The method of obtaining 3-khinuklidinilbenzilata

 

(57) Abstract:

Usage: medicine, pulmonary-selective antimuskarinovoe act occurs bronchodilators. The inventive products: 3-khinuklidinilbenzilata f-ly 1, where X is phenyl, fluoro-substituted phenyl or thienyl, Y is a 5 - membered nitrogen-containing heterocycle selected from the group comprising imidazolyl, pyrazolyl, triazolyl or tetrazolyl or its hydrochloric salt. Reagent 1: compound f-crystals 2, where X and Y are the specified values. Reagent 2: diisopropylamide lithium or sodium hydride. Reagent 3: formaldehyde. Reaction conditions: in a medium of an organic solvent under cooling. 5 C. p. F.-ly, 3 tables.

The invention relates to 3-khinuklidinilbenzilata, specific to certain 3-hinokitiol 3-hydroxy-2-hetero - cyclic-2-phenyl - or tanypodinae, which are pulmonary-selective antimuskarinovoe act occurs bronholitin - ical means. Therefore, these compounds are particularly suitable in the treatment of chronic diseases the blockage of the respiratory tract (D) and asthma.

D is a term that encompasses conditions that are, in varying degrees, several major progressively developing clinical and pathological signs, and O is, excessive growth of tissue) secretory epithelial cells, which leads to increased secretion of viscous secreting mucus, which cannot be effectively eliminated, a progressive increase in irreversible bronchospasm and decrease the elastic thrust of the lung. This difficult path leads to progressive loss of lung function respiratory distress, increased morbidity, and, finally, death.

Thus, D and asthma are diseases, reduced lung function, in which the substance antimuskarinovoe act occurs bronchodilator increase the capacity of the respiratory tract. However, existing tools are not selective for muscarinic sites in smooth muscle in the lung, and this reduces their effectiveness as bronchodilators and can cause unwanted side effects. As it is known at the present time, in the respiratory tract there are subtypes of muscarinic receptor: receptors M1present on sympathetic nerves and parasympathetic ganglia; receptors M2present on pulmonary cholinergic nerves (inhibiting presynaptic receptors and receptors M3located on smooth muscle (postsynaptic Rotz the e slightly affect other tissues, such as the brain, heart, gastrointestinal tract, eyes, and salivary gland. In addition, they typically exhibit a selectivity relative to the pulmonary postsynaptic receptors M3in contrast to pulmonary presynaptic receptors M2and cardiac receptors M2. You can provide a therapeutic effect in some other sites in smooth muscle. For example, the compounds of the invention, apparently, is suitable in the treatment of urinary incontinence.

Thus, the invention provides a compound of formula I

or its pharmaceutically acceptable salt, where X denotes a phenyl group, a fluoro-substituted phenyl or thienyl group, and Y denotes a 5-membered nitrogen-containing heterocyclic group attached to adjacent carbon atom or carbon ring or the nitrogen atom of the ring, and selected from imidazolyl, pyrazolyl, triazolyl and tetrazolyl.

X preferably denotes either (a) phenyl group, optionally substituted by 1 or 2 fluorine atoms, or ( b) a 3-thienyl group, X is most preferably denotes unsubstituted phenyl group.

Y preferably denotes unsubstituted heterocyclic group as defined above.

Specialist in the art will understand that in the compounds I are two asymmetric center, namely, provisions, identified as 2-u3'. All diastereoisomer, separated or not, are within the scope of the present invention. Preferred esters are complex 3R-hinokitiol-esters. In addition, the preferred stereochemistry at position at position 2 is R. Thus, the preferred compounds are (2R, 3'R)-3-hinokitiol propanoate, and they can be represented in the following form

< / BR>
Especially preferred compound of the invention is (2R, 3'R)-3-hinokitiol-3-hydroxy-2-(1H-imidazol-1-yl)-2-phenylpropanoate.

The compounds of formula I can be obtained by interaction of ester of formula II with a strong base, such as diisopropylamide lithium or potassium t-piperonyl potassium or sodium hydride, with the formation of a carbanion, followed by the interaction of a carbanion with formaldehyde. Formaldehyde is mostly either gaseous formaldehyde, either in the form of performedin are the following.

In one case, the ester II is subjected to interact within a few hours with diisopropylamide lithium in tetrahydrofuran at a temperature of about -78aboutC. the Reaction mixture was then slowly warmed to room temperature, and during this period of time, gaseous formaldehyde, produced, for example, by heating paraformaldehyde, intermittently goes into solution.

In another case, sodium hydride, ester II and paraformaldehyde are subjected to joint cooperation in tetrahydrofuran at room temperature.

Preferred are compounds I having the R stereochemistry at position 3', and these connections better get starting with a complex ester II with R stereochemistry at position 3', in the formula II. Similarly, esters 3S hinokitiol can be obtained from the esters II has S stereochemistry at position 3'.

Usually it is most convenient to start with forms 2RS esters II, even if the required end products 2R or 2S, not 2RS. This results in a mixture of diastereoisomeric compounds I and, if desired, they can be allocated in the form 2R and 2S traditional methods, such as fractionated crystallis the parameters are of the form (2R, 3'R) compounds I.

New esters II are also part of the present invention.

The initial substance II receive traditional ways, such as

C2-alkyl)Connection(II)< / BR>
Communication is usually carried out by heating the reactants in an organic solvent, such as toluene, at a temperature of phlegmy. Compound III is most conveniently used in the form of R and, preferably, as the methyl ester.

Source materials III are also part of the present invention.

The initial substance III is also easy to obtain by traditional methods. When the heterocycle Y attached to adjacent carbon atom with a nitrogen atom, then the following method is preferred: -

< / BR>
(IV) +U-H/Base (for example, K2CO3)_______> Compound III

Many bromoethylene IV are known, and obtaining any new bromoethane can be done in the traditional way, as described, for example, receives, 23-26.

When the heterocycle Y attached to adjacent carbon atom by the introduction of the atom operatevehicle, then the compound III can be obtained/ for example/ ledouxnebria:

< / BR>

Selectivity of compounds as antagonists of muscarinic receptor can be measured as follows.

Guinea pigs male kill, then remove the terminal ileum, trachea, bladder and right atrium and suspended in Krebs solution under tension alone 1 g 30aboutWith, hareruya 95% O2and 5% CO2. Ileal contractions, bladder and trachea register using isotonic (the ileum) or isometric transducer (bladder and trachea). The frequency of contractions spontaneously pulsating double fibrillation receive from isometrically registered cuts.

The curves of dependence "dose-effect" to carbachol determined using time contacting 1-5 min for each dose of agonist up to produce the maximum response. Bath with bodies, drain and re-fill with Krebs solution containing most of the small dose of the test compound. Test connection counterbalance cloth for 20 min and the curve of dependence "dose-effect" of the agonist (substance having affinity to the receptor) is determined up to produce the maximum response. Bath with ornia, and the above method is repeated. Usually relative to each tissue appreciate the three concentrations of the test compounds.

The negative logarithm of the molar concentration (pA2) of the test compound which causes a doubling of the concentration of the agonist with the original receipt of the response, is determined by Schild analysis.

