Derivatives of pyrimidine-4-or their pharmaceutically acceptable salts and serotoninoliticaskie, dopaminereleasing and antihistamine composition based on them

 

(57) Abstract:

Usage: biochemistry and medicine. The essence of the invention: derivatives of pyrimidine-4-it f-ly I for certain values radicals or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions containing these derivatives, pyrimidine-4-it and an inert carrier. Reagent 1: compound f-ly II. Reagent 2: compound f-ly III, where W=N-reactionary tsepliaeva the group, with the corresponding values listed radikalov. The process is conducted in an inert solvent in the presence of a base. The structure of the compounds f-l I, II, III where Alk - C1-C4- alcander; R3-C1-C4-alkyl; R4is hydrogen; R5is hydrogen, unsubstituted C1-C4-alkyl, C1-C4-alkyl, substituted phenyl, pyridinyl, C1-C4-alkylsulphonyl, C1-C4-alkylaminocarbonyl; R6is hydrogen, C1-C4-alkyl, or R4- C1-C4-alkyl, R5and R6taken together form a bivalent radical of formula-CH2-CH2- , -CH2-CH2-CH2- , -CHCH- (in-3), -NCH- (b-4), -N=CH-CH2- where one of the hydrogen atoms of the specified RA(a-1) (a-2) or (a-3) where R7is hydrogen, halogen, oxygen or nitrogen in (a-2), oxygen, or sulfur, or NH (a-3) and, if X is carbon, R1radical of formula (a-4) where R7is hydrogen, halogen, and, if X is nitrogen, R1radical of formula (a-2), where R7/is hydrogen, halogen,-Oh, nitrogen. Reagent 1 II. Reagent 2 III. 2 S. and 1 C.p. f-crystals, 8 PL.

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions based on them.

Known derivatives benzoxazoles, benzthiazoles with psychotropic, sedative, analgesic property.

The purpose of the invention is the finding in a series of pyrimidine derivatives novel compounds, low-toxic and has serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions based on them.

This is achieved by the described derivatives of pyrimidine-4-it formula I

where Alk - C11-C14-alcander; R3- C1-C4-alkyl; R4is hydrogen; R5-hydrogen, unsubstituted C1-C4-alkyl, C1-C4-alkyl, substituted F. the rod, WITH1-C4-alkyl, or R4- C1-C4-alkyl; R5and R6taken together form a bivalent radical of the formula

-CH2-CH2- (-1)

-CH2-CH2-CH2- (-2)

-CH=CH- (-3)

-N=CH- (-4) or

-N= CH-CH2- (-5), where one hydrogen atom of these radicals (-3) and (-5) can be replaced WITH1-C4-alkyl and if X=CH, R1is a radical of the formula

(a-1) (a-2) or

(a-3) where R7is hydrogen or halogen;

B is O or N (a-2) and

B is O,S or NH in (a-3) and, if X = S, R1is a radical of the formula

where R7is hydrogen or halogen, and, if X = N, R1is a radical of the formula

where R7is hydrogen, halogen, B = O, nitrogen, or their pharmaceutically acceptable salts.

For preferred compounds is derived pyrimidine-4-it formula

CH2N= C or its pharmaceutically acceptable salt.

In addition, the invention relates to a pharmaceutical composition having serotoninergicheskoi, dopaminergically and antihistaminic activity comprising as an active ingredient derivative described pyrimidine-4-it formula I or their pharmaceutically acceptable salts in an amount of 0.05-15 wt.% with an alkylating reagent of the formula III

k-W HNx-R1(X is CH or C) or piperazine (X - N) of the formula (III). In the formula (II), W is the reaction tsepliaeva group, such as, for example, halogen, for example chlorine, bromine or iodine, or a group of sulfonyloxy, for example, methanesulfonate, 4-methylbenzoyl sulfonyloxy and similar otsepleniya group

+< / BR>
This reaction of N-alkylation can be carried out simply in inert in the reaction against a solvent such as, for example, aromatic hydrocarbons such as benzene, methyl benzene, xylene and the like; lower alkanol, for example methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; a simple ether, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; dipolar aprotic solvent, for example N,N-dimethylformamide, N,N-dimethylacetamide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; or a mixture of such solvents. The addition of an appropriate base, such as, for example, a carbonate of alkali or alkaline earth metal carbonate, hydroxide, alkoxide or hydride, for example sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride and the like, or organic bases, such as the SQL, to collect the acid that is released during the reaction. In some cases, the addition of iodide, in a preferred variant of the iodide of an alkali metal, is necessary. The temperature rise in a small degree can increase the speed of reaction.

In this and the following embodiments of the method of obtaining the reaction products can be isolated from the reaction mixture and, if necessary, then clean according to methodology known in this field, for example, by extraction, distillation, crystallization, grinding into powder and chromatography.

The compounds of formula I, where R1radical of formula (a-1) and X is CH, and the above-mentioned compounds can be represented by the formula I (a-1) can be obtained by hydrolysis of the acetal of the formula IV, in which each R is C1-C6-alkyl or both radicals R, taken together, form a bivalent radical of C2-C3-alcander, thus obtaining the cyclic acetal

L-N____ L-N

Specified the hydrolysis is conveniently made by mixing acetal in water acidified environment and, if necessary, stirring the reaction mixture.

The compounds of formula I in which X is CH and R1radical of formula (a-2), in which B - O, and toroi Y - reactive leaving group such as, for example, halogen or nitro. In a preferred variant of the Y - group of halogen and more particularly fluorine

L :

The above cyclization reaction of an oxime of the formula V can be performed by treatment of the corresponding base on the preferred option in a suitable inert at the reaction solvent, at a temperature in the range from 20 to 200aboutSince, in the preferred option from 50 to 150aboutWith, and especially when the distillation temperature of the reaction mixture. If necessary, the specified base first, you can add the preferred option at room temperature, after which the thus obtained Sol is subjected to cyclization, the preferred option at elevated temperatures and the preferred option when the distillation temperature of the reaction mixture. Appropriate bases are, for example, carbonates of alkali and alkaline earth metals, carbonates, hydroxides, alkoxides, amides or hydrides, for example sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium amide, sodium hydride and the like bases. Suitable solvents for this method alsogenetically hydrocarbons, for example dichloromethane, trichloromethane, carbon tetrachloride, 1,1,1-trichloroethane, 1,2-dichloroethane and the like; lower alkanols, for example methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1,2-ethanediol and the like; ketones, such as 2-propanone, 4-methyl-2-pentanone and the like; ethers, e.g. 1,1-oxybisethane, 1,1-oxybisethane, 1,4-dioxane, tetrahydrofuran, 1,1-oxybis(2-methoxyethane) and the like; dipolar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethylsulfoxide, triamide hexamethylphosphoric acid and the like; or mixtures of these solvents.

The compounds of formula (1-a-2-1) can also be obtained by cyclization of a derivative of activated oxime of formula VI, where V is an acid residue, and more specifically, (C1-C6is alkyl or aryl)carbonyl, for example formyl, acetyl, propionyl, benzoyl and the like; and (C1-C6is alkyl or aryl)oxycarbonyl, such as methoxycarbonyl, etoxycarbonyl (1,1-dimethyl)etoxycarbonyl, phenoxycarbonyl and the like; and (C1-C6is alkyl or aryl)sulfonyl, for example methanesulfonyl, benzazolyl, 4-methyl-benzazolyl, 2-naphthalenesulfonyl and the like; N-acylaminoalkyl, for example, trichlorocarbanilide the mules VI convenient to carry out by treatment with a suitable base, in the preferred variant in a suitable inert in the reaction against the solvent, at a temperature of 20-200aboutSince, in the preferred option from 50 to 150aboutC and preferably at a temperature of distillation of the reaction mixture. In some cases, however, it is beneficial not to add a base to the reaction mixture and to remove the acid released during the reaction, by distillation under normal pressure or, if necessary, under reduced pressure. Another option specified cyclization can also be carried out by heating oximoula derivative (VI) under vacuum without solvent. Suitable bases are, for example, carbonates of alkali and alkaline earth metals, carbonates and amines, for example sodium carbonate, potassium carbonate, sodium bicarbonate, N,N-diethylethanamine, 4-ethylmorpholine, 1,4-diazabicyclo(2,2,2)octane, pyridine and the like of the base.

