2.3 g /-/-N[/1-/ethoxycarbonylmethylene/pyrrolidin the 2 in EtOH).

Example 19. A solution of 2 g /-/-N'-[/pyrrolidin-2-yl/carbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine and 0,83 g of powdered potassium carbonate in a mixture of 16 ml of acetonitrile and 5 ml of 1,2 - dichloroethane are added dropwise to the mixture of 0.82 ml of acrocallosal in 2 ml of acetonitrile, keeping the temperature below 10oC using an ice/water. After 30 min of reaction under stirring, the reaction mixture was diluted with 70 ml of water, extracted with ethyl acetate (CH ml) and dried over sodium sulfate. The solvent is removed under reduced pressure, then the residue is crystallized from ethyl acetate to obtain 1.8 g /-/-N'-[/1-/ ethoxalyl /pyrrolidin-2-yl/carbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4 - yl] piperazine, so pl. 197-199oC []D= 14.9o(C = 0.5 in EtOH).

Example 20. In the solution of /L/-BOC-Proline in 60 ml of anhydrous THF, cooled to -10oC salt solution, type of 6.1 ml of triethylamine and 1 g of molecular sieves four Angstrom, then, keeping the temperature below -5oC, are added dropwise to a mixture solution of 4.16 ml of ethylchloride in 5 ml of anhydrous THF. After 30 min stirring, the reaction mixture is filtered to remove fallen triethylammonium and the filtrate is concentrated to 30 ml volume under reduced pressure. The resulting solution cap on the rum. After 2 h, the reaction mixture is diluted with 200 ml of a saturated aqueous solution of sodium dihydrophosphate, keeping the temperature at 0oC with a mixture of ice/water, the mixture is then extracted with ethyl acetate (CH ml). The combined organic extracts washed again with a saturated solution of sodium chloride (g ml), dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is crystallized from hexane to obtain 6,1 g /L/-BOC-prolinol, so pl. 59-60oC []D= 54,9o(C = 0.2 in EtOH).

Example 21. 0.29 grams of carbonyldiimidazole add portions to a solution of 0.3 g /L/-BOC-prolinol in 10 ml of anhydrous THF, cooled to 0oC a mixture of water/ice, with stirring in an atmosphere of inert gas, and then the reaction mixture is heated to room temperature and continue stirring for 3 h In the resulting solution add a solution of 0.45 g of N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine portions and continue stirring for 18 hours the Reaction mixture is diluted with 40 ml of a saturated aqueous solution of sodium dihydrophosphate and extracted with ethyl acetate (CH ml). The combined organic extracts dried over sodium sulfate and the solvent is removed in vacuum under reduced pressure. Osteonecrosis/pyrrolidin-2-yl/ methoxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl(pyrimidine-4-yl]piperazine so pl. 147oC []D= -32o(C = 0.25 EtOH).

Example 22. 0,174 ml triperoxonane acid are added dropwise into a solution of 100 mg /-/-N'-[/1-/tert-butoxycarbonyl/pyrrolidin - 2-yl/methoxycarbonyl] -N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine in 4 ml of methylene chloride. After 18 h, the reaction mixture was diluted with 1N aqueous solution of sodium hydroxide and extracted with methylene chloride (3x3 ml). The combined organic extracts washed with water (2 × 2), dried over sodium sulfate and remove the solvent under reduced pressure. The residue is crystallized from a mixture of 9: 1 diisopropyl ether/ ethyl acetate to obtain 65 mg /+/-N[/pyrrolidin-2-yl/methoxycarbonyl]-N-[2,6-bis/ pyrrolidin-1-yl/pyrrolidin-1-yl/pyrimidine-4-yl/piperazine, so pl. 137-138oC []D= 8,7o(C = 0,23 in EtOH).

Example 23. In a solution of 0.37 g of monoethylene ether of 2,2 - dimethylmaleic acid in 10 ml of acetonitrile add portions of 0.54 g of 1-ethyl-3-/3-dimethylaminopropyl/carbodiimide hydrochloride. After 15 min to the reaction mixture was added 1 g 3+/-N'-[/pyrrolidin-2-yl/ methoxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine under stirring in an atmosphere of inert gas. After 3 h the reaction mixture was diluted with 100 ml of water and re-extracted with utilize nom pressure to obtain 1.1 g /-/-N'-[/1-//2', 2'-dimethyl/ethylmalonyl/ pyrrolidin-2-yl/methoxycarbonyl/-N-[2,6-bis/pyrrolidin-1-yl/pyrimidine - 4-yl] piperazine, so pl. 118-120oC []D= -40,8o(C = 0.13 in EtOH).

