The method of obtaining azetidinone derivative or its pharmaceutically acceptable salt

 

(57) Abstract:

Usage: as anti-allergic and anti-asthma drugs. The inventive product is azetidinone derivative of the formula I with certain values radicals. Reagent 1: compound of formula I, where R3H. Reagent 2: connection R3X, where R3specified, X is a halogen atom. Reaction conditions: followed, if necessary, conversion of the group R3any other value group R3table 2. Connection structure f-ly I

The invention relates to a new series of tetracyclic compounds having two or three nitrogen atoms included in the ring, which have significant anti-allergic and anti-asthma activity, provides methods and compositions for their use, as well as technologies of their production.

The compounds of this invention can be generally described as dibenzothiazepine or production benzodiazepines.diazepam. Some compounds of this type are known [1-4] and have different activity, including antidepressanta activity and antihistaminew activity. Compounds referred to earlier and which have antiallergic aktse, than it would be desirable for use as a commercial product, and often has side effects such as irritation or Central nervous system depression. It would therefore be desirable to develop therapeutic agents that, together with the manifestation of a great antihistaminic, anti-allergic and anti-asthma activity, also would have no adverse reactions, such as depression or irritation of the Central nervous system. The invention describes a new series of tetracyclic compounds that do not contain these shortcomings.

The compounds of this invention possess excellent antihistaminas, anti-allergic and anti-asthma activity without such adverse reactions as drowsiness, and moreover show inhibitory effect on secretion (slow reacting substances of anaphylaxis).

Compounds of the invention correspond to the formula I

R (I)

where Q represents a nitrogen atom or a group of the formula-CH-; R1and R2are the same or different and each represents a hydrogen atom or halogen atom; R3is a substituted alkyl group containing from 2 to 6 carbon atoms is s-R4(where R4represents a hydrogen atom, or alkyl group containing from 1 to 4 carbon atoms), groups of formula-NR5R6(where R5and R6defined below) and groups of the formula OCONR5R6(where R5and R6defined below), a group of the formula [CH2CH2O]nCH2R8in which n is 1-3, R8represents the hydroxymethyl group of the formula-R4(where R4defined above) or a group of the formula-CONR5R6(where R5and R6defined below); a group of the formula E-O-G-COOR4in which E represents alkylenes group containing from 2 to 6 carbon atoms; G is a group containing from 1 to 3 carbon atoms, and R4is as defined above; R5and R6are the same or different and each represents a hydrogen atom, an unsubstituted alkyl group containing from 1 to 4 carbon atoms, cycloalkyl group having 3-7 carbon atoms in the ring; a phenyl group; benzyl group; 2-dimethylaminoethyl or 2-[4-(n, n1-diferensial)piperazine derivatives] ethyl, or R5and R6together with the nitrogen atom to which they are attached, represent morpholino group or 4-n - chlorobenzylidene the x salts, however, therapeutic use requires that they be pharmaceutically acceptable. When they are intended for non-therapeutic use, i.e. as intermediate compounds in the technology for other and perhaps more active compounds, these limitations do not exist. Compounds of the invention include some of the basic nitrogen atoms and can, thus, to form the acid salt. Examples of such additional salts include salts with mineral acids such as hydrofluoric acid, Hydrobromic acid, itestosterone acid, hydrochloric acid, nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts of lower alkylene acids, such as methanesulfonate, triftoratsetata, or econsultation; if arylsulfonate, such as benzene acid or p-toluensulfonate; salts with organic carboxylic acids, such as formic acid, tartaric acid, oxalic acid, maleic acid, succinic acid or citric acid; and salts with amino acids, such as glutamic acid or aspartic acid. Also, the compounds can contain free carboxyl groups and in atimeline metals, such as sodium, potassium, lithium, barium, calcium or magnesium, and salts of organic bases, such as salt dicyclohexylamine.

Compounds of the invention necessarily contain several asymmetric carbon atoms in the molecules and thus can form optical isomers. Although all of the compounds presented here the same molecular formula, the invention includes both the individual isolated isomers and mixtures, including the racemates. The individual isomers can be obtained directionally using techniques stereospecific synthesis or by using as starting material an optically active compounds, on the other hand, if the mixture of isomers, an individual isomers can be obtained by standard methods.

Compounds of the invention can be obtained by various commonly known methods of preparing compounds of this type. In General, one method involves the reaction of the compound corresponding to formula II

R (II)

(in which R1, R2and Q presented earlier), with a compound corresponding to the formula III

R3X (III)

(in which R3previously defined and X is a halogen atom, p , in any other appropriate group defined for R3. The reaction is normally and efficiently in the presence of a base or of an inert solvent.

No significant restrictions on the nature of the bases used in this reaction, provided that it performs the function of deactivating agent and has no side effects on other parts of the molecule. Examples of preferred bases include: organic amines, such as triethylamine, methylmorpholine, pyridine, 4-(, -dimethylamino) pyridine, , -dimethylaniline and 1,8-diazabicyclo (5.4.0)undec-7-ene (DBu), and bases, including carbonates of alkali metals, alkaline earth metals, bicarbonates and hydroxides, such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and barium hydroxide. One of them we preferred carbonates of alkali metals and hydroxides of alkali metals.

No significant restrictions on the nature of the solvent used, provided that it has no adverse effect on the reaction or on the incoming reactants. Examples of suitable solvents include alcohols, such as methanol, ethanol and propanol, ketones such as acetone, 2-butanol, 4-methyl-2 - pentanon, and amides, OS is stitely. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical in this invention. In General, it was found that the reaction can be carried out at temperatures from 0 to 150aboutWith (most preferably 60-140aboutC). The reaction time can also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents. However, if the reaction takes place in the preferred conditions described above, it usually takes from 3 to 20 hours the Reaction can be carried out in the presence of small quantities of iodides of alkali metals, such as sodium iodide or potassium iodide, which can function as a catalyst.

The compounds obtained by this technology, can be isolated from the reaction mixture by standard methods. For example, the compounds can be isolated by removal of the solvent from the reaction mixture or, if necessary, after removal of the solvent from the reaction mixture, pouring the residue into water and then extragere it with not miscible with water, an organic solvent and finally distillation of the solvent from the extract. Moreover, if necessary, the resulting residue can be further about hromatograficheskaja methods especially column chromatography or better thin-layer chromatography.

Those compounds of formula (I) in which R3is an alkyl group having a carboxy Deputy or a group with formula E-O-G-COOH (in which E and G are described above), i.e., carboxylic acids, can be obtained by hydrolysis of the corresponding compounds in which R3is an alkyl group having a Deputy with the formula-OOR4aor is a group of formula-E-a-G-COOR4a(in which E and G are defined previously and R4ais an alkyl group having 1-4 carbon atoms). The hydrolysis may be carried out in the usual way, for example by reaction of the corresponding ester with a base in an inert solvent.

There are no significant requirements on the nature of the bases used in this hydrolysis reaction, and any common base in reactions of this type may also be used provided that it does not have an adverse impact on other parts of the molecule. Examples of suitable bases include carbonates of alkali metals such as sodium carbonate or potassium carbonate, hydroxide of alkaline or alkaline-earth metals such as lithium hydroxide, sodium hydroxide, guide CIS potassium, the most preferred. No significant restrictions on the nature of the solvent used, provided that there is no adverse effect on the reaction or on the other reagents. Examples of suitable solvents include: alcohols, such as methanol, ethanol or propanol; ketones, such as acetone, 2-butanone or 4-methyl-2 - pentanon, and ethers, such as dioxane or tetrahydrofuran. Of these the most preferred alcohols. The reaction can be carried out in a wide range of temperatures and the precise reaction temperature is critical in the invention. In General, it was found that the reaction takes place in the temperature range from 0 to 120aboutWith (more preferably 0-80aboutC). The reaction time also can vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, assuming that the reaction takes place at the preferred conditions outlined above, the reaction time is 1-10 hours

The compounds thus obtained can be isolated from the reaction mixture by ordinary methods. For example, the reaction mixture may be concentrated by distillation of the solvent or, if necessary, after removal of the solvent from the reaction mixture, the residue is poured into water, and aq is realem, after that, the desired compound can be obtained by distillation of the solvent from the extract. Additionally, if desired, the product can be further purified various well-known methods, such as recrystallization, pereosazhdeniya or various chromatographic methods, especially column chromatography or preparative thin-layer chromatography.

Compounds of General formula (II) are well known or can be obtained according to the method similar to the known methods described, for example, Filer et al. J. Org. Chem, 46, 3344 (1981); C. A. A. van Boeekel et. al. Red Trav. Chim. Pays. Bas, 104, 259 (1985); u A. Org. Lee et. al. J. Heterocyclic Chem. 20, 1565 (1983).

