The method of obtaining derivatives of n-arylpiperazine

 

(57) Abstract:

Usage: in medicine, as a hypnotic. The inventive products of the formula where Ar is phenyl, unsubstituted or substituted, pyridinyl, pyrazolyl, Q - diarylethene, 2,2-diarylethylene or 2,2-variety, where aryl means halogenfree or pyridinyl, n = 3 to 4, provided that Q cannot mean 2,2-di(halogenfree)ethyl, if the aryl means chologaster, and X - aminocarbonyl. Reagent 1: . Reagent 2: W-CH2-C(=O)-NH-Ar. Reaction conditions: inert organic solvent. 3 table.

The invention relates to the field of organic synthesis and the way to obtain new derivatives of N-oilpipe - rationalcanada.

Some of the derivatives of N-arylpiperazines are known and have been recommended as useful in protecting the heart from heart muscle damage caused by ischemia, anoxia and hypoxia.

In addition, some derivatives of N-arylpiperazines with alkyl substituents on piperazinovom remainder are described as coronary vasodilators (vasodilators), local analgesics (anestesiol), as a means of stimulating canTt way to obtain derivatives of N-arylpiperazines, having treatment of sleep disorders.

The invention relates to the production of new derivatives of N-arylpiperazines General formula

Q-(CH2)n___ NN ___CHNH_Ar

(I) where X is a C1-C4-alkyl, hydroxy-C1-C4-alkyl, aminocarbonyl, mono - and di-(C1-C4-alkyl)aminocarbonyl,

Ar is phenyl which can be substituted by up to three substituents, each independently selected from the group consisting of C1-C4-alkyl, C1-C4-alkyloxy-, halogen, C1-C4-alkylsulphonyl, di-(C1-C4-alkyl)aminocarbonyl, aminocarbonyl,1-C4-allyloxycarbonyl, nitro-, cyano-, amino-, mono - and di-(C1-C4-alkyl)-amino, (C1-C4-alkylsulphonyl) - amino-, (aminocarbonyl)-amino - and phenylmethoxy; pyridinyl which can be substituted by up to three substituents, independently selected from halogen and C1-C4-alkyl; pyrazolyl, optionally substituted with one, three times WITH1-C4-alkyl, or a radical of the formula

< / BR>
in which R3means alkyl WITH1-C4or halogen atom, and R4is hydroxyl or al which means diarylethene, 2,2-diarylethenes or 2,2-variety, where aryl - halogenfrei or pyridinyl, provided that Q is 2,2-di(haloethanol)-ethyl, if Ar is dialogforum and X - aminocarbonyl.

In the above definitions, the term "Galil" means fluorine, chlorine, bromine and iodine, and fluorine is preferred; the term "C1-C4-alkyl" refers to linear and branched saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1'-dimethylethyl, propyl, butyl.

The compounds of formula (I) receive N-alkylation of suitably substituted piperazine of the formula (II) with a reagent of formula (III)

Q-(C NN _ H + W__CH where Q, n, X and Ar have the above values, and W - detachable group, in an inert organic solvent.

Inert organic solvent can be, for example, aromatic hydrocarbons such as benzene, toluene, xylene and so on; low alkanol, for example methanol, ethanol, 1-butanol, and so forth; ketone such as acetone, 4-methyl-2-pentanon etc.; simple ether, e.g. 1,4-dioxane, diethyl ether, tetrahydrofuran, methoxyethanol etc.; polar aprotic solvent, for example N, N-dimethyl-adding the appropriate base, such as, for example, carbonate or bicarbonate of an alkali metal, sodium hydride or an organic base, such as, for example, triethylamine or N-(1-methylethyl)-2-propanamine, it may be appropriate to associate the acid that is released during the reaction. In some cases, it is appropriate to add iodide salts, preferably the alkali metal iodide. Somewhat elevated temperatures may increase the rate of reaction.

If necessary, the compounds of formula I restore when Ar is phenyl, substituted by a nitro-group, the corresponding aminosilane compounds by catalytic hydrogenation in methanol in the presence of platinum on coal or

conduct recovery N-alkylation of the compounds in the case where Ar is phenyl, substituted by a nitro-group, the corresponding mono - or di(C1-C4-alkyl) aminosilane compounds by treatment of the parent compounds WITH1-C4-alkanols or1-C4-alkanones in atmosphere hydrogen in the presence of platinum on coal or

dibenzyline connection when Ar is phenyl, substituted phenylmethoxy group, the corresponding replacement compounds ka is dinani in case when Ar is phenyl, substituted amino group, to obtain the corresponding1-C4-alkiloarylosylfoniany connection processing of the original connection allelochemical in the halogenated hydrocarbon in the presence of tretyogo amine or

make compounds in which Ar is phenyl, substituted amino group into the corresponding aminocarbonylmethyl compounds by reacting the parent compound with an alkali metal cyanate in an acidic aqueous solution and, if necessary, make new compounds of formula (I) into a therapeutically active non-toxic salt accession acid by treatment with a suitable acid.

All the above and subsequent transformations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified according to methodologies, in most cases known in this field.

Some of the intermediates and starting materials in the above ways to obtain are known compounds, while others are new. They can be obtained by known in the field methods of obtaining the above known or similarly to known compounds. Some of the techniques the floor is alsomany as such or in their salt form when joining acids. The latter can be conveniently obtained by processing the basic form of the corresponding acids, such as, for example, inorganic acids such as halomonadaceae acid, for example hydrochloric, Hydrobromic, etc., and sulfuric acid, nitric acid, phosphoric acid and so on; or organic acids, such as, for example, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylate (lemon). methansulfonate, econsultancy, benzene - sulfonic, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oxybenzone, 4-amino-2-oxybenzone and the like acids.

The use of compounds of formula (I) and their pharmaceutical acceptable salts accession acids obtained by the method of the present invention, based on their useful properties improve sleep. More specifically, they increase the total sleep, mainly by increasing melanomacrophage sleep and decrease awakening. This property is clearly proved by the results obtained from testing melanomacrophage sleep in dogs. Due to its ability to improve sleep is obvious, Thu the x sleep disorders.

An additional advantage is that the compounds of formula (I) show the above-mentioned properties to improve sleep during oral intake. In addition to their properties, improving sleep, the new compounds of formula (I) also have the same useful pharmacological properties, as already known compounds, namely, preferred compounds of this application, i.e., 3-(aminocarbonyl)-4-[4,4-bis(4-forfinal)butyl] -N-(2,6-dichlorophenyl)-1 - piperazineethanol, which in General is designated as miflin. These useful pharmacological properties include the ability to improve the perfusion of blood to the muscular tissue of the heart, protect the heart from heart muscle (myocardial) damage, protection against myocardial calcium overload and inhibition of nucleoside transport.

The compounds used in the method of the present invention, applied in the form of appropriate compositions.

