Indoline compound and method of producing said compound

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining silodosin of formula: (3). Method involves mixing a new compound 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate with oxalic acid to obtain a corresponding oxalate with subsequent hydrolysis thereof, resulting in formation of a new compound 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile and hydrolysis thereof to obtain the target compound. Methods of obtaining new intermediate compounds are described.

EFFECT: improved method of producing indoline.

12 cl, 4 ex

 

The technical field

The present invention relates to a method for obtaining compounds of indoline suitable as a drug, as well as obtaining its intermediates. In particular the present invention relates to a method for obtaining compounds of indoline (common name: silodosin)represented by the following structural formula:

[Soed]

which is useful as a therapeutic agent in disorders of urinary symptoms associated with benign prostatic hyperplasia, as well as to intermediate compounds for use in its production.

The level of technology

Silodosin has a selective inhibitory effect against the contraction of smooth muscles of the urethra and reduces the internal pressure of the urethra without much impact on blood pressure. Moreover, silodosin selectively affects α1Asubtype of adrenergic receptors and is extremely useful as a therapeutic agent in disorders of urinary symptoms associated with benign prostatic hyperplasia and the like (see patent references 1 and 2).

As an effective and efficient method of obtaining silodosin suggested or reported that optically active amine compound represented the following General formula:

[Conn. 2]

in which R1represents a hydrogen atom or a protective group for hydroxyl, introduced into reaction with the compound of phenoxyethane represented by the following General formula:

[Soed]

in which X represents a leaving group, and optionally a shot protection, and cyano turned in karbamoilnuyu group (see patent references 3 and 4).

However, in the above-mentioned methods of obtaining sometimes due to the reaction of one molecule is optically active amine compounds and two molecules of compounds phenoxyethane as a by-product formed Dulcinea compound (C)represented by the following General formula:

[Soed]

in which R1represents a hydrogen atom or a protective group for hydroxyl. Because it is difficult to remove by-product of the method of purification used in conventional industrial production, such as recrystallization and the like, for removal of by-product you want to use this method of purification, column chromatography or the like. Thus, becoming more complex and finally the cleanup process fails to meet the means of industrial production. Thus, we need to develop a purification method, more p is thedamage for industrial production.

Patent reference 1: Japanese patent publication H6-220015;

Patent reference 2: Japanese patent publication 2000-247998;

Patent reference 3: Japanese patent publication 2001-199956;

Patent reference 4: Japanese patent publication 2002-265444.

Disclosure of invention

Tasks that should be solved by the invention of

The purpose of the present invention is to provide a method for industrial preparation silodosin.

Ways of solving the problem

To achieve the above objectives, the inventors highly studied and found that by conversion of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate represented by the following structural formula:

[Soed]

in the oxalate and its allocation by means of recrystallization can be removed by-product (C-a)represented by the formula

[Soed]

forming thus the basis of the present invention.

That is, the present invention relates to a method for producing 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide represented by the structural formula (3):

[Soed]

which involves mixing 3-{7-cyano-5-[2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate, represented by the following formula (1):

[Soed]

with oxalic acid to obtain 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate, subsequent hydrolysis of oxalate to obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile represented by structural formula (2):

[Soed]

and further hydrolysis of the compounds represented by the General formula (2), and intermediate compounds used in the method of obtaining.

The effect of the invention

3-{7-Cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate monoacetate obtained as an intermediate connection according to the method of obtaining of the present invention, well-crystallized, easy to separate from by-product (C-a) and easy to handle. Thus, the oxalate becomes an excellent intermediate product in the way of industrial production.

The best variant embodiment of the invention

The method of receiving according to the present invention includes 4 stages, as explained below.

(Stage 1)

Obtain 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amine is)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate

3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate used in the method of receiving according to the present invention, can be obtained in a manner analogous to that described in Patent reference 3, by the reaction of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-1H-indole-1-yl}propylbenzoate represented by structural formula(A):

[Soed]

or its salt with the compound of phenoxyethane represented by General formula (B):

[Soed]

in which X represents a leaving group,

in an organic solvent and preferably in the presence of a base.