Similarly, the source materials of the formula (III) are known or can be obtained by methods known to get known similar compounds. However, the compound of formula (III), where R3is a group of formula-E-O-G-COOR4in which E and R4as described earlier, and G is alkilani group having 1-3 carbon atom, i.e. a compound of formula (III), the alternative can be obtained by the following reaction: X E OH + X1G1COOR4____ X E O G1COOR4< / BR>
In the above formulas, R4E, G1and X previously described and X1is the atom Ganja or solvent. There are no significant requirements to the nature of the used grounds, provided that it does not have an adverse impact on other parts of the molecules or reagents, and any base commonly used for reactions of this type may also be used here. Examples of suitable bases include hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride, alkali metals such as sodium, potassium, carbonates of alkaline or alkaline-earth metals such as lithium carbonate, sodium carbonate, potassium carbonate and barium carbonate, hydrogenated carbonates, such as hydrogenated sodium carbonate and hydrogenated potassium carbonate, alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, and organic amines, such as triethylamine, pyridine, 4-dimethylaminopyridine and DBu. Of these hydrides of alkali metals and alkali metals are preferred.

No significant restrictions on the nature of the solvent used, provided that it has no adverse effect on the reaction or on the reagents. Examples of suitable solvents include aliphatic hydrocarbons, such as pentane and hexane, alicyclic hydrocarbons such as qi is the ether, tetrahydrofuran and dioxane, amides, especially amides of fatty acids, such as dimethylformamide and dimethylacetal, and ketones, such as acetone, retaliation and methylisobutyl ketone. One of these solvents or a mixture of one or two of them may be used. Of them prefer aliphatic hydrocarbons, cyclic hydrocarbons, aromatic hydrocarbons, ethers, and amides. The reaction can be carried out in a wide range of temperatures, and the precise reaction temperature is not critical in this invention. In General, it was found that it is convenient to conduct the reaction at temperatures from -110aboutWith up to 130aboutC, more preferably at 50aboutWith up to room temperature, and even more preferably with increasing temperature increments from -50 to -20aboutC, -10 to +10aboutC and at room temperature. However, the preferred reaction temperature depends on the nature of the source material. The reaction time also varies widely depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under the preferred conditions set forth above, the reaction takes place within 1 to 20 hours (more preferably 1-6 hours). After completion of the reactions reduced pressure, if necessary, after removal of the insoluble phase by filtration or by adding to the precipitate, by extraction with water-immiscible organic solvent, and at the end of the distillation of the solvent. After that, if desired, the product can be purified by such conventional techniques as recrystallization or the various chromatography techniques, particularly preparative thin-layer chromatography or column chromatography.

The compound of formula (III), where R4is a hydrogen atom can be obtained by hydrolysis of esters of formula (III), where R4is R4asimilar to that described previously.

Geterometallicheskie compounds of the invention have, as shown in the data on the biological activity than antihistaminas and antiallergic activities and excellent inhibitory activity against receipt of SRS-A. Accordingly, the compounds are used as therapeutic agents for the treatment or prevention of allergic diseases or asthma.

Compounds of the invention can thus be used in the treatment of such ailments, and for these purposes may be molded as a convenient pharmaceuticals.

P R I m e R 1. Ethyl ester 2-(1, 2, 3, 4, 10, 14C - hexahydrobenzo (C, f) - pyrazino (1,2-a)azepine-2-yl) toxicmonkey acid.

To 80 ml of 4-methyl-2-pentanone add 2.5 g 1, 2, 3, 4, 10, 14C - hexahydrobenzo (C, f(pyrazino) 1,2-a)azepine, 2.4 g of ethyl ester of 2-chlorethoxyfos acid (obtained as described in method 1 or 2), 3,82 g of sodium carbonate and 0.14 g of sodium iodide, and the mixture is boiled in a vessel under reflux for 18 hours then the mixture is filtered and the solvent removed from the filtrate by distillation under reduced pressure. The residue is subjected to separation on a chromatographic column filled with silica gel, thus obtaining faction buervenich with ethyl acetate, 3.2 g (yield 84%) of target compound in the form of butter, light brown. IR spectrum (CHCl3),maxcm-1: 1495, 1750, 2830, 2950. To a solution of the target compound in ethanol add equimolecular quantity of oxalic acid, and the mixture is stirred at room temperature for 30 minutes then the solvent is removed by distillation under reduced of Lavinia 141-144aboutC.

P R I m e R 2. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)toxicsuse acid.

To a solution of 3.2 g of ethyl ester 2-(1, 2, 3, 4, 10, 14C - hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 1) in 20 ml of ethanol, add 7 ml of 10 wt./about. an aqueous solution of sodium hydroxide and 10 ml of water. The mixture was then stirred at room temperature for 1 h, after which the mixture is evaporated to half of its original volume by distillation under reduced pressure of 10 wt./about. an aqueous solution of hydrochloric acid, and the mixture is extracted with chloroform. The concentration of the extract by evaporation under vacuum gives 2,96 g (quantitative yield) of the target compound in the form of a foamed substance, which is recrystallized from water, getting colorless needles with a melting point 135aboutC (with decomposition).

IR-spectrum (KBR)maxcm-1: 1426, 1450, 1491, 1602, 2820, 2940.

According to the method described in example 1, and then get the following salts of this connection:

sodium salt with a melting point of 140-145aboutC (decomposition);

fumarate with a melting point 187-188aboutC (decomposition);

oxalate with thegradient (s, f) - pyrazino (1,2-a)azepine-2-yl)toxicmonkey acid.

3A. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino (1,2-a)azepine-2-yl)ethanol.

To 30 ml of ethanol is added 2 g 1, 2, 3, 4, 10, 14C - hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine, 0.84 g of 2-chloroethanol, to 3.09 g of potassium carbonate and 0.13 g of sodium iodide, and the mixture is boiled in a vessel under reflux for 16 hours then the mixture is filtered, and the solvent removed from the filtrate by distillation under reduced pressure, obtaining of 1.81 g (yield 77%) of the named compound with a melting point of 123-125aboutC. IR spectrum (KBr),maxcm-1: 1446, 1491, 2810, 3300, 3380.

The hydrochloride of this compound with a melting point 252-254aboutC (with decomposition) are obtained by the procedure similar to that described in example 17.

This compound can be obtained according to the methods presented in the following examples 3b and 3C.

3V. Ethyl ester(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)acetic acid.

To 20 ml of 4-methyl-2-pentanone add 0,546 g 1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine, 0,436 g ethyl ester bromoxynil acid, 0,692 g of sodium carbonate and 0,016 g of sodium iodide, and the mixture is boiled in a vessel with a reverse holdingdisk by evaporation under reduced pressure. The resulting residue is then subjected to separation on a chromatographic column filled with silica gel, using as eluent a mixture of hexane and ethyl acetate, taken in a volumetric ratio of 4:1. You get 0,602 g (yield 82%) of the named compound in the form of oil pale yellow color. The hydrochloride of this compound with a melting point 187-190aboutCan be obtained by the method similar to the methods described in example 17, the IR-spectrum (KBR)maxcm-1: 1450, 1550, 1600, 1745, 2870, 2950.

3C. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino (1,2-a)azepine-2-yl) ethanol.

Suspension 0,251 g sociallyengaged in 20 ml of tetrahydrofuran for 10 minutes added to a cooled with ice to a solution 2,22 g ethyl ester(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)acetic acid obtained by the method similar to that described in example 3b in 15 ml of tetrahydrofuran in a nitrogen atmosphere. The mixture of nitrogen was stirred at 0aboutC for 30 min and for 2 h at room temperature, then add 2 ml of a saturated aqueous solution of ammonium chloride. The mixture is filtered, and the filtrate is extracted with ethyl acetate. The extract is washed with water and concentrated by evaporation under in milovy ester 2-(1, 2, 3, 4, 10, 14-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)toxicmonkey acid.

0,478 g 55 wt./wt. dispersion of sodium hydride in mineral oil is added to a solution of 1.5 g 2-(1, 2, 3, 4, 10, 14C - hexahydro - dibenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)ethanol (obtained as described in stage a or C in 20 ml of toluene in a nitrogen atmosphere). The mixture is then stirred at 40aboutC for 2 hours and then add 0,924 g methyl ester bromoxynil acid, cooling the mixture with ice, and then stirred at 40aboutEven within 4 hours After the reaction the mixture is filtered, the filtrate is concentrated by evaporation under reduced pressure. The residue is subjected to separation on a chromatographic column filled with silica gel, using as eluent a mixture of hexane and ethyl acetate, taken in a volumetric ratio of 1:1. You get a gain of 0.58 g (yield 31%) of the titled compound as oil. IR-spectrum (l3),maxcm-11450, 1495, 1600, 1655, 2820, 2950, 3000.

According to the method described in example 1, this compound can be obtained fumarate with a melting point 135aboutC (with decomposition).

