Alkylenediamine derivatives or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds, having the ability to inhibit bladder contraction, which suggests the possibility of their use in medicine for the treatment of dysuria. The inventive product: alkylenediamine derivatives of the formula 1

(1)

where one of the radicals D and E represents-CH2- or-CO-and the other means -(CH2)m-R1and R1represents hydrogen, lower alkyl, phenyl, optionally substituted by halogen atom, lower alkyl or lower alkoxygroup, naphthyl, thienyl or 3-indolyl; R2is phenyl, optionally substituted by a halogen atom or a lower alkyl, thienyl or furyl; R3and R4each of the radicals represents a lower alkyl or the radicals R3and R4connected together and with the nitrogen atom to which they are attached, form a morpholine, thiomorpholine, homomorpholine, pyrrolidine, piperidine, optionally substituted by hydroxyl or lower alkoxy groups, or 4-acetylpiperidine; X and Y independently of one another, each of the radicals represents an oxygen atom or sulfur; m is an integer of 0-4; n is an integer 0-4; r is 0 or 1;efticiency acceptable salt. 2 Il., 6 table.

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient.

It is now known that flavoxate (hydrochloride), oxybutynin (hydrochloride) has the ability to inhibit bladder contraction, and therefore they can be used as drugs for the treatment of dysuria. However, because they provide direct peripheral effect on the bladder, sometimes the introduction of medicines is accompanied by side effects on other organs such as the digestive system.

Recently, in a preliminary publication of the Japan patent No. 1(1989)-319418 was revealed that the following derivatives of 1,3-oxazolidin-2-she and their pharmaceutically acceptable salts are effective means for the treatment of dysuria:

< / BR>
where Rkis a straight or branched alkyl group with 3-8 carbon atoms; Xkrepresents a hydrogen atom, halogen atom, lower alkyl group or the th derivative, having the ability to inhibit bladder contraction under conditions of high intravesical pressure, and new drugs for the treatment of dysuria.

The present invention relates to alkylenediamines derived, which can be represented by the following formula:

< / BR>
where one of the radicals D and E represents-CH2- or-CO-and the other means -(CH2)m-R1and

R1represents hydrogen, lower alkyl, phenyl, optionally substituted by halogen atom, lower alkyl or lower alkoxygroup, naphthyl, thienyl or 3-indolyl;

R2phenyl, optionally substituted by a halogen atom or a lower alkyl, thienyl or furyl;

R3and R4each of the radicals represents a lower alkyl or the radicals R3and R4connected together and with the nitrogen atom to which they are attached, form a morpholine, thiomorpholine, homomorpholine, pyrrolidine, piperidine, optionally substituted by hydroxyl or lower alkoxy groups, or 4-acetylpiperidine;

X and Y independently of one another, each of the radicals represents an oxygen atom or sulfur;

m is an integer 0-4;

n is an integer 0-4;

r 0 is>or their pharmaceutically acceptable salts.

One of the characteristic compounds of formula (I) is a compound which can be represented by the formula (3):

< / BR>
where R1, R2, R3, R4, E, X, Y, m, n, p and q have the meanings indicated above.

Another characteristic compound of formula (1) is a compound which can be represented by the formula (4):

< / BR>
where each of R1, R2, R3, R4X, Y, E, m, n, p and q have the values defined above for formula (I).

Another characteristic compound of formula (I) is a compound which can be represented by the formula (5):

< / BR>
where each of R1, R2, R3, R4, X, Y, D, m, n, p and q have the values defined above.

Another characteristic compound of formula (I) is a compound which can be represented by the formula (6)

< / BR>
where each of R1, R2, R3, R4X, Y, D, m, n, p and q have the values defined above for formulas (1) and (2).

Alkylenediamine derivatives of formula(1), (2), (3), (4), (5) and (6) and their pharmaceutically acceptable salts can inhibit bladder contractions in conditions of high intravesical pressure by exposure to n is to be used as an effective drug for the treatment of dysuria, incontinence of urine and painful urination associated with diseases such as nervous dysuria, chronic prostatitis and chronic cystitis.