Suitable solvents for the cyclization are, for example, aromatic hydrocarbons such as benzene, methylbenzol, xylene and the like; ethers, e.g. 1,1-oxybisethane, 1,1-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,1-oxybis(2-methoxyethane), 1,2-bis(2-methoxyethane)ethane and the like; dipolar who emailhosting acid, pyridine, methylpyridine, dimethylpyridine, acetic anhydride, the anhydride of N-propionic acid, anhydride, N-butyric acid and the like; halogenated hydrocarbons such as trichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1-2,2-tetrachlorethane, chlorobenzene, dichlorobenzene and the like solvents.

The compounds of formula I in which X is CH and R1radical of formula (a-2), in which B - NR8moreover , these compounds are represented by formula (I-a-2-II) can also be obtained by cyclization of the intermediate product of formula VII to the corresponding derivatives of hydrazine R8- NH-NH2(VIII) or its acid adduct

L-N+ R8NHNH2< / BR>
In the formula (VII), the corresponding tsepliaeva group such as, for example, halogen, for example fluorine or chlorine; or a nitro-group. The above cyclization reaction can be conducted by stirring and, if desired, heating the reactants in a suitable, inert in relation to the reaction mixture, the solvent in the presence of an appropriate base. Suitable solvents typically have a relatively high boiling point and represents, for example, water, alkanols, for example methanol, ethanol, 1-butanol and the like; diols, such as 1,2-ethanediol and the like; ar is the cities, for example trichloromethane, carbon tetrachloride and the like; ethers such as tetrahydrofuran, 1,4-dioxin, 1,1-oxybisethane, 1,1-oxybis-(2-methoxyethane) and the like; dipolar aprotic solvents such as N, N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and the like; or mixtures of such solvents. Suitable bases for the preferred option are carbonates of alkaline or alkaline earth metals or hydrogen carbonates, such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like; or amines, such as N,N-diethylethanamine, 4-ethylmorpholine, N-(1-methylethyl)-2-propanamine and the like. In addition, the compounds of formula (I-a-2-II) can be obtained by nitrosation of the intermediate aniline of formula IX

L-N nitrite, shelochnogo metal, such as sodium nitrite in an aqueous acidic environment and processing thus obtained nitrosoguanidine (X-a) or, if R8is hydrogen, salt, page (X-b)

< / BR>
where A is the conjugated base of the acid used above, with an appropriate reducing agent, such as, for example, hydrogen, in the presence of a metallic hydrogenation catalyst, for example, a Nickel catalyst or Raney cobalt catalysis of the formulas IX

L-N which in most cases spontaneously or, if necessary, when the temperature can cilitates with the compound of the formula (I-a-2-II).

The compounds of formula I in which X Is N and R1radical of formula (a-2), and these compounds are represented by formula (I-a-2-III) can be obtained by N-alkylation of piperazine derivative of formula XII benzazoles formula XIII

L-NH + where W is a suitable tsepliaeva group, such as halogen, for example chlorine or bromine. This reaction of N-alkylation (XII) (XIII) can be cast in the same way as described above to obtain compounds of formula I of the intermediates (II) and (III).

The compounds of formula I in which X Is N and R1radical of formula (a-2) where B Is O or R8and B is represented as B', and the above compounds of formula (I-a-2-IV) can be obtained by cyclization of the intermediate compounds of formula XIV by treatment with a suitable base in an inert in the reaction against the solvent.

< / BR>
In the formula XIV W2- suitable tsepliaeva group, such as halogen, for example fluorine or chlorine, or a nitro-group. Suitable bases for this cyclization are, for example, carbonates of alkaline drocarbons sodium, potassium carbonate, sodium hydroxide, sodium methoxide, sodium hydride, or organic bases, such as amines, e.g. N, N-diethylethanamine, 4-ethylmorpholine and similar reasons. Suitable solvents are, for example, aromatic hydrocarbons such as benzene, methylbenzol, xylene and the like; lower alkanols, for example methanol, ethanol, 1-butanol and the like; ketones, such as 2-propanone, 4-methyl-2-pentanone and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; dipolar aprotic solvents such as N,N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone and the like, or mixtures of such solvents. In order to increase the reaction rate, the temperature of the reaction mixture can be increased, and in particular specified the cyclization can be carried out at a temperature of distillation of the reaction mixture.

The compounds of formula (I-a-2-IV) in which B' Is O, and such compounds represented by formula (I-a-2-V) can also be obtained by cyclization of activated oximoula derivative of formula XV

L-NN ___ L-N

where Y is formyl, (C1-C6is alkyl or aryl)carbonyl such as acetyl, propionyl, benzoyl and the like; and (C1-C6the alkyl or the like; (C1-C6is alkyl or aryl)sulfonyl, such as trichlorocarbanilide and the like. The above cyclization reaction is conveniently conducted by processing the appropriate basis for the preferred option in inert in the reaction against the solvent, at a temperature of 20-200aboutWith, in particular 50-150aboutWith, and the preferred option when the distillation temperature of the reaction mixture. However, in some cases, it may be advantageous not to add a base to the reaction mixture and to remove the acid released during the reaction, by distillation under normal pressure or, if necessary, under reduced pressure. Another variant of this cyclization can also be carried out, fueling akimovoi derivative (XV) under vacuum without solvent. Suitable bases are, for example, carbonates of alkali and alkaline earth metals, carbonates and amines, for example sodium carbonate, potassium carbonate, sodium bicarbonate, N,N-diethylethanamine, 4-ethylmorpholine, 1,4-diazabicyclo(2,2,2)octane, pyridine and the like bases. Suitable solvents for the cyclization are, for example, aromatic hydrocarbons such as benzene, methylbenzol, xylene and the like; simple reoxidation and the like; Zapolarye aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, hexamethylphosphoric acid triamide, pyridine, acetic anhydride and the like; halogenated hydrocarbons such as trichloromethane, carbon tetrachloride 1,2-dichloroethane, chlorobenzene and the like solvents.

The compounds of formula (I-a-4) can also be obtained by subjecting the interaction of 4-piperidone (XVI) with a suitable imide (XVII) such as, for example, phosfolan (for example, R9and R10is aryl or alkyl, the reaction of Wittig (or phosphatised) for example, R9- alkyloxy and R10- O-, reaction Horner-Emmons.

L-N=O + R9- = ____ I

The reaction is conveniently conducted by processing postnasal salt XVIII (R9and R10- aryl or alkyl) or phosphonate XVIII (R9- alkyloxy and R10- O-)

R____ an appropriate base, such as, for example, utility, motility, sodium amide, sodium hydride, sodium alkoxide or potassium or sodium salt of sulfanilic(methane) and such base, in an inert atmosphere and in an inert in the reaction against a solvent such as, for example, hydrocarbons, such as hexane, heptane, cylcohexane and the like; aromatic hydrocarbons, naprelan; Zapolyarny aprotic solvent, such as dimethylsulfoxide, triamide hexamethylphosphoric acid and similar solvents; and then treating the thus obtained ylides (XVII) a ketone of formula XVI, if necessary, at a somewhat higher temperature.

Alternatively the compounds of formula (I-a-4) can be obtained by subjecting the interaction of 4-piperidine (XVI) with an ORGANOMETALLIC reagent of formula XIX, in which the M - group metal, such as lithium, halogenoalkane, magnolija and the like; and then when dehydrating the alcohol of formula XX, for example, by treating the corresponding acid, for example hydrochloric or sulfuric acid.

m L-N I-a-4

ORGANOMETALLIC reagent (XIX) it is convenient to get subjecting the interaction of the corresponding diarylethylene with metal, such as lithium or magnesium, in an inert in the reaction against a solvent such as, for example, a simple ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,2-dimethoxyethane and the like.

The compounds of formula I can also be transformed into each other by methods known in the field of transformation of functional groups. The amino group can be alkilirovanii or allievate in accordance with is-alkylation and the like methods. For example WITH1-C6-alkyl or Ar (aminocarbonyl) and similar groups, you can enter subjecting the interaction of the starting amine with an appropriate (C1-C6-alkyl or Ar)isocyanate. The compounds of formula I containing an amino group substituted by the radical Ar-CH2can be subjected to hydrogenolysis, treating the parent compound with hydrogen in the presence of a suitable catalyst, palladium-on-charcoal, in a preferred variant in alcoholic medium.

