Pyrimidine compounds, methods for their preparing (variants), intermediate substances (variants) and methods for their preparing (variants), method for preparing triazolopyrimidine compounds

FIELD: organic chemistry, chemical technology, medicine.

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

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

12 cl, 4 ex

 

The present invention relates to a pyrimidine compound useful as a pharmaceutical intermediate compounds, the method of obtaining the specified pyrimidine compounds, to intermediate compounds used in the specified way, and the application of the above pyrimidine compounds in obtaining pharmaceutical drugs.

The present invention features a compound of formula (I):

In the present invention it is also proposed a method of obtaining the compounds of formula (I), including the interaction of the compounds of formula (II):

with the salt of the compounds of formula (III):

in the presence of a suitable base (such as a hydroxide of alkaline metal (such as sodium hydroxide or potassium), tertiary amine (such as three(C1-6alkyl)amine, for example triethylamine)), a suitable solvent (such as alcohol, as, for example, aliphatic alcohol containing 1-6 carbon atoms, for example ethanol), preferably at a temperature in the range of 100 - 150°and, where this is necessary (for example, when the temperature exceeds the boiling point of the solvent), in a sealed system under autogenous pressure.

Suitable salt of the compounds of formula (III) is a salt of a mineral or organic to the slots. Suitable mineral acids include hydrochloric, Hydrobromic, idiscovered, nitric or sulfuric acid. A suitable organic acid is, for example, achiral organic acid, such as acetic, triperoxonane, oxalic acid or p-toluensulfonate acid, or organic chiral acid, such as L-tartaric acid, Dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid.

In another aspect, the present invention proposes a method of obtaining compounds of formula (I), including the hydrogenation of the compounds of formula (IV):

in which Ar represents phenyl, optionally substituted with halogen, C1-4the alkyl or C1-4alkoxy, obtaining the compounds of formula (II), and the interaction of the compounds of formula (II) with the compound of the formula (III) (as described above) to obtain the compounds of formula (I).

Preferably the hydrogenation is carried out with the use of the catalyst on the basis of heavy metal (such as platinum on coal) in a suitable solvent (such as1-6aliphatic alcohol, for example, 2-propanol (isopropanol)at a suitable temperature (such as 10 - 70°With, for example, 20 to 50° (C) and under suitable pressure (1-5 bar, for example, about 3 bar).

The compound of formula (IV) can be obtained by chlorination of compounds of formula (III):

where Ar has the meanings given above, with a suitable glorieuses reagent such as phosphorus oxychloride) in the presence of a suitable nitrogen-containing base (such as triethylamine, especially pyridine) and at a suitable temperature (such as in the range from 50°C to the boiling point of phosphorus oxychloride, for example, 70 to 90°). The compound of formula (VIII) can be obtained in the usual application of the methods described in the literature.

In an additional aspect, the present invention proposes a method, as described above, obtaining the compounds of formula (II).

The compound of formula (I) can be used to obtain the pharmaceutical compounds of the formula (A):

as is described below.

Thus, the compound of formula (A) can be obtained by removing protection from compounds of formula (V):

for example, using a strong mineral acid (such as hydrochloric acid) in a suitable solvent (such as methanol or ethanol).

The compound of formula (V) can be obtained by the combination of the compounds of formula (VI) {or its salt (such as Mandela), from which the compound of formula (VI) are obtained in situ} with the compound of the formula (VII):

for example, in the presence of a suitable base (such as tertiary AMI the, such as three(C1-6alkyl)amine, such as triethylamine) and a suitable solvent (e.g. a polar solvent such as an alcohol (such as an aliphatic alcohol containing 1 to 6 carbon atoms, for example ethanol) or a nitrile (such as acetonitrile) and at a suitable temperature (such as temperature in the range of 10 - 40°With, for example room temperature).

The compound of formula (VII) can be obtained by the coupling of compounds of formula (I) with a nitrite of an alkali metal (such as NaNO2or organic nitrite (for example, solidities) in the presence of a suitable acid (such as acetic acid) and a suitable solvent (such as water or a mixture of water and acetic acid) and at a suitable temperature (such as temperature in the range from -10 to 15°With, for example, from -10 to 10°).

Thus, in an additional aspect, the present invention proposes the use of the compounds of formula (I) in the method of obtaining the compounds of formula (A).

Salt of the compounds of formula (III) can be obtained by the coupling of compounds of formula (III) with the desired acid in a suitable solvent (such as water, an aliphatic alcohol containing 1-4 carbon atoms (e.g. ethanol)or a complex ester (such as ethyl acetate) at a suitable temperature (such as from 10 to 60°With, for example, from 30 to 50°).

With the unification of the formula (III) can be obtained by removing protection from compounds of formula (IX):

for example, by hydrogenation (as, for example, with a catalyst on the basis of heavy metal (such as palladium on coal) in the presence of a solvent such as an aliphatic alcohol containing 1-4 carbon atoms, such as ethanol) at room temperature under suitable pressure (such as 1-3 bar, for example 1.0 to 1.5 bar)).