Alkylenediamine derivatives of the present invention of formula (1) can be obtained by a method in which the compound of formula (7)

< / BR>
where each of R1X, Y, D, E, and r has the meanings given above, is subjected to reaction with the compound of the formula (9):

< / BR>
where each of R2, R3, R4n, p and q have the meanings given above, and Q is a removable group such as halogen atom, tosyloxy group or mesilate group.

Alkylenediamine derivative of the present invention can be also obtained by the method in which the compound of formula (10)

< / BR>
where each of R1, R2X, Y, D, E, Q, m, n, p, q and r have the values defined above, is subjected to reaction with the compound of the formula (12):

< / BR>
where each of R3and R4has the values defined above.

Alkylenediamine derivative of the present invention having the formula (3) can be obtained by a method in which the compound of formula (13):

< / BR>
where each of R1X, Y, E and m have the meanings defined above, subjecting, defined above, and Q is the deleted group.

Alkylenediamine derivative having the formula (3) can be also obtained by the method in which the compound of formula (14):

< / BR>
where each of R1, R2X, Y, E, Q, m, n, p and q have the meaning given above, is subjected to reaction with the compound of the formula (12):

< / BR>
where each of R3and R4has the values defined above.

Alkylenediamine derivative of the formula (3) of the present invention, where X, Y, and E is an oxygen atom, an oxygen atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (15):

< / BR>
where each of R1, R2, R3, R4, m, n, p and q have the meanings given above, is subjected to reaction with the reagent used for the synthesis of 2-oxazolidone of 1,2-amino-alcohol.

Alkylenediamine derivative of the present invention having the formula (3), where X, Y and E represent an oxygen atom, a sulfur atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (15) above, is subjected to reaction with carbon disulfide and alkylphosphonates, phosgene or dialkylammonium.

Alkylenediamine is Sloboda and CH2-, respectively, can be obtained by a method in which the compound of formula (16):

< / BR>
where each of R1, R2, R3, R4, m, n, p and q have the meanings given above, and R5represents an alkyl group, is subjected to reaction ring closure in the conditions of heating.

Alkylenediamine derivative of the present invention having the formula (3), where X, Y, and E represents an oxygen atom, an oxygen atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (17):

< / BR>
where each R1and m has the meaning defined above, is subjected to reaction with the compound of the formula (18):

< / BR>
where each of R2, R3, R4n, p and q have the meanings given above, and R6is an alkyl group.

Alkylenediamine derivatives of the present invention having the above formula(1), (2), (3), (4), (5) and (6) can be obtained in the form of pharmaceutically acceptable salts.

Alkylenediamine derivatives having the above formula and their pharmaceutically acceptable salts can be used effectively for the treatment of dysuria.

In Fig. 1 illustrates various ways recip is 2 presents the connection which in Fig.1 denoted by lowercase letters.

Alkylenediamine derivatives of the present invention of formula (1) described in more detail below.

In the formula (1) R1represents a hydrogen atom, alkyl group (such as alkyl with 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl) or phenyl, naftalina or 3-indolyl group, with the phenyl group may have a Deputy, such as the halogen atom, lower alkyl or lower alkoxygroup; and R2represents a phenyl group optionally substituted by a halogen atom or a lower alkyl, thienyl or follow group.

Preferred is thienyl or phenyl group which may have a Deputy, and more preferred is a phenyl group having no replacement group, or phenyl group, substituted lower alkyl, alkoxygroup or halogen atoms, but especially preferred is a phenyl group having no substituents.

The group represented by R3or R4in formulas(1), (2), (3), (4), (5) and (6) is preferably an alkyl group. Preferably also, to R3and R4taken together, positive examples of such alkyl group is a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc., the Above alkyl groups are especially preferred.