A number of intermediates and starting materials in the following ways to obtain are known compounds which can be obtained in accordance with known in this field by the methods of obtaining the mentioned or similar compounds. Other intermediate compounds can be obtained in accordance with known in this field techniques for similar compounds.

Intermediate compounds of formula II in General can be obtained from the corresponding alcohol of formula XXI by treatment halogenosilanes reagent, such as, for example, halogen acid, such as hydrochloric or Hydrobromic acid; thionylchloride phosphorous acid, phosphorylchloride; metasolv, what, for example, methanesulfonate, 4-methylbenzenesulfonate and the like.

< / BR>
Intermediate compounds of formula XXI, where R5and R6together form a bivalent radical of formula (b-1) to (b-3) can generally be obtained by condensation of intermediate compounds of formula XXI-a, in which R5and R6is hydrogen with an appropriate alkylating reagent. For example, the reaction of N-alkylation of an intermediate of compound (XXI-a) 1,2-dihalomethane or 1,3-dialogprepare, can give those intermediate products, in which R5and R6together form a radical ethandiyl (XXI-b-I) or propandiol (XXI-2).

< / BR>
Intermediate compounds of formula XXI-b-3 can be obtained by condensation of (XXI-a), where R5and R6together hydrogen,- haloalkene or aldehyde (XXII), where R11and R12each independently represent hydrogen, C1-C6-alkyl or phenyl, in the presence of an appropriate base or acid

l

Intermediate compounds of formula XXI-b-3, XXI-b-4 can also be obtained by condensation correspondingly substituted 2-aminoimidazole (X' = CR12or 2-aminotriazole (X' - N) formula XXIII in which R11and R12each independently represents Wollaston (XXIV) in the presence of an activating reagent, such as halogenide reagent. In some cases, the hydroxy-group can be converted in situ halide group, directly thus obtaining an alkylating agent of formula II.

R +R3_______< / BR>
In the intermediate compounds of formula XXI-b-5 and XXI-b-6 can be obtained by condensing hydrazine derivative (XXV), respectively, with haloalkenes or aldehyde (XXII) and complex orthoevra (XXVI), where R11and R12each independently represents hydrogen or C1-C6-alkyl.

< / BR>
Monocyclic 2-aminopyridine formula XXI and hydrazine derivative (XXV) can be obtained from the corresponding mercaptopyrimidine (XXVII) by alkylation first to an intermediate alkylthiophene, then this alkylthiomethyl substitute for, respectively, Amin R4R5NH or hydrazine R4NHNH2< / BR>
< / BR>
The experimental part.

A. Obtaining an intermediate product.

P R I m e R 1. a) To a stirred suspension of 90 hours 5-(2-hydroxyethyl)-2-mercapto-6-methyl-4-(3H)-pyrimidinone 320 hours of methanol add 90 hours 30%-aqueous solution of sodium methoxide. After stirring for 20 min add 72 hours iodomethane and stirred at a temperature of distillation for serout from ethanol, that gives 78 hours (78%) of 5-(2-hydroxyethyl)-6-methyl-2-(methylthio)-4-(3H)-pyrimidinone (intermediate compound (I).

b) a Mixture of 160 hours of intermediate compound I and 700 hours of monoacetate of methanamine distilled for 2 h, after cooling to 50aboutWith bubbled through the solution for 1 h, the Reaction mixture is cooled to 100aboutAnd poured it to 2000 hours of water with ice, add 100 hours of ammonium hydroxide. After 30 min, the solid product is filtered off, washed twice with 200 hours of water and twice with 80 hours of acetonitrile, dried, get 108,5 hours (74,0%) 5-(2-hydroxyethyl)-6-methyl-2-(methylamino)-3-(3H)-pyrimidinone (ex. cont.2).

(C) To a stirred mixture of 50,7 hours elapsed. cont.2, 31,8 including sodium carbonate and 376 including N,N-dimethylformamide simultaneously add 27,75 including 1-chloro-2-propane. The reaction mixture is stirred first for 2 hours at 100aboutC and overnight at room temperature. The precipitate is filtered off, the filtrate is evaporated. The residue is treated with 160 hours of acetonitrile. After cooling to 0aboutThe product is filtered and dewatered, receive 32 hours (48,5%) 5-(2-hydroxyethyl)-6-methyl-2-(methylamino)- 3-(2-oxopropyl)-4-(3H)-pyrimidinone (ex. cont.3).

A solution of 38.3 hours elapsed. cont.3 and 250 hours of acetic acid, saturated guide the Ute with 375 hours 48% solution of Hydrobromic acid in water. Everything is stirred for 5 hours at a temperature of distillation. After evaporation the residue is mixed with 400 hours and water was treated with 100 hours of ammonium hydroxide in the form of a solution. The precipitate is filtered off, washed with 40 hours of chilled ethanol and dried receive 34 hours (74,8% ) 6-(2-bromacil)-1,2,7-trimethyl-1H, 5H-imidazo(1,2-a)pyrimidine-5-it; so pl. 125aboutWith (ex. cont.4).

Similarly also prepare 6-(2-bromacil)-1,7-dimethyl-2-phenylimidazo(1,2-a) pyrimidine-5(1H)-he, so pl. 150aboutWith (ex. cont.5).

P R I m m e R 2. a) To a stirred mixture of 64 hours elapsed. cont.2, 80,6 including sodium carbonate and 329 including N,N-dimethylformamide add to 54.5 h 1-bromo-2-chlorethane. The reaction mixture is heated for 20 h at 100aboutC. After cooling, precipitated, is filtered off and the filtrate evaporated. The residue is extracted with 450 hours of trichlormethane. The extract is washed twice with 50 hours water, dehydrated, filtered and evaporated, get to 15.2 hours (20,8%) of 2,3-dihydro-6-(2-hydroxyethyl)-1,7-dimethyl-1H, 5H-imidazo(1,2-a)pyrimidine-5-it is in the form of rest (ex. cont.6).

b) a Mixture of 15.2 hours elapsed. cont.6, 32,4 hours of thionyl chloride and 300 hours of trichlormethane stirred for 2 h at the temperature of distillation. The reaction mixture Idro-1,7-dimethyl-1H, 5H-imidazo(1,2-a) pyrimidine-5-he monohydrochloride; so pl. 220aboutWith (ex. cont.7).

P R I m e R 3. a) a Mixture of 43 hours of benzoylmethylene and 77 hours elapsed. cont. 1 is stirred for 5 h at an oil bath at 150-160aboutC. After cooling, the precipitated product is stirred in water. The product is filtered, washed twice with water and crystallized from ethanol, get 78 hours (79%) of 5-(2-hydroxyethyl)-6-methyl-2-[(phenylmethyl)-amino] -4(3H)- pyrimidinone; so pl. 187,3aboutWith (ex. cont.8).

b) To a stirred suspension of 137 hours elapsed. cont.8 546 hours iodomethane add 90 including N,N-dimethylformamide. The mixture is stirred for 30 min at room temperature and add 71 including a 30% aqueous solution of sodium methoxide (exothermic reaction, the temperature rose from 22 to 40aboutC). The reaction mixture is stirred for 2 hours, the Reaction mixture is evaporated under reduced pressure and the residue treated with 1000 hours of water. The solid product is filtered off and crystallized twice: first from 80 hours of acetonitrile and then from 640 hours of acetonitrile. After cooling to 0aboutThe product is filtered and dehydrated, get 81,4 hours (59,6%) 5-(2-hydroxyethyl)-3,6-dimethyl-2-[(phenylmethyl)-amino]-4(3H)- pyrimidinone (ex. cont.9). Following por is Idasa(1,2-a)Piri-midin - 5(1H)-he monohydrobromide (ex. cont.10).

Following the method described in example 2, the intermediate product is converted into 5-(2-chloroethyl)-3,6-dimethyl-2-[(phenylmethyl)- amino]-4(3H)-pyrimidine-he monohydrochloride (ex. cont. 11).