P R I m e R 4. Ethyl ester of 2-(3-chloro-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino (1,2-a)azepine-2-yl) e is 3, 4, 10, 14b-hexahydrobenzo (C, f) - pyrazino (1,2-a)azepine named compound are obtained from the output 52% IR spectrum (l3),maxcm-1: 1490, 1600, 1745, 2820, 2950.

Following the procedure described in example 1, receive oxalate named compound with a melting point 191-192aboutC (with decomposition).

P R I m e R 5. Methyl ester of 2-(3-bromo-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid.

Following a methodology similar to that described in example 1, but utilizing 8-bromo-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine and methyl ether 2-chloroperoxidase acid, the named compound are obtained from the output 33%

IR-spectrum (l3),maxcm-1: 1455, 1490, 1715, 1760, 2850, 2975.

Following the procedure described in example 1, also receive oxalate named compound with a melting point of 183-185aboutC (with decomposition).

P R I m e R 6. 2-(2-hydroxyethoxy)ethyl-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine.

Following the procedure described in example 1, but using 2-(2-hydroxyethoxy)ethylchloride named compound are obtained from the output 65%

IR-spectrum (l3), maxcm-1: 1455, 1500, 1600, 2850, 2960.

commuting).

P R I m e R 7. 2-(2-/2-hydroxyethoxy)ethoxy)ethyl-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine.

Following the procedure described in example 1, but using 2-(2-(2-hydroxyethoxy)ethoxy)ethylchloride named compound are obtained from the output 83%

Following the procedure described in example 1, also get oxalat with a melting point 82-85aboutC (with decomposition).

P R I m e R 8. Methyl ester 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C)pyrazino(1,2 a)pyrido(5,6-C) azepin-2-yl)toxicmonkey acid.

Following the procedure described in example 1, but using 1, 2, 3, 4, 10, 14C-hexahydrobenzo(C)pyrazino(1,2-a)pyrido (1,2-a)pyrido(5,6-C)azepine and methyl ether 2-chloroperoxidase acid, the named compound are obtained from the output 67% IR spectrum (l3),maxcm-1: 1455, 1595, 1755, 2970.

Following the procedure described in example 1, also receive oxalate with a melting point 130-132aboutC (with decomposition).

P R I m e R 9-11. Using a technique similar to that described in example 1, to synthesize the following compounds from the corresponding compounds of examples 4, 5, or 6, respectively.

P R I m e R 9. 2-(8-chloro-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)ATOC who receive oxalate named compound with a melting point 167-169aboutC (with decomposition).

P R I m e R 10. 2-(8-bromo-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid with a quantitative yield.

IR-spectrum (KBR), max, cm-1: 1426, 1450, 1490, 1600, 2830, 2940.

Also get the oxalate named compound with a melting point of 177-178aboutC (with decomposition).

P R I m e R 11. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C)pyrazino(1,2-a)pyrido(5.5 sec) azepin-2-yl)toxicmonkey acid with a yield of 72%

IR-spectrum (KBR) maxcm-1: 1445, 1500, 1600, 2460, 2970.

Also get the oxalate named compound with a melting point 197-198aboutC (with decomposition).

P R I m e R s 12 and 13. Using the procedure described in example 3d, synthesize the following compounds from the corresponding compounds of examples 6 and 7, respectively.

P R I m e R 12. Ethyl ester 2-(7-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy) toxicmonkey acid with a yield of 35%

IR-spectrum (l3),maxcm-1: 1495, 1600, 1750, 2825, 2950, 3010.

Mass spectrum (m/Z):424/56, M+/, 263/100/.

P R I m e p 13. Ethyl ester 2-(2-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo)(C, f) - pyrazino(1,2-a) azepine-2-yl)ethoxy)toxicmonkey keys is/are:468/29,M+/, 263/100/.

P R I m e R s 14 and 15. Using the procedure described in example 2, synthesize the following compounds from the corresponding compound of example 12 or 13, respectively.

P R I m e R 14. 2-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)-azepin-2-yl)ethoxy)toxicmonkey acid with a quantitative yield.

IR-spectrum (l3),maxcm-1:1455, 1500, 1600, 1740, 2560, 2980.

Also get fumarate these compounds with a melting point 169-172aboutC (with decomposition).

P R I m e R 15. 2-(2-(2-(1, 2, 3, 4, 10, 14a-hexahydrobenzo) (C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy)toxicmonkey acid with a yield of 97%

IR-spectrum (l3),maxcm-1: 1455, 1495, 1600, 2810, 2960, 3010.

Also obtain hydrochloride of the above compound with a melting point 130-133aboutC (with decomposition).

P R I m e R 16. 3-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)propanol.

To 30 ml of ethanol is added 1.5 g 1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino)1,2-a)azepine, 0.74 g of 3-chloropropanol, 2,32 g of potassium carbonate and 0.10 g of sodium iodide, the mixture is boiled in a vessel under reflux for 20 hours then the reaction mixture is filtered, the structure on the chromatographic column, filled with silica gel, and the target connection get in the crystalline form of fractions, buervenich chloroform containing 5 vol. of ethanol. The substance is then recrystallized from ethyl acetate, receiving 1.28 g (yield 69%) of the named compound with a melting point 127-128aboutC. IR spectrum (KBR),maxcm-1: 1448, 1492, 2821, 2895, 2956, 3194.

P R I m e R s 17 and 18. Following the procedure described in example 16, but using 4-chlorobutanol or 6-chlorohexanol, synthesize the following compounds.

P R I m e R 17. 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)butanol with a yield of 51%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 2830, 2950.

The named compound is then dissolved in ethyl acetate, the resulting solution was added a solution of hydrogen chloride in ethyl acetate. The solvent is then removed by distillation in vacuum, obtaining the hydrochloride of the above compound with a melting point 233-235aboutC (with decomposition).

P R I m e R 18. 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)hexanol exit 34%

IR-spectrum (KBR),maxcm-1: 1440, 1494, 1590, 2813, 2944, 3204.

Also obtain hydrochloride of the above compound with temperas in example 3b, but using the relevant bromoacetamide esters, synthesize the following compounds, and then get their salts.

P R I m e R 19. Ethyl ester 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl) butane acid with a yield of 94%

IR-spectrum (l3),maxcm-1: 1450, 1500, 1600, 1735, 2840, 2960.

P R I m e R 20. Ethyl ester 5-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl) pentanol acid with a yield of 87%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 1730, 2820, 2950.

P R I m e R 21. Ethyl ester 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)hexanoic acid with a yield of 99%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 1730, 2820, 2950.

Following the procedure described in example 1 or example 17, but using the appropriate acid, receive the following salt.

The ethyl ester fumarate 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)butane acid with a melting point 139-140aboutC.

Hydrochloride ethyl ester 5-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)pentanol acid with a melting point 167-169aboutC.

The hydrochloride of ethyl EA 150-152aboutC.

P R I m e R s 22-24. Following the procedure described in example 2, but using the appropriate ester of example 19, 20 or 21, respectively, are synthesized following carboxylic acids.

P R I m e R 22. 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)butane acid with a yield of 63%

P R I m e R 23. 5-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)pentane acid with a melting point 240-243aboutC (with decomposition) opening 54%

IR-spectrum (KBR), maxcm-1: 1445, 1492, 1744, 2596, 2683, 2939, 3020.

P R I m e R 24. 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)hexanoic acid with a quantitative yield. IR-spectrum (l3),maxcm-1: 1450, 1500, 1600, 1720, 2450, 2970.

Following the procedure described in example 17, will receive the following salt.

Hydrochloride 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)butane acid with a melting point 188-189aboutC.

IR-spectrum (KBR), maxcm-1: 1447, 1492, 1595, 1729, 2362, 2949, 2981.

Hydrochloride 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl)hexanoic acid with a melting point of 193-195aboutC (with decomposition).

P R I m a CLASS="ptx2">

to 0.060 g of a dispersion of sodium hydride in mineral oil with a concentration of 55 wt. /Mac. added to a solution of 0.40 g 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a) azepine-2-yl)hexanol (obtained as described in example 18) in 10 ml of toluene in a nitrogen atmosphere. The mixture was stirred at 40aboutC for 2 h and then cooled with ice, then add 0,229 g methyl ester bromoxynil acid, and the mixture was stirred at 40aboutC for another 4 hours After that the reaction mixture is filtered, and the solvent is removed from the filter by evaporation under reduced pressure. The residue is subjected to separation on a chromatographic column filled with silica gel, using as eluent a mixture of ethyl acetate and hexane, taken in a volumetric ratio of 1:1. Thus emit 90 mg (yield 18%) of the titled compound as oil. An NMR spectrum (CDCl3), , millionths: of 1.26 (3H, triplet), 1,53-1,72 (3H, multiplet), 2,31 at 2.45 (4H, multiplet), to 2.94 (2H, doublet of doublets), 3,26-3,37-(3H, multiplet), 3,56-3,63 (2H, multiplet), 4,06-of 4.25 (4H, multiplet), 4,82 (IH, doublet), 6,86 (IH, triplet) 7,01-7,20 (3H, multiplet).