Example 24. Following the method described in examples 21, 22 and 23, on the basis of the corresponding N-substituted piperazines and monoethylene malonic esters, 2,2-diethylmalonate, 1,1-cyclopentanecarbonyl and 1,1-cyclohexanedicarboxylic acids, receive the following piperazines:

N'[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl] -N-[pyridin-2-yl] piperazine.analysis: Found/expect. %: C 59,40/59,41; H 6,87/6,93; N 13,91/13,86;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[2,6-bis/diethylamine/pyrimidine-4-yl]piperazine, so pl. 99-102oC;

N'[/1-ethoxymethyleneamino-2-yl/methoxycarbonyl]-N- [2,6-bis/allylamino/pyrimidine-4-yl]piperazine;

N'[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl] -N- [2,6-bis-/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 125-127oC;

N'[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]-N- [2,6-bis/diamino/pyrimidine-4-yl]piperazine, so pl. 107-110oC;

N'[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl] -N- [2,6-bis-/diethylamine/-5-benzoylpiperidine-4-yl]piperazine;

N-'[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl] -N- [2,6-/3-hydroxy-2-pyridinylmethyl/piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[2,6-bis/allylamino/-1,3,5-triazin-yl]piperazine, so pl. 130 - 133oC;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[4,6-bis/2-propylamino/-1,3,5-triazine-2-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[4,6-bis/diethylamine/-1,3,5-triazine-2-yl]piperazine, so pl. 140 - 142oC;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl]piperazine, so pl. 157 - 160oC;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, oil;

Found, %: C 61,62; H 8,45; N 15,47

Calculated, %: C 61,54; H 8,42; N 15,38

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[3,6-bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine, so pl. 60 - 64oC;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[3,6-bis/ethylamino/pyridine-2-yl]piperazine;

N'-[/1-ethoxypyrrolidine-2-yl/methoxycarbonyl]- N-[3,6-bis/propargylamine/pyridine-2-yl]piperazine;

-//1-ethoxypyrrolidine-2-yl/methoxycarbonyl/- N-/3-hydroxy-2-pyridinylmethyl/piperazine;

N'-//1-//2',2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl/-N-/pyridine-2-yl/piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/diethylamine/pyrimidine-4 - yl]piperazine, so pl. 99 - 100oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/allylamino/pyrimidine-4 - yl]piperazine, so pl. 120 - 121oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/diamino/pyrimidine-4 - yl]piperazine, so pl. 85 - 87oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/diethylamine/pyrimidine-5 - benzopyrene-4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/diethylamine/-5-acetylpyridine - 4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl] -N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine - 4-yl]piperazine;

N'-[/1-/2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 - yl/methoxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine - 4-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[4,6-bis/allylamino/-1,3,5-triazine - 2-yl]piperazine, so pl. 118 - 120oC;

/L/-N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2 is etil/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[4,6-bis/2-propylamino/-1,3,5-triazine - 2-yl]piperazine,

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[4,6-bis/diethylamine/-1,3,5-triazine - 2-yl]piperazine, so pl. 107 - 110oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, oil;

Found, %: C 62,55; H 8,66; N 14,58;

Calculated, %: C 62,72; H 8,71; N 14,6

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[3,6-bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine, so pl. 55 - 60oC;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/- methoxycarbonyl] -N-[3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin - 2-yl/methoxycarbonyl] -N-[3,6-bis/propargylamine/pyridine - 2-yl]piperazine, oil;

Found, %: C 62,41; H 7,0; N 15,66

Calculated, %: C 62,45; H 7,06; N 15,61

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin - 2-yl/methoxycarbonyl] -N-[3,6-bis/N-ethyl-N-allylamino/pyridine - 2-yl]piperazine,

N'-[/1-//2', 2'-dimethyl/ethoxymethyl/pyrrolidin - 2-yl/methoxycarbonyl] -N-[3-hydroxy-2-pyridylmethyl/piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1-'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-/pyridine-2-yl/piperazine,

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/diethylamin - 2-yl/methoxycarbonyl] -N-[2,6-bis/allylamino/pyrimidine-4 - yl]piperazine, so pl. 144 - 145oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/diamino/pyrimidine-4 - yl]piperazine, so pl. 123 - 124oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[2,6-bis/diethylamine/-5-benzoylpiperidine - 4-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/diethylamine/-5-acetylpyridine - 4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine - 4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine - 4-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[4,6-bis/allylamino/-1,3,5-triazine - 2-yl]piperazine, so pl. 167 - 169oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine - 2-yl] piperazine, so pl. 183 - 184oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[4,6-bis/2-propylamino/-1,3,5-triazine - 2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/ 158 - 162oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, so pl. 97 - 100oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[3,6-bis/pyrrolidin-1-Il/pyridine - 2-yl]piperazine, so pl. 124 - 125oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[3,6-bis/allylamino/pyridine-2-yl]piperazine, so pl. 115 - 118oC;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[3,6-bis/propargylamine/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[3,6-bis/N-ethyl-N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclopentane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[3-hydroxy-2-pyridinylmethyl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[pyridin-2-yl]piperazine, so pl. 83 - 85oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[2,6-diethylamino/pyrimidine-4-yl]piperazine, so pl. 146 - 147oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/meloxicam the DIN - 2-yl/methoxycarbonyl] -N-[2,6-bis/diamino/pyrimidine-4 - yl]piperazine, so pl. 130 - 138oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[2,6-bis/diethylamine/-5-benzoylpiperidine-4 - yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/diethylamine/-5-acetylpyridine-4 - yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[2,6-bis/pyrrolidin-1-yl/-5-acetylpyridine - 4-yl] piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[2,6-bis/pyrrolidin-1-yl/-5-benzoylpiperidine - 4-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[4,6-bis/allylamino/-1,3,5-triazine-2-yl]piperazine, so pl. 179 - 183oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[4,6-bis/pyrrolidin-1-yl/-1,3,5-triazine - 2-yl] piperazine, so pl. 199 - 201oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[4,6-bis/2-propylamino/-1,3,5-triazine - 2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[4,6-bis/diethylamine/-1,3,5-triazine - 2-yl]piperazine, so pl. 207 - 210oC;

