Replaced cyclopropylamino-1,3,5-triazine, their optical isomers, racemic mixture, or their salts attaching a non-toxic pharmaceutically acceptable acid exhibiting pharmacological activity, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to a new cyclopropylamino-1,3,5-triazines and their salts of General formula

< / BR>
in which R1- alkyl, cycloalkyl, alkylsilanes; R2bis (2-hydroxyethyl)amino, 3-hydroxy-1-azetidine, 3-methoxy-1-azetidine, 3-oxo-1-azetidine, morpholine-, 4-hydroxypiperidine, thiomorpholine-, S-oxide-thiomorpholine-, S, S-dioxide-thiomorpholine-, 3-thiazolidine, S-oxide-3-thiazolidine, S, S-dioxide-3-thiazolidine or 8-oxa-3-azabicyclo/3,2,1/ Oct-3-yl. These compounds suitable for treating disorders associated with Alzheimer's disease, senile dementias of the Alzheimer's type and with any evolving pathology recognition, for the treatment of depression, anxiety, mood disorders, inflammation and asthma. The invention relates to methods of producing these compounds by introducing cyclopropylamino group or a radical R2in the 1,3,5-triazine ring; through the formation of the triazine ring of the corresponding N-cyclopropylalanine; by transformation of the radical R2and pharmaceutical compositions. 6s. and 6 C.p. f-crystals, 12 tab.

The invention relates to new substituted cyclopropylamino-1,3,5-triazines, the Oia. It relates also to therapeutic compositions containing these compounds.

From a proposal in Japanese patent N 25786/78 already known 2-trifluoromethyl-1,3,5-triazine having in position 4 additional area alkyl, substituted or unsubstituted, alkylamino, dialkylamino, cyclooctylamine, morpholino - or 4-alkyl-1-piperazinilnom moiety and at position 6 of the same radicals, except for the alkyl radical. In accordance with this patent application, these compounds possess sedative and anticonvulsant properties.

On the other hand, in British patent N 1053113 describe 1,2-dihydro-1-hydroxy-1,3,5-triazine having in position 2 minorities, substituted, if necessary, alkyl, alkenyl, cycloalkyl, phenyl or nafcillin replaced, if necessary, alkyl radical/radical; in position 4 dialkylamino, dialkylamino-, N-alkylamino-, aziridinyl, azetidinone, pyrrolidinyl, piperidino-, hexahydroazepin, heptamethylnonane, octamethylene or morpholinoethyl, each of these heterocycles can be substituted by one to three alkyl radicals; and at position 6 a hydrogen atom or an alkyl, alkene is ti alkyl, Uralkali, alkylallminum, alkoxyalkyl or halogenoalkanes radical. In this patent, these compounds are antigipertenzivnye means suitable for the treatment of hypertension and shock; they are also inhibitors of secretion and the depressors of the Central nervous system. These compounds are obtained by oxidation of the corresponding 1,3,5-triazines having the same substituents in positions 2, 4 and 6. However, this patent does not indicate that an intermediate 1,3,5-triazine have any pharmacological activity. Moreover, this patent does not describe any of 1,3,5-triazine, substituted cyclopropylamines.

Finally, in the application for the European patent N 356413 on the name of the applicant company describe 2-amino-4-morpholino-6-propyl-1,3,5-triazine, in which the amino group in position 2 is substituted by various radicals, such as, for example, hydroxyl or hydroxyalkyl radical. These compounds are suitable for treatment of disorders of learning and behavior associated with age and syndromes of madness, for example, those which are associated with disease Allgamer. However, in this patent application does not describe 1,3,5-triazine, substituted cyclopropylmethyl new 1,3,5-triazine, replaced by cyclopropylmagnesium, which have valuable pharmaceutical properties and, in particular, the ability to contribute to the learning and reduce antimouse effect caused by cholinergic hypofunctioning, which is caused by cholinergic antagonist, for example, scopolamine. Cholinergic system is widely involved in the phenomena of memory and learning. For example, the introduction of young patients anticholinergics such as scopolamine, leads to the appearance of defects of memory, similar to those observed in older patients. On the contrary, cholinergic agents such as physostigmine, is able to overcome the amnesia caused by the introduction of anticholinergics (S. D. Glick et al. Behavioral Biology, 7 (1972), 245-254; U. Schindler et al. Drug Develop. Res. 4(1984), 567-576). This is why compounds according to the invention can be used to treat disorders of learning and behavior associated with age and syndromes of madness. In particular, they find application in the treatment of disorders associated with Alzheimer's disease, senile dementia of Alzheimer's type and with any evolving pathology recognition (C. G. Gottfries, Psychopharmacology, 86 (1985), 245-252; Gottfries, Neurobiology of Ageing, 4 (1983), 261-2 is d, identified by the ability they have to call in rats particular stereotype, usually denoted by the term "wet dog shake" (A. R. Green et D. J. Heal "Neuropharmacology of Serotonin, Ed. A. R. Green, Oxford Univ. Press. 1985, Chapter 12, S. 326-365). It is known that serotonin plays an important role in the regulation of neuroendocrine functions, which can be broken in such pathologies, such as depression, anxiety and mood disorders. The decrease in serotonergic activity is associated with many changes of mood and somatic functions occurring in the oppressed patients (H. Y. Meltzer et M. T. Lowy "Psychopharmacology: Ghe Ghird Generation of Progress, Ed. H. V. Meltzer, Raven Press, New-York, 1987, Chapter 52, S. 513-520). Compounds according to the invention can therefore be used to treat these various pathologies associated with slower serotonergic activity.

In addition, at the peripheral level of the compounds according to the invention also exhibit bronchospasmolytic activity and activity, the release of inhibitory mediators of mikrocytos during anaphylactic aggression. Moreover, the compounds according to the invention potentializing the effect of muscle relaxation from-adrenergic agonist (e.g., izoprenalin) on the smooth muscle, saccocia compounds according to the invention also find use in the treatment of inflammation and asthma, in particular, as a means of alternative treatment with theophylline or even bronchodilators, such as b-adrenergic means of which it is aware that they are in continuous introduction cause desensitization of b-adrenergic receptors of the bronchi to the extent that doing bronchospasm in chronic asthmatics insensitive and irreversible action of these funds.

In particular, the present invention relates to new substituted cyclopropylamino-1,3,5-triazines that meet the General formula

< / BR>
where R1alkyl radical or cycloalkyl radical, unsubstituted or substituted by at least one alkyl radical, preferably one or two alkyl radicals, and alkyl radicals have from 1 to 3 carbon atoms, and cycloalkyl radical has from 3 to 5 carbon atoms;

R2bis/2-hydroxyethyl/amino-, 3-hydroxy-1-azetidinone, 3-methoxy-1-azetidinone, 3-oxo-1-azetidinone, morpholino-, 4-hydroxypiperidine, thiomorpholine-, S-oxide-thiomorpholine-, S,S-dioxide-thiomorpholine-thiazolidinedione, S-oxide-3-thiazolidinedione, S,S-dioxide-3-thiazolidinedione or 8-oxa-3-azabicyclo(3,2,1)Oct-3-ilen radical,

and their salts, connected the of the present invention are cyclopropylamino-1,3,5-triazine, responsible of General formula I, in which R2represents morpholino, thiomorpholine - or S,S-dioxide-thiomorpholine, as well as their salts connection with non-toxic pharmaceutically acceptable acids.

Particularly preferred compounds corresponding to the invention, are:

2-cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine;

hydrochloride-2-cyclopropyl-4-cyclopropylamino-6-morpholino,3,5-triazine;

2-cyclobutyl-4-cyclopropylamino-6-morpholino-1,3,5-triazine;

2-cyclopropyl-4-cyclopropylamino-6-dimorpholino-1,3,5-triazine; and

2-cyclopropyl-4-cyclopropylamino-6-dimorpholino-1,3,5 - triazine-S,S-dioxide.