IR-spectrum (l3),maxcm-1: 1445, 1490, 1595, 1745, 2800, 2925.

P R I m e R 26. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)ASEP)pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 2) and 0.11 g of triethylamine. Then to the mixture dropwise while cooling with ice add a solution of 0.11 g of ethylchloride in 2 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. Then the reaction mixture is mixed with water and extracted with methylene chloride. The extract was concentrated by evaporation under reduced pressure, and the residue is subjected to separation on a chromatographic column filled with silica gel, using as eluent methylene chloride containing 5 vol. of methanol. While allot of 0.29 g (yield 82%) of the named compound with a melting point 66-68aboutC.

IR-spectrum (KBR),maxcm-1: 1450, 1492, 1684, 2814, 2942, 3100, 3276.

P R I m e R s 27-29. Following the procedure described in example 26, but using the appropriate amine, synthesize the following compounds.

P R I m e R 27. -(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy)-N,N-Dimethylacetamide with exit 79%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 1645, 2820, 2950, 3005.

P R I m e R 28. -(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy)-N-phenylacetamide with temperature - dependent melting point 132-133aboutWith the yield 74%

IR-spectrum (l3),maxcm-1: 1445, 1490, 1530, 160 is hydroxy)ndimethylacetamide with a melting point 92-93aboutWith the yield 74%

IR-spectrum (KBR),maxcm-1: 1453, 1491, 1516, 1676, 2813, 2938.

Following the procedure described in example 17, to obtain hydrochloride of the compound of example 27 with a melting point of 80-82aboutC (with decomposition).

P R I m e R 30. N-cyclohexyl-- (2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy)ndimethylacetamide.

To 10 ml tetrahydrofurane add 0,358 g 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 2), 0.1 g of cyclohexanone and 0.11 g of triethylamine. To the resulting mixture while cooling it with ice drops added 0.17 g diethylthiophosphate. The mixture is then stirred at room temperature for 5 h, after which it is mixed with water and then extracted with methylene chloride. The extract was concentrated by evaporation under reduced pressure, and the residue is subjected to separation on a chromatographic column filled with silica gel, using as eluent ethyl acetate containing about 10. of ethanol. Thus emit 0.4 g (yield 91%) of the named compound.

Following the procedure described in example 17, to obtain the hydrochloride of the above compound with a melting point 110-112about(From Paradise R s 31-39. Following the procedure described in example 30, but using the appropriate amine, synthesize the following compounds.

P R I m e R 31. -(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy)-N,N-dipropylacetamide exit 61%

IR-spectrum (HCl3),maxcm-1: 1455, 1500, 1645, 2345, 2900, 2980, 3020.

P R I m e R 32. N-tert-butyl--(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethoxy)ndimethylacetamide with a melting point 115-116aboutWith the release of 53%

IR-spectrum (KBr), maxcm-1: 1449, 1491, 1523, 1673, 2004, 2951, 2969, 3401.

P R I m e R 33. N-cyclopropyl--(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethoxy-ndimethylacetamide exit 83% IR spectrum (l3),maxcm-1: 1450, 1600, 1670, 1720, 2830, 3000, 3440.

P R I m e R 34. N-cyclobutyl-- (2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethoxy)ndimethylacetamide with a melting point 113-115aboutWith the release of 88%

IR-spectrum (KBr),maxcm-1: 1445, 1491, 1508, 1651, 2806, 2947, 3246.

P R I m e R 35. N-cyclopentyl--(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy) ndimethylacetamide with the release of 88%

IR-spectrum (l3),maxcm-1:1450, 1495, 1530, 1600, 1665, 2825, 2960, 3220.

P R I m e R 36. N-cyclohepta is UP>aboutWith quantitative yield.

IR-spectrum (l3),maxcm-1: 1450, 1495, 1530, 1600, 1665, 2860, 3330.

P R I m e R 37. 4-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxyacetic)morpholine with exit 84%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 1640, 1730, 2820, 2860.

P R I m e R 38. N-(2-dimethylaminoethyl)--(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a) azepine-2-yl)ethoxy)ndimethylacetamide exit 84%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1530, 1600, 1670, 2840, 2960, 3430.

P R I m e R 39. N-(2-(4-pair, pair-diferentiebaren-2-yl)ethyl)-2-) (1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino (1,2-a)azepine-2-yl-ethoxy) ndimethylacetamide with the release of 93%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1505, 1605, 1665, 2820, 2950, 3410.

Following the procedure described in example 17, will receive the following salts:

The hydrochloride of the compound from example 31 with a melting point of 82-84aboutC.

The hydrochloride of the compound of example 35 with a melting point 124-127aboutC (with decomposition).

The hydrochloride of the compound of example 37 with a melting point 110-112aboutC (with decomposition).

The dihydrochloride of the compound of example 38 with a melting point of 178aboutC (with decomposition).

P R I m e R 40. 2-(2,3-dihydroxypropyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f)Piraino(1,2-a)azepine.

It chilled with ice to a solution of 1 g 1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine in 2 ml of ethanol is added a mixture of 0.41 g gitignore alcohol and 0.9 ml of water, and the mixture is stirred at room temperature for 5 hours the mixture is Then concentrated by evaporation under reduced pressure. The residue is subjected to separation on a chromatographic column filled with silica gel, using as eluent a mixture of ethyl acetate and ethanol taken in a volumetric ratio of 10:1. Thus allocate to 0.72 g (yield 56%) of the named compound as a colourless foam. IR-spectrum (l3),maxcm-1: 1455, 1500, 1605, 1740, 2850, 2980, 3040.

Following the procedure described in example 17, to obtain the hydrochloride of this compound with a melting point 205-207aboutC (with decomposition).

P R I m e R 41. 2-(3-chloro-2-hydroxypropyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine.

To a mixture of 4.5 ml of ethanol and 1.5 g 1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine while cooling with ice add 0,832 g of epichlorohydrin, and the mixture is stirred at room temperature for 5 h P is tographically column, filled with silica gel, using as eluent hexane mixture and ethyl acetate, taken in a volumetric ratio of 1:1. Thus emit 1.56 g (yield 76%) of the named compound as a colourless foam.

IR-spectrum (l3),maxcm-1; 1498, 1600, 3200.

An NMR spectrum (DCl3), , millionths: 2,30-3,20 (5H, multiplet), 3,20-3,50 (3H, multiplet), 3,50-3,70 (2H, doublet), 3,78-4,24 (2H, multiplet), 4,82 (IH, doublet), 6,70-7,40 (M, multiplet).

P R I m e R 42. 2-(2-hydroxy-3-morpholinopropan) 1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine.

To 10 ml of 4-methyl-2-pentanol add 0.5 g of 2-(3-chloro-2 - hydroxypropyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine (obtained as described in example 41), 2.7 g of sodium carbonate, of 0.014 g of sodium iodide and 0,254 g of the research, and the mixture is boiled in a vessel under reflux for 2 hours then the reaction mixture was filtered, and the filter is then concentrated by evaporation under reduced pressure. The residue is subjected to breeding on a chromatographic column filled with silica gel, using as eluent ethyl acetate. Thus emit 0.50 g (yield 87%) of the named compound as a colourless foam.

IR-spectrum (nujol),maxcm-1: the Oia with a melting point 223-226aboutC (with decomposition).

P R I m e R s 43-46. Following the procedure described in example 42, but using the appropriate amine, synthesize the following compounds.

P R I m e R 43. 2-(3-(4-pair-chlorobenzotriazol-1-yl) -2-hydroxypropyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine with a yield of 99%

IR-spectrum (l3),maxcm-1: 1455, 1495, 1600, 2830, 2950, 3400.

P R I m e R 44. 2-(2-hydroxy-3-cyclohexylamino)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine exit 87%

IR-spectrum (l3),maxcm-1: 1450, 1495, 1600, 2850, 2940, 3400.

P R I m e R 46. 2-(2-hydroxy-3-phenylaminopropyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine exit 69%

Following the procedure described in example 1 or example 17, but using the appropriate acid, receive the following salts. The hydrochloride of the compound of example 43 with a melting point 213-215aboutC (with decomposition). Maleate of the compound from example 44 with a melting point 195-197aboutC (with decomposition). The hydrochloride of the compound from example 46 with a melting point 223-226aboutC.

IR-spectrum (KBR),maxcm-1: 1445, 1493, 1603, 2608, 2712, 2969, 3319.

P R I m e R 47. Ethyl ester 2-(1, 2, 3, 4, 10, 14C-hexa is 5 g 2-(1, 2, 3, 4, 10, 14b-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 2) in 10 ml of chloroform, containing about 2. ethanol, added 0.11 g of chloroethylamine, and the mixture is stirred at room temperature for 1 h then the mixture is washed with water, and the solvent is removed by distillation under reduced pressure. The resulting residue is subjected to separation on a chromatographic column filled with silica gel, elwira with ethyl acetate. Thus emit 0.25 g of the named compound as a colourless oil. The IR spectrum of this compound is identical to the spectrum of the compound obtained as described in example 1.