P R I m e R 4. To stir the mixture from 67,7 including 2-amino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone and 800 hours of ethanol add 80 g sodium methoxide in the form of a 30% aqueous solution. The reaction mixture is heated at the temperature of distillation and added dropwise to 62.5 hours iodomethane. After complete addition, stirring is continued for 4 hours at a temperature of distillation. The reaction mixture is evaporated the residue is suspended in 400 hours of water. The precipitated product is filtered, washed with 40 hours of ethanol and dehydrated, get 58,3 hours (79,6%) 2-amino-5-(2-hydroxyethyl)-3,6-dimethyl-4-(3H)-pyrimidinone (ex. cont.12).

Following the procedure described in example 2, the intermediate product 12 is transformed into 2-amino-5-(2-chloroethyl)-3,6-dimethyl-4(3H)-pyrimidine-he monohydrochloride (ex. cont.13). In a similar way also get 2-amino-5-(2-chloroethyl)-3-ethyl-6-methyl-4(3H)-pyrimidine-he monohydrochloride (ex. cont. 14) and 2-amino - 5-(2-chloroethyl)-6-methyl-3-propyl-4(3H)-PI rimidine-he monohydrochloride (ex. cont.15).

P R I m e R 5. a) a Mixture of 200 hours is stirred for 5 hours at a temperature of distillation. After cooling, the reaction mixture is evaporated under vacuum and the residue is solidified in the mixing process in a mixture of ethyl acetate and 2,2-oxybisethane (1:1 by volume). The solid product is filtered off, the filtrate is separated, washed with 2,2-oxybisethanol and dried receive the first fraction of 134 hours (45,9%) of 2-(acetylamino)-1,2-dihydro-1,4-dimethyl-6-oxo-5 - pyrimidinecarbonitrile (ester). The filtrate, which is separated, cooled at -10aboutC. the Precipitated product is filtered and dried, to get the second fraction of 156 hours (53,4%) of 2-acetylamino-1,2-dihydro-1,4-dimethyl-6-oxo-5 - pyrimidinecarbonitrile (ester). Total yield: 190 hours (99,3%) of 2-acetylamino-1,2-dihydro-1,4-dimethyl-6-oxo-5 - pyrimidinecarbonitrile - ester (ex. cont. 16).

b) to 19.8 hours 50% dispersion of sodium hydride suspended twice in 64 hours petroleum ether. 50% dispersion of sodium hydride is stirred 94 including N, N-dimethylformamide in a nitrogen atmosphere. A mixture of 88,2 hours elapsed. cont.16 and 282 including N, N-dimethylformamide is added dropwise to the previous mixture at 15aboutC. After complete addition, stirring is continued for 30 minutes added dropwise 57 am, iodomethane at room temperature. The reaction mixture was stirred at 50aboutC for 10 minutes After olistostromes acid and everything is stirred for 3 hours at a temperature of distillation. All evaporated, the residue was washed with 300 hours of water and treated with ammonium hydroxide. The precipitated product is filtered, washed with 40 hours of acetonitrile, dried, get 35,7 hours (54,8%) 5-(2-hydroxyethyl)-3,6-dimethyl-2-(methylamino)-4(3H)-pyrimidinone (ex. cont.17).

Following the procedure described in example 2, the intermediate product 17 is transformed into 5-(2-chloroethyl)-3,6-dimethyl-2-(methylamino)-3(3H)-pyrimidinone monohydrochloride (ex. cont.18).

P R I m e R 6. 80,0 including the monohydrate of 1-methyl-1H-imidazol-2-aminoanisole - Yes boiled in 600 hours of phosphorylchloride. All cool and phosphorylchloride decanted. The solid residue is heated on a steam bath and add 49 p.m methylbenzol. After stirring for 30 min 78 hours 3-acetyl-4,5-dihydro-2(3H)-furanone added dropwise within 20 minutes After complete addition, stirring is continued for 18 hours the Mixture is cooled rapidly, gently add 200 hours of water. The mixture is treated with ammonium hydroxide to pH 8. The precipitated product is filtered off, washed and crystallized twice from a mixture of dichloromethane, methanol and 1,1-oxybisethane. The product is filtered, washed with 1,1-oxybisethane and dried, get 90,2 hours (76,2%) 6-(2-chloroethyl)-1,7-dimethyl-1H, 5H-imidazo(1,2-a)pyrimidine-5-it; so pl. 198,2aboutWith (pronate sodium and 135 hours N,N-dimethylformamide type of 33.5 hours 1-bromo-3-chloropropane. Stirring is continued overnight at 80-90aboutC. After cooling, the reaction mixture is filtered and the filtrate evaporated. The residue is cleaned using column chromatography (silica gel: CHCl3/CH3OH 98:2). Eluent of the desired fraction is evaporated and the residue crystallized from a mixture of methylbenzene and 2,2'-oxybisethane. The product is filtered and dried, receive 28 hours (44%) 6,7,8,9-tetrahydro-3-(2-hydroxyethyl)-2-methyl-9-(phenylmethyl)-4H - pyrimido(1,2-a) pyrimidine-4-it; so pl. 150aboutWith (ex. cont.20).

b) a Mixture of 10 hours intermediates 20 and 150 hours of 48% aqueous Hydrobromic acid is stirred for 6 hours at a temperature of distillation. The reaction mixture is evaporated and the residue is cleaned using column chromatography (silica gel: CHCl3/CH3OH 95:5). Eluent of the desired fraction evaporated and the residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried, get to 5.8 hours (50%) 3-(2-bromacil)-6,7,8,9-tetrahydro-2-methyl-4H-pyrimido(1,2-a)- pyrimidine-4-one of monohydrobromide; so pl. 223,3aboutWith (ex. cont.21).

(C) To a stirred mixture of 6 hours elapsed. Conn.20, 22 o'clock N,N-diethylethanamine added dropwise 75 hours trichloro throwaway and evaporated. The residue is crystallized from a mixture of 2-propanol and 2,2'-oxybisethane. The product is filtered and dried, get 4 hours (63% ) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9- (phenylmethyl)-4H - pyrimido(1,2-a)pyrimidine-4-it; so pl. 114,0aboutWith (ex. cont.22).

P R I m e R 8. a) To a stirred mixture of 9.2 hours intermediate compounds 2 and 56.4 including N,N-dimethylformamide successively added to 8.5 hours of a solution of sodium methoxide in 30% ethanol and 8.6 hours of iodomethane. After stirring for 2 h at 40aboutWith the solvent is evaporated and the residue is diluted with 50 hours of water. The product is extracted with trichloromethane (2 x 74,5 o'clock) and the combined extract is dried, filtered and evaporated, get to 8.5 hours (80,5%) 3-ethyl-5-(2-hydroxyethyl)-6-methyl-2-(methyl - amino)-4(3H)-pyrimidinone (ex. cont.23).

b) To a stirred mixture of 8.5 hours elapsed. cont.23 and 133 hours of trichlormethane type of 16.2 hours of thionyl chloride. After refluxing for 2 h, the reaction mixture was evaporated and the residue diluted with 100 hours of water. The solid residue is filtered off and washed with water. Increase the basicity of the mixture by the addition of ammonium hydroxide. After 1/2 h, the solid residue is filtered off and evaporated, get a 3.9 hours (42.4%) of 5-(2-chloroethyl)-3-ethyl-6-methyl-2-(metelli)-4(3H)-pyrimidinone (ex. cont.24).

P R I m e R 9. Under stirring and cooling to a 33.5 hours 1 propanamine slowly add 3,6 including acetic acid, keeping the temperature in the range from - 5 to 0aboutC. Then add an 80.2 hours elapsed. cont. 1, and the mixture is distilled for 2 hours After cooling, the reaction mixture is diluted with 300 hours water and add sodium hydroxide. Stirred over night at room temperature. The product is filtered, washed with acetonitrile and dried, get 63,4 hours (75,0%) 5-(2-hydroxyethyl)-6-methyl-2-(propylamino)-4(3H)-pyrimidinone (ex. cont.26).

b) To a stirred mixture of 63,4 hours elapsed. cont.26 and 376 including N,N-dimethylformamide add 51,0 including solution of sodium methoxide in methanol 30%, and after stirring for 1/2 h at room temperature 42,6 hours of iodomethane. Stirring is continued for 2 hours the Product is filtered water (2x) and acetonitrile and dried, get 37,6 hours (55,6%) 5-(2-hydroxyethyl)-3,6-dimethyl-2-(propylamino)- 4(3H)-pyrimidinone; so pl. 240aboutWith (ex. cont.27).