Using the pharmacological methods, determine the selectivity of fabrics for antagonists Muscari - new receptor.

Activity against agonist-induced or neravnovesnogo bronchostenosis or contractility of the gut or bladder compared with the heart rate determined at shot dog, cat or Guinea pig. Oral activity is estimated at being in the mind of the dog, determining the effects of compounds on lung, heart rate, pupil diameter, and peristalsis of the intestine.

Affinity connections to other cholinergic sites evaluated in mice after intravenous or intraperitoneal administration. So, determine the dose that causes a doubling of the diameter of the pupil, as well as the dose which inhibits the response of salivation and tremor at GNC the receptors against presynaptic muscarinic receptors have shot Guinea pigs and cats can be evaluated by the following methods. Acetylcholine released by nerve stimulation, activates postsynap - political muscarinic receptors M3causing contraction of smooth muscles in the Airways and, in addition, activates presynaptic autoreceptor that inhibit further release of transmitters. Animal studies show that these pulmonary presynaptic muscarinic autoreceptor have a subtype of M2.

Non-selective agents, such as ipratropium, inhibit both sites, leading, in the case of nerve-mediated reactions, to improve the release carrier that can overcome the blockade of postsynaptic receptor. Published work indicates that ipratropium may actually allow vagus-induced broncho - tenos the shot of Guinea pigs. Thus, the effects of the tested compounds on pre - and postsynaptic muscarinic sites can be determined in vivo by comparing the effects on the reactions mediated by nerves, with impact on the response to exogenous input acetylcholine.

For example, the compound of example 1, as detected antagonisitic as acetylcholine-induced, and vagus - induced Bronkhorst is that it is significantly less potent agent against vagus-induced, than against acetylcholine-induced, bronchostenosis. In addition, at doses below 1 mg/kg of ipratropium vagus-induced bronchostenosis actually becomes possible, which confirms the presynaptic effects of this connection.

Similar results were obtained in the use of the compounds of example 1 shot on the cat. Animals pre-treated with propanol as high sympathetic tone under anesthesia by chloralose may oppose potentiation of bronchostenosis induced vagus nerve. The test results show that in addition to high potency, the compound of example 1 in contrast to ipratropium does not violate regulation with negative feedback release carrier as in Guinea pigs, and cats. This confirms demonstrated in vitro selectivity of this compound for muscarinic receptor M3in contrast, muscarinic receptors M2.

The new compounds of the invention are potent and selective antagonists at the muscarinic receptors. The accompanying table. 1 illustrates these properties by comparing the antagonism Muskham2(the atrium of the Guinea pig). As standards in table. 1 also includes laboratory data for Tropicana and applied in the clinical setting protivokashlevyh of bronchodilators: atropine and bromide ipratropium. From the above table. 1 data for RA2it is seen that the standard tools significantly aselective and nerazreshayut M2and M3the receptors. On the contrary, the compounds of the invention are selective antagonists of muscarinic receptor M2in the result, have increased bronchodilatory action as a result of a substantial reduction of unwanted side effects. From table. 1 can also be noted that in those cases when they were separated and tested two possible diastereoisomer (see examples 1,2,3,5 and 6), it is shown that much of the activity and selectivity associated with one of them. Preferred diastereoisomer, usually more slowly washed away in TLC (lower values of Rfand, as I believe, has an absolute (2R, 3'R)-configuration, which is based on the correlation between Rfand x-ray crystallographic data obtained for examples 1A and 1B. The Complainant alleges that the excellent selectivity in the lungs at the level of technique.

Compounds of the invention tested in therapeutic doses intravenously to Guinea pigs, mice and cats, as well as oral in rats and dogs, and showed no visible signs of unacceptable toxicity. One of the compounds tested orally on a man without any evidence of toxicity. More intensive testing on human subjects is conducted with the purpose of accumulation of further data on safety and on the currently available evidence of the connection can be considered toxic.

Data for RA2 in vitro, the selectivity for muscarinic receptors of Guinea-pig trachea (M3in comparison with receptor atrium (M2) are given in table. 1.

As a result of this selectivity for postsynaptic muscarinic receptors in contrast to the presynaptic muscarinic receptors of the compounds of the present invention to be more effective bronchodilators means in respiratory disease, compared with ipratropium.

Acidic agents, additive salts of compounds of formula I can be obtained in the traditional way by treating a solution or suspension of the free base of compound I pribliziteljny methods of concentration and recrystallization. Examples of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, brimstowad - native, itestosterone, sulfamic, acid, such as methanesulfonate, benzoylacetate, and related items acid.

For the treatment of various conditions described above, the compounds of formula I can be administered to the patient using a variety of conventional routes of administration, including oral administration, and the composition of aerosols or dry powder for administration by inhalation. Connections are able to be absorbed through the gastrointestinal tract, and therefore you can also use the introduction of the drug in the formulations with prolonged action (slow-release preparations - tion).

Typically, a therapeutically effective oral dosage for active compounds of the formula I is from 0.01 to 1 mg/kg of body weight of the patient, preferably, from 0.1 to 0.5 mg/kg In practice, the doctor will determine the actual dosage which will be most suitable for an individual patient and it will vary depending on age, weight and response of the individual moments, when you can enter a higher or lower dosage, and they are within the scope of the present invention.

Although the compounds of formula I can be administered separately, they are usually introduced in a mixture with a pharmaceutical carrier selected from considerations of the intended route of administration and standard pharmaceutical practice. For example, oral administration may be in the form of tablets containing such excipients as starch or lactose, in capsules either alone or in mixture with fillers, in the form of aerosols or dry powder or in the form of elixirs or suspensions containing flavoring or coloring agents.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

The invention also includes a compound of formula I or its pharmaceutically acceptable salt for use as a medicine.

The invention also includes the use of compounds of formula I or its pharmaceutically acceptable salt for the manufacture of medicines used dirout obtain compounds 1:

P R I m e R 1.

a) Monohydrate (2R, 3'R) 3-hinokitiol-3-hydroxy-2-(1H-imidazol-1-yl)-2-phenyl - propanoate

< / BR>
Sitedisability (LDA) in tetrahydrofuran (THF) (361 ml of 1.5 M solution) was added to a solution of (2R, 3'R)-3-hinokitiol 2-(1H-imidazol-1-yl)phenylacetate (see obtaining 1) (152,9 g) in tetrahydrofuran (3.5 l) at a temperature of -78aboutC. After 2 h the reaction mixture was slowly brought to room temperature, and during this time intermittently added gaseous formaldehyde (usually by heating paraformaldehyde (39 g) in a stream of nitrogen). Then add saturated aqueous solution of ameriglide and the organic layer is successively extracted with a solution of ammoniaand (5 x 250 ml) and 1M hydrochloric acid solution (2 x 250 ml). The combined aqueous extracts are extracted with ethyl acetate, alkalinized with solid potassium carbonate and extracted with additional ethyl acetate. Organic extracts, before and after alkalizing, separately dried in the presence of magnesium sulfate, evaporated under reduced pressure and crystallized from acetone. The combined solid is recrystallized from acetone to obtain (2R, 3'R)3-hinokitiol 3-hydroxy - 2-(1H-imidazol-1-yl)-2-phenylpropionate in methanol (100 ml), filtered, evaporated to dryness under reduced pressure and dissolved in cold 0.1 M hydrochloric acid (305 ml). The addition of 0.1 M solution of sodium hydroxide (305 ml) results specified in the connection header in the form of a solid white color (6,9 g, 68% ), melting point 90-91aboutC. []58925+7,6about(C = 1% in ethanol).