As the leaving group X in the General formula (B) can be examples of the chlorine atoms, bromine and iodine, lower alkylsulfonate, such as methanesulfonamido and the like, arylsulfonate, such as benzolsulfonate or toluensulfonate and the like. Among them, the lowest alkylsulfonates is preferred.

As the organic solvent used as the solvent for the reaction, may be used any organic solvent, unless it inhibits the reaction. As an example a lower alcohol, such as methanol, ethanol, propanol, is saprophilous alcohol, tert-butanol and the like; aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like, or a mixture of solvents selected from them. Among them, a lower alcohol is preferred, in particular tert-butanol is preferred.

As can be the example inorganic bases such as alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide and the like, and the carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and an organic base such as amine lower alkyl, such as triethylamine, Diisopropylamine and the like. Among them, inorganic base, particularly the carbonate of an alkali metal is preferred, and sodium carbonate is especially preferred.

The reaction is usually carried out at temperatures from room temperature up to the boiling point of the organic solvent used in the reaction in a period of time from 30 minutes to 48 hours.

After the reaction of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2 - triptoreline)phenoxy]ethyl}amino)propyl-2,3-dihydro-1H-indol-1-yl}

propylbenzoate can be obtained using a conventional method. The above by-product (C-a) is usually included in the product in quantities of from about 5 to 20%, although the th number differs depending on the reaction conditions. The number contained by-product can be calculated by the ratio of the area measured by high performance liquid chromatography under the following conditions.

The measurement conditions

Column: Inertsil ODS-2

Wavelength: 254 nm

Mobile phase: methanol:0.01 mol/l phosphate buffer (pH 7,6) = 7:3

(Stage 2)

Obtain 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate.

Crystalline 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2 - triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate monoacetate can be selected by dissolving almost equimolar quantities of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate and oxalic acid in a suitable solvent and, optionally, heating the solution before the formation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate and its crystallization. The solvent can be examples of the lower alcohol, such as methanol, ethanol, propanol, isopropyl alcohol and the like, or the above-mentioned alcohol-containing water, a mixture of solvents selected from them, and the like. Among them, a lower alcohol is preferred, especially predpochtitel the NYM is ethanol, isopropyl alcohol and a mixed solvent consisting of water and isopropyl alcohol.

Although it may depend on the solvent, the preferred amount of oxalic acid, which should be used is generally from 0.7 to 1.5 equivalents relative to 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate.

Crystalline oxalate can be bicrystalline, if left to stand above the oxalate solution. At the same time, can be used optional seed crystals of oxalate or cooling. Moreover, the oxalate can also be bicrystalline when the concentration of oxalate solution or adding to the oxalate solution to a poor solvent.

By the above method, the number contained by-product (C-a) can be reduced to 1% or less by using 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate. Thus, the oxalate can be used directly in the next reaction.

(Stage 3)

Obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile

1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-d the hydro-1H-indole-7-carbonitrile can be obtained by hydrolysis of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate in a suitable solvent.

The hydrolysis reaction can be carried out using alkali such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate and the like, or using an acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or the like. Among them, the alkali is preferred, especially preferred is a hydroxide of an alkali metal.

As the solvent used for the hydrolysis, it is possible to give examples of the water, lower alcohol, such as methanol, ethanol, propanol, isopropyl alcohol and the like; water-soluble organic solvents, such as acetone, tetrahydrofuran, dioxane and the like, and mixtures of solvents selected from them. Among them, a mixed solvent of water and a lower alcohol is preferred.

The hydrolysis reaction can usually be carried out at a temperature of from 0°C. to the boiling point of the used solvent for a time from 30 minutes to 48 hours, and then 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile can be obtained using a conventional method. The compound obtained can be used for the following is eacli directly or optionally after further purification.

(Stage 4)

Obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide

1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide can be obtained by the hydrolysis of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile in a suitable solvent.

The hydrolysis reaction can be carried out using alkali such as an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate or the like, or using an acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or the like. Among them, the alkali is preferred, especially preferred is an alkali metal hydroxide. In addition, it is preferable that the hydrolysis reaction was carried out in the presence of an oxidizing agent such as hydrogen peroxide or the like.