The compound of formula (IX) can be obtained by reduction of compound of formula (X):

in which R* is1-4alkyl (preferably ethyl), a suitable borohydride (for example, the alkali metal borohydride such as lithium borohydride, lithium aluminum hydride or DIBAL-H in a suitable polar solvent (such as tetrahydrofuran).

The compound of formula (X) can be obtained by the coupling of compounds of formula (XI):

with a suitable connection L-CH2CO2R* {R* represents C1-4alkyl (especially ethyl); and L represents a leaving group, especially a halogen (e.g. bromine)} in the presence of a suitable polar solvent (such as tetrahydrofuran) in the presence of a suitable base (such as tert-butyl potassium, sodium hydride or species With1-6ascilite).

The compound of formula (XI) can be obtained by the coupling of compounds of formula (XII):

with benzylchloride in the presence of a suitable base (such as potassium carbonate) and a suitable solvent such as a ketone (for example, 4-methyl-2-pentanone) or a hydrocarbon (e.g. toluene)).

In yet another additional aspect of the present invention proposes a method of obtaining salts of the compounds of formula (III)described earlier.

In additional aspects of the present invention offers an intermediate compound of formula (II), (IV), (VII), (VIII), (X) or (XI) or a salt of the compounds of formula (III).

The following examples illustrate the invention.

EXAMPLE 1

This example shows getting 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl]oxy}-1-ethanol, salt with L-tartaric acid (1:1).

Stage a: getting phenylmethylene ether [3aS-(3aα,4α,6α,6aα)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]carbamino acid.

Potassium carbonate (39,3 g) was added to a suspension of [3aR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-ol hydrochloride (obtained as described in WO 9905142) (27,1 g) in 4-methyl-2-pentanone (500 ml). Then added water (150 ml) followed by the addition dropwise of benzylchloride (23.1 g). The reaction mixture was stirred at room temperature for 4 h before separating the organic phase. The aqueous phase EC who was tragically 4-methyl-2-pentanone (2× 50 ml). The combined organic phases were concentrated and the residue was purified (SiO2the mixture dichloromethane:methanol, 95:5 to 90:10 as eluent) to obtain specified in the subtitle compound (39,23 g).

1H NMR (CDCl3) δ to 7.32 (5H, m), the 5.65 (1H, Shir. C)to 5.10 (2H, Shir. C), 4,59 (1H, d), 4,48 (1H, d), 4,27 (1H, m), 4,19 (1H, Shir. m), 2,24 (1H, Shir. C)1,69 (1H, d), of 1.41 (3H, s)of 1.26 (3H, s).

Stage b: getting phenylmethylene ether [3aS-(3aα,4α,6α,6aα)]-[2,2-dimethyl-6-(2-hydroxyethoxy)tetrahydro-4H-cyclopent-1,3-dioxol-4-yl]carbamino acid.

Tert-butyl potassium (3.6 g) in tetrahydrofuran (20 ml) was added over 5 min to a solution of product from step (a), (39,23 g) in tetrahydrofuran (200 ml). After 15 min was added dropwise ethylbromoacetate (3,7 ml) in tetrahydrofuran (10 ml). The mixture was stirred at 0°C for 10 min, then re-added ethylbromoacetate (3,7 ml × 4). The reaction mixture was stirred at 0°for another 2 hours

Then to the reaction mixture were added portions of lithium borohydride (2,79 g), which was stirred at <5°C for 16 hours To the cold mixture was added glacial acetic acid (23 g). After 30 min stirring was added dropwise water (100 ml) and the resulting mixture was stirred for 30 minutes and Then the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated solution of bicarb the ATA sodium and brine, was dried and concentrated. The residue was purified (SiO2, a mixture of ethyl acetate:hexane, 25:75 to 50:50 as eluent) to obtain specified in the subtitle compound (38,6 g).

MS (chemical ionization at atmospheric pressure (APCI) 218 (M+N+, 100%).

Stage C: the receipt of [3aR-(3aα,4α,6α,6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopent-1,3-dioxol-4-yl]oxy]ethanol (alternative called: 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl]oxy}-1-ethanol).

A suspension of 5% palladium on coal (4 g) in ethanol was added to a solution of product from step (b) (39,96 g) in ethanol (250 ml) and the mixture was first made under the pressure of 1.2 bar for 20 hours, the Catalyst was filtered and the filtrate was concentrated to obtain specified in the subtitle compound (23,65 g).

MS (APCI) 160 (M+N+, 100%).

Stage d: the receipt of [3aR-(3Aα,4α,6α,6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopent-1,3-dioxol-4-yl]oxy]ethanol-L-tartrate (alternative called: 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl]oxy}-1-ethanol, salt with L-tartaric acid (1:1)).

Stir a solution of the product obtained in stage (C) (545 g) in ethanol (3.8 l)was heated to 35°C. was Added L-tartaric acid (352 g) (the temperature was raised to 45° (C) and the mixture was stirred at 40 - 45°C for 1 h the Mixture was cooled on the 20° With and the resulting thick suspension was stirred for 16 h, then filtered. The collected solid was washed with two portions of 2-propanol (300 ml, then 500 ml)was aspirated to dryness, then dried in vacuum at 40°With obtaining the product as white crystals (728 g).