N'-[/1-/1'-/toxicroak;

Found, %: C 64,36; H 8,76; N 13,72;

Calculated, %: C 64,50; H 8,79; N 13,68;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl] -N-[3,6-bis/pyrrolidin-1-Il/pyridine - 2-yl]piperazine, so pl. 63 - 66oC;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[3,6-bis/allylamino/pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/ pyrrolidine-2-yl/methoxycarbonyl]-N-[3,6-bis/propargylamine/ pyridine-2-yl]piperazine;

N'-[/1-/etoxycarbonyl/cyclohexane-1'-carbonyl/ pyrrolidine-2-yl/methoxycarbonyl]-N-[3,6-bis-ethyl-allylamino| pyridine-2-yl]piperazine;

N'-[/1-/1'-/etoxycarbonyl/cyclohexane-1'-carbonyl/pyrrolidine - 2-yl/methoxycarbonyl]-N-[3-hydroxy-2-pyridinylmethyl] piperazine.

Example 25. 2,08 ml evaluarea added dropwise to a solution of 4 g /1 ethoxymethyl/-1,3-thiazolidin-2-carboxylic acid and of 2.36 ml of triethylamine in 40 ml of 1,2-dichloroethane, cooled to -10oC with the saline solution under stirring in an atmosphere of inert gas. After 15 min, keeping below -5oC in the reaction mixture was added a solution 4,89 g of N-[3,6-bis/diethylamine/ pyridine-2-yl] piperazine in 4 ml of 1,2-dichloroethane. After 30 min the reaction mixture was added 120 ml of water and separated org the points and dried over sodium sulfate and remove the solvent under reduced pressure. The residue is cleaned chromatography on silica gel (eluent: ethyl ether) and crystallized from 1:1 ethyl ether/ethyl acetate to obtain 2.66 g of N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] - N-[3,6-bis/diethylamine/pyridine-2-yl/piperazine, so pl. 111-113oC.

Example 26. Following the method described in example 25, interaction /1 ethoxymethyl/-1,3-thiazolidin-2-carboxylic acid with the appropriate N-substituted piperazine get the following piperazines:

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-/pyridine - 2-yl/piperazine;

N'-[/1-ethoxymethyleneamino/-2-yl/carbonyl]-N-[2,6 - bis/diethylamine/pyrimidine-4-yl]piperazine, so pl. 131-134oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[2,6 - bis/allylamino/pyrimidine-4-yl]piperazine;

N'[/1-ethoxybenzothiazole-2-yl]piperazine, so pl. 147-149oC,

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[2,6 - bis/diamino/pyrimidine-4-yl]piperazine, so pl. 155-158oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[2,6 - bis/diethylamine/-5-benzoylpiperidine-4-yl]piperazine;

N'-[/1-ethoxybenzothiazole-2-or/carbonyl]-N-[2,6 - bis/diethylamine/-5-acetylpyridine-4-yl]piperazine;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[2,6 - bis/pyrrolidin-1-yl/-5-acetylphenyl the Jn-4-yl]piperazine;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[4,6 - bis/allylamino/-1,3,5-triazine-2-yl]piperazine, so pl. 169-171oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[4,6 - bis/pyrrolidin-1-yl/-1,3,5-triazine-2-yl]piperazine, so pl. 182-185oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[4,6-bis/ 2-propylamino/-1,3,5-triazine-2-yl/piperazine;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[4,6 - bis/diethylamine/-1,3,5-triazine-2-yl]piperazine, so pl. 179-183oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[3,6 - bis/pyrrolidin-1-Il/pyridine-2-yl]piperazine;

N'-[/1-ethoxybenzothiazole-2-yl-/carbonyl]-N-[3,6 - bis/allylamino/pyridine-2-yl]piperazine, so pl. 111-112oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[3,6 - bis/propargylamine/pyridine-2-yl]piperazine, so pl. 120-121oC;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl] -N-[3,6 - bis/N-allylamino/pyridine-2-yl]piperazine;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-[3-hydroxy - 2-pyridinylmethyl]piperazine;

N'-[/1-ethoxybenzothiazole-2-yl/carbonyl]-N-methyl - piperazine, so pl. fumarata 126-129oC.