As the solvent used for the hydrolysis, it is possible to give examples of the water, lower alcohol, such as methanol, ethanol, propanol, isopropyl alcohol and the like; water-soluble organic solvents, such as acetone, tetrahydrofuran, dioxane, dimethylsulfoxide and the like, and mixtures of solvents selected from the same or similar. Among them, a mixed solvent of water and dimethyl sulfoxide is preferred.

The hydrolysis reaction can be conducted at temperatures from 0°C to 100°C for a time from 30 minutes to 48 hours, and then 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide can be obtained using the usual method.

EXAMPLES

The present invention is hereinafter illustrated in more detail by the following examples, but the invention is not limited to this only.

Example 1

3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl)-2,3-dihydro-1H-indol-1-yl)propylbenzoate

To a mixture of ethyl acetate (50 ml) and aqueous solution (50 ml), potassium carbonate (13.5 g) was gradually added to 3-[5-((2R)-2-aminopropyl)-7-cyano-2,3-dihydro-1H-indol-1-yl]propylbenzoate(2R,3R)monetarist (5.0 g) and the mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated and the aqueous layer was extracted with a solution of ethyl acetate (50 ml). The combined ethyl acetate layer was washed with an aqueous solution of potassium carbonate and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in anhydrous tert-butanol (25 ml)and to the solution was added 2-[2-(2,2,2-triptoreline)phenoxy]ethylmethanesulfonate (3,67 g) and sodium carbonate (1.08 g). The mixture was boiled under reflux for 24 hours. After the reaction mixture was allowed to cool and then added an aqueous solution of sodium bicarbonate (50 ml). The mixture was twice extracted with ethyl acetate (50 ml). The combined ethyl acetate layer was washed with an aqueous solution of sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, obtaining 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate (6,40 g). At this stage, the content of by-product (C-a) in the obtained product was 13.6%. The product was used for next reaction. The structure of the obtained 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate was confirmed by NMR analysis using a small amount of the pure product.

1H-NMR (CDCl3) δppm: of 1.06 (3H, d, J=6.4 Hz), of 2.15 (2H, m)2,44 (1H, DD, J=6,9, to 13.8 Hz), 2,61 (1H, DD, J=6.3, in a 13.8 Hz), 2,85-3,10 (5H, m), of 3.57 (2H, t, J=8.6 Hz), 3,74 (2H, t, J=7.2 Hz), 4,05-to 4.15 (2H, m), 4,32 (2H, square, J=and 8.4 Hz), 4,47 (2H, t, J=6.4 Hz), 6.89 in-7,06 (6H, m), 7,44 (2H, t, J=7.8 Hz), 7,55 (1H, t, J=7.5 Hz), of 8.06 (2H, d, J=8,4 Hz).

Example 2

3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate monoaxial

Isopropyl alcohol (50 ml) and the dihydrate of oxalic acid (1.20 g) to allali to 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate (6,40 g), which was obtained in example 1 and the mixture was dissolved by heating. After the introduction of the seed-target compound, and the mixture was left overnight. Precipitated crystals were separated by filtration and washed with a small amount of chilled isopropyl alcohol and dried under vacuum to obtain 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate (5,43 g). At this stage, the content of by-product (C-a) in the resulting product was 0.9%.

1H-NMR (DMSO-d6) δppm: of 1.13 (3H, d, J=6.2 Hz), of 2.08 (2H, m), 2,45-to 2.57 (1H, m), 2,88 was 3.05 (3H, m), 3,35-3,50 (3H, m), 3,60 (1H, t, J=8.6 Hz), 3,70 (2H, t, J=7,1 Hz), the 4.29 (2H, Sirs), 4,39 (2H, t, J=6,1 Hz), 4,71 (2H, square, J=the 8.9 Hz), 6,95-7,16 (6H, m), 7,51 (2H, t, J=7,7 Hz), the 7.65 (1H, t, J=7.4 Hz), to 7.99 (2H, d, J=7,4 Hz).