To prepare the pharmaceutical compositions of the present invention, the effective amount of the compounds of formula (I) in primary or salt (accession acid) form, as the active component is mixed into a homogeneous mixture together with a pharmaceutically acceptable carrier, and Ariela.

Compounds according to the present invention can be considered toxic. Compound was administered to rats at a dose of 40 mg/kg For compounds NN 30, 31, 54, 86, 94, 114, 115, 123, 134 and 141-146 mortality is not observed. Therefore, the values of LD50for these compounds significantly higher than 40 mg/kg of body weight.

The following examples are intended to illustrate the present invention.

Unless otherwise noted, all listed in the description, parts are massive.

EXPERIMENTAL PART

A. Obtaining intermediates

P R I m e R 1. a) a Mixture of 51 am 1,1'-(5-bromo-1-penten-1-ilidene)-bis-[4-fervently] , 25,4 including hexahydro-3,3-dimethylimidazo-[1,5-a]-pyrazin-1(5H)-she, of 35.5 hours of triethylamine and 270 including N,N-dimethylformamide is stirred overnight at 70aboutC. After evaporation the residue is dissolved in chloroform. The organic layer is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel, use a mixture of chloroform and methanol (96:4 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, receiving 60 hours (94,0%) 7-[5,5-bis-(4-forfinal)-4-pentenyl] -hexa - hydro-3,3-dimethylimidazo[1,5-a]- pyrazin-1(5H)-it is in the form of residual interest is(5H)-she and 850 hours of 0.5 n hydrochloric acid is stirred for 2 hours at the boiling temperature under reflux. After cooling, the reaction mixture is treated with potassium carbonate. The reaction product is extracted with chloroform. The extract was dried, filtered and evaporated. The residue is purified pomoshyu column chromatography over to silicagel using a mixture of chloroform and methanol (95:5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from diethyl ether. The reaction product is filtered off and dried, getting to 29.5 hours (50%) of the monohydrate of 4-[5,5-bis-(4-forfinal)-4-pentenyl]-2-piperazin - carboxamide; so pl. 51,3about(Intermediate 1).

Similarly also receive:

4-[5,5-bis-(4-forfinal)-pentyl] -2-PI - presencebased (intermediate 2);

4-(5,5-diphenylmethyl)-2-piperazinyl - basamid (intermediate 3).

P R I m m e R 2. A mixture of 17.7 hours N-(4-chlorobutyl)-4-fluoro-N-(4-forfinal)aniline, 23,3 including 2-piperazinecarboxamide, to 17.6 hours of triethylamine and 300 hours 2-methoxyethanol stirred for 48 hours at 70aboutC. the Reaction mixture is evaporated and the residue is dissolved in water and a small quantity of methanol. The reaction product is extracted twice with dichloromethane. United the raffia over silicagel, using a mixture of chloroform and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction is collected and the eluent is evaporated. The residue is crystallized from a mixture of diisopropyl ether and acetonitrile (80:20 by volume). The reaction product is filtered off and dried, obtaining 12,82 PM(55,0%) 4-[4-[bis-(4-forfinal)-amino] -butyl]-2-piperazinecarboxamide-Mead; so pl. 67,4about(Intermediate 4).

Similarly also receive:

4-[3-[bis-(4-forfinal)-methoxy]-Pro-MPI]-2-piperazinecarboxamide as a residue (intermediate 5);

N, N-bis-(4-forfinal)-3-methyl-1-Pipa - resinbound as a residue (intermediate 6);

3-(aminocarbonyl)-N, N-bis-(4-perfe - nil)-1-piperazineethanol as a residue (intermediate 7);

4-[5,5-bis-(4-forfinal)-pentyl]-N-me-til-2-piperazinecarboxamide as a residue (intermediate 8).

P R I m e R 3. a) a Mixture 74,2 including 1,1'-(5-bromo-1-penten-1-ilidene)-bis-[4-fervently] that 43.8 hours 4-(phenylmethyl)-2-piperazinecarboxamide, 38,9 hours of triethylamine and 1350 including N,N-dimethylformamide is stirred for 20 hours at 70aboutC. the Reaction mixture is evaporated under vacuum and the residue is stirred in dichloromethane. Drop down the precipitate is filtered off. The filtrate is washed three times with 200 hours of water and once with 200 hours of diluted rest the AI over silicagel, using a mixture of chloroform and methanol (97:3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, get 58,9 hours (61.9%) of 1-[5,5-bis-(4-forfinal)-4-pentenyl]-4-(phenylmethyl)-2-piperazinyl - oxamide as a residue (intermediate 9).

b) a Solution 56,9 including 1-[5,5-bis(4-forfinal)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide 400 h of methanol hydronaut apparatus Parra and at the 50aboutUsing the 5 o'clock 10% palladium catalyst on charcoal. After absorption of computing the amount of hydrogen the catalyst is filtered off and the filtrate is evaporated under vacuum. The residue is dissolved in acetone and the content is acidified with a mixture of hydrochloric acid and 2-propanol. After adding diisopropyl ether pop-up liquid is decanted and the drop-down residue was stirred in diisopropyl ether. Precipitating the reaction product is filtered off and dissolved in water. After washing diisopropyl ether, the aqueous layer was treated with ammonium hydroxide and the product of the reactions is extracted with chloroform. The extract is washed with sodium chloride solution, dried, filtered and evaporated (under chloroform), receiving 35,2 hours (76,3%) 1-[5,5-bis-(4-forfinal)-pentyl]-2-piperazinecarboxamide in ve - teleperson as a residue (intermediate 11).

P R I m e R 4. a) In an ice bath cooled 580 hours 1 N. aqueous sodium hydroxide solution, and then add 44 PM 3-methyl-1-(phenylmethyl)-piperazine and 82.8 hours of tetrahydrofuran. The solution 27,13 including ethyl ester harpalinae acid in to 103.5 hours of tetrahydrofuran is added dropwise at a temperature of about 5aboutC. After complete addition, stirring is continued for 4 h in an ice bath. The reaction product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (99:1 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, receiving 55 PM (87,8%) ethyl ester of 2-methyl-4-(phenylmethyl)-1-piperazinyl - oil acid as a residue (intermediate 12).

b) a Mixture of 21 o'clock the ethyl ester of 2-methyl-4-(phenylmethyl)-1-piperazinecarboxamide acid and 200 g methanol hydronaut at normal pressure and at room temperature with 3 hour 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst hoteltravel and the filtrate is evaporated. The residue is distilled twice, getting 23 hours (100% ) of the ethyl ester of 2-methyl-1-piperaz)-pentyl]-pyridine, of 7.75 hours ethyl ester of 2-methyl-1-piperazinecarboxamide acid, 8.7 hours of triethylamine, 0,1 including potassium iodide and 198 including N,N-dimethylformamide is stirred for 40 hours at 70aboutC. the Reaction mixture is evaporated and the residue is dissolved in a mixture of water and sodium carbonate. The aqueous layer was extracted with chloroform. The extract is washed with sodium carbonate solution in water and with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (98:2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, receiving 18 hours (96,7%) ethyl ester 4-[5-(4-forfinal)-5-(3-pyridinyl)-pentyl]-2 - methyl-1-piperazinecarboxamide acid as a residue (intermediate 14).

