The method of obtaining 7,7-dioxide and 5,6-dihydro-(s)-4-(alkylamino) -(s)-6-alkyl-4h-thieno(2,3-b)thiopyran-2 - sulfonamida and 7,7 - dioxide and 5,6-dihydro-(s)-4-(acylamino)-(s)-6-alkyl-4h - thieno(2,3-b)thiopyran

 

(57) Abstract:

7,7-Dioxide 5,6-dihydro-4-(ethylamino)-6-methyl-5H-thieno (2,3-b) thiopyran-sulfonamida get interaction hydroxy 7,7-dioxide thieno (2,3-b) thiopyran with acetonitrile, followed by the introduction into the second position of the heterocyclic system sulfonamidnuyu group. This method allows the synthesis of retaining the chirality of the molecule. The connection is used in pharmacology for the regulation of intraocular pressure. 2 S. and 6 C.p.

Modern therapy for regulation of increased intraocular pressure (IOP) or increased eye pressure, which are considered to be a factor in the occurrence and progression of glaucoma, usually lie in the use of different means of local application, which are divided into 4 categories: -blockers, adrenergic funds parasympathomimetics tools and cholinesterase inhibitors. Practiced auxiliary oral administration of a carbonic anhydrase inhibitor (CA1), in the case when the side effects described above means a local application limit their use and/or is unable to achieve adequate regulation (IOP). Active when administered orally the CA1 Moses. Why was undertaken intensive and ongoing search active in the local introduction of CA1, not detect such side effects because of the way the introduction and specificity of the target organ. This search led to the discovery of the class of compounds disclosed in Baldwin et al. (US Patent 4797413), the General formula

,

in which R and R1denote lower alkyl, in particular dorzolamida, in which R represents methyl and R1denotes methyl. US patent 4797413 describes new aromatic sulfonamides, applicable for the treatment of elevated intraocular pressure, and composition.

The Ritter reaction is well known in this area and it consists in the processing of aliphatic hydroxyl nitrile and a strong acid with amide formation.

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The reaction takes place through the formation of ion Carbonia at the connection point-OH so that if the original material has a chiral center, the chirality is lost during the reaction and forms a racemic product.

In the invention the Ritter reaction is used for the introduction of nitrogen-containing group at the 4th position of the molecule, and the source material is clean enantiomer, and chirality is unexpectedly saved in the resulting product.

the measuring frequency. The key stage in this new way is the Ritter reaction with unexpected and unpredictable tendency to take place with retention of chirality.

A new method of the invention can be depicted as shown in scheme 1 (see end of text).

where R and R1identical or different, denote C1-3-alkyl.

Stage A of scheme 1 is the Ritter reaction or modification involving the slow addition of approximately 10-15-fold molar excess of a strong acid such as concentrated sulfuric acid, or a mixture of concentrated sulfuric acid and fuming sulfuric acid to a stirred cold solution of 11 in the nitrile patterns RCN where R represents C1-3-alkyl, such as methyl, ethyl, propyl or isopropyl. The amount of water present during the reaction Ritter is critical for optimal preservation of chirality and it varies from 0.5 to 10%) depending on the applied acid. Industrial available sulfuric acid can enter too much water in the system and reduce the number by adding fuming sulfuric acid. However, anhydrous acid, such as methanesulfonate, triperoxonane or apirat boron TRIFLUORIDE, require UP>oC. After addition of the acid mixture is allowed to warm spontaneously under stirring to complete the reaction for approximately 12-18 hours the Reaction is stopped by adding the mixture to water, the acid is neutralized by adding a base such as sodium hydroxide, and the product is extracted with an organic solvent such as ethyl acetate.

Stage B includes sulfonylamine 111 by adding it to chilled chlorosulfonic acid or fuming sulfuric acid at approximately the 0oC at such a rate to maintain the temperature below about 20oC. the Resulting mixture was then heated at approximately 40-60oC to complete the reaction for about 10-15 hours This material is directly used in the next stage.