By the way, is similar to that described in example 17, this compound was transferred into its hydrochloride with a melting point 170-171aboutC.

P R I m e R s 48 and 49. Following a methodology similar to that described in example 8, but using the corresponding chloroethoxy connection, synthesize the following compounds.

P R I m e R 48. 2-(2-hydroxyethoxy)ethyl-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)pyrido(5,6-C)azepin exit 84%

IR-spectrum (l3),maxcm-1: 1440, 1590, 1730, 2820, 2870, 2950, 3300.

Dichlorhydrate, pravasis the p R I m e R 49. 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C)pyrazino(1,2-a)pyrido(5,6-C) aspidistrafly with a melting point of 102-104aboutC (with decomposition) with a quantitative yield.

IR-spectrum (l3),maxcm-1: 1440, 1590, 1705, 2870, 2950, 3450.

P R I m e R 50. 3-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)propellernet.

To a cooled with ice to a solution of 4 mg 3-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)propanol (obtained as described in example 16) in 20 ml of methylene chloride add 0.2 g trichloroacetimidate, and the mixture is stirred at room temperature for 2 hours then the solvent is removed by distillation under reduced pressure. The resulting residue is dissolved in 22 ml of methanol, to the solution was added 9.0 g of silica gel, and the mixture is stirred at room temperature for 15 hours then the mixture is filtered using the accelerator filter of "Celite" (trade mark) and the filtrate concentrated by evaporation under reduced pressure. The residue is subjected to separation on a chromatographic column filled with silica gel, elwira with ethyl acetate, obtaining, after recrystallization from ethyl acetate, 260 m the crown-rump length (CVG),maxcm-1: 1638, 1722, 3119, 3313.

P R I m e R 51. 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethylcarbamate.

Following the procedure described in example 50, but using 2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethanol, get the named compound with a melting point 182-184aboutC (with decomposition) opening 62%

IR-spectrum (KBR),maxcm-1: 1611, 1695, 1723, 3278, 3396.

P R I m e R s 52-57. Following a methodology similar to that described in example 1 from the corresponding chlorine-containing esters, synthesize the following compounds.

P R I m e R 52. Methyl ester 3-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) propoxyethanol acid in the form of an oil with a yield of 48%

IR-spectrum (l3),maxcm-1: 1495, 1600, 1758, 2830, 2970.

P R I m e R 53. Ethyl ester 4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) butoxyethanol acid in the form of an oil with a yield of 50%

IR-spectrum (l3),maxcm-1: 1500, 1600, 1750, 2840, 2960.

P R I m e R 54. Methyl ester 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) hexyloxybenzoic acid in the form of an oil with a yield of 72%

IR-spectrum (l3

P R I m e R 56. Ethyl ester 2-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)ethoxy) propionic acid in the form of an oil with a yield of 77%

IR-spectrum (l3),maxcm-1: 1495, 1600, 1740, 2840, 2960.

P R I m e R 57. Ethyl ester 2-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethoxy)buttonboy acid in the form of an oil with a yield of 68%

IR-spectrum (l3),maxcm-1: 1495, 1750, 2830, 2950.

Following the procedure described in example 1 given the following salts:

Oxalate ethyl ester 4-(1, 2, 3, 4, 10, 14-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) butoxyethanol acid with a melting point 157-160aboutC.

The methyl ester oxalate 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) hexyloxybenzoic acid with a melting point 140-141aboutC.

Oxalate ethyl ester 6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) hexyloxybenzoic acid with a melting point of 115-120aboutC.

Oxalate ethyl evaline 160-162aboutC (with decomposition).

Oxalate ethyl ester 2-(2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) ethoxy)butane acid with a melting point 160-162aboutC (with decomposition).

The methyl ester oxalate 3-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) propoxyethanol acid with a melting point of 102-104aboutC.

P R I m e R 58. Ethyl ester of (S) -2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid.

To 340 ml of 4-methyl-2-pentanone add 32,48 g (S)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine (obtained as described in method 3), 22,7 ethyl ester 2-chlorethoxyfos acid, for 48.9 g of sodium carbonate and 0.79 g of sodium iodide, the mixture is boiled in a vessel under reflux for 16 hours then the mixture is cooled to room temperature and filtered using celiby accelerator filtering, the filtrate is concentrated by evaporation under reduced pressure. The resulting residue is subjected to separation on a chromatographic column filled with silica gel, elwira a mixture of ethyl acetate and hexane, taken in a volumetric ratio of 1:1. You get 44,85 g (yield 91%) of these so, 2950, []D25= +275o(c 1.0, methanol).

P R I m e R 59. (S)-2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)toxicsuse acid.

To a solution of 44,85 g of ethyl ester of (S)-2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 58) and 450 ml ethanol add 65 ml of 10 wt. /about. an aqueous solution of sodium hydroxide and 200 ml of water, and the mixture is stirred at room temperature for 2 hours After that, the pH of the mixture was adjusted to 4 by addition of concentrated hydrochloric acid, the mixture is concentrated by evaporation under reduced pressure. Drop down crystals are collected by filtration and recrystallized from water, getting 39,20 g (yield 90%) of the named compound in the form of a monohydrate with a melting point 105-108aboutC.

IR-spectrum (KBR),maxcm-1: 1446, 1492, 1598, 1633, 3404, 3449 []D25+325about(1.0, dimethylformamide).

To a solution of these compounds in ethanol add about 10./about. a solution of hydrochloric acid in ethanol, and the mixture is stirred at room temperature for 30 minutes then the solvent is removed by evaporation in vacuo, and the residue is recrystallized from water, getting hydrochlorate). To a solution of these compounds in ethanol add equimolecular amount of fumaric acid, and the mixture is stirred at room temperature for 30 minutes then the solvent is removed by evaporation in vacuo and to the residue is added ethyl acetate, getting hemifumarate these compounds with a melting point 161-163aboutC. []D25+265about(1.0, dimethylformamide).

P R I m e R s 60 and 61. Following the procedure described in example 58, but using the appropriate bromoacetamide ester, synthesize the following compounds.

P R I m e R 60. Ethyl ester of (S)-4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(2,2-(a)azepin-2-yl)butane acid in the form of an oil with a yield of 97%

IR-spectrum (l3),maxcm-1: 1495, 1680, 1730, 2830, 2960. []D25= +301o(c 1,0:methanol).

Following a methodology similar to that described in example 1, get fumarate these compounds with a melting point 139-141aboutC. []D25= +215o(c 1.0, methanol).

P R I m e R 61. Ethyl ester of (S)-6-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) hexanoic acid in the form of an oil with a yield of 98%

IR-spectrum (l3), maxcm-1: 1495, 1600, 1730, 2840, � described in example 58, but using (R)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine (obtained as described in method 4) and the corresponding chloride, get ethyl ester (R)-2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid in the form of an oil with a yield of 91%

IR-spectrum (l3), maxcm-1, 1495, 1600, 1750, 2820, 2950 []D25= -303o(c 1.0, methanol).

Following the procedure described in example 1, get fumarate these compounds with a melting point 128-130aboutC. []D25241o(c 1.0, dimethylformamide).

P R I m e R s 63 and 64. Following a methodology similar to that described in example 58, but using (R)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine (obtained as described in method 4) and the corresponding bromoacetamide ester, synthesize the following compounds.

P R I m e R 63. Ethyl ester (R)-4-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) butane acid in the form of an oil with a yield of 99%

IR-spectrum (l3),maxcm-1: 1495, 1600, 1730, 2830, 2960.

[]D25-296o(c 1.0, methanol).

Following the procedure described in example 1, get fumarate these compounds with temperature plaster (R)-5-(1, 2, 3, 4, 10, 14b-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)hexanoic acid in the form of an oil with a yield of 98%

IR-spectrum (l3),maxcm-1: 1495, 1600, 1730, 2840, 2955.

[]D25-283about(C 1.0, methanol).

P R I m e R 65. Following a methodology similar to that described in example 59, receive monohydrate (R)-2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid with a melting point 104-107aboutWith exit 88% based on the ethyl ester (R)-2-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) toxicmonkey acid (obtained as described in example 62).

[]D25-322 (1.0, dimethylformamide).

Following the procedure described in example 1 or example 17, to obtain the hydrochloride and fumarate these compounds with a melting point 209-211aboutAnd 154-156aboutC, respectively. []D25-225about(1.0, dimethylformamide) for hydrochloride.

[]D25-207about(1.0, dimethylformamide) for fumarata.