The present invention relates also to the salts of joining with non-toxic pharmaceutically acceptable acids substituted, cyclopropylamino-1,3,5-triazines with formula I. as examples of pharmaceutically acceptable acids can be specified mineral acids, such as chloromethane, Hydrobromic, sulphuric, nitric, phosphoric, etc. acids, and organic acids such as acetic, citric, tartaric, benzoic, salicylic, maleic, etc. acids.

When the molecule contains one or more asymmetric centers, tera. These different forms are also included in the scope of the present invention.

Replaced cyclopropylamino-1,3,5-triazine corresponding to the present invention can be obtained by one or other of the following ways:

(a) carry out the reaction between chlorine-cyclopropylamino-1,3,5-triazine of the formula II and the amino of the formula R2H (III) by the equation

< / BR>
moreover, in these formulas, R1and R2have the above values;

(b) conducting the reaction between chlorine-1,3,5-triazine with formula IV and cyclopropylamine with the formula V by the equation

< / BR>
moreover, in these formulas, R1and R2have the above meanings;

(c) by heating at a temperature of education phlegmy for several hours in an aliphatic alcohol conduct the reaction between N-cyclopropylmethanol with formula VI and alkilany complex ester of formula VII in the presence of an alcoholate of an alkali metal by the equation

< / BR>
moreover, in these formulas, R1and R2have the above values, and Alk alkyl radical having from 1 to 4 carbon atoms, preferably ethyl radical;

(d) oxidizing cyclopropylamino-1,3,5-triazine with formula I, in which R1has the above significance, and R2timoha the SUB> S-oxide-thiomorpholine-, S, S-dioxide-thiomorpholine-, S-oxide-3-thiazolidinedione or S, S-dioxide-3-thiazolidinediones radical.

The above methods (a) and (b) is carried out by heating at high temperature for several hours in an inert solvent, preferably dioxane or isopropyl alcohol; they are typically held when heated to the boiling point of the used solvent and in the presence of a base. The basis used to capture chloroethanol acid that is released during the reaction can be either by the amine used in the reaction, or other organic base (e.g. triethylamine) or inorganic base (e.g. potassium carbonate).

The original connection with formula II receive conventional methods, conduct the reaction between 2,4-dichloro-6-R1-1,3,5-triazine with the formula VIII and cyclopropylamine with the formula V by the equation

< / BR>
moreover, in these formulas, R1has the above value.

This reaction is usually conducted at a temperature that is between -10oC and ambient temperature, in an inert solvent, such as chloroform, in the presence of inorganic or organic basis of the shares.

As for the source of compounds with formula IV, they also receive in accordance with conventional methods, carrying out the reaction between 2,4-dichloro-6-R1-1,3,5-triazine with the formula VIII and the amine with the formula, R2H (III) by the equation

< / BR>
moreover, in these formulas, R1and R2have the above values.

This reaction is usually conducted at a temperature of 0 20oC, in an inert solvent, such as chloroform, in the presence of a base, for example potassium carbonate.

2,4-dichloro-6-R1-1,3,5-triazine with formula VIII used as starting reagents, can be obtained by the method (R. Hirt et al./Helv. Chim. Acta, 33 (1950), 1365-1369), which consists in carrying out the reaction between cianurchloride and appropriate magnetogenesis compound of formula R1MgX, in which R1has the above meaning and X is halogen atom, preferably an iodine atom or bromine.

The parent compound with the formula VI used in method (C), obtained by the process comprising two stages:

(1) the reaction between cyclopropylamino with the formula V and the sodium salt of cyanoguanidine with the formula IX to obtain the N-cyano-N'-cyclopropylalanine with the formula X in accordance with equation
2H (III) to obtain N-cyclopropylalanine with formula VI in accordance with the equation

< / BR>
moreover, in these formulas, R2has the above value.

With regard to method (d), which oxidizes cyclopropylamino-1,3,5-triazine with formula I, is replaced by thiomorpholine - or 3-thiazolidinedione radical, which is obtained by one of the methods (a), (b) or (C) it leads to the formation of the corresponding S-oxide or S,S-dioxide, depending on the experimental conditions used for carrying out the oxidation. This oxidation is usually carried out using peroxomonosulfate potassium (included in trade under the name Oxon: 2SO5KHSO4K2SO4). When the reaction is carried out at a temperature of 10 20oC in the presence of from 1 to 2 mol Oksana per mole of the compounds of formula I, is subjected to oxidation, then get a connection S,S-dioxide. On the contrary, if the reaction temperature is maintained between -5oC and +5oC and if you use only about 0.5 mol Oksana per mole of the compound with formula 1, you get the connection S-oxide.

Salt accession with non-toxic pharmaceutically acceptable acids can be obtained on the basis of substituted cyclopropylamine the invention, not limiting it.

Example 1. Receipt of the initial 2,4-dichloro-6-R1-1,3,5-triazines with formula VIII.

2,4-Dichloro-6-ethyl-1,3,5-triazine

To a suspension containing one equivalent of canonicalid in toluene, are added drop by drop to 1.5 equivalent ethylacetamide dissolved in diethyl ether (obtained by the reaction of magnesium with ethylbromide), maintaining the temperature of the reaction mixture between 10 and 15oC. After the addition the mixture is kept at ambient temperature for one hour. Then add an aqueous solution containing 1.5 equivalent chloroethanol acid. Share two phases, the organic phase is dried on sodium sulfate, the solvent is then removed under reduced pressure. Clean 2,4-dichloro-6-ethyl-1,3,5-triazine by distillation under reduced pressure. Yield: 63% evaporating Temperature (TKip): 83oC/17 mbar.

The same way we obtain a connection joint in the table. I.

Example 2. Getting cyclopropylamino-1,3,5-triazines with the formula I according to the method (a).

A. Obtaining initial chlorine-cyclopropylamino-1,3,5-triazines with formula II.

2-Chloro-4-cyclopropylamino-6-methyl-1,3,5-triazine (new connection is atory -10oC, add 1 mol of cyclopropylamine dissolved in chloroform. After addition allow the mixture to return to ambient temperature. Then cool the mixture to a temperature of 0oC, add to it an aqueous solution containing 1 mol of potassium carbonate. Continue stirring for 1-2 h at ambient temperature. Separate the organic phase, dry it on sodium sulfate and the solvent is evaporated under reduced pressure. The remainder precrystallization in hexane. Thus receive the 2-chloro-4-cyclopropylamino-6-methyl-1,3,5-triazine. Yield: 75% of the melting Temperature (TPL): 117-119oC.

The same way we obtain the following new compounds:

2-Chloro-4-cyclopropylamino-6-ethyl-1,3,5-triazine.

The residue obtained after evaporation of the solvent (crude yield: 100%), used as is in the next stage.

2-Chloro-4-cyclopropylamino-6-n-propyl-1,3,5-triazine. Output: 100% TKip: 125oC/0.4 mbar.

2-Chloro-4-cyclopropylamino-6-isopropyl-1,3,5-triazine.

This connection precrystallization in hexane. Yield: 74% TPL: 79-80oC.

2-Chloro-4-cyclopropyl-6-cyclopropylamino-1,3,5-triuoride): 71.5% of the TPL: 66-67oC.

2-Chloro-4-cyclobutyl-6-cyclopropylamino-1,3,5-triazine.

The yield of the crude product (calculated on the basis of canonicalid): 23% of the Product is used as it is, without other purification in the next stage.

2-Chloro-4-cyclopentyl-6-cyclopropylamino-1,3,5-triazine.

Yield (crude product): 100% Product in crude form is used as it is, at the next stage.