Stage C, chlorination, is a slow addition of thionyl chloride to a cooled (15-25oC) the IV solution followed by heating at approximately 40-60oC for 4-8 h

The reaction is stopped by slow addition of the mixture to stir chilled water, followed by collecting the product by filtration.

Stage D, or amidation process, with the formation of sulfonamida preduster the Oh to maintain the temperature below about 0oC, followed by stirring at about 0oC for about 0.5-2 hours the Product emit bringing the pH to 3-5 concentrated sulfuric acid, separating the organic layer, dilution with water and concentration, causing crystallization.

Stage E includes restoring carbonamide compound VI by slowly adding a Lewis acid such as athirat triftoridov boron, or aluminum chloride or anhydrous strong acid, such as methanesulfonic acid or triperoxonane acid to a stirred suspension of VI and sodium borohydride in dry THF at approximately (-5) - (+5)oC, followed by stirring for about 4-6 h at (-5) - (+5)oC, and then for about 12-18 hours at approximately 25-40oC. Upon completion of the reaction, the reaction mixture was slowly added to a chilled dilute acid followed by separation according to standard methods, if desired. The person skilled in the art it is clear that the above-described reaction with sodium borohydride in dry THF and acid, such as athirat triftoridov boron or methansulfonate acid, results in balancetransfer in the process about what tetrahydrofuran or porandamaterjalides, without the use of acids.

Salt maleate VIII receive standard methods, transformed into a crude salt I hydrochloric acid and recrystallized with net education I.

These stages of the reaction are illustrated by example, where R and R1both represent methyl.

The product of the new method of the invention is effective when applied topically carbonic anhydrase inhibitor that is applicable for the treatment of elevated intraocular pressure. It is injected directly into the eye, usually in the form of a solution containing about 0.1-15 wt.% compounds 1 or 2 drops 1-4 times per day.

Example 1. Stage A: Methodology of Ritter reaction with sulfuric acid

To a mechanically stirred cooled (-55oC) the solution of hydroxysulfonic II (25,0 g, 0,114 mol: 98:2 TRANS/CIS) in acetonitrile (300 ml) was slowly added concentrated sulfuric acid (18 M, 86 ml of 1.52 mol) for 0.5 h, maintaining the internal temperature at -55oC.

Mixture is allowed to warm up to 205oC and stirred at this temperature for 12 - 18 h or until the reaction is completed (according ghvd).

Analysis method: an Aliquot (0.1 ml) was diluted to 50.0 ml with water and then analyzed using the t: H2O with 0.1% (vol./about.) H3PO4)

Eluent B: MeCN

Isocratic elution: 87:13 A:B for 7 min, then

Gradient elution: 87:13 to 35:65 A:B over 14 min

The flow rate: 2.0 ml/min

Temperature: 45oC

Injection: 10,0 ál

Detection% UV (230 nm)

Retention time: Hydroxysulfonic II (CIS-isomer) 6,0 min Hydroxysulfonic II (TRANS-isomer) of 6.6 min Acetaminoohen III (CIS-isomer) of 7.6 min Acetaminoohen III (TRANS-isomer) of 8.5 minutes

The reaction was considered complete when less than 1% of hydroxysulfonic II (US. product acetaminoohen III). At the end of the reaction the ratio of TRANS/CIS of acetaminoohen III product was 92,4:7,6.

After completion of the reaction, the reaction mixture was slowly added to a stirred mechanically pre-cooled (0 to 5oC) quenching the reaction mixture ethyl acetate (1.7 l) and water (800 ml). At the same time 50% (wt. /Mac. ) aqueous sodium hydroxide (185 ml) was added to the quenching mixture at such a rate that the pH was maintained between 3 and 5 and the internal temperature was maintained below 25oC. Then the pH was brought to 7.0 - 7.5 for further adding sodium hydroxide and the mixture was stirred 1 h at 30oC. the Mixture was filtered for udlinnjali and the mixture was divided into phases. The organic (upper) phase was combined and then concentrated in vacuum [10 mbar (1 to 103PA), 50oC] up to a volume of 100 ml. Hexane (300 ml) was added slowly and the mixture was stirred for 1 h at 20 - 22oC. the Mixture was filtered and the filter residue was washed with hexane (volume 1 layer). The product was air-dried, then dried in vacuum [100 mbar (1 to 104PA) a stream of nitrogen, 30 - 35oC] up to constant weight.