g) a Mixture of 12 o'clock ethyl ester 4-[5-(4-forfinal)-5-(3-pyridinyl)-pentyl] -2-me-Teal-1-piperazinecarboxamide acid, 16 hours of potassium hydroxide and 128 hours of 2-propanol is stirred for 4 days at the boiling point under reflux. After cooling, the reaction mixture is evaporated. To the residue water is added and the mixture is evaporated to until all traces of 2-propanol will not be deleted (this is repeated twice). The remainder razvorot in water and the reaction product is extracted with dichloromethane. Extract payagala, using a mixture of chloroform and methanol, saturated with ammonia, (95:5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting 6,7 o'clock(67,6%) 1-[5-(4-forfinal)- 5-(3-pyridinyl)-pentyl]-3-methylpiperazin - on as a residue (intermediate 15).

Similarly receive

1-[5,5-bis-(4-forfinal)-pentyl]-3-me - teleperson (intermediate 16).

P R I m e R 15. a) To a stirred solution of 49.5 hours 3-methyl-1-(phenylmethyl)-piperazine in 1350 hours of chloroform are added dropwise a solution 63,3 including bis-(1,1'-dimethylethyl)-dicarbonate 150 hours of chloroform at room temperature. After complete addition, stirring is continued overnight at room temperature. The reaction mixture is washed with water, dried, filtered and evaporated, receiving 85 hours (100%) of tert-butyl methyl ether 2-methyl-4-(phenylmethyl)-piperazinecarboxamide acid as a residue (intermediate 17).

b) a Mixture of 85 hours tert-butyl ester 2-methyl-4-(phenylmethyl)-1-piperazinyl new acid and 400 hours of methanol hydronaut at normal pressure and at room temperature with 3 hour 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate viparis is).

C) a Mixture of 5 o'clock N-(4-chlorobutyl)-N-(4-forfinal)-3-pyridinecarboxamide, 2,77 including tert-butyl ester 2-methyl-1-piperazinecarboxamide acid, 1,58 including sodium carbonate and 94 including N,N-dimethylformamide is stirred for 40 h at 90aboutC. the Reaction mixture is evaporated and the residue is dissolved in water. The reaction product is extracted twice with dichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (96:4 by volume) as eluent. The first fraction is collected and the eluent is evaporated, getting 3,5 hours (57,2%) tert-butyl ether 4-{ 4-[(4-forfinal)-(3-pyridylcarbonyl)-amino] -butyl} -2-methyl-1-piperazinecarboxamide acid as a residue (intermediate 19).

g) In a mixed solution of 3.5 hours tert-butyl ester 4-{4-[(4-forfinal)-(3-pyridylcarbonyl)-amino] -butyl} -2-me - Teal-1-piperazinecarboxamide acid in 80 g methanol miss propulsiveness gaseous hydrogen chloride. The reaction mixture is stirred for 10 minutes at boiling temperature under reflux and evaporated. The residue is dissolved in water and the contents treated with a solution of ammonium hydroxide. The reaction product of EC is%) of N-(4-forfinal)-N-[4-(3-methyl-1-piperazinil)-butyl] -3-pyridinecarboxamide as a residue (intermediate 20).

Similarly receive

4-fluoro-N-[4-(3-methyl-1-piperazinil)- butyl]-N-(3-pyridinyl)-benzamide as a residue (intermediate 21).

P R I m e R 6. To mix and boiling under reflux the Grignard reagent, previously derived from 11,34 including methyl bromide in 135 hours of tetrahydrofuran and 2,87 including magnesium, are added dropwise a solution of 9,31 including ethyl ester 4-(phenylmethyl)-2-piperazinecarboxamide acid in 135 hours of tetrahydrofuran. After complete addition, the contents stirred and refluxed for 2 hours After cooling, the mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The content is treated with concentrated ammonium hydroxide. The layers are separated and the aqueous layer was extracted with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol, saturated with ammonia, (95:5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting to 2.7 hours (38,4%) d,d-dimethyl-4-(phenylmethyl)-2-piperidinemethanol as a residue (intermediate 22).

A mixture of 6.4 h d,d-dimethyl-4-(phenylmethyl)-2-piperazineethanol water and the contents treated with 50% sodium hydroxide solution. The reaction product is extracted twice with water, dried, filtered and evaporated, getting 5 hours (85,6%) 3-(1-methylethenyl)-1-(phenylmethyl)-piperazine as a residue (intermediate 23).

Following the methods described in example 6, intermediate 47 - 3-(1-methylethenyl)-1-(phenylmethyl)-piperazine, converted into 1-[5,5-bis-(4-forfinal)-pentyl]-3-(1-methyl - ethyl)-piperazine as a residue (intermediate 24).

P R I m e R 7. a) For mixed and subjected to boiling under reflux the Grignard reagent obtained previously on the basis of 280 hours of 1-bromo-4-fervently, 34,6 including magnesium and 392 hours of diethyl ether, added dropwise a solution of 116 including ethyl ester 5-bromopentanoate acid 392 hours of diethyl ether. After complete addition, stirring is continued for 4 hours at the boiling temperature under reflux. The reaction mixture is decomposed with a saturated solution of ammonium chloride and the reaction product is extracted with diethyl ether. The extract was dried, filtered and evaporated. The residue is ground to powder in hexane. Last decanted and the residue crystallized from hexane. The reaction product is filtered off and dried at room temperature, receiving 100 PM d-(4-bromobutyl)-4-fluoro-a-(4-forfinal) be the of methanol and 714 PM concentrated hydrochloric acid is stirred and refluxed for 5 hours, the Reaction mixture is cooled and the reaction product is extracted with diisopropyl ether. The extract was dried, filtered and evaporated, receiving 92 including 1,1'-(5-bromo-1-penten-1-or - den)-bis-[4-fervently] as a residue (intermediate 26).

C) a Mixture of 92 hours of 1,1'-(5-bromo-1-penten-1-ilidene)-bis-[4-fervently] and 400 hours of methanol hydronaut at normal pressure and at room temperature with 5 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, receiving 84 hours of 1,1'-(5-bromo-1-pentylidene)-bis-[4-fervently] as a residue (intermediate 27).

Following the same techniques additionally receive

1,1'-(5-bromo-1,1-pentanediyl)-bis-[4-method sebenza] - as a residue (intermediate 28).