C. Obtaining cyclopropylamino-1,3,5-triazines with formula I.

1. 2 Cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine (compound I)

To a solution containing 43 g (0,163 mol) of 2-chloro-4-cyclopropylamino-6-n-propyl-1,3,5-triazine in 300 ml of dioxane, are added, maintaining at ambient temperature, 45 ml (0,45) of the research, dissolved in 200 ml of dioxane. After addition of heat the mixture at a temperature of education phlegmy within one to two hours. Then allow the reaction mixture to return to ambient temperature and the precipitate is filtered off. Concentrate the filtrate and the residue is again dissolved in dichloromethane. Wash the solution with water. Separate the organic phase and dry it on sodium sulfate. The solvent is evaporated under reduced pressure. OS is finally precrystallization in diethyl ether. Receive and 36.2 g of 2-cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine. Yield: 85% TPL: 104oC.

Analysis for C13H21N5O

calculated: C 59,29, H 8,04, N 26,59,

found: C 59,20, H 8,15, N 26,43.

The same way we obtain a connection joint in the table. 2

2. 2 Cyclopropylamino-4-methyl-6-(8-oxa-3-azabicyclo /3,2,1/Oct-3-yl)-1,3,5-triazine (hydrochloride) (compound 9)

To a suspension containing one equivalent of the hydrochloride of 8-oxa-3-azabicyclo/3,2,1/octane in dioxane, is added 2 equivalents of triethylamine, dissolved in the same solvent. Then add 1 equivalent of 2-chloro-4-cyclopropylamino-6-methyl-1,3,5-triazine dissolved in dioxane. The mixture is heated at a temperature of education phlegmy within a few hours. Cooled to ambient temperature and filtered the precipitate that is formed. The filtrate is evaporated under reduced pressure and the residue is again dissolved in dichloromethane. Wash the solution with water. Separate the organic phase and dry it on sodium sulfate, then the solvent is evaporated under reduced pressure. Thus obtained residue is purified by chromatography on silica (eluent dichloromethane-ethanol 98:2 (volume/volume)). Havlena one equivalent chloroethanol acid to the free base in diethyl ether. Yield: 63% TPL: 220-223oC.

Analysis for C13H19N5OHCI

calculated: C 52,44, H 6,77, N 23,52, Cl-11,92,

found: C 52,40, H 6,74, N (LK 23: 43, Cl-111,84.

8-oxa-3-azabicyclo/3,2,1/octane used as a starting reagent in this example, is a known compound; it is obtained by the method of F. H. News et al. (J. Chem. Soc. 1948, 155-158).

There the same way we obtain a connection joint in the table. 3.

Hydrochloride 3-azetidinone used as a starting reagent for the synthesis of compound 17, is known; it was obtained by the method of H. Baumann et al. (Helv. Chim Acta 71, (1988), 1035).

3. a) 2-Cyclopropyl-4-cyclopropylamino-6-dimorpholino-1,3,5-triazine (compound 18)

Mix 12.2 g of 2-chloro-4-cyclopropyl-6-cyanopropionic-1,3,5-triazine (0,057 mol), 5,97 g thiomorpholine (0,057 mol) and 8 g of potassium carbonate (0,057 mol) in 100 ml of isopropyl alcohol and heated the mixture at a temperature of 75-80oC for 2 hours Cooled, the salt is filtered off and the filtrate is evaporated to dryness. Remove residue by 200 ml dichloromethane, washed with a solution of water, dried it on sodium sulfate and the solvent is evaporated. Kristallisera received the product in a mixture of ethyl acetate-hexane 1:2 (vol/a>C.

Analysis for C13H19N5S

calculated: C 56,32, H 6,86, N 25,27, S 11,55,

found: C 56,06, H 6,93, N Of 24.90, S 11,40.

The same way we obtain the following connections:

b) 2-Cyclopropyl-4-cyclopropylamino-6-thiomorpholine,3,5-triazine-S-oxide (compound 19)

Yield: 13% TPL: 167-168oC.

Analysis for C13H19N5OS

calculated: C 53,24, H 6,48, N 23,89, S 10,92,

found: C 53,10, H of 6.52, N 23,46, S to 10.62.

C) 2-Cyclopropyl-4-cyclopropylamino-6-thiomorpholine,3,5-triazine-S,S-dioxide (compound 20)

Yield: 17% TPL: 178-179oC.

Analysis for C13H19N5O2S

calculated: C 50,49, H x 6.15, N 22,65, S 10,36,

found: C 50,72, H 6,18, N 22,56, S 10,35.

d) 2-Cyclopropyl-4-cyclopropylamino-6-(3-thiazolidine) -1,3,5-triazine (compound 21)

Yield: 61.2% of TPL: 110-111oC.

Analysis for C12H17N5S

calculated: C 54,75, H 6,46, N 26,61, S 12,17,

found: C 54,83, H 6,46, N 26,68, S 12,30.

e) 2-Cyclopropyl-4-cyclopropylamino-6-(3-thiazolidine) -1,3,5-triazine-S, S-dioxide (compound 22)

Output: 35,6% TPL: 142-143oC.

Analysis for C12H17N5O2S

calculated: C 48,81, H 5,76, N 23,73, S 10,87,
a) N-tert-butoxycarbonyl-thiazolidin

To a solution containing a 8.9 g (0.1 mol) of thiazolidine in 50 ml of dioxane and 50 ml of water, add one drop of a solution containing 24 g (0.11 mol) of dicarbonate di-tert-butyl in 50 ml of dioxane, while maintaining the pH between 10 and 10.5 by adding sodium lye. Stir the mixture at ambient temperature for 6 h formed is Filtered salt and organic solvent is evaporated under reduced pressure. Extracted the aqueous residue dichloromethane (250 ml), decanted, the organic phase is dried on sodium sulfate and the solvent is evaporated. The residue is purified in the distillation under reduced pressure. Obtain 16.3 g of N-tert-butoxycarbonyl-thiazolidine. Yield: 86.2% of TKip: 56-57oC/6.7 mbar.

b) N-tert-butoxycarbonyl-thiazolidin-1,1-dioxide

Add drop by drop in the ambient temperature, the solution containing a 30.7 g (0.05 mol) oxone (2KHSO5KHSO4K2SO4) in 300 ml of water, to the solution containing 7,3 g (0,0385 mol) of N-tert-butoxycarbonyl-thiazolidine in 100 ml of dichloromethane and 200 ml of methanol. Stirred the mixture at a temperature of 20oC for 24 h, then DUT solvent. The remainder kristallisera in 300 ml of isopropyl ether. Get to 6.58 g of N-tert-butoxycarbonyl-thiazolidin-1,1-dioxide. Yield: 74.4% of TPL: 106-107oC.

Analysis for C8H15NO4S

calculated: C 43,44, H 6,79, N 6,33, S 14, 48MM,

found: C 43,52, H is 6.78, N 6,33, S 14,36.

(C) the Hydrochloride of thiazolidin-1,1-dioxide

Mix 1.8 g (0,0081 mol) of N-tert-butoxycarbonyl-thiazolidin-1,1-dioxide and 50 ml of 2n. solution chloroethanol acid in diethyl ether. Stir the resulting suspension at a temperature of 20oC for 6 h, then leave to rest for 48 hours white Precipitate of the hydrochloride of thiazolidin-1,1-dioxide is filtered, washed in diethyl ether and dried. Get so 0,83 g of the product. Output: 65,3% TPL: 173-174oC.

Analysis for C3H7NO2S HCl

calculated: C 22,86, H 5,08, N 8,89,

found: 23,29, H 5,01, N 8,69.

Example 3. Getting cyclopropylamino-1,3,5-triazines with the formula I according to the method (b).