In formulas (1) and (3) the ring structure may have the formula (19):

< / BR>
and preferably, if this structure has the following formula (20A), (20b), (20c) and (20d):

< / BR>
< / BR>
< / BR>
< / BR>
Especially preferred is the compound of formula 20A.

In formulas (1) to(6) m is preferably 0, 1 or 2, and particularly preferably m is 1, n is preferably 0, 1 or 2, and particularly preferably n is 0, p is preferably 0, and q is preferably equal to 2.

As in formulas (1) to(6) carbon atom associated with R2-(CH2)nis asymmetric atom, the compounds represented by formulas (1) to(6) have two diastereoisomer and four optical isomers. In this case, all of the racemates, optical isomers and a mixture of optical isomers are included in the scope of the present invention.

Examples of pharmaceutically acceptable salts alkylenediamine derivative represented by the formula (1) to(6) are acid additive salts of inorganic acids (e.g. hydrochloric acid, sulfuric acid, Hydrobromic acid and phosphoric acid) and the TES acid, maleic acid, malic acid, oxalic acid, methanesulfonic acid and paratroopas acid).

Alkylenediamine derivative of the present invention can be obtained by a method in which the compound represented by the above formula (7), is subjected to reaction with the compound represented by the above formula (9).

In this method, the compound of formula (7) is subjected to reaction with the compound of the formula (9) in an organic solvent, such as acetone, methyl ethyl ketone, isobutylmethylxanthine or dimethylformamide, in the presence of carbonate, for example potassium carbonate, sodium carbonate and cesium carbonate, at temperatures ranging from room temperature to the temperature of distillation, for 2-50 hours, resulting in the receive connection of the formula (1). The preferred amounts of the compounds of formula (9) and carbonate are 1-2 M 2-8 M, respectively, per 1 mol of the compounds of formula (7). It is preferable that the compound of the formula (9) was used in the form of stable hydrochloride.

Alkylenediamine derivative of the present invention can be obtained by a method in which the compound represented by the above formula (10), is subjected to reaction with the connection of the t reaction with the compound of the formula (12) at 50-150oC for 1-7 h, resulting in the receive connection of the formula (1). This method is usually carried out without solvent, but can be used, though not necessarily, an inert solvent.

Alkylenediamine derivative of the present invention of the formula (3), where X, Y, and E is an oxygen atom, an oxygen atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (15) is subjected to reaction with the reagent used for the synthesis of 2-oxazolidone of 1,2-amerosport.

In this way examples of reagents used for the synthesis of 2-oxazoline of 1,2-amerosport are phosgene, trichlorochloroform, diethylcarbamyl and urea. This method is usually carried out in a mixed solvent consisting of water and an organic solvent, in the presence of a base.

Alkylenediamine derivative of the present invention of the formula (3), where X, Y, and E is an oxygen atom, a sulfur atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (15) is subjected to reaction with carbon disulfide and alkylchlorosilanes.

In this method, the compound of formula (15) can be subjected to reaction with CE the accordance of the base, such as triethylamine, resulting in the receive connection of the formula (3), provided that X, Y, and E is an oxygen atom, a sulfur atom and a-CH2-, respectively.

Alkylenediamine derivative of the present invention of the formula (3), where X, Y, and E is an oxygen atom, an oxygen atom and a-CH2-, respectively, can be obtained by a method in which the compound of formula (16) is subjected to reaction ring closure in the conditions of heating.

This method can be carried out by heating the compounds of formula (16) which can be obtained, for example, through reaction of compounds of formula (15) with the compound of the formula lCO2R5) at a temperature in the range of 50oC to a temperature of distillation in an organic solvent, such as sodium methoxide, ethoxide sodium and isoproxide aluminum. When implementing this method, it is preferable to remove produced as a by-product alcohol (R5OH) together with the solvent.