P R I m e R 8. a) a Mixture of 4.8 hours of a 50% dispersion of sodium hydride and 250 hours of dimethylsulfoxide is stirred for 30 min at 60aboutC in nitrogen atmosphere. To a mixture of parts added at room temperature 21,45 hours (3-carboxypropyl)-triphenylphosphorane (exothermic reaction, the temperature rises from 24 to 32aboutC). After SeverEnergia add in parts of 10.05 PM (4-forfinal)-(3-pyridinyl)-methanol at room temperature. After complete addition, stirring is continued overnight at room temperature. The reaction mixture was poured into ice-cold water and the contents acidified with 36% hydrochloric acid to pH 2. The separated aqueous layer was washed twice with toluene and treated with concentrated ammonium hydroxide to a pH of 5. The reaction product is extracted twice with chloroform. The combined extracts dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (95:5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting to 6.3 hours (46,6% ) )E+Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-pentenol acid as a residue (intermediate 29).

b) a Mixture of 22 h (E+Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-pentenol acid, 8,0 hours of concentrated sulfuric acid 68,4 including 2,2-dimethoxypropane and 320 hours of methanol is stirred for 3 hours at the boiling temperature under reflux. After cooling, the reaction mixture is treated with methanol saturated with ammonia. The reaction mixture is evaporated and the residue purified by column chromatography over to silicagel using the best 10 PM (43,8%) of methyl ester of (E+Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-pentenol acid as a residue (intermediate 30).

C) a Mixture of 4.6 hours methyl ester (E+Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-pentene - howl acid, 1 tsp solution (4%) of thiophene in methanol and 200 hours of methanol hydronaut at normal pressure and at room temperature 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst hoteltravel and the filtrate is evaporated, getting 4 hours (95,3% ) methyl ester -(4-forfinal)-3-pyridinemethanol acid as a residue (intermediate 31).

g) To stir under a nitrogen atmosphere a mixture of 6 o'clock methyl ester -(4-forfinal)-3-pyridinemethanol acid and 67.5 hours of tetrahydrofuran are added dropwise 30 PM complex borane+dimethyl sulfide in tetrahydrofuran. After complete addition, stirring is continued for 20 h at boiling temperature under reflux. After cooling, is added dropwise cautiously add 60 hours of methanol. After complete addition, stirring is continued for 1 h at temperautre boiling under reflux. After evaporation, the residue is purified by column chromatography over to silicagel, the use of which, getting 4 hours (73,4% ) -(4-forfinal)-3-pyridinemethanol as a residue (intermediate 32).

d) To 4 o'clock -(4-forfinal)-3-pyridinemethanol in parts add 64 including chloride tiomila. After completion of the addition, stirring is continued for 2 hours at the boiling temperature under reflux. The reaction mixture is evaporated and the residue is dissolved in water. The content is treated with sodium carbonate. The reaction product is extracted twice with toluene. The combined extracts are washed with water, dried, filtered and evaporated, getting to 3.7 hours (100% ) 3-[5-chloro-1-(4-forfinal)-pentyl] -pyridine as a residue (intermediate 33).

P R I m e R 9. a) To a stirred and cooled (-20aboutC) a solution of 64 hours methyl ester (E+Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-pentenol acid and 540 hours of tetrahydrofuran, add 99 including 1M solution of sociallyengaged in tetrahydrofuran. After stirring for 15 minutes at this low temperature, the reaction mixture is decomposed with 70 hours a saturated solution of sodium/potassium salts of tartaric acid in water. Drop down the precipitate is filtered off and the filter is evaporated. The residue is purified by column chromatography (GHWP) over Seeley - kagelu using a mixture of chloroform and methanol)-5-(4-forfinal)-5-(3-pyridinyl)-4-penten-1-ol as a residue (intermediate 34).

The second fraction is collected and the eluent is evaporated, receiving 20 hours (34,8%) of (Z)-5-(4-forfinal)-5-(3-pyridinyl)-4-penten-1-ol as a residue (intermediate 35).

b) To 10 hours (E)-5-(4-forfinal)-5-(3-pyridinyl)-4-penten-1-ol is added dropwise with stirring to 160 hours of chloride taanila (exothermic reaction, the temperature rises to 45aboutC). After complete addition, stirring is continued for 2 h at room temperature. The reaction mixture is evaporated. The residue is dissolved in toluene and the solvent is evaporated again. The residue is solidified in diisopropyl ether. The reaction product is filtered off, dried, getting to 11.5 hours (94,4%) of hydrochloride (E)-3-[5-chloro-1-(4-forfinal)-1-pentenyl]-pyridine (intermediate 36).

Similarly get:

(Z)-3-[5-chloro-1-(4-forfinal)-1-Penta-Neil]-pyridine (intermediate 37);

(E)-2-[5-chloro-1-(4-forfinal)-1-Penta-Neil]-pyridine (intermediate 38).

P R I m e R 10. a) To a stirred solution of 60.3 hours (4-forfinal)-(3-pyridinyl)-methanol in 240 hours of methanol in parts add 17,1 g sodium borohydride. After complete addition, stirring is continued for 15 h at room temperature. The reaction mixture is evaporated and to the residue water is added. Then add medlinelike using 10 N. solution of sodium hydroxide and the reaction product is extracted three times (h and h, h) dichloromethane. The combined extracts dried, filtered and evaporated. The residue is converted into hydrochloric salt in 2-propanol at room temperature. The salt is filtered off and dried, obtaining 63 hours (87,6%) of the hydrochloride of d-(4-forfinal)-3-pyridinemethanol, so pl. 158,3about(Intermediate 39).

b) To a stirred and heated (50about(C) a mixture of 15 hours d-(4-forfinal)-3-pyridinemethanol, 3,4 including N,N,N-triethylmethylammonium chloride, 50 hours 50%-aqueous solution of sodium hydroxide and 135 hours of toluene are added dropwise 10 am, 1-bromo-3-chloropropane. After complete addition, stirring is continued for 4 hours Another portion of the 5 o'clock 1-bromo-3-chloropropane added and the contents stirred for 4 h at 50aboutC. After cooling to room temperature the reaction mixture was poured into ice water and the reaction product is extracted twice with toluene. The combined extracts washed with sodium carbonate solution, dried, filtered and evaporated. The excess 1-bromo-3-chloropropane distilled using an oil vacuum pump. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol, LF. (34,3%) of a mixture of 55% 3-[(3-chloropropoxy)-(4-forfinal)-methyl]-pyridine and 45% 3-[(3-chloropropoxy)-(4-forfinal)-methyl] -pyridine of monochlorohydrin as a residue (intermediate 40).

Similarly receive 1,1'-[(3-chloropropoxy)-methylene] bis[4-fluoro - benzene] as a residue (intermediate 41).