A. Obtaining initial chloro-1,3,5-triazines with formula IV.

2-Chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine

To a solution containing 5,7 (0.03 mol) of 2,4-dichloro-6-cyclopropyl-1,3,5-triazine in 50 ml of chloroform and cooled to a temperature of 3 5oC, then cooled to 5oWith and add drop by drop a solution containing to 4.14 g (0.03 mol) of potassium carbonate in 15 ml of water. Then stir the mixture at ambient temperature for 2 hours Add 30 ml of water and separate the organic phase. Wash the solution with water, dried on sodium sulfate and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent-dichloromethane-ethyl acetate to 96.5:3,5 (volume/volume), and then precrystallization in hexane. Get so 5.5 g of 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine. Output: 76,2% TPL: 99-100oC.

Analysis for C10H13Cl N4O

calculated: C 49,89, H 5,41, N 23,28, Cl of 14.76,

found: C 49,91, H 5,44, N 23,06, Cl of 14.46.

C. Obtaining cyclopropylamino-1,3,5-triazines with formula I.

2-Cyclopropyl-4-cyclopropylamino-6-morpholino-1,3,5-triazine

To a solution containing 5.1 g (0,021 mol) of 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine in 50 ml of dioxane, are added at ambient temperature 2.85 g (0,050 mol) of cyclopropylamine dissolved in 20 ml of dioxane. Heat the mixture at a temperature of education phlegmy for 5 hours Then the solvent is evaporated under reduced pressure and arevut the solvent under reduced pressure. The remainder kristallisera on cold hexane. Get with 5.22 g of the product. This product forms a hydrochloride in a mixture of ethanol-diethyl ether. Get a 5.1 g of the hydrochloride of 2-cyclopropyl-4-cyclopropylamino-6-morpholino-1,3,5-triazine, which is identical to the compound 3 obtained in example 2.In.1. Output: 81,7% TPL: 183-184oC (acetonitrile).

Analysis for C13H19N5O HCl

calculated: C 52,44, H 6,72, N 23,53, Cl-11,93,

found: C 52,46, H 6.73 x, N 23,44, Cl-11,89.

Example 4. Getting cyclopropylamino-1,3,5-triazines with the formula according to the method (C).

A. N-Cyano-N'-cyclopropylamino

Prepare a suspension containing 9,36 g (0.1 mol) of the hydrochloride of cyclopropylamine and 8.9 g (0.1 mol) of sodium salt of cyanoguanidine in 100 ml of n-butanol and 8 ml of water. Heat the mixture at a temperature of education phlegmy within 2 hours Filter the suspension and wash the filter layer on the filter with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual liquid oil is extracted in 300 ml of acetonitrile. Is brought to a temperature of education phlegmy, filtered hot and washed filter layer on the filter with acetonitrile. The filtrate is evaporated and slowly kristallisera Poluchenie diethyl ether).

Analysis for C5H8N4in

calculated: C 48,37, H of 6.49, N 45,13,

found: C 48,40, H 6,50, N 45,14.

C. Obtaining the original N-cyclopropylamino with formula VI.

1. N/imino(cyclopropylamino)methyl/-4-morpholine-carboxamidine (hydrochloride)

Heat the mixture containing 4.0 g (32,3 mmol) of N-cyano-N'-cyclopropylidene and 3,98 (32,3 mmol) of the hydrochloride of the research, at a temperature of 160oC in nitrogen atmosphere for 2.5 hours Dissolve the resulting solid mass in 200 ml of isopropyl alcohol by boiling. Filtered hot and concentrated the filtrate until the suspension with solid particles. The mixture is then cooled to ordinary temperature and add 200 ml of diethyl ether. The reaction product crystallizes. Filtered, washed product in diethyl ether and dried. Obtain 6.8 g of the hydrochloride of N-/imino(cyclopropyl-amino)methyl/-4-morpholinobenzenediazonium. Yield: 85% TPL: 195-196oC.

Analysis for C9H17N5O HCl

calculated: C 43,63, H 7,32, N Of 28.27, Cl-14,21,

found: C 43,60, H 7,35, N 27,93, Cl-14,18.

2. N/imino(cyclopropylamino)methyl/-4-thiomorpholine-carboxamide-S, S-tioxide (hydrochloride)

This compound was obtained as previous what clopramide at a temperature of 160oC for 6 hours Yield: 58.4% Of the resulting product, which is pure 90% (chromatography), is used as is in subsequent reactions.

C. Obtaining cyclopropylamino-1,3,5-triazines with formula I.

1. 2 Cyclopropylamino-4-/1-methylcyclopropyl/-6-morpholino-1,3,5-triazine (compound 24)

Dissolve to 0.48 g (20 mmol) of sodium in 20 ml of anhydrous ethanol. Add this solution to the solution containing ethanol 2,48 g (10 mmol) of the hydrochloride of N-/imino(cyclopropylamino)methyl/-morpholinylcarbonyl, then another added to the mixture 2,82 g (22 mmol) of 1-methylcyclohexanecarboxylic ethyl. Then heat the mixture at a temperature of education phlegmy in nitrogen atmosphere during 88 hours Cooled, alcohol is evaporated under reduced pressure and the residue is again dissolved in 50 ml of water and 200 ml dichlormethane. Separate the aqueous phase, washed twice with organic phase with 50 ml of water and dried on magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is recrystallized in a mixture of petroleum ether-dichloromethane 1:1 (volume/volume). Get 0,49 g 2 cyclopropylamino-4-/1-methylcyclopropyl/-6-morpholino-1,3,5-triazine. Yield: 17% TPL: 94-95oC.

Analysis for C14H21N5O
2. 2 Cyclopropylamino-4-/2-methylcyclopropyl/-6-morpholino-1,3,5-triazine (hydrochloride) (compound 25).

Heating time: 62 hours Output: 38,7% TPL: 177-178oC.

Analysis for C14H21N5OHCl

calculated: C 53,93, H 7,06, N 22,47, Cl-11,40,

found: C 54,01, H 7,14, N 22,19, Cl-11,27.

3. 2-Cyclobutyl-4-cyclopropylamino-6-dimorpholino-1,3,5-triazine-S, S-dioxide (hydrochloride) (compound 26)

Heating time: 18 hours Yield: 39% TPL: 220-225oC (decomposition).

Analysis for C14H21N5O2SHCl

calculated: C 46,73, 6,12 H, N 19,47, S 9,87, Cl-8,90,

found: C 46,24, of 6.02 H, N 19.14 Per, S 9,78, Cl-8,70.

4. 2 Cyclopropylamino-4-(2-methylcyclopropyl)-6-dimorpholino-1,3,5-triazine-S,S-dioxide (compound 27)

Heating time: 27 hours Output: 93,9% TPL: 180-182oC.

Analysis for C14H21N5O2S

calculated: C 52,01, H 6,50, N 21,67, S TO 9.91,

found: C 51,00, H is 6.54, N 21,36, S 9,89.

5. 2 Cyclopropylamino-4-(2,2-dimethylcyclopropane)- 6-dimorpholino-1,3,5-triazine-S, S-dioxide (compound 28)

Heating time: 6 days. Output: 40,1% TPL: 170-172oC.

Analysis for C15H23N5O2S

calculated: C 53,41, H is holino-1,3,5-triazine-S,S-dioxide (compound 29)

Heating time: 20 hours in an autoclave at a temperature of 110oC. Yield: 28.7% Of TPL: 148-149oC.

Analysis for C16H25N5O2S

calculated: C 54,70, H 7,12, N 19,84,

found: C 54,71, H 7,10, N 20,05.

Example 5. Getting cyclopropylamino-1,3,5-triazines with the formula I according to the method (d).