Found, % : C 63,53; N 7,06; N 11,73.

WITH19H23N3ABOUT3H2O.

Calculated, % : C 63,49; N 7,01; N Of 11.69.

b) Hemihydrate (2S, 3'R)3-hinokitiol-3-hydroxy-2-(1H-imidazol-1-yl)-2 - phenylpropanoate.

Concentration of the acetone mother solutions from part (a) results, with a slow crystallization specified in the connection header 2S in the form of a solid white color, melting point 143-145aboutC [ ]58925-8,8about(C= 1% in ethanol).

Found, % : C 65,06; N 6,76; N Of 11.69.

WITH19H23N3O31/2 H2O.

Calculated, % : C 65,12; N 6,90; N 11,99.

P R I m m e R 2. Dihydrochloride (2R, 3'R) and (2S, 3'R) 3-hinokitiol-3-hydroxy-2-phenyl-2-(1H-1,2,4-triazole-1-yl) propanoate

< / BR>
Sitedisability (13,77 ml of 1.5 M solution in tetrahydrofuran) was added to RA the ri -78aboutC. After 2 h the reaction mixture was slowly brought to room temperature, and during this period of time c intermittent added gaseous formaldehyde (generated by heating paraformaldehyde (10 g) in a stream of nitrogen). Then add saturated aqueous solution of ameriglide, tetrahydrofuran evaporated and the aqueous residue partitioned between 10% aqueous potassium carbonate solution and ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and evaporated under reduced pressure to get crude product, which was purified by chromatography on silica gel performing a gradient elution using dichloromethane and methanol (2 ->10% ) as eluent. Evaporation of the appropriate fractions yields a remainder (330 mg) which is purified by chromatography on silica gel, elwira a mixture of ethyl acetate(simple ether)-diethylamine/methanol (50: 50: 5: 5) to give after evaporation of the appropriate fractions and processing ethereal hydrogen chloride two mentioned in the title compounds as white amorphous phone

Diastereoisomer I (higher Rfwhen thin-layer chromatography) (110 mg, 2.8 per cent )

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2,1

1,8 (m, 4P CLASS="ptx2">

Diastereoisomer II (lower Rfwhen thin-layer chromatography) (150 mg, 3.8 percent ):

1H-NMR (300 MHz, CDCl3), : to 1.2-1.8 (m, 4H), 2,1 (m, 1H), 2,6-2,9 (m, 5H), of 3.25 (m, 1H), 4,4-4,7 (m, 2H), 5,0 (m, 1H), 7,2-7,5 (m, 5H), 7,98 (s, 1H), 8,07 (s, 1H) ppm

Mass spectrum: m/e (M+) = 342.

Does not explain what diastereoisomer has the stereochemistry 2R, and a 2S.

P R I m e R 3. Dihydrochloride (2R, 3'R) and (2S, 3'R)-3-hinokitiol-3-hydroxy-2-phenyl-2- (1H-1,2,3-triazole-1-yl)propanoate.

< / BR>
(2RS, 3'R) 3-hinokitiol 2-phenyl-2-(1H, 1,2,3-triazole-1-yl)acetate (see 3) (2.1 g) in tetrahydrofuran (60 ml) was worked up as described in example 2, lifedisabilities (5,15 ml of 1.5 M solution in tetrahydrofuran) and gaseous formaldehyde (4 g). The crude product is purified by chromatography on silica gel, elwira a mixture of ethyl acetate /simple ether/ diethylamine/-methanol(50: 50: 5: 5), obtaining after evaporation of the appropriate fractions and processing of ethereal hydrogen chloride two mentioned in the title compounds as white amorphous solid phone does Not explain what diastereoisomer has the stereochemistry 2R, and a 2S.

Diastereoisomer I (higher Rfwhen thin-layer chromatography) (155 mg, 11.2 per cent ):

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2,1 (m, 1H), 2,6-3,0 (m, 5H), 3,low Rfwhen thin-layer chromatography) (80 mg, 5.8 percent ):

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2,1 (m, 1H), 2,6-3,0 (m, 5H), 3,3 (m, 1H), 4,5-4,9 (m, 2H), 501 (m, 1H), 7,2-7,5 (m, 6N), and 7.8 (s, 1H) ppm

Mass spectrum: m/e (M+) = 342.

P R I m e R 4. The dihydrochloride (2RS, 3'R) 3-hinokitiol-3-hydroxy-2-phenyl-2-(1H-pyrazole-1-yl)propanoate.

*(R, S)

(2RS, 3'R) 3-hinokitiol-2-phenyl-2-(1H, pyrazole-1-yl)acetate (see obtaining 4) (1.18 g) in tetrahydrofuran (30 ml) was worked up as described in example 2, lifedisabilities (3,03 ml of 1.5 M solution in tetrahydrofuran) and gaseous formaldehyde (2.4 g) to give the crude product, which after treatment with ethereal hydrogen chloride gives specified in the title compound, mixture of diastereoisomers, in the form of an amorphous white solid (1,33 g, 85% ).

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2,1 (m, 1H), 2,6-3,0 (m, 5H), of 3.25 (m, 1H), 4,4-4,8 (m, 2H), 5,1 (m, 1H), and 6.3 (s, 1H), 7,15 (s, 1H), 7,2-7,5 (m, 5H), the 7.65 (s, 1H) ppm.

Mass spectrum: m/e (M+) = 341.

P R I m e R 5. (2R, 3'R) and (2S, 3'R) 3-hinokitiol 3-hydroxy-2-phenyl-2-(1H-tetrazol-1-yl)propanoate

*(R,S)__

*(RandS)< / BR>
Sodium hydride (23 mg, 80% dispersion in oil) was added to a mixture of (2RS, 3'R) 3-hinokitiol 2-phenyl-2-(1H-tetrazol-1-yl)-acetate (see obtaining 5) (0.7 g) and preformulation of ameriglide, the tetrahydrofuran evaporated under reduced pressure and the aqueous residue extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and evaporated under reduced pressure, obtaining a residue, which is purified by chromatography on silica gel performing a gradient elution using dichloromethane and methanol (2 ->10% ) as eluent. Evaporation of the appropriate fractions produces two listed in the connection header. It is not clear which isomer has the stereochemistry 2R, and a 2S stereochemistry.

Diastereoisomer I (higher Rfwhen thin-layer chromatography) as a yellow oil (21 mg, 5.4 percent ):

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2,1 (m, 1H), 2,6-3,0 (m, 5H), 3,3 (m, 1H), 4,7 (m, 2H), of 5.05 (m, 1H), 7,2-7,6 (m, 5H), 8,9 (s, 1H) ppm. Mass spectrum m/e (M+) = 343.