P R I m e R s 66 and 67. Following a methodology similar to that described in example 59, and then the method similar to that described in example 17, synthesize the following hydrochloride on the basis of the corresponding complex everone(1,2-a)azepine-2-yl)hexanoic acid hydrochloride with a yield of 85% melting at 255-259aboutC (with decomposition).

[]D25+256about(1.0, dimethylformamide).

P R I m e R 67. (R)-8-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)hexanoic acid hydrochloride with a yield of 92% melting at 243-250aboutC (with decomposition).

[]D25-254o(c 1.0, dimethylformamide).

Method 1. Ethyl ester of 2-chlorethoxyfos acid.

A suspension of 25.0 g of sodium hydride (60 wt./wt. suspension in mineral oil) in 100 ml of dimethylformamide are added dropwise to a solution of 50 g of 2-chloroethanol and 104 g of ethylbromoacetate in 350 ml of dimethylformamide at a temperature lying between -45 ° and -40aboutC, and the mixture was stirred at the same temperature for 1 h, at temperatures from -30 to -25aboutC for 2 h, at a temperature of from -5 to 5aboutC for 1 h and at room temperature for 2 hours then the mixture is concentrated by evaporation in a vacuum, to the residue was added 100 ml of toluene. Then the solution is washed with water, the solvent is removed by evaporation in a vacuum. Distillation gives 77,6 g (75% yield) of the named compound, boiling at a temperature 57-58aboutWith the 2.5 mm RT. Art. (33 PA).

An NMR spectrum (CDCl3), , millionths: of 1.30 (3H, triplet, J atrophy ether 2-chloroperoxidase acid.

A solution of 30 g of 2-(2-chloroethoxy)ethanol in 300 ml of acetone are added dropwise to a mixture of 240 ml of Jones reagent prepared by dissolving 133,5 g of chromium trioxide by adding 115 ml of concentrated sulfuric acid and water and then adding an additional amount of water to a total volume of 500 ml and 1050 ml of acetone at a temperature lying in the range from -5 to 0aboutC, and the mixture was stirred at the same temperature for 30 minutes then to the mixture is added 150 ml of isopropanol, the mixture was then stirred at room temperature for 1 h then the mixture is filtered, the filtrate is concentrated by evaporation under reduced pressure, the pH adjusted to 3 by addition of an aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate, and the solvent is evaporated from the extract, receiving 24,9 g (75% yield) 2-chlorethoxyfos acid as a pale green oil. Through a solution 24,9 g of this acid in 250 ml of ethanol miss gaseous hydrogen chloride, the mixture is boiled in a vessel under reflux for 3 hours, the mixture is concentrated by evaporation under reduced pressure. Distillation gives 29,2 g (yield 95%) of the named compound as a colourless oil, boiling at a temperature of 96aboutSince p is

3A. Ethyl ester of (S)-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine)carboxylic acid.

A solution of 5.32 g (S)-1, 2, 3, 4, 10, 14-hexahydro-2 - methyldibenzo(C, f) - pyrazino(1,2-a)azepine (obtained as described in method 6) in 30 ml of toluene are added dropwise to a solution of 6.8 g of ethylchloride in 50 ml of toluene at 80aboutC for 10 min, the mixture is boiled in a vessel under reflux for 3 hours then drop down the crystals are removed by filtration and the solvent evaporated from the filtrate under reduced pressure. You get to 5.57 g (yield 98%) is caused by a connection in the form of oil is pale yellow in color.

IR-spectrum (l3),maxcm-1: 1240, 1435, 1495, 1600, 1690, 3010, []D25+286about(C 1.0, methanol).

3V. (S)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino)1,2-a)azepine.

A solution of 10.2 g of potassium hydroxide in 34 ml of water are added to a solution 6,54 g of ethyl ester of (S)-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl) carboxylic acid (obtained as described in methods 3A) in 85 ml of ethylene glycol, the mixture is boiled in a vessel under reflux for 16 hours then the mixture was poured into ice water and extracted with ethyl acetate. Evaporation of the solvent from EXT is SUP>aboutC.

IR-spectrum (KBR),maxcm-1: 1489, 2791, 2899, 3191, []D25+488about(C 1.0, methanol).

Method 4. (R) 1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine,

4A. Ethyl ester (R)-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)carboxylic acid.

Following the procedure described in method 3A, but using (R)-1:2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine, get a named connection with exit 98%

IR-spectrum (l3),maxcm-1: 1240, 1435, 1495, 1600, 1690, 0,3010.

[]D25-255about(C 1.0, methanol).

4B. (R)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine.

Following the procedure described in method 3, but using ethyl ester (R)-(1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine-2-yl)carboxylic acid, get a named connection with the release of 95% melting at 122-124aboutC. []D25-486about(C 1.0, methanol).

Method 5. (S)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(c, f) - pyrazino(1,2-a)azepine and (R)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine.

12,01 g of the acid chloride --methoxy--(trifloromethyl) phenylacetic acid are added dropwise to a solution of canie 15 min, and the solution is stirred and cooled with ice, the mixture is then stirred at a temperature of 0-5aboutC for 1 h then the mixture was added water, the mixture extracted with chloroform. Evaporation of the solvent from the extract gives the remainder. This residue is subjected to separation on a chromatographic column filled with silica gel, elwira a mixture of ethyl acetate and hexane, taken in a volumetric ratio of 1:19. You get 8,39 g (yield 42% ) of the less polar substances in the form of colorless needles, melting at 159-161aboutWith, and 9,06 g (yield 45%) of the more polar substances in the form of colorless prisms, melting at 224-227about[]D25+171about(1.0, dimethylformamide) for the less polar substances. []D25of 211about(1.0, dimethylformamide) to a more polar substances.

23,7 ml of 1.5 M solution of diisobutylaluminium in toluene are added dropwise to a solution 8,30 g of the less polar compound, obtained as described above, in 140 ml of toluene at -160aboutC for 40 min, the mixture was stirred at the same temperature for 1.5 hours then to the mixture is added saturated aqueous solution of ammonium chloride, the temperature was raised to room temperature. The mixture is then filtered, filtrating separation on a chromatographic column, filled with silica gel, elwira mixture of methanol and methylene chloride, taken in a volumetric ratio of 1:19. Thus obtain 2.30 g (yield 52%) (S)-1, 2, 3, 4, 10, 14C-hexahydrobenzo (C, f) - pyrazino(1,2-a)azepine, melting at 128-130aboutC. []D25= +504about(1.0, dimethylformamide).

Following the method described above, but using 9.00 g of the more polar compounds, receive 3.12 g (yield 65%) (R)-1, 2, 3, 4, 10, 14C-hexahydrobenzo(C, f) - pyrazino(1,2-a)azepine, melting at 129-131aboutC.

IR-spectrum (KBR),maxcm-1: 1489, 2791, 2898, 3189, []D25-483o(c 1.0, dimethylformamide).

Methodology 6. (R)-1, 2, 3, 4, 10, 14C-hexahydro-2 - methyldibenzo(C, f) - pyrazino(1,2-a)azepine and (S)-1, 2, 3, 4, 10, 14C-hexahydro - 2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine.

A solution of 10.8 g of Dibenzoyl L-tartaric acid in 20 ml of methanol are added to a solution of 15 g of the racemate 1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine in 180 ml of methanol. Drop down the crystals are filtered and dried, obtaining salt, melting at 186aboutC (with decomposition), [D25-266o(c 1.0, dimethylformamide).

All this salt is suspended in 10 wt./about. an aqueous solution of potassium carbonate and extragere the(s, f) - pyrazino(1,2-a)azepine.

[]D25-457o(c 1.0, methanol). A solution of 10.8 g of Dibenzoyl-L - tartaric acid in 30 ml of methanol are added to a solution of 15 g of the racemate 1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine in 270 ml of methanol. Drop down the crystals are filtered and dried, obtaining salt, melting at 186aboutC (with decomposition).

[]D25+243o(c 1.0, dimethylformamide). All this salt is suspended in 10 wt. /about. aqueous potassium carbonate solution and extracted with ethyl acetate. Evaporation of the solvent from the extract gives 4,79 g (yield 32%) (S)-1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine.

[]D25+469about(C 1.0, methanol).

Methodology 7. (R)-1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine and (S)-1, 2, 3, 4, 10, 14C-hexahydro-2 - methyldibenzo(C, f) - pyrazino(1,2-a)azepine.

A solution of 2.66 g of diacetyl-L-tartaric acid in 20 ml of ethanol are added to a solution of 5 g of the racemate 1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine in 180 ml of ethanol. Drop down the crystals are filtered and dried, obtaining salt, melting at 188-189aboutC (with decomposition). []D25-274o(c 1.0, dimethylformamide). All of this is the shape with ethyl acetate. Evaporation of the solvent from the extract to give 1.5 g (yield 30% ) (R)-1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine, []D25= 474o(c 1.0, methanol).