A. 2-Cyclopropyl-4-cyclopropylamino-6-(3-thiazolidine) -1,3,5-triazine-S, S-dioxide (compound 22)

To a solution containing a return of 6.58 g (0,025 mol) 2-cyclopropyl-4-cyclopropylamino-6-(3-thiazolidine)-1,3,5-triazine (compound 21) in 75 ml of dichloromethane and 150 ml of methanol is added drop by drop at a temperature of 10 15oC solution containing a 30.7 g (0.05 mol) oxone (2KHSO5KHSO4K2SO4) in 75 ml of water. Stir the mixture at ambient temperature for 3 h, then add another 3 g oxone dissolved in 10 ml of water and maintain stirring for 2 hours Add 200 ml of water, extracted with dichloromethane (3100 ml), separated and the organic phase is dried on sodium sulfate and the solvent is evaporated. The residue is purified by chromatography on silica (eluent: dichloromethane-ethanol 98: 2 (volume/volume)). Get 3 g 2-cyclopropyl-4-cyclopropylamino-6-/3-diazolidinyl/ -1,3,5-triazine-S, S-dioxide, ID is"ptx2">

Century 2-Cyclopropyl-4-cyclopropylamino-6-(3-thiazolidine) -1,3,5-triazine-S-oxide (compound 23)

To a cooled to a temperature of 0oC the solution containing 11.85 g (0.045 mol) of 2-cyclopropyl-4-cyclopropylamino-6 -(3-thiazolidine)-1,3,5-triazine (compound 21) in 150 ml of dichloromethane and 300 ml of methanol is added drop by drop, without exceeding a temperature of 5oC, a solution containing 15,35 g (0,025 mol) oxone in 150 ml of water. Then stirred the mixture at a temperature of 5oC for 30 minutes the precipitate is Filtered off of mineral salts on Hiflo-Zell. Remove the organic phase by decantation, dilute aqueous phase by 400 ml of water and extracted with her dichloromethane (2200 ml). Dried the organic phase on sodium sulfate and the solvent is evaporated. Extract the residue after evaporation in 100 ml of dichloromethane, filtered and concentrated. Get the first batch weighing 2.83 g of solid product. The aqueous phase is alkalinized and extracted with her dichloromethane (3100 ml), the organic phase is dried on sodium sulfate and remove the solvent. Get thus to 8.41 g of the solid residue (the second party). Both parties are combined and purified by chromatography on silica (eluent:dichloromethane-ethanol 93:3 (volume/volume)). Get 7,66 g 2-cycloprop(1:3 volume/volume). Yield: 61% Tpl.: 136-137oC.

Analysis for C12H17N5OS

calculated: C 51,61, H 6,09, N 25,03, S 11,47,

found: C 51,79, H 6,10, N 26,09, S 11,50.

As mentioned above, is replaced by cyclopropylamino-1,3,5-triazine with formula I and their salts connection with non-toxic pharmaceutically acceptable acids have the ability to correct the effects of hypofunctioning cholinergic system and have thus activity conducive to processes associated with memory. In addition, they have a Central serotonergic and bronchospasmolytic activity; they counteract the release of mediators of mastocytes, have anti-inflammatory and anti-edema activity and potentializing the effect of-adrenergic agonist on muscle relaxation.

Described below pharmacological tests reveal these various favorable properties.

1. Impact on processes associated with memory.

Compounds of the present invention were studied in order to identify, on the one hand, their ability to foster learning, expressed by the reduction in the number of experiments required to achieve a predefined criterion, and the other is about used method of passive avoidance with multiple tests. This method is well known to assess the effects provided by the connection of learning and memory (A. Fine et. al. Proc. Natl. Acad. Sci. USA, 82 (1985), 5227-5230).

The test is performed on male rats Spraque-Dawley (160-200 g), which in the course of the experiment are contained in the standard cells. The device used is a transparent cell with a square base (side 35 cm, height 25 cm), equipped with a mesh covering, which may be supplied electric current. Insulating Mat (1017 cm) of rubber is placed on the floor in one corner of the cell.

In order to assess whether the connection is conducive to learning, there are the following experience.

Each animal is placed on a rubber Mat, and note the time that the animal spends in order to decide to leave this position for examination of cells. After 20 s after the examination, the animal receives a shock (3) feet, causing the escape response. The rat is immediately removed from the device and stored in their original cage. Repeat this experiment until the moment when the animal remains at least 180 with a rubber Mat to avoid electric shock.

Trained the Oh 180 C.

The time value of 180 with rubber Mat is considered as a maximum results, subject to the implementation of the animal to avoid electric shock. Rats that are in the course of this time on the Mat, acquired reflex evasion and placed in its original cell that is not receiving an electrical shock.

In order to assess whether the connection to favor the consolidation of memory in time, carry out the following experiment. Each animal is subjected to four tests at time points: 0, 4, 24, and 28 hours In the first test (time 0), the animal is placed on a rubber Mat, and note the time it takes to decide to leave this position for examination of cells. After 20 seconds after the examination, the rat gets an electric shock (duration 3) feet, causing the escape response. The rat is immediately removed from the device and stored in their original cage. In the three subsequent experiments (days: 4, 24 and 28 h) the animal is again placed on the rubber Mat, and note the time taken to leave this position. As soon as the four legs of the animal are on the net, it receives an electric shock and it it is animal. Thirty minutes before each test, each group of animals subjected to some processing:

group 1 receives an intraperitoneal injection of saline;

group 2 receives an intraperitoneal injection of the test compounds;

group 3 receives an intraperitoneal injection of 0.5 mg of scopolamine; and

group 4 receives an intraperitoneal injection of 0.5 mg of scopolamine and intraperitoneal injection of the test compounds at the same time.

Groups 1 and 2 used in the first experiment (training), and groups 3 and 4 in the second experiment (consolidation of memory).

The results obtained in this test for compounds according to the invention, are given in table. 4. In this table indicate the connection is subjected to the test (column 1), and the dose injected by intraperitoneal and expressed in mg/kg (column 2).

In columns 3 and 4 shows the results obtained in the experiment used to measure learning. The numbers indicate the average number of trials necessary to control animal (group 1) and the animal treated with the compound (group 2), would have learned to stay within 180 with a rubber Mat to avoid electric shock. The results were keeping the Sabbath. Sportsmemo to assess the consolidation of memory. In columns 5-8 figures represent average days of stay observed respectively at time 0, 4, 24 and 28 h, the animals of group 3, treated only by scopolamine, and in columns 9-12 are the corresponding figures for the animals of group 4, treated both scopolamine and study the connection (with the dose specified in the second column). A beneficial effect of the compounds on the counter amnesia induced by scopolamine, is proved by the increase in time spent on the Mat in each observation. The observed differences are analyzed statistically by the method of Mann-Whitney.

From this table it follows that:

the connection according to the invention are favorable for the acquisition of conditioned avoidance: the average number of trials needed to achieve a predefined criterion (the maximum stay time value with 180 on the Mat), is less high for the treated animals (column 4) than for control animals (column 3);

antimouse effect of scopolamine is very noticeable: it is evident that the time of stay of animals from group 3 (columns 5-8) is clearly less than 180 with that achieved by witnesses after the average number of experiments (column 3); and under these conditions, PTS is of the scopolamine: animals of group 4, processed simultaneously by scopolamine and connection according to the invention, have the time of stay (in each observation) is significantly higher than the animals of group 3, treated only by scopolamine (compare the results of column 5 with the results of column 9, 6, 10 and so on);

physostigmine has a beneficial effect, opposing antiregime effect of scopolamine, which is similar to the effect of the compounds according to the invention, but the dose has side effects and is very close to the toxic dose, which does not occur for compounds according to the invention.