(C) To a stirred mixture of 36 hours elapsed. Conn.27 and 373 hours of trichlormethane added slowly to 48.6 hours of thionyl chloride. After refluxing for 2 h, the reaction mixture was evaporated. The residue is diluted with 300 hours of water to the mixture and DOB is revival and evaporated, the residue is triturated with acetonitrile. The product is filtered at 0aboutWith and dried, get to 34.8 hours (89,2% ) 5-(2-chloroethyl)-3,6-dimethyl-2(propylamino)-4(3H)-pyrimidinone; so pl. 150aboutWith (ex. cont.28).

Similarly elapsed. cont. 1 also converted into 5-(2-chloroethyl)-2-{ [(4-forfinal)methyl] amino} -3,6-dime - Tyl-4(3H)- pyrimidinemethanol (ex. cont.29); 2-butylamino-5-(2-chloroethyl)-3,6-dimethyl-4(3H)-pyrimidinone, so pl. 115aboutWith (ex. Conn.30); 5-(2-chloroethyl)-2-(ethylamino)-3,6-dimethyl-4(3H)-Piri - midine, so pl. 160aboutWith (ex. cont. 31).

Next, following the same procedures (2-d) methylamino-5-(2-hydroxyethyl)-6-methyl - 4(3H)-pyrimidinone converted into 5-(2-chloroethyl)-2-(dimethylamino)-3,6-dimethyl-4(3H)-pyrimidinone (ex. cont. 32); 5-(2-chloroethyl)-2-(dimethylamino)-6-methyl-3-propyl-4(3H)-pyrimidinone (ex. cont.33); 5-(2-chloroethyl)-2-(dimethylamino)-3-ethyl-6 - methyl-4(3H)-pyrimidinone monohydrochloride (ex. cont.34).

P R I m e R 10. a) a Mixture of 25 including 4-of methoxybenzylideneamino, 33 elapsed. Conn.2, 6,3 including acetic acid and 133,2 including 1,2-atendido stirred for 4 h at 150aboutTo add 39 PM 2-propanol and 9 o'clock sodium hydroxide. Stirring is continued for 15 min at 0-5aboutC. the Product is filtered, PR is imaginon; so pl. 180aboutWith (ex. cont.35).

b) a Mixture of 300 hours elapsed. cont.35, 6,5 including sodium hydroxide and 77,1 hours of dimethylsulfoxide is stirred for 1/2 h at 70aboutC. After cooling to 10aboutWith added dropwise 16 hours of iodomethane. All stirred over night at room temperature and then poured 200 hours of water. After stirring for 15 min the solid precipitate is filtered off, washed with water and dissolved in trichloromethane. This solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone at -10aboutC. the Product is filtered and dried, get 23 PM (72,5%) 5-(2-hydroxyethyl)-2-{[2-(4-methoxyphenyl)ethyl] amino} -3,6-dimethyl - 4(3H)-pyrimidinone; so pl. 210aboutWith (ex. cont.36).

(C) To a stirred mixture of 21 hours elapsed. cont.36 373 hours of trichlormethane added dropwise to 40.5 hours of thionyl chloride. After refluxing for 1 h and then cooling the reaction mixture is evaporated. The residue is stirred in acetonitrile at 40aboutC. the Product is filtered and dried, get 21 PM (85,6%) 5-(2-chloroethyl)-2-{[2-(4-methoxyphenyl)ethyl]- amino} -3,6-dimethyl-4(3H)- pyrimidinemethanol; so pl. 185aboutWith (ex. Conn.37).

Similarly also receive 5-(2-chlore e R 11. a) a Mixture of 80 hours elapsed. cont.1, 23 hours methylhydrazine and 372 hours 2-ethoxyethanol stirred for 7 hours at a temperature of distillation and for 8 h at room temperature. After cooling to 0aboutThe product is filtered, washed with acetonitrile (2x) and dried receive 65 hours (82,0% ) 5-(2-hydroxyethyl)-6-methyl-2-(1-methylhydrazino)-4(3H)-pyrimi-Winona; so pl. 180aboutWith (ex. cont.39).

b) To a stirred and heated mixture (40about(C) from 63,4 including intermediate 39, 36,2 including sodium carbonate and 470 including N,N-dimethylformamide is added slowly to 33.3 hours 1 chlorpropamide. Stirring is continued for 4 h at 110aboutWith and for 8 h at room temperature. The reaction mixture is filtered and the filtrate evaporated. The residue is dissolved with acetonitrile. The product is filtered, washed with acetonitrile and dried, get 38 PM (50,3%) 1,4-dihydro-7-(2-hydroxyethyl)-1,3,8-trimethyl-6N-pyrimido[2,1 - c] [1,2,4]triazine-6-it; so pl. 140aboutWith (ex. cont.40).

(C) To a stirred mixture of 2,35 hours elapsed. cont.40 and 74,5 hours of trichlormethane add to 4.9 hours of thionyl chloride. After refluxing for 2 h, the reaction mixture was evaporated and the residue triturated with acetonitrile. The product is filtered and dried, receive 2.5 hours (98,1%) 7-(2-HLR> P R I m e R 12. a) To a stirred mixture of 9,9 hours elapsed. cont.39, 7,41 including triethoxysilane and 94 including N,N-dimethylformamide add 3 drops of formic acid. Stirring is continued over night at 100aboutC and for 3 h at 140aboutC. the Reaction mixture is evaporated and the residue triturated with acetonitrile. The product is filtered and dried, get to 6.8 hours (65,3%) 6-(2-hydroxyethyl)-1,7-dimethyl-1,2,4-triazolo[4,3-a] pyrimidine-5(1H)- it; so pl. 215aboutWith (ex. Conn.42).

b) To a stirred mixture of 22.9 hours elapsed. Conn.42 596 hours of trichlormethane add simultaneously 32,4 hours of thionyl chloride. After refluxing for 2 h, the reaction mixture was evaporated and the residue triturated with acetonitrile. The product is filtered at 0aboutAnd dry, get the 5.7 hours (99,8%) 6-(2-chloroethyl)-1,7-dimethyl-1,2,4-triazolo[4,3-a] pyrimidine-5(1H)-he monohydrochloride; so pl. 260aboutWith (ex. cont.43).

Similarly also receive 6-(2-chloroethyl)-1,3,7-trimethyl-1,2,4-triazo - lo[4,3-a]pyrimidine-5(1H)-he; so pl. 140aboutWith (ex. cont.44).

P R I m e p 13. a) a Mixture of 74,7 h 1-acetyl-4-(4-perbenzoic)piperidine, 46,5 h 1,2-ethanediol, 3 hours 4-methylbenzenesulfonate and 810 hours of benzene is stirred for 108 hours at a temperature of distillation using water Sep'a. the odes. The organic layer is dried, filtered and evaporated. The residue is cleaned using column chromatography (silica gel; CHCl3/CH3COCH350:50). Eluent of the desired fraction evaporated, get 50 hours (56,8%) of 1-acetyl-4-[2-(4-forfinal)-1,3-dioxolane - 2-yl]piperidine (ex. cont.45).

b) a Mixture of 5 hours elapsed. cont.45 and 100 hours 10% sodium hydroxide is stirred overnight at a temperature of distillation. After cooling, the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is stirred in 2,2'-oxybisethane. The product is filtered and dried in vacuum at 40aboutWith, get 3.5 hours(82%) 4-[2-(4-forfinal)-1,3-dioxolane-2-yl]piperidine (ex. cont.46).