EXAMPLE 2

This example shows obtaining TRANS-(1R,2S)-2-(3,4-differenl)-2-cyclopropylamino R-mandelate (alternative called TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine (2R)-2-hydroxy-2-phenylethanoic).

Stage 1: obtaining (E)-3-(3,4-differenl)-2-propanolol acid.

Stir a mixture of pyridine (15.5 kg) and piperidine (0.72 kg) was heated to 90°C. was Added malonic acid (17.6 kg), then slowly for 50 min 3,4-differentally (12.0 kg). The reaction mixture was stirred at 90°C for another 4 h 36 min was Added water (58.5 kg) and then 32 l of a mixture of pyridine/water was evaporated from the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) for 40 min, then was cooled to 25°With vigorous stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 litres per serving), once with water (61 l) and then carefully remove the liquid passing through the filter. The product was dried under vacuum at 40°C for 24 h 40 min with getting 13,7 kg crystallites is on the product.

Stage 2: obtaining (E)-3-(3,4-differenl)-2-propenonitrile.

Stir a mixture of (E)-3-(3,4-differenl)-2-propanolol acid (8.2 kg), toluene (7.4 kg) and pyridine (0.18 kg) was heated to 65°and then for 30 min was added thionyl chloride (7.4 kg). The reaction mixture was stirred for another 2 h 15 min after complete addition, and then was diluted with toluene (8,7 kg). The excess thionyl chloride, sulfur dioxide and hydrogen chloride and then drove together with toluene (10 l) under reduced pressure to obtain a solution of (E)-3-(3,4-differenl)-2-propenonitrile (about 9 kg) in toluene.

Stage 3: obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-differenl)-2-propenoate.

A solution of L-menthol (7,1 kg) in toluene (8.5 kg) was added over 20 min to a solution of (E)-3-(3,4-differenl)-2-propenonitrile (obtained in stage 2) and pyridine (0.18 kg, 2.28 mol)while stirring at 65°C. the Reaction mixture was stirred at 65°C for 4 h 40 min after complete addition, then cooled to 25°and was stirred for another 14 hours the Solution was diluted with toluene (16 kg), washed with 5% aqueous solution of sodium chloride (6.4 kg), then 6% sodium bicarbonate solution (6,47 kg), then water (6.1 kg). The solution was dried by azeotropic distillation of the solvent (20 l) under reduced pressure. Added dimethylsulfoxide (33,9 kg) and the remaining toluene drove demoted when the pressure obtaining of 47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-differenl)-2-propenoate (approximately 13,3 kg) in dimethyl sulfoxide.

Stage 4: getting dimethylsulfoxide matilida (dimethyl(methylene)oxo)-λ6-Sultana.

Powdered sodium hydroxide (1.2 kg)obtained by grinding pellets of sodium hydroxide in a rotary mill with a metal sieve of 1 mm, and trimethylsulfoxonium iodide (6.2 kg) was stirred in dimethyl sulfoxide (25,2 kg) in nitrogen atmosphere at 25°C for 90 minutes the Solution is directly used to obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-2-(3,4-differenl)cyclopropanecarboxylate.

Stage 5: obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-2-(3,4-differenl)cyclopropanecarboxylate.

A solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-differenl)-2-propenoate (approximately 8.6 kg) in dimethyl sulfoxide (approximately 27.9 kg) was added with stirring over 20 min to a mixture of dimethylsulfoxide matilida (approximately 2.6 kg obtained as described above), sodium iodide (about 4.2 kg), water (about 500 g) and sodium hydroxide (approximately 56 g) in dimethyl sulfoxide (27.7 kg) at 25°C. The reaction mixture was stirred for another 2 h 50 min at 25°With, then directly used to obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylate.

Step 6: obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonyl elata.

The crude solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-2-(3,4-differenl)cyclopropanecarboxylate, obtained as described in stage 5, was heated with stirring from 25°C to 50°C for 1 h and the temperature was maintained for a further one hour. The mixture is then cooled with stirring from the 50°to 35°C for 4 h, kept at 35°C for 1 h, then was cooled to 26°C for 4 h, kept at 26°C for 1 h, then was cooled to 19°C for 3 h and kept at 19°C for 5 h 10 min the Product was collected by filtration to obtain crystalline solid (2.7 kg), which, as we have seen, consisted of a mixture of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylate (1,99 kg) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl-TRANS-(1S,2S)-2-(3,4-differenl)cyclopropanecarboxylate (85 g).

Step 7: obtain TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonyl acid.