2. Serotonergic activity.

The decrease in serotonergic activity was in correlation with the appearance of effective disorders such as depression and anxiety. Injection of rats serotonin or 5-hydroxytryptophan (5-GTP), agonist of serotonin, causing these animals pripadochnaya shake of the head, neck and torso, which resemble shudder wet dog that shakes off. This behavior is called "wet dog shake" (LCA) and is used as a model to identify energicheskoj and, in particular, serotonergic properties, which detect antidepressants (P. Bedard et C. J. Pycock, Neuropharmacoloqy 16 (197 the animals in cages stay.

The cell used for testing, is a transparent chamber size 12 x 24 x 30 cm high, the bottom of which is covered with a layer of sand.

Test compounds, dissolved in either saline or citrate buffer solution at pH 5, introduced by intraperitoneal with dose, different for each treated group. The control group receiving intraperitoneal injection of the same solvent (either saline or citrate buffer solution). After product introduction animals are immediately placed in a cell for testing groups of four rats at a time, and after a period of adjusting a duration of 10 min count the number of concussions (LCA), which occur within 30 minutes

Calculate the average values of the results and analyzed statistically by the method of Mann-Whetney.

In the following table. 5 gives the average number of shocks obtained for the compounds according to the invention, introduced by intraperitoneal with the specified dose (expressed in mg/kg).

This table shows that the compounds according to the invention cause the rats behavior "wet dog shake", comparable to the behavior that caused the Zech.

3. Bronchospasmolytic activity.

This activity was determined in Guinea pigs Dunkin-Hartley according to the method of H. Konzett et R. Roessler (Naunyn Schmiedebergs Arch exp Path Pharmacol 195 (1940), 71-74) and compared with the activity of theophylline.

Shot (urethane) and paralyzed (Gallatin) Guinea pig is under artificial respiration. Registered endotracheal pressure. Recurring spasms of the bronchi is called consistent (every 5 min) intravenous injection, respectively, serotonin, histamine or acetylcholine with a dose that can cause an increase endotracheal pressure from 20 to 50 cm of water column.

Subject the test compound is also administered intravenously by two minutes prior to the introduction of spasmogen, and then in 3-4 cumulative doses in ever-increasing numbers with an interval of 15 minutes Using 6 animals per test connection and one spasmogen.

In the following table. 6 shows dose products (DI50in Ámol/kg), which inhibit 5% (on average, one group of animals) caused by bronchospasm.

From this table it follows that the compounds according to the invention show a significant bronchospasmolytic activity from protivovospalitelnoe and anti-edema activity.

The reaction between the soluble antigen and antibodies in the body can cause acute inflammatory reaction accompanied by the release of histamine, changes in vascular permeability and the formation of local edema.

The purpose of the test, "the opposite of a passive phenomenon Artus" (PPFA) is to identify anti-inflammatory properties of compounds in relation to plantar edema induced experimentally by immune complexes in rats, Sprague-Dawley (P. J. Bailey et A. Sturm, Biochem. Pharmacol. 32 (1983), 475).

For this cause the reaction artusa by pomodorino injection of 0.1 ml heterologous opposing antialbumin serum in the right hind paw and by simultaneous intravenous injection of 1 ml/kg of ovalbumin (25 mg/ml). The test compound is injected intravenously over 30 to evoke reactions artusa with at least 3 different doses. Use a group of 6 rats per dose of the test compound.

The volume of the paw is measured by plethysmometry to reaction artusa and after 3-5 h after inducing reaction artusa as the control animals and the treated animals.

The effect of compounds on the reduction of swelling for each dose and each momie table. 7 given dose products (DI30in Ámol/kg), which inhibit 30% (average for the group of animals), the amount of swelling observed in control animals.

From this table it follows that the compounds according to the invention have anti-inflammatory and anti-edematous activity, clearly exceeds the activity of theophylline.

5. The inhibition of the anaphylactic release of histamine.

This test has a dual purpose: on the one hand, to evaluate the in vitro inhibitory effect of the substance on the anaphylactic release of histamine caused by degranulation of mastocytes in the lungs of Guinea pigs, and, on the other hand, to identify the possible effect of potentialization (synergism/inhibitory activity of b-adrenergic agonist, such as izoprenalin in respect of the same release histamine (E. S. K Assen et H. O. Scluld, Jut Arch Allergy, 40 (1971), 576-589).

Use Guinea pigs Dunkin-Hartley, which at first passively sensibiliser intravenous injection of 1 ml ethological antialbumin serum. Then after twenty-four hours after injection, the lungs are the perfusion buffer solution of Tyrode to remove blood, then extracted and cut in layers 1 through mm EV, easy-on-one Guinea pig.

A positive control group of layers of the light is stimulated by addition of a solution of ovalbumin (0.1 mg/ml) to start anaphylactic release of histamine, and is used to determine the maximum number of histamine (100%), which may be released.

"Negative" control group, is not stimulated by ovalbumin is used for determining the amount of histamine released by natural (spontaneous release).

In the three other groups of layers of light are incubated at a temperature of 37oC for 30 min in a solution of ovalbumin in the presence of three different doses of the test compounds (one dose per group).

To discover potentialities the influence of the compounds according to the invention on the inhibition of the izoprenalin release of histamine, three other groups of layers of light are processed in the same manner as above, but the environment for incubation contains, inter alia, izoprenalin with a dose of 10-7mol/L. At this dose izoprenalin inhibits 30 40% release of histamine, which is checked in the control group, which is processed by only one izoprenalin with this dose.

In addition, additional monitoring of histamine under the effect of the highest dose of the studied compounds.

For each group of histamine. released in the incubation medium is quantified by the method of spectrofluorimetry (D. P. Evans et al. Life Sci. 12 (1973), 327-336).

The obtained results allow to determine for each connection minimum inhibitory dose (mid) (net effect), i.e. the dose of a compound for which the amount of released histamine is smaller than the analogous quantity for "positive" control group, and for which this difference is statistically significant, and the minimum potentialities dose (MTD), which represents the dose of a compound that causes an inhibition greater than the inhibition from izoprenalin with a dose of 10-7mol/L.

In the following table. 8 are given the minimum inhibiting dose (MFA) and the minimum potentialities dose (MTD), expressed in Ámol/l, which is obtained in this test with compounds according to the invention and with theophylline as a matter of comparison.

From this table it follows that the compounds according to the invention are much more active than theophylline in the inhibition of the anaphylactic release of histamine (net effect), and have at the same time in small doses, potential>6. Potentialization muscle relaxant action of izoprenalin on the ileum of the Guinea pig (see. R. A. Turner, "Screening Methods in Pharmacology," Ed. Acad. Press. Som Diego 1965, Chapter IV, S. 43-47).

Fragments of the longitudinal muscle of the ileum of Guinea pigs Dunkin-Hartley (from 250 to 500 g) connected to an isometric pointer force, immersed in a solution of Toroda (371oC, pH 7,6; 5.6 mmol/l glucose) saturated with oxygen, the passage of the gas stream (a mixture of 95% O25% CO2), and are tightened with a force of 1 year After the voltage regulation consistent cycles of injection of histamine (dichlorhydrate histamine concentration of 3.2 Ámol/l) by means of a pump for perfusion type brown.

Each injection cycle includes 6 of the following sequential phases: resting phase (duration 25 (C), the phase of injection of histamine (duration 6 (C), the period of contraction of the muscles (duration 24), the first washing water (duration 25), the stabilization period, during which the muscle is returned to the initial voltage (duration 35), followed by a second washing with water (duration 25).

Cycle inhibition: when a consistent reduction caused by the injection of histamine, Amenia, caused by the subsequent injection of histamine, is measured and compared with the average of the three previous cuts by the repeated injection of histamine (reference abbreviations). Based on the obtained results, calculate the percentage inhibition of the contractions. Then again there are several cycles of injection of histamine to the moment when the muscle contraction again be reproducible; in this case, the muscle is ready for testing other compounds.