Example 3

1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile

3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate monoacetate (10.0 g) was dissolved in methanol (40 ml), then slowly added aqueous potassium hydroxide solution prepared from potassium hydroxide (2,93 g) and water (10 ml)and the mixture was stirred at room temperature overnight. To the reaction mixture were added water (150 ml), then was extracted with ethyl acetate (150 ml and 50 ml). The combined ethyl acetate layer washed with the saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, obtaining 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (7,86 g).

1H-NMR (CDCl3) δppm: of 1.05 (3H, d, J=6,1 Hz), 1.85 to 1,95 (2H, m), 2,43 (1H, DD, J=13,5 that 6.8 Hz), 2,60 (1H, DD, J=13,7, 6.3 Hz), 2,80-3,10 (5H, m), of 3.57 (2H, t, J=8,8 Hz)to 3.67 (2H, t, J=7.2 Hz), 3,80 (2H, t, J=6.0 Hz), 4,05-4,15 (2H, m), 4,32 (2H, square, J=8,4 Hz), 6,85-7,05 (5H, m).

Example 4

1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide

1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (6,00 g) was dissolved in dimethyl sulfoxide (75 ml) and to this solution was added 5 mol/l aqueous solution of sodium hydroxide (4,50 ml). To the reaction mixture was gradually added 30% hydrogen peroxide (2,63 ml) at a temperature not exceeding 25°C. the Reaction mixture was stirred at a temperature of from 20 to 25°C for 5 hours. To the reaction mixture was carefully added to an aqueous solution of sodium sulfite prepared from sodium sulfite (2.1 g)dissolved in water (150 ml). The reaction mixture was twice extracted with ethyl acetate (50 ml). The combined ethyl acetate layer was twice extracted with 2 mol/l hydrochloric acid. Extracted aqueous solution of hydrochloric acid was neutralized with sodium bicarbonate and was extracted twice with ethyl acetate (50 ml). Unite the military ethyl acetate layer was washed saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was cooled to obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide (of 4.49 g).

1H-NMR (CDCl3) δppm: a 1.08 (3H, d, J=6.2 Hz), 1,75-of 1.85 (2H, m), 2,53 (1H, DD, J=13,6, 6,7 Hz), 2,68 (1H, DD, J=13,6, and 6.6 Hz), 2,90-3,10 (5H, m), 3,19 (2H, t, J=6,7 Hz)to 3.41 (2H, t, J=8,5 Hz in), 3.75 (2H, t, J=5.6 Hz), 4,05-4,15 (2H, m), 4,30 (2H, square, J=8,4), 5,79 (1H, Sirs), of 6.65 (1H, Sirs), 6,85-7,05 (5H, m), 7,16 (1H, s).

1. The way to obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide represented by the structural formula (3):
[3]

includes mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate represented by structural formula (1):
[Compound 1]

with oxalic acid with the formation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate with subsequent hydrolysis of oxalate with the formation of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile represented by structural formula (2):
[Compound 2]

and the hydrolysis is connected to the I, represented by the structural formula (2).

2. The method of receiving according to claim 1, including the allocation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate.

3. The method of receiving according to claim 1 or 2, comprising the hydrolysis of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate hydroxide of an alkali metal.

4. The method of receiving according to claim 1, in which 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile hydrolyzing in the presence of an oxidizing agent.

5. The method of receiving according to claim 4, in which the oxidizing agent is hydrogen peroxide.

6. Method for the preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate represented by structural formula (1):
[Compound 6]

including the interaction of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate represented by structural formula (A):
[Compound 4]

with the connection of phenoxyethane represented by the General formula (I):
[Compound 5]

where X represents a leaving group.

7. Method for the preparation of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)Fe is hydroxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate, includes mixing 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate and oxalic acid.

8. The way to obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile represented by structural formula (2):
[Compound 7]

including the hydrolysis of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate of monoacetate.

9. The way to obtain 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide represented by the structural formula (3):
[Compound 8]

including the hydrolysis of 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile.

10. 3-{7-Cyano-
5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl)propylbenzoate.

11. 3-{7-Cyano-
5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate monoacetate.