Alkylenediamine derivative of the present invention of the formula (3), where X, Y, and E is an oxygen atom, an oxygen atom and a-CH2-, respectively, can be obtained by a method in which the compound of the above formula (17) and the compound of formula (18) is heated to melting or heated under stirring in the presence of a catalyst to stimulate the reaction. As a catalyst can be used bases such as triethylamine, halide salt of Quaternary ammonium, n-piperonyl lithium, sodium hydroxide and lithium hydroxide, as well as a Lewis acid such as zinc bromide, zinc chloride and ferric chloride. This method is preferably carried out at 100-150oC for several hours.

Alkylenediamine derivative of the present invention can be obtained by any of the methods mentioned above or by combining well-known reactions. Different ways of synthesis of 5-benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-it [the Compound (1)] described in example 1 shown in Fig. 1. In Fig.1 scheme of obtaining compound (1) from compound (2) and compound (e) corresponds to the first method and a circuit for obtaining compounds (1) from the compound (a) and compounds (3), which is produced from compound (2), corresponds to the second method. Each of lowercase letters in Fig.1 indicates a proper connection is shown in Fig.2.

Optical isomers alkylenediamine derivative of the present invention can be obtained by synthesis using optically active intermediates or by sequential separation of four Opti is the first derivative) using column chromatography on silica gel and optical resolution of each diastereoisomer known methods. When the compound of the formula (3) are obtained by reaction of compounds of formula (17) and the compounds of formula (18), then, for example, optically active compound of the formula (3) can be synthesized, provided that both the compounds of formula (17) and (18) are optically active. If optically active is the only one of these compounds, the optically active compound of the formula (3) can be obtained by stepwise separation of the diastereomers using conventional column chromatography on silica gel.

Typical examples alkylenediamine derivatives of the formula (3), which correspond alkylenediamine derivative of formula (1), where r is 0, are presented in the following table. 1, in which in the column "example" shows the number of examples describing the synthesis of this compound.

Examples of typical alkylenediamine derivatives having the formula (1), where r is 0 except alkylenediamine derivatives of the formula (3), are presented in the following table. 2, where in the column "Example" shows the number of examples, which describe the synthesis of this compound.

Examples of typical alkylenediamine derivatives of the formula (4), which correspond alkylenediamines production is of Kerov, in which is described the synthesis of these compounds.

Examples of typical alkylenediamine derivatives of the formula (5), which correspond alkylenediamine derivative of formula (1), where r is 0, is shown in the table below. 4, where in the column "Example" shows the number of examples, which describe the synthesis of these compounds.

Examples of typical alkylenediamine derivatives of the formula (6), which correspond alkylenediamine derivative of formula (1), where r is equal to 1, are presented in the following table. 5, where in the column "Example" shows the number of examples, which describe the synthesis of these compounds.

(1) the Test for inhibition of the contraction of the bladder during urination

The ability of the compounds of the present invention to inhibition of contraction of the bladder during urination was evaluated as follows.

Method:

Male Wistar rats were anestesiologi using urethane (1.5 g/kg, subcutaneously) and fixed them backs down on a special Board. In the trachea of rats were injected tracheotomies tube to ensure the passage of air, and then made an incision in the midline and expose the bladder. Then in the upper part of the bladder was making small the Colo 1 mm). The urethra and ureter was ligated to make the bladder closed system.

Using the infusion pump in the bladder of rats was injected with saline solution, with a speed of 0.05 ml/min in order to induce rhythmic bladder contractions. Then measured intravesical pressure using a pressure transducer and recorded on a chart recorder. The test compound was dissolved in physiological solution, and then injected into the femoral vein via a polyethylene cannula.

Assessment

The efficiency of inhibition of bladder contractions was evaluated by measuring the period of time (the period of inhibition), during which inhibited the contraction of the bladder. As a drug used every connection, obtained as described in the examples. Each of the measured periods of inhibition is indicated in the table. 6.

With regard to the toxicity of the compounds of the present invention, the magnitude of LD50mg/kg, measured by the method of "up and down", also presented in table. 1.