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylate (9.6 kg, 91.8% of the excess diastereoisomer) was dissolved in ethanol (13,8 kg) and was heated under stirring up to 46°C. for 20 min was added 45% aqueous solution of sodium hydroxide (3.1 kg) and the mixture was stirred for another 2 h 27 min Solvent (28 l) drove from the mixture under reduced pressure, the eat the mixture was cooled to 24° C and was diluted with water (29.3 kg), after which the selected menthol was extracted with toluene (3 servings at 3.3 kg each). The remaining water substance was acidified to pH 2 with 37% hydrochloric acid (3.3 l) and the product was extracted with toluene (8.6 kg, then 2 more portions of 4.2 kg and 4.3 kg). The combined toluene extracts were washed with 1% hydrochloric acid (4.9 litres), then diluted with more toluene (4.2 kg) and dried by azeotropic distillation of the solvent (25 l) under reduced pressure. After the final dilution with toluene (24,2 kg) solvent evaporated under reduced pressure (10 l) with a solution containing TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonyl acid (approximately 3.45 kgs), the right to obtain TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonitrile.

Step 8: obtain TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonitrile.

Pyridine (70 ml) was added to a solution of TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylic acid (approximately 3.45 kgs) in toluene (approximately 12-15 kg), obtained as described above, and the mixture was then heated to 65°C. thionyl chloride (2.3 kg) was added over 1 h and the mixture was stirred at 70°C for 3 hours was Added thionyl chloride (0.5 kg) and the mixture was stirred for another 2 h at 70°C. Added the last portion of thionyl chloride (0.5 kg) and the reaction mixture was stirred for 1 h at 70°C, then cooled to 40° C. During the distillation of the solvent (about 60 l) from the mixture under reduced pressure was periodically added toluene (45 kg 3 introduction 15 kg each), then a solution of TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonitrile (approximately 3.8 kg) in toluene (approximately 6-9 l) was cooled to 20°C.

Step 9: obtain TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylate.

A solution of TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarbonitrile (approximately 3.8 kg) in toluene (approximately 6-9 l), obtained in stage 8, 1°C was added over a period of 74 minutes to a mixture of sodium azide (1.24 kg), tetrabutylammonium bromide (56 g) and sodium carbonate (922 g) in water (6.2 kg), stirring with 1.5°C. the Mixture was stirred at 0°C for 1 h 55 min then the aqueous layer was diluted with cold water (3.8 kg), quickly mixed, and then divided. Toluene layer is again washed at 0°With water (3.8 kg), followed by 20% aqueous solution of sodium chloride (3.8 l), then kept at 3°for later use.

Step 10: obtain TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine.

A cold solution of TRANS-(1R,2R)-2-(3,4-differenl)cyclopropanecarboxylate, obtained as described in stage 9, was added over 41 min for toluene (6.0 kg), stirring at 100°C. the Mixture was stirred for 55 min at 100°C, then cooled to 20°and was added during 2 hours and 15 minutes for the hydrochloric acid 3 M, 18,2 kg), stirring at 80°C. After 65 min the solution was diluted with water (34 kg) and was cooled to 25°C. the Toluene layer was removed and the aqueous layer was podslushivaet to pH 12 45% aqueous solution of sodium hydroxide (3.8 kg) and then the product was extracted with ethyl acetate (31 kg) and twice washed with water (13.7 kg per serving) to produce a solution containing TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine (2.6 kg, 91.8% of the excess enantiomer) in ethyl acetate (29.5 litres).

Stage 11: obtain TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine (2R)-2-hydroxy-2-phenylethanoic.

R-(-)-almond acid (2.26 kg) was added to a solution containing TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine (2.6 kg, 91.8% of the excess enantiomer), stirring with 17°in ethyl acetate (45,3 l). The mixture was stirred at 25°C for 3 h 8 min, then filtered and twice washed with ethyl acetate (total of 13.8 kg). The crystalline product was dried at 40°C under reduced pressure for 23 h to obtain TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine (2R)-2-hydroxy-2-phenylethanoic (4,45 kg).

EXAMPLE 3

This example shows the receipt of 4,6-dichloro-2-(propylsulfonyl)-5-pyrimidinamine.

Stage 1: 4,6-Digerati-2-(propylsulfonyl)pyrimidine.

Water (670 ml) was added to 2-thiobarbituric acid (200 g). The resulting mixture was stirred and added portions guide Oakes sodium (126,3 g). The mixture was stirred for 40 min, then was diluted with water. Was added 1-methyl-2-pyrrolidinone (400 ml) and 1-iodopropane (140,9 ml). The resulting suspension was stirred at 20°C for 22 hours, the pH Value of the mixture was brought to 6.5 by adding 1 M HCl (600 ml) for 30 min, then to a pH of 2.5 by adding 6 M HCl (180 ml) for a further 30 minutes the resulting suspension was stirred for 18 h and the product was isolated by filtration and then washed with water (4×100 ml), ethanol (200 ml) and water (2×200 ml). The product was dried under reduced pressure overnight at 50°obtaining specified in the header of the product as a white powder (185 g).

Stage 2: 4,6-Dihydroxy-5-[(E)-2-(4-were)diazenyl]-2-(propylsulfonyl)pyrimidine.

Ethanol (25 ml), 4,6-dihydroxy-2-(propylsulfonyl)pyrimidine (stage 1, 5 g) and water (25 ml) was stirred together at room temperature. Was added sodium hydroxide (1,02 g) and received a clear solution. The resulting solution was cooled to 0°and then added sodium acetate (9,42 g) to obtain solution A.