Diastereoisomer II (lower Rfwhen thin-layer chromatography) as a waxy yellow solid (10 mg, 2.5 percent ):

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), of 2.05 (m, 1H), 2,6-2,9 (m, 5H), 3,2 (m, 1H), 4,7 (m, 2H), 5,1 (m, 1H), 7,2-7,6 (m, 5H), cent to 8.85 (s, 1H) ppm.

Mass spectrum: m/e (M+) = 343.

P R I m e R 6. The dihydrochloride (2R, 3'R) and (2S, 3'R) 3-hinokitiol-3-hydroxy-2-(1H-imidazol-1-yl)-2- (Tien-3-yl)propanoate.

*(R,S)___

*paraformaldehyde (0.12 g) in tetrahydrofurane (20 ml) is treated, as described in example 5, sodium hydride (31 mg) to give the crude product, which was purified by chromatography on silica gel using a mixture of ethyl acetate /simple ether/methanol/diethylamine (50: 50: 5: 5) as eluant. Evaporation of the appropriate fractions and processing of ethereal hydrogen chloride results in the two mentioned in the title compounds (non-characterized stereochemistry) in the form of an amorphous solid white.

Diastereoisomer I (higher Rfwhen thin-layer chromatography) (220 mg, 33% ):

1H-NMR (300 MHz, CDCl3) : 0,8-1,8 (m, 4H), 2.0 (m, 1H), 2.4 to 2.8 (m, 5H), of 3.25 (m, 1H), 4,3-4,6 (m, 2H), 4.95 points (m, 1H), 7,0-7,8 (m, 6N),

Mass spectrum: m/e (M+) = 347.

Diastereoisomer II (lower Rfwhen thin-layer chromatography) 180 mg, 27% ):

1H-NMR (300 MHz, CDCl3) : 0,8-1,8 (m, 4H), 2.0 (m, 1H), 2,6-2,8 (m, 5H), 3,2 (m, 1H), 4,3-4,6 (m, 2H), 5,0 (m, 1H), 7,0 (m, 3H), of 7.4 (m, 2H), and 7.7 (s, 1H).

Mass spectrum: m/e (M+) = 347.

P R I m e R 7. The dihydrochloride (2RS, 3'R)-3-hinokitiol-2-(4-forfinal)-3-guide - Roxy-2- (1H-imidazol-1-yl)propanoate.

*(R,S)___

*(R,S)< / BR>
(2RS, 3'R)-3-hinokitiol-2-(4-forfinal)-2-(1H-imidazol-1-yl)acetate (see obtaining 7) (0.73 g) in tetrahydrofuran (25 ml) was worked up as described in example 2, litigaiton is clear that by chromatography on silica gel, performing gradient elution with dichloromethane containing methanol (0 ->10% ) and concentrated ammonia (0 ->1% ). Evaporation of the appropriate fractions and processing of ethereal hydrogen chloride yield specified in the title compound, mixture diesterase - Mer, in the form of an amorphous solid white (0,59 g, 61% ).

1H-NMR (300 MHz, CDCl3) : 0,8-2,2 (m, 5H), 2,6-3,6 (m, 6N), 4,2-4,6 (m, 2H), 5,0 (m, 1H), 7,0-7,8 (m, 7H).

ppm Mass spectrum: m/e (M+) = 359.

P R I m e R 8. The dihydrochloride (2RS, 3'R)-3-hinokitiol-2-(2-forfinal)-3-guide - Roxy-2- (1H-imidazol-1-yl)propanoate.

*(R,S)__

____ *(R,S)< / BR>
Specified in the title compound is obtained from (2RS, 3'R)-3-hinokitiol-2-(2-forfinal)-2-(1H-imidazol-1-yl)acetate (see getting 8) (0.96 g), sitedisability and gaseous formaldehyde by the method described in example 7, in the form of an amorphous solid white (0.51 g, 40.5 percent ).

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2.0 (m, 1H), 2,5-3,0 (m, 5H), of 3.25 (m, 1H), 4,3 (m, 2H), 5,0 (m, 1H), 6,8-of 7.3 (m, 6N), and 7.9 (s, 1H) ppm

Mass spectrum: m/e (M+) = 359.

P R I m e R 9. The dihydrochloride (2RS, 3'R)-3-hinokitiol-3-hydroxy-2-(1H-them - Gasol-4(5)-yl)-2 - phenylpropanoate.

*(R,S)___

*(R,S)< / BR>
(2RS, 3'R)-3-hinokitiol-2-Hairdryer is e 2, lithium-diisopropylamide (2,45 ml of 1.5 M solution in tetrahydrofuran) and gaseous formaldehyde (1 g) to give the crude product, which was purified by chromatography on silica gel performing a gradient elution using a mixture of dichloromethane / concentrated ammonia (80: 1) and 5 ->20% methanol as eluant. Evaporation of the appropriate fractions and processing of ethereal hydrogen chloride yield specified in the title compound, a mixture of diastereoisomers, in the form of an amorphous solid white (173 mg, 23% ).

1H-NMR (300 MHz, DMCO-D6) : of 1.4-2.3 (m, 5H), 3,0-3,3 (m, 5H), 3,6 (m, 1H), 4,2-4,5 (m, 2H), 5,1 (m, 1H), 7,2-7,6 (m, 6N), and 9.1 (s, 1H) ppm

Mass spectrum: m/e (M+) = 341.

P R I m e R 10. The dihydrochloride (2RS, 3'R)-3-hinokitiol-3-hydroxy-2-phenyl-2-(1H-pyrazole-4-yl)propanoate.

*(R, S) ___

*(R,S)< / BR>
Specified in the header of the get connection similar to that described in example 9 by means of (2RS, 3'R)-3-hinokitiol-2-phenyl-2-(1H-pyrazole-4-yl)acetate (see 10) (0.9 g). Specified in the title compound, mixture of diastereoisomers receive in the form of an amorphous solid white (290 mg, 24% ).

Found, % : C 55,27; N 6,50; N 9,90.

WITH19H23N3O32HCl.

*(R,S)___

___ *(R,S)< / BR>
Specified in the header of the get connection similar to that described in example 9 by means of (2RS, 3'R)-3-hinokitiol-2-phenyl-2-(1H-pyrazole-3(5)-yl) acetate (see 11) (0.71 g). Specified in the title compound, mixture of diastereoisomers receive in the form of an amorphous white solid (500 mg, 53% ).

Found, % : C 53,53; N 6,03; N 9,46.

WITH19H23N3O32HCl 1/2 H2O.

Calculated, % : C 53,91; N Is 6.19; N 9,92.

Following receipt illustrate the preparation of the new starting compounds used in the previous examples.

Receiving 1.

(2RS, 3'R)-3-hinokitiol-2(1H-imidazol-1-yl)phenylacetate.

< / BR>
Sodium hydride (4.6 g as an 80% dispersion in oil) after washing with toluene is added to (R)-3-hinokitiol (100,8 g) and (RS)methyl-2-(imidazol-1-yl)phenylacetate (see obtaining 12) (132 g) in toluene (2.5 l). The mixture is heated under reflux for two hours with continuous removal of distillate, adding, when necessary, fresh toluene. Add saturated salt solution, the toluene is decanted and the aqueous residue partitioned between brine and ethyl acetate. Extracts of ethyl acetate and toluene separately is related to the title compound as orange oil (152,2 g, 82% ).