Example 27. 13,28 ml of diethylazodicarboxylate /DEAD/ added dropwise within 30 min to a solution of S/-/-/N-benzylpyrrolidine-2-yl/methanol (6 ml), tributyl the under stirring in an atmosphere of inert gas.

After 5 h of reaction at 0oC, the reaction mixture is subjected to removal of solvent in vacuo. To the residue add 120 ml of ethyl acetate and washed again with water (I ml). The organic phase is dried over sodium sulfate and remove the solvent under reduced pressure. The residue (40 g) clean chromatography on silica gel (eluent 3:1/ petroleum ether: diethyl ether) to give 9.8 g S-/-/-[/1-benzyl-pyrrolidin-2-yl/-N,N-decret - butoxycarbonyl]methylamine,

1H-NMR /200 MHz, CDCl31.52m/s, 18H/, 1,72 /m, 4H/, 2,21 /m 1H/, 2,86 /m, 2H/, 3,53 /l, 1H/, 3,71 /m, 2H/, 4,11 /l, 1H/, 7,31 /m, 5H/.

Example 28. to 5.4 g S/-/-[1-benzylpyrrolidine-2-yl/-N,N - distritbution] methylamine are dissolved in 80 ml of methanol and the resulting solution was cooled to 0oC. Gaseous hydrogen chloride propulsive in the reaction mixture for 2 h, then remove the solvent under reduced pressure to obtain 3 g S/-/-/1-benzylpyrrolidine-2-yl/methylamine hydrochloride.

1H-NMR /200 MHz/ D2O 2,1 /m, 3H/, of 2.51 /m 1H/, 3,4 /m, 4H/, 3,95 /m 1H/, 4,4 /l, 1H/, 4,65 /l, 1H/, 7,56 /s, 5H/.

Example 29. In the suspension S-/-/-/1-benzylpyrrolidine-2-yl/ methylamine hydrochloride (0.3 g) in 8 ml of THF is added dropwise with stirring a solution of triethylamine (0,19 ml) in 2 ml of THF. After 15 min of ethyltryptamine. The resulting solution was warmed to room temperature, stirred for 2 h in nitrogen atmosphere and then immediately add 0.4 g N-/2,6-bis/ pyrrolidin-1-yl/pyrimidine-4-yl/piperazine and stirring is continued for 18 hours, the Reaction mixture was concentrated in vacuo, diluted with 10 ml ethyl acetate and washed with water (35 ml). The organic phase is dried over sodium sulfate and remove the solvent under reduced pressure, the residue (0.5 g) clean chromatography on silica gel (eluent methylene chloride/methanol 93: 5) to obtain 0.35 g /S/-N-2,6 - bis/pyrrolidin-1-yl/pyrimidine-4-yl/-N//1-benzylpyrrolidine-2-yl/ methylaminomethyl/piperazine.

1H-NMR /200 MHz/ D6-benzene 1,58 /m, 12H/, 1,92 /m 1H/, 2,44 /m 1H/, 2,85 /m 1H/, 2,98 /l, 1H/, 3,35 /m, 8H/, 3,52 /m, 4H/, 3,72 /m, 7H/, 4,86 /C, 1H/, 5,08 /b, 1H/, 7,18 /m, 5H/.

Example 30. 0.18 g /S/-N-/2,6-bis/pyrrolidin-1-yl/-N-//1 - benzylpyrrolidine-2-yl/methylaminomethyl/piperazine dissolved in 2 ml of methanol, then add 100 ml of monitorate and 4 mg of 10% Pd/C and the reaction mixture is refluxed for 6 hours, the Suspension is filtered through celite and the solvent is removed under reduced pressure to obtain 0.25 g of residue. After chromatographic purification on silica gel (eluent methylene chloride/methanol 92/8) get the Hz/ CDCl31,25 /t, 3H/, 1,45 /6H/, 1,85 /m, 12H/, 3,45 /m, 21H/, 4,2 /q, 2H/, 4,48 /b, 1H/, 6,4 /t, 1H/.