In a separate container was prepared a solution of p-toluidine (3,01 g) in water (10 ml). Thereto was added concentrated hydrochloric acid (37% wt./wt. aqueous solution, 8,45 ml). The resulting mixture was cooled to 0°C, and a solution of sodium nitrite (2.16 g) in water (10 ml) was cooled to 0°and added on the apply to containing toluidine reaction mixture for 30 minutes The temperature during the addition was maintained between 0 and 5°C. the resulting mixture was cooled to 0°and added to a cold (0° (C) the solution (the temperature rose to 8°). The obtained yellow suspension was stirred overnight and the pH of the mixture was brought to pH 1 by addition of 6 M HCl. The mixture was filtered and the collected product was washed with water (25 ml) and ethanol (10 ml). The product was dried under reduced pressure at 50°C for 24 h to obtain the product as yellow solid (6,97 g).

Stage 3: 4,6-Dichloro-5-[(E)-2-(4-were)diazenyl]-2-(propylsulfonyl)pyrimidine.

Pyridine (2,58 ml) was added to a stirred, heated (70° (C) suspension of 4,6-dihydroxy-5-[(E)-2-(4-were)diazenyl]-2-(propylsulfonyl)pyrimidine (stage 2, 5 g) in toluene (15 ml). To the mixture was added dropwise phosphorus oxychloride (18.7 ml) for 15 min (temperature increase to 94°). The reaction mixture was heated for a further 4.5 h, then evaporated. The residue was twice subjected to the azeotropic distillation with toluene (2×30 ml). The residue was dissolved in toluene (50 ml) and filtered to remove solid particles. The collected solid was dissolved in toluene (50 ml) and filtered to remove some solids. The collected solid was washed with toluene and the combined filtrates were washed with water (30 ml) and saturated the aqueous solution of sodium bicarbonate (30 ml). Evaporation gave specified in the header of the product (to 4.98 g) as a red oil which slowly crystallized upon standing.

Stage 4: obtain 4,6-dichloro-2-(propylsulfonyl)-5-pyrimidinamine.

Mix a solution of 4,6-dichloro-5-[(E)-2-(4-were)diazenyl]-2-(propylsulfonyl)pyrimidine (stage 3, 1.1 kg) in 2-propanol (16.6 kg) was first made for 1 h at 40°/3,2 bar over a platinum catalyst at an angle (0,81 kg, 50% wt./wt. Pt/C). Under pressure gaseous hydrogen was released and the reactor was filled with nitrogen. The reaction mixture was filtered. The collected solid was washed with 2-propanol (1.7 kg) and the combined filtrates were concentrated under reduced pressure. The remaining oil was cooled to 20°and was dissolved in ethyl acetate (5 kg) was added water (5.5 l). The pH value of the mixed mixture was brought to pH 2 by addition of 3 M aqueous solution of hydrochloric acid (800 ml). The phases were allowed to separate and the aqueous phase was discarded. Was added water (2,75 l) to the organic phase and the pH was brought to 2 by adding a small amount of 3 M HCl (45 ml). The aqueous phase was separated and the organic phase was concentrated under reduced pressure at 30 - 50°to obtain 4,6-dichloro-2-(propylsulfonyl)-5-pyrimidinamine in the form of a reddish viscous oil containing ethyl acetate, which was dissolved in ethanol (8.5 kg). C is the solvent (6.5 liters of ethanol/ethyl acetate) was removed by evaporation under reduced pressure. To the residue was added another portion of ethanol (4.5 kg) and evaporation was repeated to remove 6.5 liters of solvent. The ethanol solution of the product was used without further purification in the next stage.

EXAMPLE 4

This example shows the receipt of [1S-[1α,2α,3β-(1S*,2R*),5β]]-3-[7-[2-(3,4-differenl)cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (alternative called (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-differenl)cyclopropyl]amino}-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol).

Stage 1: obtain [(3aR-(3Aα,4α,6α,6aα)]-2-[[6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-an-cyclopent[d][1,3]-dioxol-4-yl]oxy]ethanol (alternative called 2-[((3aR,4S,6R,6aS)-6-{[5-amino-6-chloro-2-(propylsulfonyl)-4-pyrimidinyl]amino}-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl)oxy]-1-ethanol.

Ethanol solution of 4,6-dichloro-2-(propylsulfonyl)-5-pyrimidinamine (obtained as in example 3, stage 4) was added to 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl]oxy}-1-ethanol, salt L-tartaric acid (1:1) (1,18 kg). To the obtained mixed thick suspension was added triethylamine (0.95 kg), keeping the temperature between 20 and 25°C. the Reactor hermit zerouali and the temperature was raised to 120 125°C. the Reaction mixture is kept at this temperature interval for 30 h, then was cooled to 75°and the pressure dropped. The temperature of the mixture was brought to 50°and the solvent is kept under reduced pressure at 30 - 40°C. was Added ethyl acetate (4,95 kg) and water (5.5 l), the pH of the mixture was brought to pH 5 by addition of 3 M hydrochloric acid (100 ml) and the phases were separated. The organic phase was washed with 15% brine wt./wt. (5.5 l), then separated. The organic phase was concentrated under reduced pressure (4,81 l solvent is removed) to obtain 2-[((3aR,4S,6R,6aS)-6-{[5-amino-6-chloro-2-(propylsulfonyl)-4-pyrimidinyl]amino}-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl)oxy]-1-ethanol as a brown-red viscous oil containing ethyl acetate. The product was used without further purification in the next stage.