As the results, presented in table. 1, the compounds of the present invention are effective inhibitors)

The bladder strips were obtained from male Japanese white rabbits (weight 2,00-2,80 kg). Each strip suspended in the bath for bodies containing Krebs solution. This bath was maintained at 37oC and was constantly aziraphale with Carbogen. Then curves were constructed according to the "cumulative concentration response to acetylcholine and norepinephrine.

Test the connection [connection example 2, i.e. 5-benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-it fumarate] was introduced in Krebs solution for 5 min before injection of acetylcholine or norepinephrine in order to identify the contractile effect.

Assessment

Pre-processing the test compound is introduced in a concentration in the range from 1x10-5up to 3x10-5not showed any effective influence on the contraction induced by acetylcholine and norepinephrine. Hence we can conclude that the test compound inhibits bladder contraction by acting not on the peripheral nervous system of the body, and on his Central nervous system.

Thus, alkylenediamine derivative of formula (1) and its pharmaceutically acceptable salt can be successfully used in quality for the treatment of dysuria can be used either as a standard dosage forms for oral administration, either in the form of a parenteral composition, for example, injection or suppository. Dosage forms for oral administration can be produced in the form of tablets, capsules, powders, granules, syrups them, etc., Dosage forms for parenteral administration may be made in the form of injections, suppositories, etc. For the preparation of these drugs can be used typically used in pharmacy practice additives such as fillers, disintegrant, binder, sizing, pigments, diluents, etc., Examples of fillers can serve as dextrose, lactose, etc., as disintegrants can be used starch, calcium carboxymethylcellulose, etc., as sizing can be used stearate, talc, etc., Examples of the binder can serve as hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc.

The daily dose may be about 1.0-10.0 mg / day in the case of the use of drugs by injection, and about 1.0 to 500 mg / day in the case of oral administration (for an adult, including in both cases). The dose can be increased or decreased depending on the age and condition of the patient.

at Central action, not lowers blood pressure and exerts a selective effect on the bladder.

The following examples illustrate in more detail the present invention.

Example 1

5-Benzyl-3-3-morpholino-1-phenylpropyl-1,3-oxazolidin-2-he

5-Benzyl-1,3-oxazolidin-2-he (825 mg, 4,7 mm), 4-[(3-chloro-2-phenyl)propyl] -the research hydrochloride (1,415 mg, 5.1 mm), potassium carbonate (2,12 g, 15.4 mm) and methyl ethyl ketone (25 ml), stirred and then heated under reflux for 23 hours the resulting solution was cooled to room temperature, any insoluble matter was removed by filtration and the solvent was removed by distillation under reduced pressure. To the obtained residue was added ethyl acetate. The mixture is then washed with water and saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. The solvent is kept under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) and resulted 376 mg of diastereoisomer And in the form of a colorless oily product (yield: 21% ), and 556 mg of diastereoisomer In the form of a pale yellow oily product (yield: 31%).

1H-NMR (CDCl3) Delta:

diastereomer the 2 (1H, t, J=8 Hz, 3.5 to 3.8 (4H, m), and 4.68 (1H, m) 5,00 (1H, t, J=7 Hz), 6,8-7,4 (10H, m).

Example 2

5-Benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-it fumarate

5-Benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-he (diastereoisomer A) (376 mg, 1.0 mm), obtained in accordance with the description in example 1, was dissolved in ethanol (5 ml). To the resulting solution was added fumaric acid (115 mg, 1.0 mm) and heating, was dissolved. Then a solution of ethanol was removed by distillation under reduced pressure, and the residue was led from a mixture of ethanol and hexane (3:1). The resulting crystalline product was collected by filtration, washed with a mixture of ethanol and hexane (3:1) and dried at room temperature and reduced pressure during the night, resulting in a received 234 mg of the target compound in the form of white crystalline powder (yield: 46%).

So pl. 133-135oC (decomposition).