P R I m e R 11. To a stirred mixture of 28.2 including 3-of pyridinoline, 59 hours of triethylamine and 450 hours of toluene is added dropwise 39 PM acid chloride of 4-fermenting acid (exothermic reaction, the temperature rises to 40aboutC). After completion of the addition, stirring is continued for 2 hours at the boiling temperature under reflux. After cooling, the precipitated reaction product is filtered off and dissolved in chloroform. The organic layer is washed twice with water, dried, filtered and evaporated. The residue is suspended in diisopropyl ether. The reaction product is filtered off and dried, obtaining 52,3 hours (80,6%) 4-fluoro-N-(3-pyridinyl)-benzamide; so pl. 150,2about(Intermediate 42).

b) To a stirred solution of 21.6 hours 4-fluoro-N-(3-pyridinyl)-benzamide 235 including N, N-dimethylformamide added in portions 5,76 including 50% dispersion of sodium hydride in less than 25aboutC in nitrogen atmosphere. After stirring for those who nnuu the mixture is stirred for 3 h at 60aboutC. After cooling, the content was poured in 1000 hours of ice water and the reaction product is extracted twice with toluene. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (99:1 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting to 7.4 hours (24,1%) of N-(4-chlorobutyl)-4-fluoro-N-(3-pyridinyl)-benzamide as a residue (intermediate 43).

Similarly receive N-(4-chlorobutyl)-N-(4-forfinal)-3-pyridi - carboxamide residue (intermediate 44).

P R I m e R 12. a) a Mixture of 35 hours 4-fluoro-N-(4-forfinal)-aniline, 107 h of the acid chloride of 4-harpalani acid and 130 hours of toluene is stirred for 2 hours at the boiling temperature under reflux. The reaction mixture is washed with sodium chloride solution, dried, filtered and evaporated. The residue is distilled to remove the excess of acid chloride of 4-harpalani acid, receiving 47 PM (95,0%) 4-chloro-N,N-bis-(4-forfinal)-butanamide as a residue (intermediate 45).

b) To a stirred and cooled (0aboutC) a solution of 48 hours 4-chloro-N,N-bis-(4-forfinal)-butanamide in 108 hours of tetrahydrofuran, add 240 hours of solution is the atur, the reaction mixture is decomposed with 160 hours of methanol. After evaporation the residue is purified by column chromatography over to silicagel using a mixture of chloroform and petroleum ether (20: 80 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting 32,5 h (91,5%) of N-(4-chlorobutyl)-4-fluoro-N-(4-forfinal)-aniline as a residue (intermediate 46).

P R I m e p 13. To a mixed solution of 20 hours of 2,6-dimethyl-4-(phenylmethoxy)-aniline and 270 hours of toluene added in portions to 10.9 hours of acid chloride of 2-Chloroacetic acid (exothermic reaction, the temperature rises to 30aboutC). After complete addition, the reaction mixture was stirred for 1 h at boiling temperature under reflux. After cooling, the precipitated reaction product is filtered off and dried, obtaining 23,8% h (89%) of 2-chloro-N - [2,6-dimethyl-4-(phenylmethoxy)-phenyl] - ndimethylacetamide; so pl. 165,3about(Intermediate 47).

Similarly get:

ethyl ester of 3,5-dichloro-4-[(2-chloroacetyl)-amino]-benzoic acid, so pl. 182,0about(Intermediate 48);

N-(2-acetyl-4-nitrophenyl)-2-chlorate-Tamid, so pl. 161,5about(Intermediate 49);

3,5-dichloro-4-[(2-chloroacetyl)-amino]- N,N-dimethylbenzamide, so pl. 250,6about(Neil]-2-chloroacetamide (intermediate 52);

2-chloro-N-(2-chloro-3-pyridinyl)-aceta-MFA (intermediate 53);

2-chloro-N-(2,6-dichloro-3-pyridinyl)-AZE - Tamid (intermediate 54);

N-(3-acetyl-2,6-dimetilfenil)-2-chloro - ndimethylacetamide; so pl. to 131.4about(Intermediate 55);

2-chloro-N-(3,5-dimethyl-4-pyridinyl)-AZE - tamide monochlorohydrin (intermediate 56);

2-chloro-N-(4-methoxy-2,6-dimetilfenil) -ndimethylacetamide; so pl. 186,3about(Intermediate 57);

monochlorohydrin 2-chloro-N-(2,4,6-trimethyl-3-pyridinyl)-ndimethylacetamide); so pl. 200,0about(Intermediate 58);

monochlorohydrin 2-chloro-N-(5,6,7,8-tetrahydro-3-methyl-4-chinoline)-ndimethylacetamide (intermediate 59); 2-chloro-N-(3-chloro-2,5,6,7-tetrahydro-2-oxo-1H-1-pyridin-4-yl)-ndimethylacetamide (intermediate 60);

monochlorohydrin 2-chloro-N-[2,6-dichloro-4-(dimethylamino)-phenyl] -ndimethylacetamide (intermediate 61);

monochlorohydrin 2-chloro-[2,6-dichloro-4-[(1-methylethyl)-amino]-phenyl]-ndimethylacetamide (intermediate 62);

2-chloro-N-(tetrahydro-2-oxo-1H-1-PI-ri nden-4-yl)-ndimethylacetamide (intermediate 63);

N-(3-bromo-5,6,7,8-tetrahydro-2-methyl-4-chinoline)-2-chloracetamide; so pl. 203,0about(Intermediate 64).

N-(3-bromo-5-methyl-4-pyridinyl)-2-chlorine - R ndimethylacetamide (intermediate 65);

2-chloro-N-(3-chloro-5,6,7,8-tetrahydro-2-methyl-4-chinoline)-ndimethylacetamide; so pl. 196,4about(Intermediate 66);

2-chloro-N-(3,5-dichloro-4-pyridinyl)-AZE - Tamid (intermedi the Noli - Neil)-2-chloroacetamide (intermediate 69);

N-(3-bromo-6,7,8,9-tetrahydro-5H-cyclo - hepta-[b]-pyridine-4-yl)-2-chloroacetamide as a residue (intermediate 70).

P R I m e R 14. a) To a stirred solution of 50 hours 3-(phenylazo)-2,4-pentanedione and 35 hours of monochlorohydrin ethanamide in 711 hours of ethanol is added a solution of 8.5 g sodium 126 including ethanol. After stirring overnight at room temperature pull down the precipitate is filtered off and the filtrate is stirred for 2 days at room temperature. The mixture is evaporated and the residue diluted with 10% sodium hydroxide solution. The separated aqueous layer was extracted with toluene. The extract was dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (98:2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated with toluene, getting to 7.5 hours (13,8%) of 4,6-dimethyl-5-(phenylazo)-2-pyridylamine as a residue (intermediate 71).

b) a Mixture of 7.5 hours 4,6-dimethyl-5-(phenylazo)-2-pyridylamine and 200 hours of methanol hydronaut at normal pressure and at room temperature 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. About Semenovo ammonia (97:3 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting to 3.3 hours (72,8% ) of 4,6-dimethyl-2,5-pyridinediamine as a residue (intermediate 72).