Output: 31.0 g (95% purity according to HPLC, wt.%) the crude of acetaminoohen III in the form of a white solid. The crude product also contains a small amount of ndimethylacetamide and sodium acetate.

1H-NMR: (DMSO - d6) to 8.57 (Shir. d, 1H, J = 8.5 Hz), 8,53 (Shir. d, 1H, J = 11.7 Hz), of 7.96 (d, 1H, J = 5.0 Hz), 7,94 (d, 1H, J = 5.0 Hz), 7,03 (d, 1H, J = 5.0 Hz), to 6.95 (d, 1H, J = 5.0 Hz), to 5.21 - 5,14 (m, 2H), 3,84 is 3.76 (m, 2H), of 2.51 - of 2.36 (m, 2H), 2,29 - 2,2 (m, 2H), 1,84 (c, 3H), 1,75 (c, 3H), of 1.35 (d, 3H, J = 6.8 Hz), 1,32 (d, 3H, J = 6.2 Hz).

Jhud: 93:7 TRANS/CIS (see above)

Microanalysis: calculated Analytically for C10H13NO3S2:

C 46,32, H OF 5.05, N OF 5.40, S 24,73.

Determined: C 46,41, H 4,94, N 5,34, S RUB 24.55.

Stage A (Alternative): Methodology of Ritter reaction with sulfuric acid fuming sulfuric acid

To mechanically stir the cooling gap is alali concentrated sulfuric acid (18 M, 9,0 ml, 162 mol), maintaining the internal temperature at 10oC, followed by addition of 30% fuming sulfuric acid (1.2 ml). The mixture was stirred for 2 h at 15 - 20oC, then 3 h at 20 - 22oC (at temperatures above 25oC are formed of a significant number of ndimethylacetamide). The course of the reaction was observed using ghvd (method described in example 1). The reaction was considered complete when less than 1% of hydroxysulfonic II (US. product acetaminoohen III). At the end of the reaction the ratio of TRANS/CIS product acetaminoohen III was to 93.5:6.5 in. After completion of the reaction the mixture was poured into ice (100 g) and the pH of the mixture was brought to 3.5 by 5.5 by slowly adding 50% aqueous sodium hydroxide (approximately 20 ml). The mixture was extracted with ethyl acetate (2 x 100 ml). The extracts were combined and washed with brine (1 x 50 ml). Then the solution was concentrated in vacuum [100 mbar (1 to 104PA), 35 - 40oC] up to a volume of 20 ml was Added ethyl acetate (100 ml) and concentration was repeated (final volume 20 ml) to ensure complete removal of acetonitrile. Hexane (100 ml) was added slowly to the mixture was stirred 2 h at 20 - 22oC (1 layer volume). The product was air-dried, then dried in vacuum [100 mbar (1 to 104PA), the stream of nitrogen, 30 - 35oC] up constantly is the case of the crude product contains no ndimethylacetamide and sodium acetate.

1H-NMR: consistent.

Jhud: 93,5 : 6.5 TRANS/CIS (method described above).

Stage B: Methodology sulfonylamine

To a mechanically stirred, cooled (0oC) chlorosulfonic acid (70 ml, 1.05 mol) was added the crude acetamidomalonate III (29,7 g, 0,114 mol, 93: 7) in parts at a speed suitable to maintain the internal temperature < 20oC. the Dark reaction mixture to sulfonylurea was heated to 50oC for 12 h or until completion of the reaction according ghvd. (Note: during the reaction was separated hydrochloric acid (0,114 mol).