1H-NMR (300 MHz, CDCl3) : 1,2-1,8 (m, 4H), 2.0 (m, 1H), 2,75 (m, 5H), 3,3 (m, 1H), 5,0 (m, 1H), 5,95 (s, (1H), 7,25 (s, 1H), and 7.3 (s, 1H), and 7.4 (m, 5H), and 7.6 (s, 1H) ppm.

Mass spectrum: m/e (M+) = 311.

Get 2-11.

The following are listed in the table. 2 preparations of the General formula.

receive in the form of oils similar to those described in obtaining ways I using (R)-3-hinokitiol and the corresponding methyl ester in toluene, using as a catalyst sodium hydride. Exchanged heterocyclic proton in drugs 9, 10 and 11 causes the use of an additional equivalent of sodium hydride. In preparation 10 connection turned into the dihydrochloride using gaseous hydrogen chloride in a simple ether as the last stage. Clearing, where necessary, is a chromatography gradient elution on silica gel, using these solvents.

Getting 12.

(RS)Methyl-2-(imidazol-1-yl)-2-phenyl-acetate.

N

(RS)Methyl-2-bromo-2-phenylacetate (171,75 g), imidazole (102 g) and potassium carbonate (227,7 g) is stirred in acetone (1,75 l) for 60 hours. After settling the supernatant liquid is decanted and the residue washed thoroughly with acetone. Acetone ParisHiltonnude acid. The combined acid extracts after simple washing with ether, acidified with solid potassium carbonate and extracted with toluene containing 10% of ethyl acetate. The organic extracts are dried in the presence of magnesium sulfate and evaporated under reduced pressure to obtain specified in the title compound as yellow oil (132 g, 82% ).

1H-NMR (300 MHz, CDCl3) : 3,85 (s, 3H), 5,95 (s, 1H), 7,05 (s, 1H), and 7.1 (s, 1H), 7,2-7,5 (m, 5H), and 7.6 (s, 1H) ppm.

13.

(RS) Methyl-2-phenyl-2-(1H-1,2,4-triazole-1-yl)acetate.

*(R, S)

A mixture of (RS)methyl-2-bromo-2-phenylacetate (25 g), 1,2,4-triazole (of 8.28 g) and potassium carbonate (16.5 g) in acetonitrile (200 ml) is heated under reflux for 3 hours, cooled, evaporated under reduced pressure and the residue distributed between ethyl acetate and 10% potassium carbonate solution. The organic extracts washed with water, twice extracted with 2M hydrochloric acid and the combined acid extracts after simple washing with ether, acidified with solid potassium carbonate and extracted with ethyl acetate. The organic extracts are dried in the presence of magnesium sulfate and evaporated under reduced pressure to obtain specified in the connection header in the form of a yellow oil is>/P>Obtain 14-19.

These are shown in table preparations of the General formula:

get the same described in the getting 12 or 13 of ways, using appropriate complex bromo-ether and a heterocycle (N-Het). Separate experimental variants are given in table. 3. Clearing, where it is needed, is a chromatography on silica gel with gradient elution using the indicated solvents.

20.

(RS)Methyl-2-(1H-imidazol-4(5)-yl)-2 - phenylacetate.

*(R,S)*(R,S)< / BR>
(RS)-2-(1H-imidazol-4(5)-yl)-2-phenyl-cetamide (see getting 27) (1.3 g) in methanol (25 ml) is stirred at reflux in an atmosphere of gaseous hydrogen chloride for 1.5 h, evaporated under reduced pressure and distributed between ethyl acetate and 10% aqueous solution of potassium carbonate. The organic layer is dried in the presence of magnesium sulfate, evaporated under reduced pressure and the residue proscout simple ether to obtain specified in the connection header in the form of a solid body in white (830 mg, 59% ), melting point 96-98aboutC.

Found, % : C 66,52; N To 5.57; N 12,97.

WITH12H12N2O2.

R>
Specified in the header connection receive in accordance with the method described in obtaining 20 using (RS)-2 - phenyl-2-(1H-pyrazole-4-yl)ndimethylacetamide (see on - torching 28) (1.9 grams). Specified in the title compound in the form of a solid white color is obtained by poroshkovaya hexane (1,74 g, 85% ), melting point 100-103aboutC.

Found, % : C 66,54; N 6,63; N 12,90.

WITH12H12N2O2.

Calculated, % : C 66,65; N 5,59; N 12,96.

Getting 22.

(RS)Methyl-2-phenyl-2-(1H-pyrazole-3-(5)-yl)acetate

*(R,S)< / BR>
Specified in the header connection receive in accordance with the method described in obtaining 20 using (RS)-2-phenyl-2-(1H-pyrazole-3(5)-yl)aceta - MFA (see getting 29) (2.0 g). The connection specified in the form of a solid white color is obtained by poroshkovaya hexane (1.6 g, 74% ), melting point 83-85aboutC.

Found, % : C 66,60; N 5,59; N 12,95.

WITH12H12N2O2.

Calculated, % : C 66,65; N 5,59; N 12,95.

23.

(RS)Methyl-2-bromo-2-(Tien-3-yl)acetate

S

A mixture of (RS)methyl-2-hydroxy-2-(Tien-3-yl)acetate (see getting 24) (4,49 g), triphenylphosphine (8,21 g) and chetyrehpostovye carbon (10.4 g) in acetonitrile (100 ml) load misty carbon (3 g), followed by heating under reflux for 2 hours After cooling, the mixture is used directly, without further purification, in obtaining 17.

Obtaining 24.

(RS)Methyl-2-hydroxy-2-(Tien-3-yl)ACE - tat

S

A mixture of ( RS ) 2 - hydroxy - 2 -( Tien-3-yl ) acetic acid (obtained as described in Akiv. CEM. 58,519, 1957) (6,32 g), methyl iodide (17 g) and potassium carbonate (6.0 g) in acetone is heated under reflux for 2 hours, evaporated under reduced pressure and the residue distributed between ethyl acetate and water. Organic extracts, after drying in the presence of magnesium sulfate is evaporated to obtain specified in the title compound as a yellow oil (4,49 g, 67% ).

1H-NMR (300 MHz, CDCl3) = 3,85 (m, 3H), to 5.35 (m, 1H), 7,15 (d, 1H), 7,35 (m, 2H) ppm.

Getting 25.

(RS)Methyl-2-bromo-2-(4-forfinal)ACE - tat

< / BR>
4-florfenicol acid (30,6 g), phosphorus trichloride (2 g) and bromine (36 g) in benzene (100 ml) is heated under reflux for 2 days, cooled, add thionyl chloride (47 g) and N, N-dimethylformamide (0.2 g), after which the reaction mixture is heated under reflux for 1 h, cooled and added methanol (100 ml). The resulting mixture was heated under reflux for 1/2 hour, cooled, evaporated under POI (35 g, 71% ), boiling point 104aboutWith/ 2 mm RT. senior 1H-NMR (300 MHz, CDCl3) = 3,8 (3H, s), to 5.35 (s, 1H), and 7.1 (m, 2H), 7,55 (m, 2H).

Getting 26.