C) To a stirred solution of 3.3 hours 4,6-dimethyl-2,5-pyridinediamine 30 PM acetic acid add up to 4.7 hours of acid chloride of 2-Chloroacetic acid at room temperature. The reaction mixture was stirred over night at room temperature. The reaction mixture is diluted with toluene and neutralized with sodium carbonate. The reaction mixture is filtered over diatomaceous earth and the filtrate is evaporated, getting to 2.6 hours (50,7%) of N-(6-amino-2,4-dimethyl-3-pyridinyl)-2-chloroacetamide as a residue (intermediate 73).

P R I m e R 15. A mixture of 20 hours N-(4-amino-2,6-dichlorophenyl)-ndimethylacetamide, 10 am, acetone, 2 h solution (4%) of thiophene in methanol, 400 hours of methanol, 5 g potassium fluoride and 18 hours of 2-propanol saturated with hydrogen chloride, hydronaut apparatus Parra and at the 50aboutWith the help of 2 hours 5% of a catalyst of platinum on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from acetonitrile. The reaction product is filtered off and dried, obtaining a 15.7 hours (66,7% ) of N-[2,6-dichloro-4-[(1-methylethyl)-amino] -Fe-Neil]-ndimethylacetamide (InterMedia (4%) of thiophene in methanol and 200 hours methanol hydronaut apparatus Parra and at the 50aboutWith the help of 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the reaction mixture is evaporated. The remainder hydronaut at normal pressure and at 50aboutWith in 6 hours of acetic acid. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from toluene. The reaction product is filtered off and dried under vacuum at 40aboutWith getting 10 hours (66,7%) of N-[2-acetyl-4-(dimethylamino)-phenyl]-ndimethylacetamide as a residue (intermediate 75).

P R I m e R 17. a) a Mixture of 15 hours N-hydroxy 6,7,8,9-tetrahydro-4-nitro-5H-cyclohepta -[in]-pyridine and 320 hours of methanol hydronaut at normal pressure and at room temperature 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue was stirred in diisopropyl ether. The reaction product is filtered off and dried, obtaining of 10.73 hours (91,8% ) 6,7,8,9-tetrahydro-5H-Cycloheptane-(in)-pyridine-4-amine as a residue (intermediate 76).

Similarly receive

5,6,7,8-tetrahydro-3-methyl-4-quinoline - min as ostad the ina 170 hours acetic acid is added dropwise 16 hours of bromine at room temperature. After complete addition, stirring is continued over night. The reaction mixture is evaporated and the residue is dissolved in water. The aqueous solution is treated with a solution of ammonium hydroxide and the reaction product is extracted twice with dichloromethane. The combined extracts dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol, saturated with ammonia (98:2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated, getting to 8.2 hours (51,5%) of 3-bromo-6,7,8,9-tetrahydro-5H-cyclohepta-(in)-pyridine-4-amine as a residue (intermediate 78).

Similarly get:

3-bromo-6,7-dihydro-5H-1-pyrindine-4-amine (intermediate 79);

3-chloro-5,6,7,8-tetrahydro-2-methyl-4-hee - alinamin (intermediate 80);

3-bromo-5,6,7,8-tetrahydro-4-quinoline - min (intermediate 81)

3-bromo-5,6,7,8-tetrahydro-2-methyl-4 - chinoline; so pl. 176,8about(Intermediate 82).

Relevant source materials for the specified technique described.

P R I m e R 18. A mixture of 9 o'clock 4-amino-N,N-dimethylbenzamide, 137 hours of concentrated hydrochloric acid and 90 hours of water is stirred in to the group of 4 h at room temperature. The reaction product is extracted three times with dichloromethane. The combined extracts dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (98:2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from diisopropyl ether. The reaction product is filtered off and dried, obtaining 5,78 hours (46%) of 4-amino-3,5-dichloro-N,N-dimethylbenzene-Yes; so pl. 134,2about(Intermediate 83).

P R I m e R 19. A mixture of 40 hours N-(3-acetyl-2,6-dimetilfenil)-ndimethylacetamide and 300 hours of concentrated hydrochloric acid re - mesilat for 20 h at boiling temperature under reflux. After cooling, the reaction mixture is treated with ammonium hydroxide. The reaction product is extracted twice with dichloromethane. The combined extracts are washed with water, dried, filtered and evaporated, getting to 35.5 hours (100%) 1-(3-amino-2,4-dimetilfenil)-ethanol as a residue (intermediate 84).

Similarly also receive:

1-[2-amino-5-(dimethylamino)-phenyl]- Etalon (intermediate 85);

3,5-dichloro-11-(1-methylethyl)-1,4-phenyl - Indiamen (intermediate 86).

P R I m e R 20. To 146,4 hours of concentrated sulfuric acid added is the stirring is continued overnight at room temperature. The reaction mixture is poured into 500 h of crushed ice with stirring. Precipitating the reaction product is filtered off and suspended in water. Precipitating the reaction product is filtered off, washed with water and suspended in 20 hours of acetonitrile. The reaction product hoteltravel, boiled for 20 hours of acetonitrile and filtered, after cooling, getting to 10.4 hours (61,6%) 3-acetyl-4-[(2-chloroacetyl)-amino-benzamide (intermediate 87).

B. obtain the final compounds.

P R I m e R 21. A mixture of 3.6 hours 1-[5,5-bis-(4-forfinal)-pentyl]-3-methylpiperazine, 3 o'clock N-(4-acetyl-2,6-dichlorophenyl)-2-chloracetamide, 1,9 hours of triethylamine and 45 o'clock N,N-dimethylformamide is stirred for 20 h at 70aboutC. the Reaction mixture is evaporated and the residue dissolved in a mixture of sodium carbonate and water. The reaction product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (98:2 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into hydrochloric salt in 2-propanol and diisopropyl ether. The reaction product is filtered off and dried under vacuum)-4-[5,5-bis-(4-forfinal)-pen - Tyl]-2-methyl-1-piperazinecarboxamide; etc., 176,3about(Compound 29).

P R I m e R 22. A mixture of 6.1 hours 1-[5,5-bis-(4-forfinal)-pentyl]-2-piperazinecarboxamide - Mead, 4,3 including monochlorohydrin 2-chloro-N-(2,4,6-trimethyl-3-pyridinyl)-acetamide", she 3,7 including sodium carbonate and 90 including N,N-dimethylformamide is stirred for 15 h at 70aboutC. the Reaction mixture is filtered, washed with N,N-dimethylformamide and the filtrate is evaporated under vacuum. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (92,5:to 7.5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is optionally purified by column chromatography over to silicagel using a mixture of chloroform and methanol (90: 10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into hydrochloric salt in acetone and 2-propanol. The salt is filtered off, washed twice with acetone and once with diisopropyl ether and dried over night at 100-110aboutWith getting to 6.58 PM (61,2% ) of the hemihydrate of trichlorohydrin 3-(aminocarbonyl)-4-[5,5-bis-(4-forfinal) -pentyl] -N-(2,4,6-trimethyl-3 - pyridinyl)-1-piperazinyl; so pl. 224,7about(Compound 58).