(C) a Mixture of 33 G. of ethyl-4-bromobutyrate, 41 hours elapsed. cont.46, 35 including sodium carbonate and 200 hours of 4-methyl-2-pentanone stirred for 6 hours at a temperature of distillation. After cooling, the reaction mixture is filtered and the filtrate evaporated. The residue is cleaned using column chromatography (silica gel; CHCl3/CH3OH 97:3). Eluent of the desired fraction evaporated, get 59 PM (98%) of ethyl 4-[2-(4-forfinal)-1,3-dioxolane-2-yl]-1 - piperidineacetate (ex. cont.47).

d) To a stirred and cooled (ice bath) mixture and smeshivanie continued for 1 h at 0aboutC and overnight at room temperature. The reaction mixture is evaporated and the residue is placed in water. This solution is neutralized with acetic acid and extracted with 2,2-oxybisethanol. The extract is dried, filtered and the residue is crystallized from 2,2'-oxybisethane receive 4 hours (28%) ethyl-4-[2-(4-forfinal)-1,3-dioxolane-2-yl] --hydroxy - methylene)-1-piperidinemethanol; so pl. of 116.7aboutWith (ex. cont.48).

e) To a stirred mixture of 7.2 hours thiourea, 20 g sodium methoxide in the form of a solution in 30% methanol and 160 hours of methanol are added 20 hours elapsed. Conn. 48. Stirring is continued for 4 hours at a temperature of distillation. The reaction mixture is evaporated and water is added to the residue. All acidified with acetic acid and extracted with chlormethine. The extract is dried, filtered and evaporated, and the residue is crystallized from 2-propanol. The product is filtered and dried, receive 16 PM(70%) 5-{2-[4-(2-/4-forfinal/-1,3-dioxolane-2-yl)-1-piperidinyl] ethyl} - 2-mercapto-4-pyrimidinediamine (1:1); so pl. 182aboutWith (ex. Conn.49).

f) To a stirred suspension of 14 hours elapsed. Conn.49 160 hours of methanol add 11 o'clock solution in 30% methanol of sodium methoxide and after stirring for 1/2 h to 4.5 h of iodomethane. Mixing food is extracted with dichloromethane and the extract is dried, filtered and evaporated. The residue is cleaned using column chromatography (silica gel; CHCl3/CH3OH 15:5). Eluent of the desired fraction evaporated and the residue is crystallized from 2-propanol. The product is filtered and dried, receive 10 PM(80%) 5-{2-[4-(2-/4-forfinal/-1,3-dioxolane-2-yl)-1-piperidinyl]ethyl}-2- (methylthio)-4-pyrimidine; so pl. 206,1aboutWith (ex. cont.50).

g) a Mixture of the 10.8 hours elapsed. cont.50 and 3.2 hours of benzoylmethylene stirred for 2 h at 190aboutC. After cooling, the precipitate is filtered off and crystallized from 2-propanol, get 11,3 PM(94%) 5-{2-[4-(2-/4-forfinal/-1,3-dioxolane-2-yl)-1 - piperidinyl] ethyl} -2- (phenylmethyl)amino-4-pyrimidone; so pl. 245,4aboutWith (ex. cont.51).

B. obtain the final compounds.

P R I m e R 14. A mixture of 5,6 including intermediate compounds 18, 7,3 hours 4-[bis(4-forfinal)methylene] piperidineacetate - Mead, 8,5 including sodium carbonate, 0.1 to including potassium iodide and 200 hours of 4-methyl-2-pentanone is stirred overnight at a temperature of distillation. Hot reaction mixture is filtered, the filtrate evaporated. The residue successively triturated with acetonitrile and recrystallized from 4-methyl-2-pentanone. The product is filtered and dried, get to 6.4 hours(68,9% ) 5-{2-[4-(Ni 39).

P R I m e R 15. A mixture of 11 hours elapsed. Conn. 13,9 h 3-(1-piperazinil)-1,2-benzisoxazole, 5 g sodium carbonate, 5 g sodium bicarbonate, and 0.2 g potassium iodide and 160 hours of 1-butanol is stirred for 12 hours at a temperature of distillation. The reaction mixture was hot filtered and the filtrate evaporated. The residue is crystallized from a mixture of acetonitrile and 2-propanol. The product is filtered and dried under vacuum at 100aboutTo receive 14 hours (84,4% ) 2-amino-5-{ 2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinil]-3,6 - dimethyl-4(3H)-pyrimidinone; so pl. 201,2aboutFrom (57).

P R I m e R 16. A mixture of 2 hours elapsed. cont.41, 1,5 hours 3-(1-piperazinil)-1H-indazole, 2 tsp of sodium carbonate, 0.1 to including potassium iodide, 81 including 1-butanol and 40 hours of 4-methyl-2-pentanone dephlegmator for 20 hours, the Reaction mixture was filtered while it was hot, and the filtrate evaporated. The residue is cleaned using column chromatography (silica gel; CHCl3/CH3OH 92:8). Eluent of the desired fraction evaporated and the residue crystallized from acetonitrile, get to 1.7 hours (57,8%) 1,4-dihydro-7-{2-[4-(1H-indazol-3-yl)-1-piperazinil] ethyl} - 1,3,8 - trimethyl-6N-pyrimido[2,1-c] 1,2,4 triazine-6-he; so pl. 198,6about(Part 116).

P R I m e R 17. A mixture of 4,4 hours elapsed. Conn.30, 3,3 including 6-fluoro-3-(4-piperidinyl)-1,2-benisons the ü is evaporated, and the rest put in 50 hours of water. The product is extracted with trichloromethane (2 x 74,5 hours) and combined extracts dried, filtered and evaporated. The residue is cleaned using column chromatography (silica gel; CHCl3/CH3OH 90:10). Eluent of the desired fraction is evaporated and the residue is converted into the hydrochloride salt (1: 2) in acetonitrile and 2-propanol. Salt is triturated with acetonitrile. The product is filtered and dried, get to 4.0 hours (51,8% ) 2-(butylamino)-5-{ 2-[4-(6-fluoro-1,2-Benzino-xazal-3-yl)-1-piperidinyl] ethyl} -3,6-dimethyl-4(3H)-pyrimidinethione; so pl. 265,7aboutWith (23).

P R I m e R 18. To a stirred mixture of 3 hours Conn.57 and 285 hours of trichlormethane simultaneously add 2 hours of isocyanatobenzene. The mixture is heated at the temperature of distillation, cooled and evaporated. The residue is crystallized from acetonitrile. The product is filtered and dried, get 4 hours (100%) N-{5-[2-(4-/1,2-benzisoxazol/3-yl)-1-piperazinil]-ethyl}-3,4-dihydro - 3,6-dimethyl-4-oxo-2-pyrimidinyl-N-phenylace - guilt; so pl. 218,1aboutWith (58).

P R I m e R 19. A mixture of 2,5 hours Conn.36 and 43.2. hours of acetic anhydride is stirred for 4 hours at a temperature of distillation. The reaction mixture is evaporated and to the residue add 40 hours of water. All the process hydroc is atok crystallized from acetonitrile. The product is filtered at 0aboutWith and dried, get a 1.6 hours (59,1%) N-{ 5-[2-(4-bis-/4-forfinal/-methylene-1-piperidinyl)ethyl] -3,4-dihydro - 3,6-dimethyl-4-oxo-2-pyrimidinyl}ndimethylacetamide; so pl. 141aboutFrom (55).

Physico-chemical characterization of the obtained compounds are given in table.1-6.

Were conducted biological testing of the compounds according to the invention.

(C) Pharmacological examples.

Useful properties of strengthening sleep with compounds of the first sub-group, in which R1radical of formula (a-4) and X, can be clearly demonstrated using the following test procedures.

The test compounds on the strengthening of sleep in rats.

Under anesthesia with phenobarbital (50 mg/kg body weight) adult male rats Wistar rats weighing 240-260 g were implanted standard electrodes for recording the electroencephalogram (EEG), electrooculogram (EOG) and electromyograms. 8-10 days after the healing of surgical wounds and habituation to the recording conditions (12-hour cycle of light and darkness, the light was lit at 9 am) was initiated pharmacological test. Animals were injected with 0.04, 0,16, or 0.63 mg/kg of compound 39, dissolved in 1 mm tartaric acid, and injected parenterally in a period when there was a visually and classified as wakefulness (B), shallow sleep (NRS) with a slow wave deep sleep (G2) with a slow wave or paradoxical sleep (PS). The parameters of the sleep-wakefulness were analyzed for each of two consecutive four-hour periods following the introduction of drugs, and compared with the main line (the introduction of the medium in the same conditions). Sleep and wakefulness expressed as a percentage of the results of the records of the main line, which represented the values of two quantities of the main line on the animal. Statistical tests were carried out by t-test on dvuhhodovoy student test.