Analysis method: an Aliquot (0.1 ml) was diluted to 100.0 ml with water and then analyzed according to the following method ghvd.

Device: Spectra Physics 88800/

Column: 4.1 x 250 mm Ultrasphere C-8 (Altex Inc.)

Eluent A: H2O (0,1% vol./about. H3PO4).

Eluent B: MeC/

The gradient of 97:3 to 35:65 A:B over 25 minutes

The flow rate: 2.0 ml/min

Temperature: 45oC.

Injection: 10,0 ál.

Retention time: Sulfonic acid IV (CIS/TRANS isomers) 5,0 min Acetaminoohen III (CIS-isomer) 9,0 min Acetaminoohen III (TRANS-isomer) of 10.0 minutes

The reaction sulfonylamine please take: Methods of chlorosulfonylisocyanate

After completion of the reaction stage B and the mixture was cooled to 20oC. and Then slowly added thionyl chloride (70 ml, 0.96 mol) at a speed that allows you to control the allocation of hydrogenchloride (0,114 mol) and sulfur dioxide (0,114 mol). After the addition the mixture was heated to 50oC for 6 h or until completion of the reaction according ghvd.

Analysis method: an Aliquot (0.1 ml) was diluted to 50.0 ml of acetonitrile and then immediately analyzed according to the above method ghvd (to reduce hydrolysis of sulphonylchloride V).

Retention time: Sulfonic acid IV (CIS/TRANS-isomers) 5,0 min Sulphonylchloride V (CIS/TRANS-isomers) 19 minutes

The reaction was considered complete when less than 1% of the sulfonic acid IV US. product sulphonylchloride V). After completion of the reaction the mixture was cooled to 15 - 20oC and then were dosed out slowly in intensively mixed water (1.4 l), pre-cooled to 0 to 5oC, at a speed that allows you to maintain the temperature < 5oC. (note: the internal temperature should not exceed 5oC to reduce the hydrolysis product of sulphonylchloride V).After adding approximately 10% of the reaction mixture, quenched mixture is cooling is you. The mixture was stirred for 1 h at 0 to 5oC, was filtered and the filter cake is then washed with cold (5oC) water ( 1 liter). The filter cake well was aspirated to remove more water.

Yield: 68 g of the crude sulphonylchloride Y in the form of wet solids (about 40 wt.% water), which was immediately used in the next stage.

1H-NMR: (CDCl3) 7,74 (c, 1H), 8,07 (Shir.d, J=8.1 Hz), 5,45 to 5.35 (m, 1H), 3,63 of 3.56 (m, 1H), 2,64 - of 2.56 (m, 2H), 2,09 (s, 3H), 1.57 in (d, 1H, J = 6,9 Hz).

Stage D: Methods of amidation

To a mechanically stirred, cooled (-105oC) solution of concentrated aqueous ammonia (15 M, 43 ml) of 0.65 mol) in tetrahydrofuran (THF, 300 ml) was added in parts of sulphonylchloride Y (68 g wet, about of 40.9 g, 0,114 mol) at speeds that support the internal temperature below 0oC. After complete addition, the mixture was stirred at 0 - 5oC for 1 h or until the reaction is completed according ghvd.

Analysis method: an Aliquot (0.1 ml) was diluted to 50.0 ml of acetonitrile, and then immediately analyzed by the method Ehud described in example 3 (to reduce hydrolysis of the source material sulphonylchloride V).

Vieillard V (CIS/TRANS-isomer) 19 minutes

The reaction was considered complete when less than 1% of sulphonylchloride V (US. product acetamidomalonate VI). After completion of the reaction the pH of the mixture was brought to 3 - 5 by adding dropwise concentrated sulfuric acid (18 M, around 12.2 ml, 0,218 mol), maintaining the internal temperature below 20oC. the Mixture was allowed to settle and the layers were separated. Aqueous (lower) phase was extracted with THF (70 ml). The two organic layers were combined and then diluted with water (250 ml). Then the solution was concentrated by distillation to a volume of 125 ml while the concentration of the product spontaneously crystallized. The suspension was diluted with water to a volume of 250 ml and the mixture then was stirred for 12 - 18 hours at 20 - 25oC. the Mixture was filtered and the filter residue was washed with water (150 ml). The product was air-dried, then dried in vacuum [100 mbar, 1104PA), the stream of nitrogen, 55oC] up to constant weight.