Stage 2: getting [3aR-(3aα,4α,6α,6aα)]-2-[[6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]tetrahydro-2,2-dimethyl-an-cyclopent[d][1,3]dioxol-4-yl]oxy]ethanol (alternative called 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl}oxy)-1-ethanol).

2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylsulfonyl)-4-pyrimidinyl]amino}-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl)oxy]-1-ethane is l, obtained in stage 1, was dissolved in acetic acid (5,75 kg) and water (650 ml). The resulting solution was cooled to 2°With (with stirring) and the solution was added sodium nitrite (232 g) in water (1.25 l) so that the temperature of the mixture was maintained below 7°C. Then the mixture was allowed to warmed up to 7°With, then added ethyl acetate (8.9 kg). Was added an aqueous solution of potassium carbonate (4 years, 37% wt./wt.). The mixture was separated and the organic phase is again washed with an aqueous solution of potassium carbonate (3.8 kg, 21% wt./wt.). The aqueous phase was discarded and the organic phase was concentrated under reduced pressure to obtain specified in the subtitle compound as a red-brown viscous oil, used without further purification in the next stage.

Stage 3: obtain {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4-differenl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl)oxy]ethanol (alternative called 2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-differenl)cyclopropyl]amino}-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl}oxy)-1-ethanol).

TRANS-(1R,2S)-2-(3,4-differenl)cyclopropylamine(2R)-2-hydroxy-2-phenylethanoic (0,77 kg) were loaded to capacity with a subsequent payment of R is the target 2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl}oxy)-1-ethanol (obtained in stage 2), dissolved in acetonitrile (3,85 kg). To the resulting stirred mixture was added triethylamine (0,81 kg) with such speed that the temperature of the reaction mixture was maintained within 20 - 25°C. the Reaction mixture was stirred for 13 h, then concentrated under reduced pressure at 30°C. To the residue was added ethyl acetate (8.1 kg) and water (4.6 liters). The pH value of mixed two-phase mixture was brought to pH 4 by addition of 3 M HCl (450 ml). Then the mixture was allowed to settle and separate. The aqueous phase was separated and the remaining organic phase is washed with 15% wt./wt. aqueous solution of sodium chloride (4,15 kg), the organic phase was concentrated under reduced pressure at 30 - 50°obtaining crude specified in the title compound as a red oil, which was directly used in the next stage.

Stage 4: getting [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[2-(3,4-differenl)cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (alternative called (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-differenl)cyclopropyl]amino}-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol).

An aqueous solution of hydrochloric acid (3 M, 4.8 l) was added to a stirred solution of 2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-differenl)Cyclops is filing]amino}-5-(propylsulfonyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethylether-an-cyclopent[d][1,3]dioxol-4-yl}oxy)-1-ethanol (1,931 kg) in methanol (13,4 kg), maintaining the temperature while adding within 20 - 25°C. Then the mixture was stirred for 24 h at 20°C. Then was added sodium hydroxide (45% wt./wt. aqueous solution of 780 ml) to bring the pH of the mixture to a pH of 7.2. Then the methanol was removed by distillation under reduced pressure was added ethyl acetate (14,3 kg). The mixture was heated to 45°and the water layer was separated. Then the organic phase was washed with 15% wt./wt. aqueous solution of sodium chloride (7.2 kg). Ethyl acetate (10 l) was removed by distillation under reduced pressure. Added a fresh portion of ethyl acetate (7,2 kg) and the mixture was filtered. The filter was rinsed with ethyl acetate (1.5 kg). The combined filtrates were dried by repeated addition/distillation of the ethyl acetate. When the solution was dry, determined the content of the product in an ethyl acetate solution analysis by chromatography and found that it contains 1016 g of the product, the concentration of ethyl acetate drove until they reached a concentration of 5 ml of ethyl acetate/g crude product. An ethyl acetate solution was heated to 47°and then isooctane was added (2.5 ml/g, 2540 ml) for 15 minutes, the resulting suspension was stirred for 30 min and then added another isooctane (2540 ml) for 5 minutes the mixture was mixed with 48 - 50°C for 30 min, then was cooled to 20°C for 3 hours, the Suspension was stirred at 20°C for 6.5 h, then filter the Wali and washed with a mixture, consisting of isooctane (1.25 kg) and ethyl acetate (1.6 kg). The collected solid was dried in vacuum to obtain specified in the connection header (920 g).

If desired, the crude product can be cleaned in addition to using one of the following three ways.