Example 31. To a solution of 0.13 g /S/-N-/2,6-bis/pyrrolidin-1-yl/ pyrimidine-4-yl/-N-//pyrrolidin-2-yl/methylaminomethyl/piperazine in THF (5 ml) was added 90 mg of N-hydroxybenzotriazole, and then the resulting solution is cooled to -5oC. To the reaction mixture are added 60 mg of monoethylene ether of 2,2-dimethylmaleic acid, 0.036 ml of N-methylmorpholine and 125 mg of 1-ethyl-3-/3-dimethylaminopropyl/ carbodiimide hydrochloride, and then allow the temperature to rise to 25oC and continue stirring for 18 hours to Remove the solvent under reduced pressure and the residue is dissolved in 5 ml ethyl acetate and washed again with water (35 ml). The organic phase is dried over sodium sulfate and remove the solvent under reduced pressure to obtain 150 ml dark purple foam that cleans chromatography on silica gel (eluent methylene chloride/methanol 97/3) to give 70 mg /S/-N-/2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl/-N'//1-// 2',2'-dimethyl/ethoxymethyl/pyrrolidin-2-yl/methylaminomethyl/ piperazine.

1H-NMR /200 MHz/ CDCl31,25 /t, 3H/, 1,45 /6H/, 1,6-2,1 /m, 12H/, 3,1-3,6 /m, 20H/, 4,2 /q, 2H/, 4,45 /m 1H/, 4,85 /C, 1H/, 6,45 /t, 1H/.

Example 32. Following the methods described in examples 29, 30 and 31, the new esters of malonic, 2.2-diethylmalonate acids have the following piperazines:

N-[/1-ethoxypyrrolidine-2-yl/methylaminomethyl] - N'-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, so pl. 119-121oC;

N-[/1-ethoxypyrrolidine-2-yl/methylaminomethyl] - N'-[2,6-bis/pyrrolidin-2-yl/pyrimidine-4-yl/piperazine, so pl. 127-130oC;

N-[/1-ethoxypyrrolidine-2-yl/methylaminomethyl] - N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl]piperazine, so pl. 136-140oC;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methylaminomethyl] -N'-[3,3-bis/diethylamine/pyridine-2-yl/ piperazine, so pl. 93-95oC;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methylaminomethyl] -N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5 - triazine-4-yl] piperazine, so pl. 143-144oC;

Example 33. Following the methods described in examples 29, 30 and 31 and replacing in example 29 carbonyldiimidazole on thiocarbonyldiimidazole on the basis of /N-benzylpyrrolidine-2-yl/methylaminopropane corresponding N-substituted piperazines and nanometrology of malonic ether or 2,2-dimethyl acids, obtain the following N,N'-disubstituted piperazines:

N-[/1-ethoxypyrrolidine-2-yl/methylenedioxyphenyl] -N'- [3,6-bis/diethylamine/pyridine-2-yl] piperazine, oil; element. analysis: Found/rcsclean-2-yl/pyrimidine-4-yl]piperazine, so pl. 160-161oC;

N-[/1-ethoxypyrrolidine-2-yl/methylenedioxyphenyl] -N'- [2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl]piperazine, so pl. 189-192oC;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methylenedioxyphenyl]-N'-[3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methylenedioxyphenyl]-N'-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine, so pl. 150-153oC;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methylenedioxyphenyl] -N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl] piperazine, so pl. 190-191oC..

Example 34. Following the methods described in examples 21, 22 and 23, on the basis of the corresponding N-substituted piperazines and monoethylene malonic esters or 2.2-diethylmalonate acids and replacing in example 21 carbonyldiimidazole on thiocarbonyldiimidazole receive the following piperazines:

N-[/1-ethoxypyrrolidine-2-yl/methoxydibenzoyl] -N'- [3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N-[/1-ethoxypyrrolidine-2-yl/methoxydibenzoyl] -N'- [2,6-bis/pyrrolidin-2-yl/pyrimidine-4-yl]piperazine, so pl. 110-112oC;

N-[/1-ethoxypyrrolidine-2-yl/methoxydibenzoyl] -N'- [2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl]piperazine, so pl. 139-140oC;oC;

/L/-N-[/1-/2',2'-dimethyl/ethoxypyrrolidine-2-yl/ methoxydibenzoyl]-N'-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine, so pl. 123-124oC;

N-[/1-/2', 2'-dimethyl/ethoxypyrrolidine-2-yl/ methoxydibenzoyl] -N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl] piperazine, so pl. 140-143oC.

Example 35. Following the methods described in examples 21, 22 and 23, on the basis of their respective N-substituted piperazines and /4-thiomorpholine-1-yl/ morpholine-1-yl or /4-methylpiperazin-1-yl/ acetic acid will receive the following piperazines:

N-[/-//4-thiomorpholine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl]-N'-[3,6-bis/diethylamine/pyridine-2-yl/piperazine so pl. 77-78oC,

N-[/1-//4-thiomorpholine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl]-N'-[2,6-bis/pyrrolidin-2-yl/pyrimidine-4-yl] piperazine, so pl. 137-140oC;

N-[/1-//4-thiomorpholine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl] piperazine, so pl. 180-182oC;

N-[/1-//morpholine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl]-N'-[3,6-bis/diethylamine/pyridine-2-yl]piperazine;