1H-NMR (CDCl3) Delta: 1,9-2,3 (2H, m), 2,4-2,7 (2H, m), 2,7-3,1 (6N, m), 3.1 to 3.4 (2H, m), 3,6-3,9 (4H, m), 4.5 to 5.0 (2H, m), at 6.84 (2H, m) and 7.1 to 7.4 (10H, m)

IR (KBr) cm-1: 3420, 2920, 2580, 1725, 1425, 1360, 1290, 1250, 1215, 1040, 980, 970, 750, 640.

Example 3

(-)-5-Benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-he-fumarate

5-Benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-he is rastvoritele (isopropyl alcohol acetone water 50 g 20 g 6.2 g) (15 ml). To the resulting solution was added D - (-)-tartaric acid (1,17 g), dissolved in the above mixed solvent (30 ml). After keeping this solution at room temperature for 3 hours, the precipitated crystals were collected by filtration, washed with the above mixed solvent (45 ml) and was dried by the air, resulting received a white crystalline powder (1,82 g).

White crystalline powder (2,39 g), obtained as described above was added to the above mixed solvent (65 ml) and was dissolved in 80oC. Then the solution was kept overnight at room temperature, precipitated crystals by filtration, washed with the above mixed solvent (15 ml) and was dried under reduced pressure, resulting in the obtained white powder (2.1 g). This powder is suspended in water (50 ml). The resulting suspension was podslushivaet by adding saturated aqueous sodium bicarbonate, and then was extracted twice with dichloromethane (30 ml). The extract was washed with saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent was removed by distillation under reduced pressure and obtained oily product (1.5 g). This is in ethanol (10 ml). Then added 5 ml of n-hexane and the solution stirred overnight at room temperature. Precipitated crystals were collected by filtration, washed with a mixture of ethanol/n-hexane (4/1) (15 ml) and ethanol/n-hexane (1/1) (10 ml), was dried by air, and was dried at 50oC and at reduced pressure during the night, resulting in the obtained target compound (1.1 g).

So pl. 131-132oC (decomposition).

[]2D3-1o(from 0.6, methanol)

HPLC: found free body

column: CHIRALCEL OG control: at 254 nm eluent: n-hexane/ethanol 5/1

speed: 1 ml/min, temperature: room tR: 19,5 min

1H-NMR (CD3OD) Delta: from 2.1 to 2.2 (2H, m), 2,4-2,6 (2H, m), 2,8-3,3 (8H, m), 3,7-3,9 (4H, m), 4,7-4,9 (2H, m), 6.73 x (2N, C) of 7.2 to 7.4 (10H, m).

IR (KBr) cm-1: 3400, 1730, 1710, 1425, 1245, 980, 750, 690, 640.

Example 4 (+)-5-Benzyl-3-(3-morpholino-1-phenylpropyl)-1,3-oxazolidin-2-it fumarate

The filtrate obtained sequential collection of crystals formed due to reaction of diastereoisomer a and D(-)-tartaric acid, described in example 3 evaporated under reduced pressure and under reduced pressure and at a temperature not exceeding 45oC in order to remove solvent, and the obtained oily pronate, and then was extracted twice with dichloromethane (30 ml). The extract was washed with saturated aqueous sodium chloride and then dried with anhydrous sodium sulfate. After that, the solvent was removed by distillation under reduced pressure and obtained oily product (1.64 g). This oily product was dissolved in a mixed solvent (isopropyl alcohol/acetone/water 50 g/20 g/6.2 g) (15 ml). To the resulting solution was added L - (+)-tartaric acid (647 mg) in the above mixed solvent (16 ml). Then the resulting solution was kept overnight at room temperature, precipitated crystals were collected by filtration, washed with the above mixed solvent (25 ml), was dried by air and got a white crystalline powder (1.78 g).