Potentialities action of the compounds measured in the course of the cycle, called "potentialization", which includes the sequential cycle inhibition. In the first cycle inhibition determine the percentage of inhibition of the reduction obtained by injecting one izoprenalin with a dose of 10-7mol/L. At this dose, the percentage of inhibition of the reduction is usually 10 to 25% during the second cycle inhibition determine the percentage of inhibition of the reduction obtained with the test compound, which is introduced one at a given dose. In the third cycle inhibition izoprenalin and test compound are introduced, and the percentage of inhibition of the reduction is calculated for the used dose and/P> Based on the results, determine for each test connection minimum potentialities dose (MTD), which corresponds to the dose of the product for which the inhibition obtained with a mixture of the compound+izoprenalin significantly greater than (p < 0,05) the amount of each of the obtained ingibirovanii, when the connection and izoprenalin are entered separately.

In the following table. 9 for compounds according to the invention in comparison with theophylline is given the minimum dose, expressed in Ámol/l, which potentialities muscle relaxant action of izoprenalin entered with a dose of 10-7mol/L.

This table shows that the compounds according to the invention are much more active than theophylline for potentialization muscle relaxant action of izoprenalin.

7. Steps on polymorphically neutrophilic granulocytes.

Polymorphically neutrophil (PMN) granulocytes represent cells that are mobilized in inflammatory processes and which can be stimulated by various substances, such as, for example, formylmethyl-leucyl-phenylalanine (FMLP) or prostaglandin E (PGEI). PMN granulocytes respond to these extracellular SNA response of PMN granulocytes can cause painful inflammation and is accompanied by the reduction of cyclic adenosine monophosphate (camp) in these cells. Hence, compounds that inhibit the respiratory pressure PMN granulocytes or which increase the concentration of camp can be considered as very important for the treatment of arthritis and asthma. Purpose described below pharmacological tests show that the compounds according to the invention have a dual character: on the one hand, they inhibit the stimulation of PMN granulocytes, and, on the other hand, they increase the content of camp in these cells.

Inhibition of stimulation of PMN granulocytes.

Stimulation of PMN granulocytes detected by chemiluminescence, which is accompanied by activation of the metabolism of oxygen, when these cells are stimulated in the presence of lyuminola (5-amino-2,3-dihydro-1,4-phthalazinedione).

PMN granulocytes from rats (5106/ml) pre are incubated in phosphate buffer solution (150 mmol/l, pH 7,4) containing luminal concentration of 10-5mol/l for 15 min at a temperature of 37oC, then for 5 min in the presence of test compounds with a concentration of 10-6mol/L.

The response to stimulation of PMN granulocytes is initiated by addition of the specified environment FMLF with the final concentration of 3,210-7mol/L. Luminescen the et O. Stendahl (Infection and Immunoligy 37 (1982), 34-39). Experimental cycle lasts 38 C. the Reaction is repeated 9 times for each of the studied compounds, and calculate the average value of the obtained results.

In the following table. 10 for the compounds according to the invention and theophylline (compound comparison) gives the average percentage of residual chemiluminescence, calculated with respect to the test of experience, during which PMN granulocytes are incubated and stimulated by FMLP in the absence of test compounds (10% chemiluminescence).

From this table it follows that at a concentration of 10-6mol/l, i.e., at a concentration at which tested all connections according to the invention, theophylline is completely inactive. On the other hand, shows that when the concentration of the compounds according to the invention cause a significant decrease in chemiluminescence and, therefore, lead to a significant inhibition of the stimulation of PMN granulocytes.

Also noticed that you need a 100 times higher concentration (10-4mol/l) to obtain the effect, comparable to theophylline (residual chemiluminescence 65%).

The increase in the content of camp.

PMN granulocytes is P>C for 3 min in the presence of test compounds with a concentration of 3,2106mol/l and PGEIwith a concentration of 10-6mol/L. Then the reaction is terminated by adding 1 ml of propanol. After centrifugation acceleration 15000 g for 3 min surfaced phase is extracted, evaporated, and the residue is determined by the number of camp using a radioimmunological method according to the method recommended by the supplier of the reagent used for this purpose (Anursham).

Supervisory experience is carried out in the same conditions but in the absence of the test compound.

In the following table. 11 given the quantity of camp (expressed in pmol) obtained in the course of these experiments, in comparison with theophylline, also used with a concentration of 3,210-6mol/L.

This table shows that the compounds according to the invention are more active than theophylline, and significantly increase the content of camp in PMN granulocytes stimulated by PGEI.

8. The toxicity.

The toxicity of the compounds according to the invention was determined in male NMRI mice using test Irvine (S. Irwin Psychopharmacologia, 13 (1968), 222-257).

Increasing doses of connection to be the second dose (dose, causing the death of two animals of the three after 48 h).

In the following table. 12 is given a lethal dose observed for the compounds according to the invention. From this table it follows that the compounds according to the invention are very few toxic unlike physostigmine.

9. Dosage and administration.

Pharmaceutical compositions containing the compounds according to the invention, can be oral, parenteral or rectal route. Pharmaceutical compositions suitable for oral administration may be solid or liquid, for example in the form of tablets (coated or uncoated), pills, pills gelatin capsules, solutions, syrups, etc. Similar compositions suitable for administration by parenteral, are pharmaceutical forms known for this type of administration, such as solutions, aqueous or oil suspensions, or emulsions.

For administration by rectal compositions containing the compounds according to the invention are usually in the form of candles.

Such pharmaceutical forms as injectable solutions, injectable suspensions, tablets, drops, suppositories, etc. are prepared in accordance with the methods commonly used by pharmacists.

FA is. mesilat compounds according to the invention with solid or liquid media, non-toxic, pharmaceutically acceptable, and, if necessary, a dispersing agent, dezintegriraat agent, stabilizer and so on, there Can be added, if necessary, sweetening agents, colorants, etc. the Percentage of active product in the pharmaceutical compositions can vary within very wide limits, depending on the patient and the route of administration, in particular depending on the frequency of administration.

As for daily dosage, it may vary in a wide range of individual doses, for example from 0.05 to 0.5 g of active product, depending on the method of introduction. For example, it can be from 0.1 to 0.5 g, preferably 0.1 g, from one to several times a day, when the connection is introduced in the form of tablets.

As a non-limiting example of a composition containing the compound with the formula 1, which can be entered oral route, below is the recipe for tablets, mg:

Connection 1 50

Methylcellulose (Methocel KM) 200

Dry lactose 154

Aerosil 5

Anhydrous citric acid 60

Talc 11

Magnesium stearate 20

Below is Greece contains, wt.

Connection 1 10,0

Methylcellulose (Methocel KM) 40,0

Lactose dry 30,8

Aerosil 1,0

Anhydrous citric acid to 12.0

Talc 2,2

Magnesium stearate 4,0

Just 100,0

An example of the formulation 2. The composition comprises, by wt.

Connection 1 73,5

Lactose dry 26,2

Magnesium stearate 0,3

Just 100,0

To get the pill, mix the various ingredients, homogenize the mixture at room temperature and pressed the resulting homogeneous mixture in the usual way.

To obtain a gelatin capsule, let dry lactose and connection 1 through a sieve of 0.6 mm Introducing the mixture in a planetary mixer and homogenize the mixture for 20 minutes Add magnesium stearate and homogenize the mixture for 5 minutes Finally, fill the pill of the appropriate size required amount of powder mixture.

1. Replaced cyclopropylamino-1,3,5-triazine General formula I

< / BR>
where R1C1C3-alkyl or C3- C5-cycloalkyl, unsubstituted or substituted with at least one C1C3-alkyl;

R2bis(2-hydroxyethyl)amino, 3-hydroxy-1-azetidine, 3-methoxy-1-azetidine, 3-oxo-1-azetidine, morphoid-3-thiazolidine, S, S-dioxide-3-thiazolidine or 8-oxa-3-azabicyclo(3,2,1)Oct-3-yl,

their optical isomers, racemic mixture, or their salts attaching a non-toxic pharmaceutically acceptable acid exhibiting pharmacological activity.