N-[/1-/morpholine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[2,6-bis/pyrrolidin-1-/pyrimidine-4-yl]piperazine, so pl. 140-144oC;oC;

N-[/1-//4-methylpiperazin-1-/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl]-N'-[3,6-bis/diethylamine/pyridine-yl]piperazine, so pl. 130-131oC;

N-[/1-//4-methylpiperazin-1-/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl]-N'-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl]piperazine;

N-[/1-//4-methylpiperazin-1-/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[2,6-bis/pyrrolidin-1-yl/-1,3,5-triazine-4-yl] piperazine, so pl. 207-208oC;

N-[/1-//piperidine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[3,6-bis/diethylamine/pyridine-2-yl]piperazine, so pl. 93-95oC;

N-[1-//-piperidine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[2,6-bis/pyrrolidin-1-yl/pyrimidine-4-yl] piperazine;

N-[1-//-piperidine-1-yl/methylcarbamyl/pyrrolidin-2-yl/ methoxycarbonyl] -N'-[2,6-bis/pyrrolidin-1-yl/1,3,5-triazine-4-yl] piperazine, so pl. 200-201oC

Example 36. In the solution (L)-BOC-Proline (5 g) in 60 ml of anhydrous tetrahydrofuran, cooled to 0oC, added to 4.14 g of carbonyl-diimidazole. After approximately 2 hours in parts added 5,86 g of N-(diphenylmethyl)piperazine. After 5 hours the solvent is boiled away under reduced pressure then the residue was diluted with ethyl acetate and washed with water. The organic phase is dried besod on silica gel (elwira a mixture of petroleum ether/ethyl acetate 1:1) to obtain 9,.3 g (L)-N-[(1-BOC-pyrrolidin-2-yl)carbonyl-N'-(diphenylmethyl)piperazine as a white foam. []D= -20,09 C = 0,214 in ethanol..

Example 37. Into a solution of the compound from example 36 (9,05 g) in 90 ml of methylene chloride cooled to 0oC, drop by drop added 18.5 ml triperoxonane acid, then allowed the mixture to warm up to room temperature. After 6 hours the reaction mixture was cooled to -5oC and one drop was added 18 ml of 35% sodium hydroxide. Then the organic phase was separated, dried with anhydrous sodium sulfate and boiled away the solvent under reduced pressure, obtaining 7 g (L)-N-[(pyrrolidin-2-yl)carbonyl]-N'-(diphenylmethyl)-piperazine as a white foam.

6.9 g of mono-benzyl ether of 2,2-dimethylmaleic acid was dissolved in 65 ml of toluene and one drop was added 32 ml of thionyl chloride, and then the reaction mixture was heated to 90oC for 3 hours then the solvent and thionyl chloride evaporated under reduced pressure and the residue was dissolved in 50 ml of toluene. The resulting solution drop by drop added to a solution of (L)-N-[(pyrrolidin-2-yl]-N'-(diphenylmethyl)piperazine (7 g) and triethylamine (4.3 ml) in 70 ml of toluene, cooled to -10oC. After 45 min, the reaction mixture was added a saturated solution of sodium bicarbonate, then the separated organic phase was washed with water, dried with sodium sulfate and boiled away rastvoriteleyj ether/ethyl acetate 1:1) to obtain 9,13 g (L)-N-[(1- (1'-benzyloxy-2', 2'-demetillo-3'-yl)pyrrolidin-2-yl)carbonyl]-N'-(diphenylmethyl)piperazine.

[]D-37,23o(c=0,188 in ethanol).

Example 38. A mixture of (L)-N-[(1-(1'-benzyloxy-2', 2'-demetillo-3'-yl) pyrrolidin-2-yl)carbonyl] -N'-(diphenylmethyl)piperazine (example 37; of 8.9 g) and 10% palladium on carbon (0.9 g) in 80 ml of methanol was first made at room temperature under atmospheric pressure for 1 h, then filtered to remove the catalyst. The residue was purified by chromatography on silica gel (eluent is a mixture of methylene chloride/methanol 85: 15) to obtain, after crystallization from a mixture of AcOEt /ethanol, 3.13 g N-[(1-(2'2'-demetillo-3'-yl)pyrrolidin-2-yl)carbonyl] - N'- (57) (diphenylmethyl)piperazine.

Found,%: C 67,40; H 7,24; N 8,12.

Calculated,%: C 67,34; H 7,33; N 8,73

Example 39. The methods described in examples 36 and 37 and using N-(4-forfinal)piperazine instead of N-(diphenylmethyl)piperazine was obtained 9.5 g (L)-N-[(1'-benzoyloxy-2'2'-demetillo-3'-yl)pyrrolidin-2-yl) (57) carbonyl]-N'-(4-forfinal)piperazine.

Found,%: C 63,31; H 6,62; N 8,77; F 3,94.

Calculated,%: C 63,36; H Of 6.65; N 8,73; F 3,95.