P R I m e R 23. The mixture 5,04 PM 4-[5,5-bis-(4-forfinal)-pentyl]-2-PIP is 4-methyl-2-pentanone is stirred and refluxed for 18 hours After cooling, the reaction mixture is washed with water. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (95:5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted into hydrochloric salt in acetonitrile and 2-propane - Les. Drop down the precipitate is filtered off and the filtrate is evaporated. The residue is dried at 80aboutWith getting 5,48 hours (71% ) monochlorohydrin 2-(aminocarbonyl)-4-[5,5-bis-(4 - forfinal)-pentyl] -N-(5-fluoro-2 - were)-1-piperazinecarboxamide; so pl. 148,2about(Compound 2).

P R I m e R 24. A mixture of 7 including 3-(aminocarbonyl)-4-[5,5-(4-forfinal)-pentyl] -N-(2,6 - dichloro-4 - nitrophenyl)-1-piperazineethanol, 1 h 4% solution of thiophene in methanol and 120 hours of methanol hydronaut apparatus Parra and at the 50aboutWith the help of 2 hours 5% platinum catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is converted into hydrochloric salt in 2-propanol and acetonitrile. The salt is filtered off and dried, obtaining of 5.55 PM (77,7%) trichlorohydrin 3-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4- [5,5-bis-(4-Ftotal-4-AMINOPHENYL)-4-[5,5 - bis-(4-forfinal)-pentyl]-2-methyl-1-piperazineethanol, 3 o'clock poly-(oxyethylene), 1 PM to 4% of a solution of thiophene in methanol and 120 hours of methanol hydronaut apparatus Parra and at the 50aboutWith the help of 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol (95:5 by volume) as eluent. The appropriate fraction is collected and the eluent is evaporated. The residue is converted into hydrochloric salt in 2-propanol and diisopropyl ether. The salt is filtered off and dried, obtaining 1,47 hours (25,1%) dichlorhydrate N-[2-acetyl-4-(dimethylamino)-phenyl] -4-[5,5-bis-(4-forfinal)-pentyl] -2-methyl-1-piperazineethanol, so pl. 122,0about(Compound 42).

P R I m e R 26. A mixture of 5.2 hours 4-[5,5-bis(4-forfinal)-pentyl]-N-[2,6-dimethyl-4-(Fe-dimetoxy)- phenyl]-2-methyl-1-piperazineethanol and 120 hours of methanol hydronaut at normal pressure and at room temperature 2 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue is converted into hydrochloric salt in acetonitrile and 2-propanol. Salt is 2,6-dimetilfenil)-2 - methyl-1-piperazinecarboxamide; so pl. 174,2about(Compound 20).

P R I m e R 27. To a stirred solution of 4.5 hours N-(2-acetyl-4-AMINOPHENYL)-3-(aminocarbonyl)-4-[5,5-bis-(4-forfinal) - pentyl]-1-piperazineethanol 60 hours of chloroform add 1,17 hours of triethylamine. The solution 0,78 including acid chloride of propionic acid in 45 hours of chloroform is added dropwise at room temperature (weak exothermic reaction, the temperature rises from 24 to 30aboutC. After complete addition, the contents stirred for 3 h at room temperature. The separated organic layer was washed with aqueous sodium carbonate solution and water, dried, filtered and evaporated. The residue is crystallized from acetonitrile. After cooling to 0aboutC, the reaction product is filtered off and dried under vacuum, first at the 50aboutAnd then at 100aboutWith getting 2,93 hours (57,7%) N-[2-acetyl-4-[(1-oxopropyl)-amino] -phenyl]-3-(aminocarbonyl)-4-[5,5 - bis-(4-forfinal)-pentyl]-1-piperazineethanol, so pl. 163,4about(Compound 17).

P R I m e R 28. To a stirred solution of 4.5 hours N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4-forfinal)-pentyl] -2-me - Teal - 1-piperazineethanol 60 hours of acetic acid is added dropwise a solution of 1.02 g potassium cyanate in 17 hours water. After d is the residue is dissolved in water. The content is treated with a solution of ammonium hydroxide and the reaction product is extracted twice with dichloromethane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over to silicagel using a mixture of chloroform and methanol, saturated with ammonia (96:4 by volume) as eluent. The second fraction is collected and the eluent is evaporated. The residue is suspended in diisopropyl ether. The reaction product is filtered off and dried, obtaining 2,49 hours (51,9% ) N-[4-[(aminocarbonyl)-amino]- 2,6-dichlorophenyl]-4-[5,5-bis-(4-forfinal)-pentyl] -2-me - Teal-1-piperazineethanol. so pl. 119,9about(Compound 35).

All other compounds listed in table.1 and 2, receive the same methods as described in examples 21-28, and the actual method of obtaining is shown in column 2 ("N example").

P R I m e R 29. The following compounds receive in accordance with techniques similar to those described in examples 21 and 22:

3-(aminocarbonyl)-4-[5,5-bis-(4-fluoro-phenyl)-4-pentenyl] -N-(2,6 - dichlorophenyl)-1-piperazineethanol; so pl. 150about(Compound 78);

3-(aminocarbonyl)-4-[5,5-bis(4-perfe - nil)of pentyl]-N-(2,6-dichloro-4-cyanophenyl)-1-piperazineethanol di is IP-(4-forfinal)- 4-pentenyl-1-piperazineethanol; so pl. 150about(Compound 80);

N-(4-acetyl-2,6-dichlorophenyl)-3-(amino - carbonyl)-4-[5,5-bis(4-forfinal) pentyl]-1-piperazineethanol the dihydrochloride; so pl. 181about(Compound 81);

3-(aminocarbonyl)-4-[5,5-bis(4-perfe - nil)of pentyl] -N-(2,4,6-trichlorophenyl)-1-Pipa - resinated the dihydrochloride, so pl. 175about(Compound 82);

3-(aminocarbonyl)-N-[4-(aminocarb-nil)-2,6-dishartened] -4-(5-(4- forfinal)-5-(3-pyridinyl)pentyl] -piperazineethanol trihydrochloride-dihydrate; so pl. 173about(Compound 83);

3-(aminocarbonyl)-4-[5,5-bis(4-perfe - nil)of pentyl] -N-(2-methoxyphenyl)-1-Pipera - sinated the dihydrochloride, so pl. 196about(Compound 84); 4-[5,5-bis(4-forfinal)pentyl]-N-(2,6-dimetilfenil)-2-(hydroxymethyl)-1-Pipa-romanogermanic, so pl. 237about(Compound 85);

4-[5,5-bis(4-ftorfyenil)-2-(dime - delamination)-N-(2,6-dimetilfenil)- 1-piperazineethanol the dihydrochloride, so pl. 165about(Compound 86);

(E)-N-(4-acetyl-2,6-dichlorophenyl)-3-(s - noncarbonyl)-4-[5-(4-forfinal)- 5-(2-pyridinyl)-4-pentenyl]-1-piperazineethanol; so pl. 138about(Compound 87); 4-[5,5-bis-(4-forfinal)-4-pentenyl]-3-[(methylamino)carbonyl] -N-(2,4,6 - trimetilfenil)-1-piperazineethanol; so pl. 131about(Compound 88);

N-(4-acetyl-2,6-dichlorophenyl)-4-[3-[(4-perfe is ine of 89); N-(4-acetyl-2,6-dishartened)-4-{3-[(4-forfinal)-(3-pyridinyl)-methoxy] propyl}-2-methyl-1-piperazinecarboxamide trihydrochloride-trihydrate; so pl. 171about(Compound 90).