Introduction connections 39 (of 0.04 to 0.63 mg/kg) for one light period caused a dose-dependent enhancement of deep sleep deficit wakefulness, shallow sleep and paradoxical sleep over a period of 8 h, during which it is recorded. Significant effects were observed with increasing the very small doses. Changes in sleep and wakefulness occurred mainly during the first 4 h of the registration period after drug administration, but continued in the next 4 hours

As can be seen from the data table.7 strengthening of the connection 39 on the waves of deep sleep was due to a significant lengthening of the episodes deep with the species also decreased, while their duration tended to increase.

Comparison with the action of ritanserin.

The effect of doses of 6-{2-[4-(bis/4-forfinal/methylene)-1-piperidinyl]ethyl}-7-me - til-5H - thiazolo[3,2-a]pyrimidine-5-it, which from the outset is known as ritanserin (0.04 to 2.5 mg/kg) was tested previously on a separate group of 8 rats. The dose 0,63 mg/kg ritanserin caused a significant increase in G2 for 8 h at the expense of B, GS and PS. Conversely, doses between 0.04 and 0.16 mg/kg ritanserin not acted in a noticeable extent on the pattern of wakefulness, whereas the same dose of compound 39 caused a significant reaction of the sleep-wakefulness. Thus, compound 39 was effective at a dose 10 times lower dose of ritanserin. Moreover, the net reaction on the dose received when using the connection 39, but not ritanserin.

Useful neuroleptic properties of the second subgroup of compounds of formula I in which R1radical of formula (a-1), (a-2) or (a-3), and X is CH or X Is N, if R1radical of formula (a-2), and these compounds are given in table. 1,3,4 and 6, it can be clearly demonstrated using the combined test with apomorphine, tryptamine and norepinephrine in rats. Further, the activity of the target loadingdone damage caused by compound 48/80 in rats". Antihistamine activity can be demonstrated, for example, the results obtained in the test of "Protection of rats from mortality caused by compound 48/80". All tests were carried out in accordance with the described procedures, and the experimental data are given in table.8.

The following compositions are examples of typical pharmaceutical compositions in the form of unit dosages suitable for systemic application to warm-blooded animals in accordance with the present invention.

Active constituent (A. I.), which is used in all of these examples relates to a compound of formula I, pharmaceutically acceptable acid adduct or its stereochemical isomeric form.

Tematicheskie drops. 500 g of A. I. dissolved in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at 60-80aboutC. After cooling to 30-40aboutWith added 35 l of polyethylene glycol and the mixture well stirred. Then add a solution of 1750 g of saccharin sodium 2.5 l spices cocoa and polyethylene glycol as necessary up to a volume of 50 l with education solution somaticheskih drops containing 10 mg/ml A. I. the resulting solution is poured into appropriate containers.

The wall of water. In 3 l of this solution are dissolved first 10 g of 2,3-dioxabicyclo and then 20 g of A. I. the Latter solution is combined with the remaining part of the 1st solution and add 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 40 g of saccharin sodium are dissolved in 0.5 l of water and add 2 ml of raspberry essences and 2 ml essences gooseberry. The latter solution is combined with the 1st, add water as necessary up to a volume of 20 l, which gives somatic solution containing 5 mg A. I. teaspoon (5 ml). The resulting solution is poured into appropriate containers.

The capsule. 20 g A. I., 6 g of lauryl sulfate sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously stirred. The resulting mixture is subsequently filled into 1000 suitable hard gelatin capsules, each containing 20 mg A. I.

The coated tablets. A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K 90) about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sterotex). All of this choir is LASS="ptx2">

The application shell. To a solution of 10 mg of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 MLM 1,2,3-propantriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the 1st and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension (Opaspray K-1-2109) and all homogenized. Core tablets cover the thus obtained mixture in the apparatus for covering.

Injectable solutions. 1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate dissolved in about 0.5 l of boiling water for injection. After cooling to 50aboutIn the process of stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to room temperature and mixed with water for injections as necessary up to a volume of 1 l with obtaining a solution containing 4 mg A. I. 1 ml. of the Solution is sterilized by filtration (U S P. XVII p.811) and poured into sterile tanks.

The candles. 3 g A. I. dissolved in a solution of 3 g of 2,3-dioxabicyclo in 25 ml polyethylene glycol 400. 12 g of surfactant (SPAN) and TAROM. Thus the resulting mixture is cast into molds at 37-38aboutWith, you get a 100 suppositories each containing 30 mg A. I.

As a result of the tests (see table.7 and 8) found that the described derivatives of pyrimidinone have low toxicity and have serotoninergicheskoi, deaminations standard and antihistaminic activity. It was found that the effective amount entered in the body of the active ingredient is 0.01-4 mg/kg of body weight, according to a preferred variant, 0.04 to 2 mg/kg of body weight.

DERIVATIVES OF PYRIMIDINE-4-OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS AND SEROTONINOLITICASKIE, DOPAMINERELEASING AND ANTIHISTAMINE COMPOSITION BASED ON THEM.

1. Derivatives of pyrimidine-4-it General formula I

< / BR>
where Alk - C1- C4-alcander;

R3- C1- C4-alkyl;

R4is hydrogen;

R5is hydrogen, unsubstituted C1- C4-alkyl, C1- C4-alkyl, substituted phenyl, pyridinyl, C1- C4-alkylsulphonyl, C1- C4-alkylaminocarbonyl;

R6is hydrogen, C1- C4-alkyl

or

R4- C1- C4-alkyl, R5and R6together form bivale the
-N=CH (b - 4);

-N=CH-CH2- -(b - 5),

where one of the hydrogen atoms of these radicals (b - 3) and (b - 5) may be substituted C1- C4-alkyl and if X is CH, R1radical of the General formula

< / BR>
< / BR>
< / BR>
where R7is hydrogen, halogen;

B is oxygen or nitrogen in (a - 2);

B is oxygen or sulfur, or NH (a - 3)

and, if X is carbon, R1radical of the General formula

< / BR>
where R7is hydrogen or halogen,

and, if X is nitrogen, R1radical of formula (a - 2) where R7is hydrogen, halogen;

B is oxygen or nitrogen,

or their pharmaceutically acceptable salts.

2. Derived by p. 1 formula

< / BR>
or its pharmaceutically acceptable salt.

3. Serotoninoliticaskie, dopaminereleasing and antihistamine composition containing an active ingredient and an inert carrier, characterized in that as the active ingredient it contains derivatives of pyrimidine-4-it General formula

< / BR>
where Alk - C1- C4-alcander;

R3- C1- C4-Alcide;

R4is hydrogen;

R5is hydrogen, unsubstituted C1- C4-alkyl, C1- C4-alkyl, substituted phenyl, pyridinyl, C1- C4-SUB>4- C1- C4-alkyl;

R5and R6together form a bivalent radical of the formula

-CH2-CH2- (b - 1);

-CH2-CH2-CH2- (b - 2);

-CH=CH- (b - 3);

-N=CH- (b - 4);

-N=CH-CH2- (b - 5),

where one of the hydrogen atoms in the radicals (b - 3) and (b - 5) may be substituted C1- C4-alkyl and if X is CH, R1radical of the formula

< / BR>
< / BR>
< / BR>
where R7is hydrogen, halogen;

B is oxygen or nitrogen, (b - 2) or oxygen, sulfur or NH (a - 3), and if X is CH, R1radical of General formula

< / BR>
where R7is hydrogen, halogen,

and if X is nitrogen, R1radical of General formula (a - 2),

where R7is hydrogen, halogen, B is oxygen or nitrogen,

or their pharmaceutically acceptable salts in a quantity of 0.05 to 15.0 wt.%.