Output: 29,5 g (yield 76% of hydroxysulfonic 11) acetamidomalonate VI in the form of a white crystalline solid.

Jhud: 95:5 TRANS/CIS (method described above).

1H-NMR: (DMSO-d6) 8,65 (Shir. d, 1H, J = 9.5 Hz), 8,60 (Shir. d, 1H, J = 9.5 Hz), 8,05 (Shir. C. 4H), 7,42 (s, 1H), 7,31 (s, 1H), 5,32 - of 5.15 (m, 2H), 4,10 - of 3.80 (m, 2H), 2,53 - to 2.41 (m, 2H), 2,34 - to 2.18 (m, 2H), 1.91 a (s, 3H)/SUB>O5N2S3:

C 35,49, H 4,17, N 8,28, S 28,42.

Determined: C 35,60, H Of 4.04, N 8,21, S 28,40.

Stage E: Methods of recovery via formed in situ borane

To a mechanically stirred, cooled (0 to 5oC) suspension of acetamidomalonate VI (29.5 g, 87,1 mol, 95:5 TRANS/CIS) and sodium borohydride (16,9 g, 447 mmol) in dry THF (290 ml) was added undiluted apirat trichlorothe boron (8,13 M, 73 ml, 593 mmol) for 0.5 h, maintaining an internal temperature below 5oC. (Caution: the reaction produces hydrogen as borohydride sodium and/or DIBORANE reacts with protons sulfonamida). After complete addition, the mixture is stirred for 5 h at 0 to 5oC and then at 30 - 35oC for 12 - 18 h or until completion of the reaction according ghvd.

Analysis method: an Aliquot (0.1 ml) was diluted to 50.0 ml with water and then analyzed by way Ehud described in example 3.

Retention time: Aminosulfonic VII (CIS-isomer) 4,5 minutes

Aminosulfonic VII (TRANS-isomer) 5,0 min, Acetamidomalonate VI (CIS-isomer) 9,0 min Acetamidomalonate VI (TRANS-isomer) 10,0 min Complex amine-borane 14 - 20 minutes

The reaction was considered complete when he left IU is slowly to a mechanically stirred, pre-cooled (0 to 5oC) a solution of 1 M aqueous sulfuric acid (400 ml) at such a rate to maintain the internal temperature below 20oC (caution: during the slaking reaction is that hydrogen). The mixture was stirred for 2 hours at 20 - 25oC or until until stopped the release of hydrogen. Then the mixture was concentrated by distillation (1 ATM.) up to a total volume of 400 ml of the resulting aqueous solution was cooled to 10oC and the pH carefully brought up to 4 to 5 by adding dropwise a 50% aqueous sodium hydroxide (for example, 37 ml, 0.7 mol), maintained the internal temperature below 20oC. was Added ethyl acetate (600 ml) and the pH was brought forth to 7.5 to 8.0 by adding saturated aqueous sodium bicarbonate (about 75 ml, 90 mmol). The mixture was filtered to remove the sodium sulfate formed during the initial setting the pH, and the filter cake was washed with ethyl acetate (100 ml). The filtrate and washing the precipitate were combined and the resulting mixture was divided into phases. Aqueous (lower) phase was extracted with ethyl acetate (100 ml). The organic layers were combined and then washed with brine (100 ml). This solution containing the crude product aminosulfonic VII (approximately 27.9 g) was used in this form in the maleic acid

The solution in ethyl acetate of aminosulfonates VII (approximately 27.9 g, 86 mmol, 95:5 TRANS/CIS) of stage 5 was concentrated by distillation (1 ATM) (1,0133105PA) up to a volume of 70 ml was Added acetone (250 ml) and concentration was repeated up to a volume of 70 ml of This operation is repeated, concentrating this time up to a volume of 160 ml) was Added maleic acid (9,98 g, 86 mmol). The mixture was stirred until the salt is crystallized, and then was stirred for 12 - 18 h at 20 - 22oC. the Mixture was filtered and the precipitate was washed with acetone (volume 1 layer). The product was air-dried, then dried in vacuum [100 mbar, (1104PA), the stream of nitrogen, 75oC] up to constant weight.