Example 40. A mixture of (L)-N-[(1-(1'-benzoyloxy-2'2'-dimethyl - Malone-3'-yl)pyrrolidin-2-yl)carbonyl]-N'-(4-forfinal)piperazine (example 39; 9.5 g) and 20% palladium on plastics technology: turning & is, then filtered to remove the catalyst and the solvent is evaporated under reduced pressure. The residue was dissolved in 45 ml of ethyl acetate and stirred and the precipitate discarded. The solid was filtered and dried under vacuum at 50oC to obtain 5.6 g N-[(1-(2'2'-demetillo-3'-yl)pyrrolidin-2-yl)carbonyl]-N'- (4-forfinal)piperazine, melting point 166 - 168oC. []D=-59,14o(c = 0,2367 in absolute ethanol).

Found,%: C 61,31; H 6,74; N 10,79; F 4,90.

Calculated,%: C 61,37; H 6,70 Of 10.73 N; F 4,85.

Example 41. To a suspension of (L)-N-[(pyrrolidin-2-yl)carbonyl] -N'- [4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] piperazine (example 4; 5.5 g), potassium carbonate (2,052 g) and triethylmethylammonium bromide (0,92 g) in 30 ml of acetonitrile drop added chlorocatechol and left the reaction mixture at room temperature overnight. The reaction was initiated by addition of water and ethyl acetate (500 ml). The organic phase was separated and dried with anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure to obtain 5 g (L)-N-[(1-(2'- chloroacetyl)pyrrolidin-2-yl)carbonyl]-N'-[4,6-bis(pyrrolidin-1-yl) (57) -1,3,5-triazine-2-yl] piperazine as a white solid.

Found,%: C 55,31; H 6,97; N (LK 23: 43; Cl 7,40.

Reservata potassium mixed with acetonitrile (40 ml) and dimethylformamide (10 ml) interacted with the 40oC for about 4 hours Separating the potassium chloride was filtered and the reaction mixture was diluted with plenty of water and re-extracted with ethyl acetate. Organic extracts were collected and dried with sodium sulfate, then the solvent is evaporated under reduced pressure to obtain 4.5 g of a white solid. This substance was purified by chromatography on silica gel (elwira a mixture of hexane/ethyl acetate 1:2, then methylene chloride/methanol 9:1) to give after recrystallization from ethyl acetate 3 g (L)-N-[(1-(2'-thiomorpholine)acetyl)pyrrolidin-2-yl) carbonyl] -N'-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] piperazine, melting point 205 - 207oC.

Example 43. The method described in examples 41 and 42, using as the starting material the appropriate prolinnova derived and the appropriate amine were obtained the following compounds:

(L)-N-[(1-(2'-(4-thiomorpholine)acetyl)pyrrolidin-2-yl) -carbonyl] -N'-[3,6-bis(diethylamino)pyridine-2-yl] piperazine, melting point 173 - 175oC, in the form of a hydrochloric salt;

(L)-N-[(1-(2'-(4-thiomorpholine)acetyl)pyrrolidin-2-yl) -carbonyl] -N'-[2,6-bis(pyrrolidin-1-yl)pyrimidine-4-yl]piperazine, melting point 225 - 226oC;

(L)-N-[(1-(2'-(morpholinoethyl)p is C;

(L)-N-[(1-(2'-(piperidine)acetyl)pyrrolidin-2-yl)-carbonyl] -N'-[2,6-bis(pyrrolidin-1-yl)pyrimidine-4-yl] piperazine, melting point 165 - 166oC;

(L)-N-[(1-(2'-(4-methylpiperazin)acetyl)pyrrolidin-2-yl)- carbonyl]-N'-[2,6-bis(pyrrolidin-1-yl)pyrimidine-4-yl]piperazine, melting point 122 - 123oC. []D= -16,06oc = 0,2117 in ethanol.

Example 44. To a solution of 0.5 g of (-)-N'-[(1-ethoxypyrrolidine-2-yl)carbonyl] -N-[4,6-bis(pyrrolidin-1-yl)-1,3,5-triazine-2-yl] piperazine in 5 ml of methanol was added under nitrogen atmosphere were mixed with 80 μl of 35% aqueous sodium hydroxide solution. The reaction mixture was kept under stirring for 20 hours , then neutralized by adding sodium bicarbonate and filtered through zelany layer. The solvent is then evaporated under reduced pressure and the residue (0.52 g) was purified by chromatography on silica gel (eluent: methylene chloride/methanol 9: 1), receiving of 0.43 g of (-)-N'-[(1-(1'- malonyl)pyrrolidin-2-yl)carbonyl] -N-[4,6-bis(pyrrolidin-1-yl)- (57) 1,3,5-triazine-2-yl]piperazine, so pl. 208 - 211oC.

[]D= -21,7o(c = 0.3 in ethanol).