(RS)methyl-2-bromo-2-(2-forfinal)ACE - tat.

r

Treatment 2-florfenicol acid (30,6 g) in accordance with the receipt of 25 results specified in the connection header in the form of a light fluid (28 g, 57% ), boiling point 90-92about(2 mm RT. Art. ).

1H-NMR (300 MHz, CDCl3) = 3,85 (s, 3H), of 5.75 (s, 1H), 7,0-7,8 (m, 4H).

Getting 27.

(RS) 2-(1H-imidazol-4(5)-yl)-2-phenylacetamide.

< / BR>
(RS) 2-(1H-imidazol-4(5)-yl)-2-phenylacetonitrile (see 30) (1,69 g) in concentrated sulfuric acid (6 ml) is stirred for 18 hours at a temperature of 0aboutWith carefully alkalinized 50% aqueous sodium hydroxide solution and extracted with ethyl acetate containing 5% methanol. The organic layer is dried in the presence of magnesium sulfate, evaporated under reduced pressure and the residue crystallized from ethyl acetate to obtain specified in the connection header in the form of a solid white color (1,36 g, 73.5 percent ), melting point 146-147aboutC.

Found, % : C 65,05; N 5,43; N 20,76.

WITH11H11N3O.

Vici Specified in the header connection receive in accordance with the method, described in obtaining 27, using (RS) 2-phenyl-2-(1H-pyrazole-4-yl) acetonitrile (2.14 g) (see getting 31).

The specified connection receive in the form of a solid white color (1,94 g, 82.5 percent ), melting point 193-195aboutC.

Found, % : C 65,40; N Vs. 5.47; N 20,96.

C11H11N3O .

Calculated, % : 65,66; N. Of 5.50; N To 20.88.

Getting 29.

(RS) 2-phenyl-2-(1H-pyrazole-3(5)-yl)ndimethylacetamide.

< / BR>
Specified in the header connection receive in accordance with the method described in obtaining 27, using (RS) 2-phenyl-2-(1H-pyrazole-3(5)-yl)acetonitrile (3.0 g) (see getting 32). The specified connection is obtained from dichloro - methane in the form of a solid white color (2,33 g, 71% ), melting point 65-67aboutC.

Found, % : C PHP 64.00; H 5,38; N 20,08.

WITH11H11N3O 1/4 H2O.

Calculated, % : C 64,21; N 5,63; N 20,42.

30.

(RS) 2-(1H-imidazol-4(5)-yl)-2-phenylacetonitrile

< / BR>
(RS) 2-(1H-imidazol-4(5)-yl)-2-phenylethanol (see getting 33) (3,74 g) was added to thionyl chloride (35 ml) at a temperature of 0aboutC, stirred for 45 min and evaporated under reduced pressure to obtain an oily residue. Double-add chloroform (30 Iniciando (11,14 g) in dichloromethane (150 ml). After 15 min at a temperature of 0aboutC and 30 min at room temperature, the solvent evaporated and the residue distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer is dried in the presence of magnesium sulfate and the residue after evaporation purified by chromatography on silica gel with ethyl acetate as eluant, receiving, after evaporation of the appropriate fractions and crystallization from ethyl acetate, specified in the title compound in the form of solid white (1,69 g, 51,4% ), melting point 124-126aboutC.

Found, % : C 71,94; N 4,89; N 22,94.

WITH11H9N3.

Calculated, % : C 72,11; N. Of 4.95; N 22,94.

Getting 31.

(RS) 2-phenyl-2-(1H-pyrazole-4-yl)acetonitrile

*(R,S)< / BR>
Specified in the header connection receive in accordance with the method described in obtaining 30 using (RS) 2-phenyl-2-(1H-pyrazole-4-yl)methanol.

The connection specified in the form of a solid white color is obtained by chromatography on silica gel using a mixture of simple ether /dichloromethane (50: 50) as eluant (2.2 g, 60% ), melting point 124-127aboutC.

Found, % : C 72,00; N. Of 4.95; N 22,86.

WITH11H9N3

< / BR>
Specified in the header connection receive in accordance with the method described in obtaining 30 using (RS) 2-phenyl-2-(1H-pyrazole-3(5)-yl)methanol instead of (RS) (1H-imidazol-3(5)-yl)phenylmethanol. Specified modifications materialize in the form of a solid white color is obtained by chromatography on silica gel using as ale - Anta simple mixture ether /dichloromethane (50: 50) (3.0 g, 75% ), melting point 57-60aboutC.

Found, % : C 71, 94; N To 4.87; N 22,96.

WITH11H9N3.

Calculated, % : C 72,11; N. Of 4.95; N 22,94.

Receive 33.

Hydrochloride (RS) 1-(1H-imidazol-4(5)-yl)-1-phenylethanol.

+PhMgBr_______Ph*(R, S)

Imidazol-4(5)-carboxaldehyde (2.9 g) in tetrahydrofuran (180 ml) was added to magnirostris (23,6 ml of 3M solution in a simple ether) in tetrahydrofuran (40 ml) at a temperature of 0aboutC. After 18 h was added a saturated aqueous solution of ameriglide and the mixture is extracted with ethyl acetate. The organic layer is dried in the presence of magnesium sulfate and the residue, after evaporation, purified by chromatography on silica gel by gradient elution using as eluant mixture of dichloromethane with 0-2% methanol, receiving the settlement is 3.1 g, 59% ), melting point 146aboutC.

Found, % : C 56,73; N 5,13; N 12,99.

WITH10H10N2O HCl.

Calculated, % : 57,01; N 5,26; N To 13.29. (56) Brit J. Pharmacol, 1959, 14. c. 48-58.

Fryer and Maclagan, Eur. Jou Pharmaca, 1987, 139, 1987-191.

Mashkovsky M. D. Medicines, including I, M. : Medicine, 1987, S. 159, 233, 246.

1. The METHOD of OBTAINING 3-KHINUKLIDINILBENZILATA General formula I

HOCO

where X is phenyl, fluoro-substituted phenyl or thienyl;

Y is a 5 - membered nitrogen-containing heterocyclic group selected from the group comprising imidazolyl, pyrazolyl, triazolyl or tetrazolyl, and attached to adjacent carbon atom or heterocyclic carbon atom or the heterocyclic nitrogen atom,

or hydrochloric salts, characterized in that 3-hinkleyville General formula II

< / BR>
where X and Y are the specified values,

subjected to interaction with a strong base - diisopropylamide lithium or sodium hydride followed by treatment of the resulting carbanion formaldehyde and selection of the target product or a translation of it if you want a hydrochloric salt.

2. The method according to p. 1, characterized in that the gain of the compounds of General formula the persons under item 2, wherein the receiving of the compounds of General formula I, where X is phenyl, Y IS 1H-imidazol-1-yl, 1H-1,2,3-triazole-1-yl, 1H-1,2,4-triazole-1-yl, 1H-pyrazole-1-yl, 1H-tetrazol-1-yl, 1H-imidazol-(4)(5)-yl, 1H-pyrazole-4-yl or 1H-pyrazole-3-(5)-yl.