Output: 33,0 g (92%) of the maleate salt VIII in the form of a white crystalline solid.

Jhud: 99:1 TRANS/CIS (method described above)

1H-NMR: (DMSO - d5) 8,17 (Shir. s, 2H), 7,81 (s, 1H), equal to 6.05 (s, 2H), br4.61 (Shir. s, 1H), 4,08 - 4,00 (m, 1H), 3,24 - 3,14 (m, 1H), 3,06 - of 2.93 (m, 1H), 2,7 - of 2.45 (m, 2H), 1.39 in (d, 3H, J=6,7 Hz) of 1.20 (t, 3H, J=7,1 Hz).

Microanalysis: calculated Analytically for C14H20N2O4S3:

C 38,17 H 4,58, N 6,39, S 21,83.

Determined: C 38,19, H 4,58, N 6,29, S 21,60.

Stage G: the Method of obtaining the crude salt of hydrochloric acid

To mechanically mix I (33,0 g, 75 mmol 99: 1 TRANS/CIS). The mixture was stirred at 20 to 25oC until complete dissolution of the solids, when the two phases became clear. The mixture was allowed to settle and then separated the layers. Aqueous (lower) phase was extracted with ethyl acetate (50 ml). The organic layers were combined and then washed with saturated aqueous sodium chloride (50 ml). To a well stirred solution in ethyl acetate was slowly added concentrated hydrochloric acid (12 M, 6,25 ml, 75 mmol). While adding the product crystallized. The mixture was concentrated in vacuo (200 mbar (2104PA), replacing ethyl acetate as needed, as long as the water content of the solution was less than 0.1 mg/ml at a volume of 150 ml and the Mixture was cooled to 20 - 22oC and then stirred for 12 - 18 h at this temperature. The mixture was filtered and the filter cake was washed with ethyl acetate (CH ml). The product was air-dried, then dried in vacuum [100 mbar (1104PA) a stream of nitrogen, 45 - 50oC] up to constant weight.

Output: 26,4 g (98% yield, 64% of the total output of hydroxysulfonic 11) of the crude hydrochloride aminosulfonic 1 in the form of a white crystalline solid.

Jhud: more than 99% (method described above).

Stage H: Methodology pmida 1 (26,4 g, 73 mmol) in water (70 ml) was heated at 90 - 95oC to dissolve the solid. To a hot solution was added activated charcoal (Darco kV, 0.26 g) and the mixture was stirred for 15 min at 90 - 95oC. the Mixture was filtered hot (85 - 90oC) through the well-washed layer accelerator filtering (Super Cel). The filtered precipitate was washed with boiling water (9 ml). The filtrate and washing the precipitate were combined and the product was allowed to crystallize by cooling a well-mixed solution to 60oC. the Mixture was stirred for 1 h at 60oC or up until the product has not been turned into a thermodynamically more stable polyhydrate crystalline form. The mixture is then slowly cooled to 3oC and then was stirred for 1 h at this temperature. The mixture was filtered cold filtering using the mother solution for rinsing the precipitate. The product was air-dried, then dried in vacuum [100 mbar (1104PA), the stream of nitrogen, 45 - 50oC] up to constant weight.

Output: 24.2 g (92% yield, 59% of the total output of hydroxysulfonic 11) pure hydrochloride salt of aminosulfonates 1 in the form of a white crystalline solid.