12. 1-(3-Hydroxypropyl)-
5-[(2R)-2-({2-[2-(2,2,2-triptoreline)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile.



 

Same patents:

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EFFECT: end product with high output and high purity.

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7 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the selective method for preparation of "АХЭ" inhibitor - perindopril with usage as initial reagent of the sterospecific amino acid N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine which is activated by tetramethyl-uronium salts in the presence of tertiary organic base and following interreaction with (2S,3aS,7aS)-octahydroindolo-2-carbonic acid or its ester. After completing of the reaction the protective group is removed by the hydrogenation, interphase hydrogenation or extraction.

EFFECT: obtaining of perindopril with usage of tetramethyl-uronium salts as reagents of coupling reaction.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to compounds with formula I, active towards receptors, activated by peroxisome proliferators (PPAR), and can be used in medicine, formula I, where U, W, X and Y represent CH, V represents CR8; R1 represents-C(O)OR or a carboxylic acid isoster, where R is a hydrogen atom, substituted alkyl, aryl or heteroaryl; R2 represents -S(O)2R21; R6 and R7 represent a hydrogen atom, substituted alkyl or cycloalkyl; R8 represents a hydrogen atom, halogen, -OR9, substituted inferior alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl or heteroaralkyl; R9 represents a substituted alkyl or cycloalkyl; R21 represents a substituted heteroaryl or phenyl; n equals 1.

EFFECT: obtaining new biologically active compounds and pharmaceutically active compositions based on these compounds.

46 cl, 134 ex, 4 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new use of compounds of 2-arylacetic acid and amides with formula (I) and their pharmaceutically used salts, where A comprises an atom X and is phenyl or a 5-6 member heteroaromatic ring, optionally containing a heteroatom, chosen from N; corresponding positions on ring A are marked by numbers 1 and 2; atom X is chosen from N (nitrogen) and C (carbon); R represents a substituting group on ring A, chosen from: a group in 3 (meta) positions, chosen from a group comprising straight or branched C1-C5-alkyl, C2-C5-acyl; a group in 4 (para) positions, chosen from a group, comprising C1-C5-alkyl, C1-C5-alkanesulphonylamino, substituted with halogens; Hy represents a small hydrophobic group with steric inhibition constant ν between 0.5 and 0.9 (where ν is Charton steric constant for substitutes), comprising methyl, ethyl, chlorine, bromine, group Y chosen from O (oxygen) and NH; when Y represents O (oxygen), R' represents H (hydrogen); when Y represents NH, R' is chosen from groups: -H, - residue with formula SO2Rd, where Rd represents C1-C6-alkyl. The invention can be used in making medicinal agents, which are inhibitors of induced IL-8 PMN chemotaxis (CXCR1) or induced GRO-α PMN chemotaxis (CXCR2).

EFFECT: new use of compounds of 2-arylacetic acid and amides and their pharmaceutically used salts.

14 cl, 2 tbl, 44 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention claims ethers of substituted 1H-indol-3-carboxylic acid of the general formula 1 or their pharmaceutically acceptable salts. Compounds can be applied as active substance for pharmaceutical compositions and for application of these compositions in production of medicine for virus disease prevention and treatment, especially for diseases caused by infection hepatitis viruses (HCV, HBV) and influenza A viruses. In the general formula 1 R1 is aminogroup substitute selected out of hydrogen, optionally substituted inferior alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl selected out of phenyl, naphthyl or 5-6 member heteroaryl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur, and possibly condensed with benzene ring of optionally substituted heterocyclyl, which can be optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring selected out of nitrogen and oxygen; R2 is alkyl substitute selected out of hydrogen, optionally substituted hydroxyl group, optionally substituted mercapto group, optionally substituted arylsulfinyl group; optionally substituted amino group, optionally substituted 5-6-member heterocyclyl containing 1-2 heteroatoms selected out of nitrogen, oxygen and sulfur; R3 is hydrogen or optionally substituted inferior alkyl; R14 and R24 are independently substitutes of cyclic system, selected out of hydrogen or halogen atom, cyano group, trifluoromethyl, optionally substituted phenyl or optionally substituted heterocyclyl which is an optionally substituted 5-6-member heterocyclyl with 1-2 heteroatoms in heterocyclic ring, selected out of nitrogen, oxygen or sulfur, possibly condensed with benzene ring.