P R I m e R 30. The mixture of 5.53 PM 4-[5,5-bis(4-forfinal)pentyl]-2-piperazinyl-oxamide, 3,4 including 3,5-dichloro-4-[(2-chloroacetyl)amino]-N,N-dimethylbenzamide, 1,98 including N,N-diethylethanamine and 90 including N,N-dimethylformamide is stirred for 20 h at 70aboutC. After evaporation the residue is placed in a solution of a small amount of sodium carbonate in water. The product is extracted twice with dichloromethane. The United extracts washed with water, dried, filtered and evaporated. The residue is purified column chromatography on silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction is collected and the eluent is evaporated. The residue is suspended in 2,2'-oxybisethane. The product is filtered and dried, obtaining of 2.25 hours (34,1%) of 2-(aminocarbonyl)-4-[5,5-bis-(4-forfinal) pentyl] -N-(2,6-dichloro)- 4-[(dimethylamino)carbonyl]phenyl-1-piperazinecarboxamide; so pl. 150,8aboutC.

C. Pharmacological examples

Useful for improving the sleep of the properties of the compounds of formula (I) used in the method of the present invention may be the R> Fourteen adult dogs bloodhounds mass 15,20,79 kg were implanted with cortical and deep (powerful) electrodes. Minimum period of 4 weeks elapses between implantation and study dogs. During this period of time they have been adapted to the sound and lighted cell. The behavior of the dogs was monitored with a closed circuit television system.

Account shestnadtsatietazhnogo sleep were made from 15.00 to 07.00 hours the First 3 hours were recorded on paper and the entire 16-hour period was analyzed by computer. Visual and computer analyses were made at 30-second periods, which were classified on bissonnet, go to sleep, easy medlennovolnovoj sleep, deep medlennovolnovoj sleep and sleep with rapid eye movement (REM-sleep). One of the cortical branch (left fronto-occipital), mediated (ammonul horn of the brain), electromyogram (EMG) and electrooculogram (EOG) were analyzed line-by-line using the computer DDR 11/23. Energy (power) spectral analysis using fast Fourier transformation was done on the fronto-occipital branch every 30 sec.

Was calculated capacity (power) of the frequency bands (0.5 to 3.5 Hz), Q (3.5 to 7.5 Hz and fusiform activity EMG and EOG-amplitude. On the basis of these parameters was made automatic classification sleepy stage, using the method of minimum distance Electroencept. clin. Neurophysiol, 46 (1979) 33-48.

The compounds of formula (I) were given to animals orally at doses of 0.16 and 0.63 mg/kg, only preceding the beginning of the countdown. Table 4 shows the average percentage difference melanomacrophage sleep with the control (equivalent to 0% ), based on the duration of steps (phases).

The METHOD of OBTAINING DERIVATIVES of N-ARYLPIPERAZINE General formula I

Q-(CH2)n___ NN ___CHNH_Ar< / BR>
where X - C1- C4-alkyl, hydroxy-C1- C4-alkyl, aminocarbonyl or mono - or di-(C1- C4-alkyl)aminocarbonyl;

AG - phenyl, which can have up to three substitutes independently selected from the group consisting of C1- C4-alkyl, C1- C4-alkyloxy, halogen, C1- C4-alkylsulphonyl, aminocarbonyl, di-(C1- C4-alkyl)aminocarbonyl,1- C4-allyloxycarbonyl, nitrocine-, amino-, mono - and di-(C1- C4-alkyl)amino, C1- C4-alkylsulphonyl(amino), (aminocarbonyl)amino - and phenylmethoxy, pyridinyl, to whom was Salil, substituted one-triple C1- C4-alkyl, or a radical of General formula

< / BR>
where R3- C1- C4-alkyl or halogen;

R4is hydroxyl or1- C4-alkyl;

S-3 or 4 - integer;

-(CH2)n- bivalent radical, in which N=3 or 4 integer;

Q - diarylethene, 2,2-diarylethenes or 2,2-variety, where aryl - halogenfrei or pyridinyl, provided that Q cannot mean 2,2-di(halogenfree)ethyl, if Ar - dehalogenans;

X - aminocarbonyl,

or their pharmaceutically acceptable acid additive salts, characterized in that the piperazine of General formula II

Q-(CH2)n___ NN _ H

where Q, n, and X have the above values,

subjected to interaction with the compound of General formula III

W-CH2--NH-Ar

where W is tsepliaeva group,

in an inert organic solvent and, if necessary, restore the compounds of formula I, where AG is phenyl, substituted by a nitro-group, the corresponding aminosilane compounds by catalytic hydrogenation in methanol in the presence of platinum on coal or conduct restoration N-alkylation of compounds of formula I, where AG is phenyl, substituted ampute connection processing WITH1- C4-alkanols or1- C4-alkanones in hydrogen atmosphere in the presence of platinum on coal or dibenzyline the compounds of formula I where Ar is phenyl, substituted by phenylmethoxy, obtaining relevant hydroxylamine compounds by catalytic hydrogenation in methanol in the presence of palladium on coal or conduct N-acylation of compounds of formula I where Ar is phenyl, substituted amino group, to obtain the corresponding1- C4-alkiloarylosylfoniany compounds by treating compound allelochemical in the halogenated hydrocarbon in the presence of a tertiary amine, or make connections, where Ar is phenyl, substituted amino group into the corresponding aminocarbonylmethyl compounds by the interaction of the compound with an alkali metal cyanate in an acidic aqueous solution and, if necessary, convert the compound of formula I in a therapeutically active non-toxic salt accession acid by treatment with a suitable acid.

 

Same patents:

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with 1,2-diaminepropane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 44-52 hours. Yield of target product is 73-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

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EFFECT: improved method of treatment, enhanced and valuable medicinal properties of compounds.

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FIELD: medicine; cosmetology.

SUBSTANCE: invention contains antiperspirant, continuous phase and structure-forming agent containing cyclic depeptide derivative, method of production thereof, method of hidropoiesis prevention or reduction, derivative of cyclic depeptide and gel base for antiperspirant.

EFFECT: compositions have higher activity.

46 cl, 10 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

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