Example 45. Pharmaceutical composition for compounds according to the invention, Tablets receive conventional mixing and pressing the following component,00

Talc - 60,00

Colloidal krasnozem - R 40,00

1. Heterocyclic amines of General formula I

< / BR>
where X is-CH2-group or-S-group;

In - group, selected from a number containing-CO-, -CH2OCO-, -CH2OSS-, -CH2The NO - and CH2NS-group;

D - benzhydrylidene or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-C1- C6-alkylamino, mono-C3- C7-alkenylamine, mono-C3- C7-alkynylamino and pyrrolidin-1-idgruppo;

Y - simple carbon-carbon bond or a group of formula-CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, a C1- C3-alkyl or taken together with the carbon atom to which they are bound, form a3- C6-cycloalkyl;

And selected from the group comprising (a) carboxyl group optionally esterified WITH1- C4-alkylmercury, inorganic salts of the formula - CONRcRd, sulfonamide of the formula is s, a hydrogen atom, a C1- C6-alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diseasein, 4-C1- C4-alkylpiperazine, Rf- tolyl; Rg- C1- C4-alkyl, (b) (C1- C3-alkyl, (C) the group - NRcRdwhere Rcand Rdhave the specified values, (d) cyano, if Y does not mean a simple carbon-carbon bond,

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases.

2. Connection on p. 1, in which D is selected from the group consisting of 2-pyridyl, (3-hydroxy-2-pyridinyl)methyl, [2,6-bis (diethylamino)-4-pyrimidinyl], [2,6-bis(pyrrolidin-1-yl-)-4-pyrimidinyl] , [2,6-bis(diethylamino) 5-benzoyl-4-pyrimidinyl] , [4,6-bis(2-allylamino)-1,3,5-triazine-2-yl], [4,6-bis(2-propylamino)-1,3,5-triazine-2-yl] , [4,6-bis(pyrrolidin-1-yl) -1,3,5-triazine-2-yl], [4,6-bis(diethylamino) -1,3,5-triazine-2-yl], [3,6-bis (diethylamino)pyridine-2-yl] , [3,6-bis(allylamino) -pyridine-2-yl], [3,6-bis(propargylamine) pyridine-2-yl] , [3,6-bis(N-ethyl-N-allylamino)-pyridine-2-yl].

3. Connection PP.1 and 2, which represents a-CO-, -CHaRbwhere Rathat is the same as Rb, is a hydrogen atom or methyl, or Raand Rbtaken together with the carbon atom to which they are linked, represent cyclopentyl or cyclohexyl, And - etoxycarbonyl, tolyl, sulfonamide, pyridine-2-yl - aminocarbonyl, N-methyl-hydroxylaminopurine, N-(4,5-diseasein) carbonyl, N-(4,5-diseasein).

4. Connection PP.1 to 3, in which X is-CH2group.

5. Connection PP. 1 to 4, with antiemetics activity and anti-inflammatory effects on the respiratory tract.

6. The method of obtaining compounds of General formula I, characterized in PP. 1 to 4, and their salts with pharmaceutically acceptable acids and bases, wherein interact compounds of General formula II

< / BR>
where X, and D is the specified value;

with a compound of General formula III

< / BR>
where Y has the above meanings;

A' has the same meaning as A, except the free carboxyl group, or, if Y does not mean a simple carbon-carbon bond, And' may be a halogen atom such as chlorine, bromine, IIA General formula Ia

< / BR>
that is, if A' is a halogen atom, is subjected to the interaction with the amine HNRcRdwhere Rcand Rdhas the specified values, to obtain the compounds of General formula I, where a is the group-NRcRdor, if A' is an ether group, if necessary, converted into the compound of General formula I, where a is the free carboxyl group by hydrolysis with a mineral base, such as hydroxide of alkali metal, and the target product is isolated in free form or in the form of salts with pharmaceutically acceptable acids or bases.

7. The method of obtaining compounds of General formula I on p. 1, where In - group-CO-, and X, Y, A and D have the abovementioned meanings, and their salts with pharmaceutically acceptable acids and bases, characterized in that the compound of General formula (IId)

< / BR>
where Y and A' have the above values,

subjected to interaction with the amine of General formula IIc

< / BR>
where D is the specified values,

with subsequent isolation of the target product in free form or in the form of salts with pharmaceutically acceptable acids or bases.

8. Pharmaceutical composition having antiemetics activity and anti-inflammatory effect on dejatelnesti acceptable excipient, characterized in that as the active component contains a compound of General formula I on PP.1 to 4, or its salt with pharmaceutically acceptable acids or bases in an effective amount.

9. The intermediate compound of General formula Ia, as described under item 6, where Y has a value other than simple carbon-carbon link, and A' is a halogen atom, to obtain compounds of General formula I, as described in paragraph 1, where a is the group - NRcRdwhere Rcand Rdhave the specified values.

 

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< / BR>
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< / BR>
< / BR>
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< / BR>
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< / BR>
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