Recrystallization from ethyl acetate/isooctane

The crude product is dissolved in ethyl acetate (4.8 ml/g) at 55°C, then filtered to remove particles. The clear solution is transferred back to the reactor for recrystallization and the temperature is set at 50°C. Then add isooctane (4.8 ml/g) for 10 minutes the Suspension is allowed to stand for 30 min, after which it is cooled to 20°C for 2-3 h and at the end of the temperature of the support at 20°C for about 30 minutes Then the product filtered and washed with isooctane (2×1.5 ml/g). The product is dried under reduced pressure at 50°obtaining the pure product (purity >98% according to HPLC).

Suspension with n-butyl acetate

The crude product is suspended in n-butyl acetate (4 ml/g and stirred at room temperature for 10 hours, the Suspension is cooled to 0°C for 3-4 h and then maintained at 0°C for 1 h the Product was filtered and washed with cold n-butyl acetate at the rate of 2 ml/g (<0°). Then the product is dried in vacuum at 50°obtaining Chistov the product (purity > 98% according to HPLC).

Suspension with isopropanol

The crude product is suspended in isopropanol at the rate of 3 ml/g and stirred at 50°within 72 hours Then the suspension is cooled to 20°C for 3 h and the temperature maintained at 20°C for about 30 minutes and Then the product was filtered and washed with cold isopropanol at a rate of 1 ml/g (<0°). Finally, the product is dried under reduced pressure at 50°obtaining the pure product (purity >98% according to HPLC).

1. The compound of formula (I)

2. The method of obtaining the compounds of formula (I), including the interaction of the compounds of formula (II)

with the salt of the compounds of formula (III)

3. The method of obtaining the compounds of formula (I) according to claim 2, which is used as a compound of the formula (II)obtained by hydrogenation of compounds of formula (IV)

in which Ar represents phenyl, optionally substituted with halogen, C1-4the alkyl or C1-4alkoxy.

4. The method of obtaining the compounds of formula (A)

including

a) interaction of the compounds of formula (I) with an alkali metal nitrite in the presence of a suitable acid to obtain the compounds is of formula (VII)

b) the combination of the compounds of formula (VII) with the compound of the formula (VI)

obtaining the compounds of formula (V)

and

(C) removing the protection from the compounds of formula (V) to obtain the compounds of formula A.

5. The method of obtaining salts of the compounds of formula (III)

including the interaction of the compounds of formula (III) with the desired acid.

6. The method of obtaining salts of the compounds of formula (III)

includes stage

(a) obtaining compounds of formula (XI)

the interaction of the compounds of formula (XII)

with benzylchloride in the presence of a suitable base and a suitable solvent;

b) obtaining the compounds of formula (X)

the interaction of the compounds of formula (XI) with connection L-CH2CO2R* (where R* represents C1-4alkyl and L is a leaving group);

(C) obtaining compounds of formula (IX)

the restoration of the compounds of formula (X);

d) receiving the connection f is rmula (III)

removing the protection from the compounds of formula (IX), and

e) obtaining salts of the compounds of formula (III) interaction of the compounds of formula (III) with the desired acid.

7. The intermediate compound of the following formula:

where both R' simultaneously represent Cl or both R' simultaneously represent IT, and X stands for a group Ar-N=N-, where Ar is phenyl, which is optionally substituted with halogen, C1-4-alkyl or C1-4-alkoxy.

8. The intermediate connection according to claim 7 of the formula (IV)

where Ar is defined as specified in item 7.

9. The intermediate connection according to claim 7 of the formula (VIII)

where Ar is defined as specified in item 7.

10. The intermediate compound of formula (VII)

11. Intermediate compound which is a salt of the compounds of formula (III)

12. The intermediate compound of formula (X)

where R* is C1-4-alkyl.



 

Same patents:

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to novel 3,7-diazabicyclo[3.3.0]octanes of the formula (I): wherein wavy lines mean the possible relative cis- or trans-stereochemistry; R means (C1-C12)-alkyl (possibly substituted and/or terminating by one or more groups chosen from aryl, Het1, -C(O)R5a, -OR5b, -N(R6)R5c, -C(O)XR7, -C(O)N(R8)R5d and -S(O)2R9), Het2, -C(O)R5a, -C(O)XR7 or -S(O)2R9 wherein R5a - R5d in each case mean independently hydrogen atom (H), (C1-C6)-alkyl (possibly substituted and/or terminating by one or more substitute chosen from -OH, (C1-C6)-alkoxy-group, cyano-group, aryl, Het3 and -NHC(O)R10), aryl or Het4; R10means H, (C1-C4)-alkyl; R6 means H, aryl; X means oxygen atom (O); R7 means in each case (C1-C12)-alkyl (wherein alkyl group can be substituted and/or terminating by one substitute chosen from -OH, cyano-group, (C1-C6)-alkoxy-group, -SO2R13a, -C(O)R13b and Het5) wherein R13a and R13b mean independently (C1-C6)-alkyl; R8 means in each case H, (C1-C12)-alkyl, (C1-C6)-alkoxy-group (wherein two latter groups are substituted possibly and/or terminating by one substitute chosen from -OH, (C1-C4)-alkyl and (C1-C4)-alkoxy-group), -D-aryl, -D-Het6, -D-S(O)2R15a wherein R15a means independently aryl; D means a direct bond or (C1-C6)-alkylene; R9 means in each case (C1-C6)-alkyl (possibly substituted and/or terminating by one substitute chosen from aryl) or aryl; R2 means H, -E-OR16, -E-N(R17)R18 or in common with R3 represent =O; R3 means H or in common with R2 represent =O; R16 means H, (C1-C6)-alkyl or -E-aryl; R17 means H; R18 means H; E means in each case a direct bond or (C1-C4)-alkylene; A means -G-; B means -Z-, -Z-N(R22)-Z-, -Z-S(O)n-. -Z-O- (wherein in two latter groups Z is bound to carbon atom carrying R2 and R3); G means a direct bond or (C1-C6)-alkylene; Z means a direct bond or (C1-C4)-alkylene; R22 means independently H; R4 means aryl or het13 wherein both these groups are substituted possibly with one or more substitute chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; Het13 means 5-6-membered heterocyclic group comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur; Het1 - Het6 in each case mean independently 5-6-membered heterocyclic groups comprising one or more heteroatoms chosen from oxygen, nitrogen and/or sulfur wherein these heterocyclic groups are substituted possibly with one or more substitutes comprising (C1-C6)-alkyl or -C(O)R24c wherein R23c means in each case independently (C1-C6)-alkyl; R24c means in each case H or (C1-C6)-alkyl; n means 0, 1 or 2 in each case; Ra - R1 mean independently H or (C1-C4)-alkyl wherein each aryl or aryloxy-group (if not indicated otherwise) is substituted possibly with one or more substitutes chosen from -OH, cyano-group, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -C(O)R24c or -S(O)nR23c; or it pharmaceutically acceptable derivative under condition that: (a) when R2 means -E-OR16 or -E-N(R17)R18 wherein E means a direct bond then: (1) A can't mean a direct bond; and (2) B doesn't mean -N(R22)-, -S(O)n-. -O- or -N(R22)-Z- (wherein in the latter group -N(R22) is bound to carbon atom carrying R2 and R3; (b) this compound is not 3,7-bis-(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane, 3-methyl-7-benzyl-3,7-diazabicyclo[3.3.0], 3-cyclohexyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(thiazol-2-yl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(2-pyrimidyl)-7-benzyl-3,7-diazabicyclo[3.3.0]octane, 3-(5,5-dimethoxy)pentyl-7-benzyl-3,7-diazabicyclo[3.3.0]octane; (c) when R in common with R3 represent =O, and B means -Z-N(R22)- or -N(R22)-Z- then G is not a direct bond. Compounds of the formula (I) can be used as components of a pharmaceutical composition in treatment or prophylaxis of arrhythmia. Also, invention describes methods for its synthesis and intermediate compounds used in these methods.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

38 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and its pharmaceutically acceptable salts possessing properties of tumor necrosis factor (TNF-α) and to pharmaceutical composition based on thereof wherein R1 means substituted or unsubstituted phenyl wherein substitutes are chosen from halogen atoms or halide-(C1-C6)-alkyl; R4b is substituted or unsubstituted with 1-3 aryl substituted chosen from phenyl, naphthyl wherein substitutes are chosen from halogen atoms, (C1-C6)-alkyl, halide-(C1-C6)-alkyl, (C1-C6)-alkoxyl, cyano-, amino-, (C1-C6)-acylamino-group, (C1-C6)-alkanesulfonyl, or two adjacent substitutes in benzene ring form dioxol group, or unsubstituted or substituted 6-membered nitrogen-containing heteroaryl with 1-3 nitrogen atoms in ring wherein substitutes are chosen from halogen atoms.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 9 sch, 10 tbl, 15 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

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

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

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

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

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

20 cl, 3 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

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

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to sulfoxides or sulfones grafted on polymers, polymeric compositions, a method for grafting and method for stabilization of polymers. Invention describes polymers comprising a grafted compound of the formula (I): [R1-SOm]n-R-SOp-R2 (I) wherein total symbols have values given in cl. 1 of the invention claim and represents a composition comprising thereof, a method for grafting compound of the formula (I) on polymers and a method for stabilization of polymers. Polymers comprising grafted sulfoxides or sulfones possess high stability against oxidative, thermal, dynamic destruction caused by the light effect and/or destruction caused by ozone effect.

EFFECT: improved preparing method, improved and valuable properties of polymers.

14 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane of the formula (I): and its salts. Method involves direct reaction of 5-(4-fluorophenyl)pyridine-3-carbaldehyde of the formula (II): with 2-aminomethylchromane or its salts under reductive conditions resulting to formation of compound of the formula (I). Synthesized compound of the formula (I) is converted to one of its salts by treatment with acid. Method provides simplifying process based on decreasing amount of by-side products formed.

EFFECT: improved method of synthesis.

8 cl, 2 dwg, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

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