Royal solutions, the resulting recrystallization named salts, evaporated, and the residues treated with potassium carbonate as described above, while receiving 2,73 g (R) and (S) mixture 1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine. A mixture of 2.27 g of the racemate 1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine combined and dissolved in 180 ml of ethanol. To the solution add a solution of 2.66 g diatsetilvinny acid in 20 ml of ethanol. Drop down the crystals are filtered and dried, obtaining salt, melting at 189-190aboutC (with decomposition). []D25+250o(c 1.0, dimethylformamide). All this salt is recrystallized from methanol and treated with an aqueous potassium carbonate in a manner analogous to that described above, receiving of 1.65 g (yield 33%) (S)-1, 2, 3, 4, 10, 14C-hexahydro-2-methyldibenzo(C, f) - pyrazino(1,2-a)azepine. []D25+467o(c 10,0, methanol).

The control example 1. Inhibition of passive cutaneous anaphylaxis (PCA) in rats.

In accordance with the method of Mota (I. Mota, Immunology 681-699, 1964 prepare anticipo saline. As experimental animals in groups, each of which includes 4 animals, use of male rats kinds of SD at the age of 5 weeks). Rats sensibiliser intradermal injection of 0.05 ml of diluted antisera in the supine position. After 48 h after injection, the rats, starving for 1 day, entering through the mouth suspension of the test compound in 0.5/about. aqueous solution of tragakant and 60 min later, the rats in the caudal vein at a rate of 5 ml/kg of body weight administered physiological saline solution containing 0.4 wt./about. personal albumin and 0.1 wt./about. blue Evans. After 30 min after the last injection rats killed using carbon dioxide and in accordance with the method Haradah (Harada and others J. Pharm. Pharmach. 23, 218-219, 1971 determine the reddish Evans blue in the dorsal skin area.

The results obtained on the test groups, which were treated with test compounds analyzed to determine the degree of inhibition by comparing with the average amount of dye that becomes visible in the control group that was not treated with the test compound.

The degree of inhibition calculated by the following equation. The degree of ing the higher dye in the test group. (Sodium salt(1, 2, 3, 4, 10, 14-tetrahydro-2H, 10H-pyrazino(1,2-a)pyrrolo (2,1-C)(1,4)the growing presence - zipin-2-yl)acetic acid.

Known compounds and are defined earlier in the discussion of contemporary problems.

Control example 2. Impact on antigonadotropin bronchostenosis in sensitized Guinea pigs.

As the use of experimental animals male Guinea pigs line Hartley weight of about 400-500, These animals sensibiliser by the method of Morris, R. Morris, Br. Pharmac. 67, 179-184, 1979). Guinea pigs subcutaneously and intraperitoneally twice injected each time (25 mg) egg albumin (grade 5 manufactured by Sigma) at weekly intervals. Seven days after the second of these weekly injections of animals not fed for one day and then exposed to aerosol egg albumin (10 mg/ml). All treated animals react to this convulsion, which indicates a disorder of breathing caused by narrowing of the Airways, in the continuation of 6 minutes For 60 minutes prior to the processing of egg albumin to each of the animals orally administered one of the test compounds shown in table. 1. A compound is considered effective if the animal is ing azetidinone derivative of General formula

< / BR>
where Q is nitrogen or a group of formulas-;

R1, R2the same or different and each is hydrogen or halogen;

R3substituted alcalina group containing 2 to 6 carbon atoms and having at least one Deputy, selected from hydroxyl groups, halogen atoms and groups of formula-COOR4(where R4hydrogen or an alkyl group containing 1 to 4 carbon atoms), groups of formula-NR5R6-OCONR5R6(where R5and R6have the specified values), a group of the formula [CH2CH2OH]nCH2R8where n is 1 to 3;

R8the hydroxymethyl group of the formula-COOR4(where R4has the specified value) or a group of the formula-CONR5R6(where R5and R6have the specified values) a group of formula-E-O-G-COOR4where E - Allenova group containing 2 to 6 carbon atoms; G Allenova group containing 1 to 3 carbon atoms;

R4has a specified value;

R5and R6the same or different and each is hydrogen, asamasinda an alkyl group containing 1 to 4 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms in the ring; a phenyl group; benzyl group; 2-dimethylaminoethyl or 2-[4-(n, n-diferensial)PI is a or 4-p-chlorobenzotriazol,

or its pharmaceutically acceptable salt, wherein interact compounds of General formula

< / BR>
where R1, R2and Q have the indicated values,

with a compound of General formula

R3X,

where R3has the specified values;

X is halogen,

and then, if required, convert the group represented by R3in any other group, are included in the definition of R3groups.

Priority signs:

05.10.89 when R3a group of the General formula [CH2CH2O]CH2R8where n is 1 to 3; R8- hydroxymethyl group of General formula-COOR4where R4hydrogen or C1WITH4is an alkyl group.

29.03.90 when R3substituted alkyl group containing 2 to 6 carbon atoms and having at least one Deputy, selected from hydroxyl groups and groups of formula-COOR4(where R4hydrogen or C1C4is an alkyl group), (CH2CH2O)n- CH2R8(where n is 1 to 3) or a group of the formula-CONR5R6(where R5and R6< / BR>
the same or different and each is hydrogen, C1- C4-unsubstituted alkyl group, a C3WITH7-cycloalkyl group, FeNi and R6together with the nitrogen atom to which they are attached, morpholinopropan or 4-p-chlorobenzotriazol;

04.10.90 when R3WITH2WITH6-alcalina group having at least one Deputy, selected from the halogen atoms and groups of formula R5R6where R5and R6have the specified values.

 

Same patents:

The invention relates to new heterocyclic compounds having valuable biological properties, in particular to derive dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN иNOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS

The invention relates to the field of organic chemistry, to the class of heterocyclic compounds - derivatives of 1,2,3,4-tetrahydroquinoxaline, namely to a new way to obtain previously unknown connections - 2,3-bis-koimeterion - 1,2,3,4-tetrahydroquinoxaline formula

< / BR>
(Ia, b) where R = Br(a), NO2(b) that may find application in medicine as drugs with antimicrobial action

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action

The invention relates to new derivatives of alkinoos acid, pyridine, or rather to new 1,3-dioxane-5-Illinois acids containing the residue of pyridine in position 4 1,3-dioxane rings

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

FIELD: biology, medicine.

SUBSTANCE: invention relates to chemical compounds and compositions that can be used as modulating agents of phototoxicity of skin cells. Proposed "modulators" relate to material that can either accelerate or decelerate damage of cells, for example, skin cells caused by effect (exposition) of light, for example, UV-rays of type A. Modulators are chosen from group consisting of 3-hydroxyproline pharmacophor or proline, 4-hydroxyproline or its alkyl ester. Invention provides modulating effect of phototoxicity of cells wherein modulators relate to molecule that can be molecule of skin components, in particular, collagen.

EFFECT: improved and enhanced method of modulation.

14 cl, 2 tbl, 13 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of converting group >C=O (I) in a compound into group >C=S (II) or into a tautomeric form of group (II) in a reaction resulting in a thionated reaction product when using the crystalline P2S5·2C5H5N as a thionizing reagent, as well as to a thionizing agent, that is a crystalline P2S5·2C5H5N and has the melting point of 167-169 °C.

EFFECT: proposed is a novel method of converting group >C=O (I) in a compound into group >C=S (II).

22 cl, 3 tbl, 4 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3,5-dimethylpyridine. Method involves reaction of propanol-1, formaldehyde and ammonia in presence of granulated binder-free zeolite Y-BS in Η-form at 250–450 °C and volume rate of supply of raw material (w), equal to 2-7 h-1, molar ratio of propanol-1: formaldehyde: ammonia is 1.0:0.2–2.0:1.5–5.

EFFECT: use of present method enables to obtain 3,5-lutidine with high volume rate of supply of raw material with high output.

1 cl, 1 tbl, 1 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds inhibiting activity of hormone-sensitive lipase and represented by structure of the formula: (XXXXIVa)

and the formula (XXXXIVb): wherein R1ap and R2ap are chosen independently from (C1-C6)-alkyl, aryl wherein each (C1-C6)-alkyl and aryl can be substituted optionally with one or some substitutes chosen independently from halogen atom, (C1-C6)-alkyl under condition that if R1ap and R2ap are similar then they are not methyl or ethyl, and wherein between substitutes R1ap and R2ap can be a covalent bond optionally, and wherein R5ap, R6ap and R7ap are chosen independently from hydrogen atom and fluorine atom (F), and R4ap is chosen from hydrogen atom, sulfanyl, halogen atom, amino-, nitro-group, (C1-C6)-alkyl, heteroaryl, (C3-C8)-heterocyclyl wherein each among sulfanyl, amino-group, (C1-C6)-alkyl, heteroaryl, (C3-C8)-heterocyclyl can be substituted optionally with one or some substitutes chosen independently from hydroxy-, oxo-group, halogen atom, (C1-C6)-alkyl, aryl, heteroaryl wherein each among (C1-C6)-alkyl, aryl, heteroaryl can be substituted optionally with one or some substituted chosen independently from oxo-group, halogen atom, amino-group, (C1-C6)-alkyl, (C3-C8)-heterocyclyl wherein each among amino-group, (C1-C6)-alkyl, (C3-C8)_heterocyclyl can be substituted optionally with one or some substitutes chosen independently from oxo-group, (C1-C6)-alkyl wherein (C1-C6)-alkyl can be substituted optionally with one or some substitutes chosen independently from oxo-group under condition that R4ap is not methyl. Also, invention relates to a pharmaceutical composition and using these compounds for preparing a medicinal agent used for inhibition of lipolytic activity of hormone-sensitive lipase. Invention describes compounds that can be useful in treatment and prophylaxis of clinical disorders wherein decrease of activity of hormone-sensitive lipase is desirable.