4. The method according to p. 3, characterized in that the compound of General formula I, where Y IS 1H-imidazol-1-yl.

5. The method according to any of paragraphs. 1 to 4, characterized in that the gain of the compounds of General formula

H

where X and Y are the specified values,

in which each of the two asymmetric centers is R-configuration, by using the 3R-hinkleyville ether compounds of General formula II followed by the separation of the desired (2R, 3'R)-form from (2S, 3'R)-forms.

6. The method according to p. 5, characterized in that the compound of General formula I, which is (2R, 3'R)-3-hinokitiol-3-hydroxy-2-(1H-imidazol-1-yl)-2-phenylpropanoate.

 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to aryl-substituted pyrazoles or triazoles of the general formula (I): and their pharmaceutically acceptable salts, prodrugs or solvates wherein X means oxygen (O) or sulfur atom (S); Het means one of group of the formula wherein R1 means hydrogen atom (H), (C1-C6)-alkyl, aminocarbonyl, -C(O)R10; R2 and R3 mean independently hydrogen atom (H) or aminocarbonyl; R5, R6, R7 and R8 mean independently hydrogen (H), halogen atom, (C1-C6)-alkyl, -NO2; R10 means -OR11 wherein R11 means hydrogen atom (H), (C1-C6)-alkyl. Compounds of the formula (I) are useful for treatment of neuronal damages observing as result of total or focus ischemia, for treatment or prophylaxis of neurodegenerative states, such as amyotrophic lateral sclerosis and for treatment, prophylaxis or reducing intensity of acute or chronic pains, as agents against entotic sound, anticonvulsant agents, and as anti-maniacal depressants, topical analgesic agents, anti-arrhythmic agents and for treatment or prophylaxis of diabetic neuropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: in acidified indanylamines of general formula (I) R1-R4 have values given in description, A represents CH2, CHOH, B represents CH2 and R5 represents aryl or heteroaryl group, possibly substituted with substituents, listed in description. Said compounds are useful in regulation of endothelial nitrogen oxide synthase (eNOS) and, therefore they can be useful for production of medications for treatment of stable and unstable angina pectoris, Prinzmetal's angina, acute coronary syndrome, impaired heart function, cardiac infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, hypertension, lung hypertension, symptomatic hypertension, renovascular hypertension, erectile dysfunction, diabetes or diabetes complications, nephropathy, retinopathy, limited memory function, limited learning ability.

EFFECT: increase of composition efficiency.

37 cl, 441 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to 3 - (2-methoxy-4-pyrazol-1-ilfenil) -2,5-dimethyl-7-(3-methylpyridine-2-yl) pyrazolo [1.5-a] pyrimidine or its pharmaceutically acceptable salts, solvate, stereoisomer, having the following structural formula, which are antagonists of CRF-receptors and can be used in treatment of various disorders that cause hypersecretion of CRF in warm-blooded animals, such as at the sudden attack. Also the invention refers to intermediate compounds, pharmaceutical compositions on the basis of this compound and method of treating disorder causing hypersecretion of CRF in mammals.

EFFECT: improvement of composition.

15 cl, 14 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts wherein r represents 1; Ar is specified in and , R1 is specified in -COOR1a, -NHSO2R1b, -SO2NHR1d, -SO2OH, -O-CH(R1e)-COOH and tetrazol-5-yl, R1a represents H, -C1-6alkyl, -C1-3alkylenaryl, -C1-3alkyleneheteroaryl, - C3-7cycloalkyl, -CH(C1-4alkyl)OC(O)R1aa, or R1aa represents -O-C1-6alkyl or -O-C3-7cycloalkyl; R1b represents R1c; R1d represents -C1-6alkyl or -C0-4alkylenaryl; R1d represents -C(O)R1c or -C(O)NHR1c; R1e represents -C1-4alkyl; Y represents -C(R3)-, Z represents -N-, Q represents -C(R2)-, and W represents a bond; Y represents -N-, Z represents -C(R3)-, Q represents -C(R2)-, and W represents a bond; Y represents -C(R3)-, Z represents -N-, Q represents -N-, and W represents a bond; or Y represents -C(R3)-, Z represents -CH-, Q represents -C(R2)-, and W represents -C(O)-; R2 is specified in H, halogen, -C1-6alkyl, -C3-6dicloalkyl, and -C0-5alkylene-OR2b; wherein R2b is specified in H and -C1-6alkyl; R3 is specified in -C1-10alkyl and -C0-5alkylene-O-C0-5alkylene-R3b; and R3b represents -C1-6alkyl; X represents -C1-12alkylene-, where at least one group -CH2- in alkylene is substituted by the group -NR4a-C(O)- or -C(O)-NR4a-, wherein R4a is specified in H, -OH, and -C1-4aalkyl; R5 is specified in -C0-3 alkylene-SR5a, -C0-3alkylene-C(O)NR5bR5c, -C0-3alkylene-NR5b-C(O)R5d, -NH-C0-1alkylene-P(O)(OR5e)2, -C0-2alkylene-CHR5g-COOH and -C0-3alkylene-C(O)NR5h-CHR5i-COOH; R5a represents H or -C(O)-R5aa; R5aa represents -C1-6alkyl, -C0-6alkylene-C3-7cycoalkyl, -C0-6alkylenaryl, or -C0-6alkylenemorpholine; R5b represents -OH, -OC(O)R5ba, -CH2COOH or -OC(S)NR5bbR5bc; R5ba represents -C1-6alkyl, -OCH2-aryl or -CH2O-aryl; R5bb and R5bc independently represents -C1-4alkyl; R5c represents H; R5d represents H; R5e represents H; R5g represents H or -CH2-O-(CH2)2-O-CH3; R5h represents H; R5i represents -C0-3alkylenaryl; R6 is specified in -C1-6alkyl, -C0-3alkylenaryl, -C0-3alkyleneheteroaryl and -C0-3alkylene-C3-7cycloalkyl; and R7 represents H or together with R6 to form -C3-7cycloalkyl; where each ring in Ar and each aryl and heteroaryl in R1-3 and R5-6 are optionally substituted by 1-3 substitutes optionally specified in -C1-6alkyl, -CN, halogen, -O-C1-6alkyl, -phenyl, -NO2, wherein each alkyl is optionally substituted by 1-5 fluorine atoms; each carbon atom in X is optionally substituted by one or more groups R4b, and one group -CH2- in X may be substituted by -C4-8cycloalkylene- and -CH=CR4d-; where R4b is specified in -C0-5alkylene-COOR4c and benzene, where R4c represents H; and R4d represents -CH2-thiophen; each alkyl and each aryl in R1-3, R4a-4d and R5-6 are optionally substituted by 1-7 fluorine atoms; where aryl represents monovalent aromatic hydrocarbon having one ring or condensed rings, and contains 6-10 carbon atoms in the ring; and heteroaryl represents a monovalent aromatic group having one ring or two condensed rings, and having 5-10 atoms in large in the ring with one atom of the ring represents a heteroatom specified in nitrogen, oxygen and sulphur. Besides, the invention refers to a pharmaceutical composition based on the compound of formula

,

to a method for preparing the compound of formula (I), to intermediate compounds used in synthesis of the compound of formula (I), to the use of the compounds of formula (I).