EFFECT: improved efficiency of compositions.

15 cl, 3 tbl, 1 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel statin derivatives of formula: or its pharmaceutically acceptable salt or stereoisomer, where: X represents -O-, R represents statin residue of formula:

, Y represents a) straight or branched C1-C20alkylene, mainly C1-C10, optionally substituted with one or more OH;

b)

,

where n equals from 0 to 20, and n1 from 1 to 20; on condition that when Y represents b), group -ONO2 is bonded with -(CH2)n1;

g)

,

where X2 represents -O, n3 from 1 to 6, mainly from 1 to 4, R2 represents H or CH3.

EFFECT: obtaining compounds which possess anti-inflammatory, antithrombotic and antithrombocytic activity, which allows to use them for production of medication for reduction of cholesterol and triglycerides levels and/or for increasing HDL-C level.

14 cl, 6 tbl, 9 ex

Crystal habits // 2334738

FIELD: chemistry.

SUBSTANCE: invention concerns crystal habits of fluvastatin sodium salt hydrates referred to as polymorphic crystal habits C, D, E and F. Production method of these crystal habits, pharmaceutical composition for 3-hydroxy-3-methylglutaryl- coenzyme YMG-CoA inhibition based on these crystal habits C, D, E, F are described.

EFFECT: production of crystal habits of fluvastatin sodium salt hydrates.

8 cl, 6 dwg, 6 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.

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

31 cl, 5 tbl, 68 ex

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to new hydroxyindole General formula

< / BR>
where R1- C1-C12-alkyl, linear or branched, if necessary monosubstituted monocyclic saturated or polyunsaturated carbocycles with 6 ring members, WITH6-aryl group and closed carbocyclic substituents on its part, if necessary, can be mono - or polyamidine R4; R5- monocyclic polyunsaturated carbocycles with 6 ring members, mono - or politeley atoms, halogen or a monocyclic polyunsaturated heterocycles with 6 ring members, one of which is N as heteroatom, mono - or politeley atoms of halogen; R2and R3can be hydrogen or HE, and at least one or both of the Deputy should be-HE; R4means-H, -OH, -F, -Cl, -J, -Br, -O-C1-C6-alkyl, -NO2; A -, or a bond, or -(CHOZ)m-(C= 0)-, and m= 0

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to derivatives of 2-phenylindole, mixtures of their isomers or individual isomers of General formula I, where R1is unbranched or branched C1-C8is alkyl or hydrogen; R2- the remainder of the formula CO-NH2or-CH2-OH

The invention relates to 1H-indol-3-acetamide General formula I where X is oxygen; R1selected from groups (i), (iii), where (i)6-C20-alkyl, C4-C12-cycloalkyl; (iii) - (CH2)n-(R80), where n is 1-8 and R80is the group specified in (i); R2is hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy; R3each independently is hydrogen or methyl; R4- R7each independently - C1-C10-alkyl, C2-C10alkenyl,3-C8-cycloalkyl,1-C10-alkoxy,

WITH4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -C(O)O(C1-C10-alkyl), hydrazide, hydrazino, NH2, NO2, -C(O)NR82R83where R82and R83independently is hydrogen, C1-C10-alkyl or a group of formula (a), where R84and R85independently is hydrogen, C1-C10-alkyl; p= 1 to 5; z is a bond, -O-, -NH-; Q is-CON(R82R83), -SO3H, phenyl, a group of formula b), C), (d), where R86independently selected from hydrogen, C1-C10-alkyl, and their pharmaceutically acceptable salts or their esters, or Amida

Derived indole // 2137759

The invention relates to new compounds of General formula I, where R1-R4is hydrogen, halogen, lower alkyl or trifluoromethyl, R5and R6is hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy and R7- lower alkyl, and pharmaceutically acceptable additive salts of acid compounds of the formula I

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.

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

31 cl, 5 tbl, 68 ex

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