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

8 cl, 1 tbl, 602 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds selected from a group comprising piperazine compounds of formula I: , where X is -CH2- or a bond; n equals 1; R1 is alkyl; cycloakyl; hydroxyethyl; benzo[1,3]dioxolyl; phenyl, which can be mono-substituted with a halide, alkyl, alkoxy, -CF3 or alkylcarbonyl; or phenyl which is di- or tri-substituted with substitutes independently selected from alkyl and halide; pyridyl which can be mono-substituted with a halide, alkyl or -CF3; furanyl which can be mono-substituted with methyl, hydroxymethyl or bromine, or furanyl which is disubstituted with an alkyl; thienyl which can be mono-substituted with methyl or chromium; pyrimidinyl; isoquinolinyl; benzhydryl; imidazolyl optionally mono-substituted with an alkyl; or thiazolyl; or X is -C(=O)- and R1 is hydrogen; R2 is indolyl, imidazolyl optionally mono-substituted with alkyl; phenyl which can be mono-substituted with a halide, alkyl, hydroxy or cyano, or phenyl which is disubstituted with a halide; pyridyl; benzothienyl; thiazolyl or thienyl; R3 is indolyl, pyridyl which can be mono-substituted with alkoxy, alkoxyalkoxy, NR31R32, morpholine, piperadine, oxopiperidinyl, oxopyrrolidinyl, pyridyl or phenyl; or phenyl which is mono-substituted with phenyl, pyridyl, alkyl, alkoxy, dialkylamino, morpholine, N-benzyl-N-alkylamino, (dialkylamino)alkoxy, phenylalkoxy or tetrahydroisoquinolinyl; or R3 denotes the group: , where Z is phenyl or pyridyl; R31 is 2-C1-C5alkoxyethyl, phenyl, pyridyl, phenylalkyl, hydroxyalkylcarbonyl, alkylcarbonyl, cycloalkylcarbonyl or phenylcarbonyl; R32 is hydrogen or methyl; R35 is alkyl, alkylcarbonyl, phenyl, pyridyl or pyrimidinyl; and R4 is phenyl-CH=CH-, where the phenyl can be mono-, di- or tri-substituted with substitutes independently selected from halide, alkyl, alkoxy and -CF3; or phenyl-CH2-CH2, where the phenyl is disubstituted with -CF3; and to optically pure enantiomers thereof, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and mesoforms, such as salts of such compounds. The invention also relates to a pharmaceutical composition, as well as to use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds with antimalarial activity.

8 cl, 138 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound and specifically 4[(4'-nicotinoylamino)butyroylamino]butanoic acid of formula (I) , as well as a method of producing said compound.

EFFECT: novel compound is obtained and described, which exhibits high nootropic activity and has low toxicity.

2 cl, 1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein: X and Y independently mean a nitrogen atom or the chain -CR4-, wherein R4 means a nitrogen atom; A means an aryl or heteroaryl group, with the above aryl or heteroaryl groups are optionally substituted by one or more groups specified in a halogen atom, a hydroxyl group, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkoxy group optionally substituted by (C1-C4)alkoxy group, a halogen alkyl group, a halogen alkoxy group; W means a halogen atom; Z means (C1-C4)alkylene group optionally substituted by one or more groups specified in a halogen atom and (C1-C4)alkyl group; B means the group -NR4R5, wherein R4 and R5 independently mean (C1-C4)alkyl group; R1 and R2 mean: - or R1 means a hydrogen atom and R2 mean (C1-C4)alkyl group, - or R1 and R2 together with a carbon atom whereto attached form a mono- or polycyclic system specified in: (C3-C8)cycloalkyl group, a bicyclic bridge group or a tetracyclic bridge group; the above system may be substituted by one or more hydroxyl groups; R3 means either the group C(O)R5, wherein R5 means (C1-C4)alkoxygroup optionally substituted by (C1-C4)alkoxygroup, or the group NR6R7, wherein R6 and R7 independently mean a hydrogen atom, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkylsulphonyl group, a halogenalkyl group, or the group -CH2XR8, wherein: - X means an oxygen atom and R8 means a hydrogen atom or (C1-C4)alkyl group, - or the nitrile group (CN); p means an integer equal to 0 or 1; the aryl group represents an aromatic monocyclic group containing 5 or 6 carbon atoms; the above cycle may be fused with a partially saturated heterocyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as an oxygen atom; the heteroaryl group represents an aromatic cyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as nitrogen; in the form of a base or an additive salt with an acid or base, as well as to their enantiomers and diastereoisomers, including to their racemic mixtures. Besides, the invention refers to methods for preparing the compound of formula I, as well as to a therapeutic agent and a pharmaceutical composition which possess antagonist action on an urotensin II receptor and contain the compound of formula I.

EFFECT: there are prepared and described the new compounds which possess urotensin II receptor antagonist action.

9 cl, 44 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 means hydrogen atom (H) or (C1-C8)-alkyl; R2 means (C1-C8)-alkyl, -CH2-O-(C1-C8)-alkyl, -OH or -CH2OH; R2a means H; or R2 and R2a for in common -CH2-CH2-; R3 means halogen atom, perhalogenalkyl, -CN, -SR5, -NHR5, -N(R5)2, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; R4 means H, halogen atom, perhalogenalkyl, -CN, -OR5, -SR5, -NHR5, -N(R5)2, -OH, aryl or heteroaryl wherein indicated aryl can comprise optionally up to two substitutes chosen from (C1-C8)-alkyl, halogen atom, perhalogenalkyl and alkoxy-group, and indicated heteroaryl can comprise optionally up to two substitutes chosen from halogen atom and (C1-C8)-alkyl; or R3 and R in common with atoms to which they are added can form 5- or 6-membered heterocyclic ring comprising one oxygen atom (O); each R5 means independently (C1-C8)-alkyl, (C2-C8)-alkenyl, aryl, heteroaryl, arylalkyl, alheteroarylalkyl, perhalogenalkyl or allyl; R6 means H or (C1-C8)-alkyl, or their pharmaceutically acceptable salts, solvates or hydrates under condition that if R6 differs from H then R4 can't mean H; if R1 and R2 mean methyl and R4 means H then R3 can't -NHR5 or -N(R5)2; if R1 and R2 mean methyl and R4 means H then R3 can't imidazole, substituted imidazole or imidazole derivative. Also, invention relates to a pharmaceutical composition used for modulation of 5-HT2C receptors, a method for modulation of 5-HT2C receptors, a method for prophylaxis or treatment of disorders of the central nervous system and obesity, a method for reducing food consumption in mammals, a method for inducing the satisfying sense in mammals and to a method for preparing the composition. Invention provides synthesis of novel compounds possessing useful biological properties and preparing pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

70 cl, 1 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-R derivatives of 4H-bis[1,2,5]-oxadiazolo[3,4-b:3',4'-f]azepine-8,9-diamine of general formula (I), where R denotes H, an NH2 group, an alkyl substitute or a substituted alkyl substitute. The compounds are obtained by reducing 7-R substituted derivatives of tris[1,2,5]oxadiazolo[3,4-b:3',4'-d:3",4"-f]azepine-1-oxide, where R denotes H, an NH2 group, an alkyl substitute or a substituted alkyl substitute, with reducing agents selected from: hydrazine in free form, hydrazine in form of salts of hydrazine and mineral acids, hydrazine in form of salts of hydrazine and organic acids, hydrogen in the presence of a suitable reducing catalyst, known as a hydrogenating catalyst. The 4H-bis[1,2,5]oxadiazolo[3,4-b:3',4'-f]azepine-8,9-diamine derivatives are suitable for synthesis of annelated derivatives of imidazole, 1,2,3-triazole, pyrazine etc.

EFFECT: improved properties of the derivatives.

2 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-α]-[2]-benzazepin-10-carboxylic acid and a novel compound used in the method, and specifically to tert-butyl(methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate.

EFFECT: method is easier to implement and is more efficient than the existing method.

8 cl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

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