2. Connection on p. 1, where R2morpholino, thiomorpholine - or S,S-dioxide-thiomorpholine, and their salts connection with non-toxic pharmaceutically acceptable acids.

3. Connection on p. 1, representing 2 cyclopropylamino-4-morpholino-6-n-propyl-1,3,5-triazine and salts thereof joining with non-toxic pharmaceutically acceptable acids.

4. Connection on p. 1 representing 2-cyclopropyl-4-cyclopropylamino-6-morpholino-1,3,5-triazine and salts thereof joining with non-toxic pharmaceutically acceptable acids.

5. Connection on p. 1 representing 2-cyclobutyl-4-cyclopropylamino-6-morpholino-1,3,5 - triazine and salts thereof joining with non-toxic pharmaceutically acceptable acids.

6. Connection on p. 1 representing 2-cyclopropyl-4-cyclopropylamino-6-dimorpholino-1,3,5-triazine and salts thereof joining with non-toxic pharmaceutically acceptable acids.

7. Connection on p. 1, p is the means with pharmaceutically acceptable acids.

8. The method of obtaining substituted cyclopropylamino-1,3,5-triazines and their salts, as defined in paragraph 1, characterized in that they are subjected to the interaction of chlorocyclopropane 1,3,5-triazine of the formula II

< / BR>
in which R1has the meaning specified in paragraph 1,

with an amine of the formula III

R2H,

in which R2has the meaning specified in paragraph 1, and, if necessary, transform the received cyclopropylamino-1,3,5-triazine formula I and their salts connection with non-toxic pharmaceutically acceptable acids.

9. The method of obtaining substituted cyclopropylamino-1,3,5-triazines and their salts, as defined in paragraph 1, characterized in that subject interaction chloro-1,3,5-triazine of the formula IV

< / BR>
in which R1and R2have the values listed in paragraph 1,

with cyclopropylamino formula V

< / BR>
and, if necessary, transform the received cyclopropylamino-1,3,5-triazine of the formula I and their salts connection with non-toxic pharmaceutically acceptable acids.

10. The method of obtaining substituted cyclopropylamino-1,3,5-triazines and their salts, as defined in paragraph 1, characterized in that the N-cyclopropylmethanol General formula VI

< / BR>
where R2has the specified values,
has a specified value;

Alk C1C4is an alkyl radical,

and, if necessary, transform the obtained substituted cyclopropylamino-1,3,5-triazine General formula I and their salts connection with non-toxic pharmaceutically acceptable acids.

11. The method of obtaining substituted cyclopropylamino-1,3,5-triazines of General formula I, where R2radical, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, 3-thiazolidine-S-oxide or a 3-thiazolidine-S,S-dioxide, and salts, as defined in paragraph 1, characterized in that oxidizes cyclopropylamino-1,3,5-triazine of General formula Ia

< / BR>
where R1has the specified values;

R2radical, thiomorpholine or 3-thiazolidine,

and, if necessary, make obtained in this way cyclopropylamino-1,3,5-triazine General formula I and their salts connection with non-toxic pharmaceutically acceptable acids.

12. Pharmaceutical composition having pharmacological activity towards the mnemonic processes, as well as serotonergically, bronchospasmolytic, anti-inflammatory and anti-edematous activity, activity inhibition of anaphylactic excretion of histamine, miorelaksantnoe deystviye beginning and pharmaceutically acceptable excipients, characterized in that the effective beginning it contains replaced cyclopropylamino-1,3,5-triazine in PP.1 7 or its pharmaceutically acceptable salt in an effective amount.

 

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FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: pharmacology, fluorinated quinolone-based drug, in particular ofloxacine for injections.

SUBSTANCE: claimed composition contains therapeutically acceptable amount of ofloxacine and trilon-B, sodium chloride, water for injections as additives.

EFFECT: high therapeutic effectiveness; non-crystallized active agent for a long-time storage.

1 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states that involves inhibition of activity of enzyme that catalyzes hydrolysis of ester functional groups and wherein indicated state represents obesity or accompanying disorder, and wherein compound of the formula (1):

is prescribed, or its pharmaceutically acceptable salt, ester, amide or a precursor. Also, invention relates to a method for manufacturing the medicinal preparation used for prophylaxis or treatment of states wherein inhibition of activity of enzyme is required wherein indicated enzyme catalyzes hydrolysis of ester functional groups. In the formula (1) A means a 6-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute is taken independently among the following group: halogen atom, alkyl, alkyl substituted with halogen atom, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, nitro-group, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6 or lipid, or steroid (natural or synthetic) under condition that any substituting heteroatom in R1 or R2 must be separated from exocyclic nitrogen atom by at least two carbon atoms (preferably, saturated atoms), and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12, preferably, from 2 to 10; m = from 1 to 3; R5 means preferably (C2-C10)-alkyl; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compound of formulae (II), (IIa) and (IIb) given in the description and a method for preparing compound of formulae (II), (IIa) and (IIb), pharmaceutical composition used for prophylaxis or treatment of obesity and/or accompanying disorder, nutrition product, a method for prophylaxis or treatment of obesity or accompanying disorders, a method for inhibition of activity of enzymes, a method for reducing fat content in animals, a cosmetic method for maintaining this weight and a new intermediate compound of the formula (IV) indicated in the description. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

33 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of aryl carboxylic acids and describes a compound of the formula (I):

, wherein groups R1, R2, R3, R4 and groups R5 and R6 when they are joined to carbon atom can be similar or different and mean hydrogen, halogen atom, hydroxy-group or optionally substituted group taken among alkyl, alkoxy-group, phenyl, carboxylic acid or sulfonic acid; one or both substitutes R5 and R6 can mean oxo-group also if they are joined to carbon atom; if R5 and R are joined to nitrogen atom then they mean hydrogen atom, hydroxy-group or optionally substituted alkyl or benzyl; X means heteroatom taken among oxygen and sulfur atom or NH; Ar means optionally substituted bivalent a single or condensed aromatic or heterocyclic group wherein aromatic ring represents phenyl, naphthyl and heterocyclic group represents furan; R7 means hydrogen, halogen atom, alkoxy-group, alkyl, or it forms a bond with the adjacent group R8; R8 means hydrogen atom, hydroxy-, alkoxy-group, alkyl or optionally substituted benzyl; or R8 forms a bond in common with R7; R9 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; R10 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; Y means oxygen atom or NR12 wherein R12 means hydrogen atom, alkyl or benzyl; R10 and R12 can form in common five- or six-membered cyclic structure comprising carbon atoms that involves optionally one or some heteroatoms taken among oxygen, sulfur or nitrogen atoms; a binding group represented by the formula: -(CH2)n-(O)m- can be joined through nitrogen atom or through carbon atom and wherein n means a whole number from 1 to 4; m means a whole number from 0 to 1 under condition that when a binding group is joined through carbon atom then R5 either R6 represents oxo-group; Y means oxygen atom; R9 doesn't mean hydrogen atom; or its derivatives, analogs, its tautomeric forms, its stereoisomers, its polymorphic forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. Also, invention describes methods for preparing compounds of the general formula (I), intermediate compounds and methods for their preparing, a pharmaceutical composition eliciting activity with respect to hPPRα, hPPRγ and inhibitory activity with respect to HMG-CoA-reductase and involving compound of the formula (I). Also, invention relates to methods for prophylaxis and treatment of different diseases caused by above said activity, a method for reducing the total cholesterol level and a method for reducing the glucose level. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

27 cl, 64 ex

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