EFFECT: there are prepared new compounds possessing activity of a type 1 angiotensin II (AT1) receptor antagonist and activity of neprilysin inhibition.

38 cl, 36 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: bioorganic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel aspartyl derivatives of histamine of the general formula (I): , wherein R means hydrogen atom (H), or , or that are able to modulate activity of enzymes of antioxidant protection - superoxide dismutase (SOD) and catalase. Also, invention relates to using the known compounds of the general formula (I) for the same designation wherein at the same values of X the value R represents acetyl group, and to their pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition possessing capacity to modulate activity of SOD and catalase and comprising the effective amount of compound of the general formula (I), and to a method for synthesis of compounds of the general formula (I). Method involves interaction of pentafluorophenyl ester Nα-Z-, β- or α-benzyl ester of aspartic acid with histamine followed by hydrogenolysis without isolation of intermediated protected derivatives of aspartyl histamine.

EFFECT: improved method of synthesis, valuable biochemical properties of derivatives.

12 cl, 3 tbl, 2 sch, 2 dwg, 8 ex

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

SUBSTANCE: invention relates to novel 2-(2,6-dichlorophenyl)diarylimidazoles of the general formula (I): possessing inhibitory effect on activity of protein-tyrosine kinase and first of all c-met kinase, and can be used in treatment of oncological diseases. In the compound of the general formula (I) X means hydrogen atom, -OR1, -SR2, -(SO2)R2 or group A1-Q wherein A1 means (C1-C3)-alkylene group; Q means -OR1, -NR3R4, -NHCH2CH2NR3R4; R1 is chosen from group comprising hydrogen atom, (C1-C)-alkyl, dimethylphosphonylmethyl, (R)-2,3-dihydroxy-1-propyl, (S)-2,3-dihydroxy-1-propyl, 1,3-dihydroxy-2-propyl, 3-hydroxy-2-hydroxymethyl-1-propyl, 2-methoxyethoxymethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or group A1-Q1 wherein Q1 means (C1-C2)-alkoxy, cyano group, carboxyl, (C1-C6)-alkoxycarbonyl, and if A1 means 1,2-ethylene- or 1,3-propylene group then Q1 means hydroxy group; R2 means (C1-C6)-alkyl or A1-Q; R3 and R4 are chosen independently from group comprising hydrogen atom, (C1-C6)-alkyl, or form in common 6-membered saturated cycle comprising two heteroatoms chosen from nitrogen (N) or oxygen (O) atoms; Y means hydrogen atom or group A2-R wherein A2 means (C1-C5)-alkylene optionally substituted with (C1-C6)-alkyl, phenyl or hydroxy group; R means hydroxy group, linear or branched (C1-C6)-alkoxy, amino, dimethylamino, diethylamino, tert.-butyloxycarbonylamino group, carboxyl, (C1-C6)-alkoxycarbonyl, triazolyl, 1-pyrrolidinyl, morpholino group, 4-methylpiperazin-1-yl, O-A1-NR3R4, S-A1-NR3R4, 4-carboxyphenyl, furan-3-yl, thiophen-2-yl or 3-methylthiophen-2-yl; Z means one or two substitutes chosen independently from group comprising halogen atom, hydroxy, allyloxy group, methyl, (C1-C5)-alkoxy, methoxymethoxy, (2-methoxyethocy)methyloxy, methylthio, ethoxymethoxy group, ethynyl and benzyloxy group optionally substituted with halogen atom, methoxy, cyano, ethoxy group, and its pharmaceutically acceptable salts. Also, invention elates to novel intermediate compounds and synthesis of compounds, and to their using for preparing drugs and pharmaceutical composition.

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

13 cl, 97 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

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

8 tbl, 11 ex

FIELD: chemistry; pharmaceutical compositions.

SUBSTANCE: imidazole derivatives have general formula (I) where each of R1 and R2 independently represents hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl; n=0.1 or 2; each of R3, R4, R5 and R6 independently represents hydrogen or (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulphonyl or (C1-C6)alkoxycarbonyl; R3 and R6 together with their carrier phenyl ring can also form N-methylbenzotriazole and to its acidic-additive salts, solvates and stereoisomer forms. Also, the given invention relates to pharmaceutical compositions, inhibitory aromatiser and application of derived imidazole of formula (I) for producing of medication.

EFFECT: new compounds, with useful biological properties.

23 cl, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining derivatives of substituted imidazole with general formula (I) and their acid-additive salts, where Y represents -CH2- or -CO-, R1 represents H, halogen or hydroxyl, R2 represents H or halogen, and R3 represents H or low alkyl. The method involves the following stages: a) halogenation of formula II compound, in which Y, R1 R2 and R3 assume values given above, with use of formula III compound, in which Y, R1 R2 and R3 assume values give above, and X represents a halogen atom, b) reaction of the obtained formula III compound with an amine with formula R4NH2, in which R4 represents an easily removable leaving group, and thiocyanate of an alkaline metal with obtaining of formula IV compound, in which Y, R1 R2, R3 and R4 assume the values given above, c) removal of the mercapto group from the formula IV compound with obtaining of formula V compound, in which Y, R1 R2, R3 and R4 assume values give above, d) removal of R4 group from formula V compound with obtaining of formula I compound, and if desired, e) conversion of the obtained formula I compound to its acid-additive salt. The invention also relates to intermediate compounds and the method of obtaining them.

EFFECT: method of obtaining formula I compound with good output and large-scale process.

20 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: agriculture.

SUBSTANCE: they use 2-(1H-1-pyrrolyl)-4-dipropylamino-6-(4-ethoxycarbonyl-5-methyl-1,2,3-triazole-1-yl)-1,3,5-triazine (PDET) with the following formula: , as antidote against phytotoxic effect of herbicide of 2,4-dichlorophenoxyacetic acid at germinated sunflower seeds.

EFFECT: increased length of roots and hypocotyl of germs.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula I where A represents an optionally substituted aryl or heteroaryl, B - a benzene or thiophene cycle, C - a benzene or aliphatic hydrocarbon cycle, while values of other radicals are disclosed in the description. The compound according to the present invention, and the based pharmaceutical compositions exhibit a strong antagonistic effect in relation to GnRH receptor that makes them applicable for treatment of GnRH-related diseases, particularly prostate cancer, benign prostatic hyperplasia, breast cancer, endometriosis and/or uterine fibroid tumour.

EFFECT: improved clinical effectiveness.

11 cl, 70 tbl, 765 ex

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods and reagents of labelling a vector such as a peptide, involving reaction of a compound of formula

with a compound of formula R*-L2-N3 (II) in the presence of a Cu (I) catalyst.

EFFECT: obtained labelled conjugates are useful as diagnostic agents, for example, as radiopharmaceutical preparations, more specifically for use in positron emission tomography (PET) or single-photon emission computed tomography (SPECT) or for radiotherapy.

7 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: agent having fungicidal activity, containing substituted ethyl(1,2,3-triazol-4-yl) dinitro acetates of formula Ia-c:

, where Ia, b R=CH3, R1=H; Ic R=H; R1=CH3 in concentration of 30 mg/l.

EFFECT: high efficiency.

1 cl, 1 tbl, 1 ex

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