 

Same patents:

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find application in medicine

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to piperidine- and piperazine-substituted N-hydroxyformamides of the general formula (I) or their pharmaceutically acceptable salts wherein B represents phenyl group monosubstituted at 3- or 4-position with halogen atom or trifluoromethyl group or bisubstituted at 3- and 4-position with halogen atom (that can be similar or distinct); or B represents 2-pyridyl or 2-pyridyloxy-group monosubstituted at 4-, 5- or 6-position with halogen atom, trifluoromethyl group, cyano-group or (C1-C4)-alkyl; or B represents 4-pyrimidinyl group possibly substituted with halogen atom or (C1-C4)-alkyl at 6-position; X represents carbon or nitrogen atom; R1 represents trimethyl-1-hydantoin-(C2-C4)-alkyl or trimethyl-3-hydantoin-(C2-C4)-alkyl group; or R1 represents phenyl or (C2-C4)-alkylphenyl monosubstituted at 3- or 4-position with halogen atom, trifluoromethyl group, thio-group, (C1-C3)-alkyl or (C1-C3)-alkoxy-group; or R1 represents phenyl-SO2NH-(C2-C4)-alkyl; or R1 represents 2-pyridyl or 2-pyridyl-(C2-C4)-alkyl; or R1 represents 3-pyridyl or 3-pyridyl-(C2-C4)-alkyl; or R1 represents 2-pyrimidine-SCH2CH2; or R1 represents 2- or 4-pyrimidinyl-(C2-C4)-alkyl possibly monosubstituted with one of the following substitutes: halogen atom, trifluoromethyl, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, 2-pyrazinyl possibly substituted with halogen atom, or 2-pyrazinyl-(C2-C4)-alkyl possibly substituted with halogen atom. Also, invention describes a method for synthesis (variants) of compounds of the formula (I) and a pharmaceutical composition. Compounds can be used as inhibitors of metalloproteinases and useful in such morbidity states as inflammatory and allergic ones.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

12 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to amidines of formula (I) and to their derivatives, methods for making thereof and pharmaceutical compositions containing amidines of formula (I). According to said invention, amidines are applicable for inhibition of IL-8 induced chemotactic factor, and can be applied to produce medicine agents for treating psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and for preventing and treating injuries caused by ischemia and reperfusion.

EFFECT: higher clinical effectiveness.

7 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing formula I compounds and their salts, , where R1 is H or F; and Boc is tert-butoxycarbonyl. These compounds are useful as intermediate products during production of tryptase inhibitors.

EFFECT: invention also relates to intermediate products, which can be used when producing said compounds, as well as to methods of producing such intermediate products and their use in production of said compounds.

20 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general structural formula:

or to pharmaceutically acceptable salts, where Z denotes -O- or -CH2- or -CH2-CH2-; X1 denotes a covalent bond or -O-; Y1 denotes a covalent bond or C1-C10 alkylene, provided that Y1 is a covalent bond only when X1 denotes a covalent bond; R1 denotes a) (C3-C7)cycloalkyl or b) phenyl or heteroaryl, which is a monovalent heteroatomatic monocyclic radical ring containing 1-2 heteroatoms, independently selected from nitrogen and sulphur, possibly substituted with 1-3 groups, independently selected from fluorine, chlorine, bromine, (C1-C6)alkyl or (C1-C6)-alkoxy; R2 denotes -OC(O)(NH2), -OC(O)(NHR9), -NHC(O)OR9, -C(O)R9, -C(O)(NH2), -C(O)(NHR9) or -NHC(O)H, where R9 denotes a linear or branched C1-C5 alkyl or a linear or branched (C1-C5)alkoxyalkyl; R3 denotes H, C1-C5 alkyl, -NHC(O)R10 or OH, where R10 denotes C1-C3 alkyl, provided that when R3 denotes -OH, X1 is not O and R2-Y1-X1 is not -OC(O)(NH2), -OC(O)(NHR9), -NHC(O)OR9 or -NHC(O)H; -Q denotes

, where N and N are bonded by bonds denoted by a wavy line; R4 denotes H; R5 and R6 independently denote: a) H, (C1-C10)alkyl, (C4-C10)cycloalkylalkyl, hydroxylated (C4-C10)cycloalkylalkyl, halo(C4-C10)cycloalkylalkyl, (C1-C2)alkyl(C4-C10)cycloakylalkyl, (C4-C10)bicycloalkyl(C1-C3)alkyl, (C1-C5)alkoxy(C1-C5)alkyl; or a saturated heterocyclyl(C1-C3)alkyl, where the saturated heterocyclic ring is selected from 5-, 6- or 7-member heterocyclic rings which contain 1 heteroatom independently selected from N and O; or b) phenyl(C1-C2)alkyl, phenoxymethyl, each of which is possibly with 1-3 groups independently selected from fluorine, chlorine, (C1-C3)alkyl, (C1-C3)alkoxy; provided that both R5 and R6 are not H; G denotes NH2 or NHR7; R7 denotes (C1-C6)alkyl; or R5 and R7 together denote -CH2, -(CH2)2 or -(CH2)3, possibly substituted with 1-2 groups independently selected from (C1-C8)-alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl or (C1-C8)alkoxy. The invention also relates to compounds selected from the group, pharmaceutical compositions, a method for antagonising one or more aspartate proteases, as well as methods of treating aspartate protease-mediated disorders.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

35 cl, 33 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

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

12 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b can be similar or differ from each other, and each represents hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl or 4-10-member non-aromatic heterocyclic group, and R11a and R11b can be substituted with substituent selected from group of substituents A or group of substituents B, and R1 can be substituted with substituent selected from group of substituents A or group of substituents B; R2 and R3 represent hydrogen; R4, R5, R6 and R7 can be similar or differ from each other, and each represents hydrogen, halogen, C1-6 alkyl; R8 represents hydrogen or C1-6 alkyl; R9 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b have the same values as described above; n represents integer 1 or 2; and X represents group, represented by formula -C(R10)=, or nitrogen, where R10 represents hydrogen; where group of substituents A consists of halogen, hydroxyl and oxogroup; where group of constituents B consists of C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl, 3-10-member non-aromatic heterocyclic group, C1-6 alkoxy, 5-10-member heteroaryloxy, 4-10-member non-aromatic heterocyclic oxygroup and group represented by formula -T1-T2-T3, and each group in group of substitutes B can be substituted with substituent selected from group of substituents C, where T1 represents direct bond or C1-6 alkylene, T2 represents group represented by formula -NRT1-, T3 represents hydrogen or C1-6 alkyl, and RT1 represents hydrogen or C1-6 alkyl; and where group of substutuents C consists of hydroxyl, C1-6 alkyl, 3-10-member non-aromatic heterocyclic group and di-C1-6 alkylaminogroup, to pharmaceutical composition possessing anti-tumor activity, to inhibitors of: hepatocyte growth factor receptor, angiogenesis and cancer dissemination, as well as to anti-tumor medication.

EFFECT: obtaining novel compounds which demonstrate anti-tumor activity.

31 cl, 111 ex, 18 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula I, as well as to their diastereoisomers, enentiomers and/or pharmaceutically acceptable salts, which possess inhibiting action with respect to cyclin-dependent kinases and/or tyrosinekinases of VEGF receptor. In compound of general formula (I) Q stands for group where D, E, G, L, M and T in each case represent carbon, R1 represents hydrogen, halogen or CF3, R2 represents C1-C10-alkyl, which can optionally be disrupted with one group-C(O), C2-C10-alkinyl, C3-C10-cycloalkyl or phenyl, which is optionally substituted in one or more places in similar or different way by hydroxyl, halogen, C1-C6-alkoxy, C1-C6-alkyl, C3-C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl or -COR8, X represents oxygen, sulphur or group -NH-, R3 represents hydroxy, halogen, CF3 or C1-C6-alkoxy, m represents 0-4, R4 represents hydrogen or group -COR8, NO2 or -SO2R7, or represents C1-C10-alkyl or C3-C10-cycloalkyl, R5 represents C1-C10-alkyl, which can be optionally substituted in one or more places, in similar or different way, by hydroxyl or C3-C10-cycloalkyl, or C3-C10-cycloalkyl, R7 represents C1-C10-alkyl, which is optionally substituted by group trimethylsilanyl (TMS), R8 represents C1-C6-alkyl, C1-C6-alkoxy. Invention also relates to intermediate compounds.

EFFECT: compounds can be applied for obtaining medication intended for treatment of cancer, selected from Kaposhi's sarcoma, Khodgkin's disease, leukemia or solid tumour, such as carcinoma of mammalian gland, kung, large intestine or prostate gland, autoimmune disease, such as psoriasis, and/or proliferative diseases, such as hemangioma or angiofibroma.

21 cl, 3 tbl, 5 ex

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