Jhud: 99,9% (by area) (254 nm)UB> = -17,1oC (C = 1.00 m H2O)

So pl.: 238oC (DS, C, tilt 2oC /min)

1H-NMR (DMSO - d6) to 9.91 (Shir. S., 1H), 9,63 (Shir. s, 1H), 8,21 (c, 2H), 8,02 (s, 1H), 4,68 (Shir. S., 1H), 4,37 (m, 2H), 3,19 (Shir. S., 1H), 3.04 from (Shir. s, 1H), 2,80 (d, 1H), to 2.55 (m, 1H), 1.39 in (d, 3H), of 1.29 (d, 3H).

13C-NMR: (DMSO - d6) 149,7 (C), 141,9 (C), 137,4 (C), 130,7 (C), 51,6 (C), and 49.2 (C) and 40.8 (C) 30,7 (C) and 11.1 (C) 10,0 ().

Microanalysis: calculated Analytically for C10H17N2O4S3Cl:

C 33,28, H 4,75, N 7,76, S 26,66, Cl 9.84.

Determined: C 33,33, H 4,70, To 7.67 N, S 26,60, Cl 9,77.

1. The method of obtaining 7,7-dioxide and 5,6-dihydro-(S)-4-(alkylamino)-(S)-6-alkyl-4H-thieno(2,3-b)thiopyran-2-sulfonamida General formula I

where R and R1the same or different and represents a C1- C3-alkyl,

in optical form on C-6and in crystalline form, preserving transderivational ratio among deputies of C-4and C-6or its hydrochloric salt, characterized in that a) a compound of General formula II

< / BR>
treated with a nitrile of the formula

RCN

and a strong acid so that the amount of water present, depending on the used acid was in the range of 0.5 to 10.0 wt.%, with the formation of compounds of General formula III


< / BR>
c by treating compound IV with thionyl chloride to form compounds of formula V

< / BR>
d by treating compound V ammonia with the formation of the compounds of formula VI

< / BR>
e by treating compound VI with sodium borohydride and hydrocyanic acid or a complex of borane-tetrahydrofuran or brandibelle with the formation of the compounds of formula I

< / BR>
f selection of compound I in free form or in the form of a salt of maleic acid VIII, g the transformation of compounds VIII in salt hydrochloric acid I and h cleaning hydrochloride compounds of formula I.

2. The method according to p. 1, characterized in that R and R1represent methyl.

3. The method according to p. 1, characterized in that R is methyl, R1- n-propyl.

4. The method of obtaining 7,7-dioxide and 5,6-dihydro-(S)-4-(acylamino)-(S)-6-alkyl-4H-thieno(2,3 - b)thiopurine General formula III

< / BR>
in which is fixed the chirality at C-6and saved Transstroimost the ratio between C-4and C-6deputies;

R and R1are the same or different and represents a C1-C3-alkyl,

characterized in that the compound of formula II

< / BR>
treated with a nitrile of the formula

RCN

and strong is adalah 0.5 to 10.0 wt.%.

5. The method according to p. 4, characterized in that R and R1is methyl.

6. The method according to p. 4, characterized in that R is methyl, R1- n-propyl.

7. The method according to p. 1, wherein the strong acid is a concentrated sulfuric acid, a mixture of concentrated sulfuric acid and fuming sulfuric acid, methanesulfonate, triperoxonane acid, apirat boron trichloride or aluminum chloride and the amount of water present is 1 to 2 wt.%.

8. The method according to p. 1, characterized in that the purification of the hydrochloride of the compound of structural formula I is carried out as follows: dissolve the crude hydrochloride of the compound of formula I in an aqueous solution at approximately 90 - 95oC, add activated charcoal, stirred the mixture, filtering the mixture through a layer of filter additives, wash the precipitate on the filter with hot water solution, combine the filtrate and washing the precipitate, crystallized hydrochloride compounds of formula I by cooling the solution to approximately 1 to 5oC, the mixture is filtered, the precipitate is collected and dried.

 

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EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.

6 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

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

40 cl, 51 tbl, 741 ex

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