White crystalline powder (2.28 g), obtained as described above was added to the above solvent (62 ml) and was dissolved in 80oC. the resulting solution was kept overnight at room temperature, precipitated crystals were collected by filtration, washed with the above mixed solvent (15 ml) and was dried under reduced pressure, resulting in the obtained white powder (2,08 g). This white powder suspended in water (50 ml). P who was xtraceroute dichloromethane (30 ml). The extract was washed with saturated aqueous sodium chloride and was dried with anhydrous sodium sulfate. Then the solvent was removed by distillation under reduced pressure and obtained oily product (1,49 g). This oily product was dissolved in ethanol (10 ml). To the resulting solution was added fumaric acid (455 mg) in ethanol (10 ml). Then added 5 ml of n-hexane and the resulting solution was stirred overnight at room temperature. Precipitated crystals were collected by filtration, washed with a mixture of ethanol/n-hexane (4/1) (15 ml) and ethanol/n-hexane (1/1) (10 ml), was dried by air and then dried at 50oC and reduced pressure during the night, resulting in the obtained target compound (1.08 g).

So pl. 133-135oC (decomposition).

[]2D3+1< / BR>
where one of the radicals D and E represent-CH2- or-CO-and the other means (CH2)mR1;

R1hydrogen, lower alkyl, phenyl, optionally substituted by halogen atom, lower alkyl or lower alkoxygroup, naphthyl, thienyl or 3-indanyl;

R2phenyl, optionally substituted by a halogen atom or a lower alkyl, thienyl or furyl;

R3and R4each lower Alimardan, homomorpholine, pyrrolidine, piperidine, optionally substituted by hydroxyl or lower alkoxygroup, or 4-acetylpiperidine;

X and Y each independently of one another oxygen or sulfur;

m 0 4;

n 0 4;

r is 0 or 1;

p and q each independently from each other an integer of 0 to 5, provided that p + q 1 5,

or their pharmaceutically acceptable salts.

 

Same patents:

The invention relates to new oxazolidone derivative having the formula:

to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is a bivalent radical having the formula

-CH CH-CH CH- (a-1),

-N CH-CH CH- (a-2)

-CH N-CH CH- (a-3)

-CH CH-N CH- (a-4),

-CH CH-CH N- (a-5),

-N CH-N CH- (a-6) or

-CH N-CH N- (a-7), where one or two hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-alkyl, C1-C6-alkyloxy, hydroxy, or trifluoromethyl; R represents hydrogen or C1-C4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to organic chemistry, specifically to new chemical compounds, of General formula:

< / BR>
in particular 1,3-bis(2'-hydroxy-3'-morpholinopropan)-6-methyluracil(a); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-6-stands-rallu (b); 3-bis(2'-hydroxy-3'-morpholinopropan)-5-hydroxy-6-methyluracil (); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)- 5-hydroxy-6-methyluracil (g); 1,3-bis(2'-hydroxy-3'-morpholinopropan)-5-(2'-hydro - XI-3'-morpholinoethoxy)-6 - methyluracil (d) and 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-5-(2'-hydroxy-3'-piperidino - poxy)- 6-methyluracil (E), showing immunotropic and anti-inflammatory activity

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

FIELD: organic chemistry, anti-microbial preparations.

SUBSTANCE: invention relates to compounds useful as anti-microbial agents. Claimed compounds are effective against to certain human and animal pathogens, including Gram-positive aerobic bacteria such as multi-resistant staphylococcus, streptococcus and enterococcus, as well as anaerobic organisms such as species Bacterioides spp. and Clostridia spp., and acid resistant organisms such as Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium spp.

EFFECT: new anti-microbial agents.

2 ex, 5 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.

EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.

47 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula I and their pharmaceutically acceptable salts. Claimed compounds display PPAR agonistic effect. In the general formula I A is O; X is a link or CH2; R1 is selected out of C1-C3alkyl; each R4 is independently selected out of group including halogen or -OC1-C3alkyl, where -OC1-C3alkyl can be optionally substituted by 1-3 F; each R5 is independently selected out of group including F, CI; R6 is selected out of group including C2-C5alkyl and -CH2cyclopropyl; m is 0; n is integer 1-2; p is integer 0-1.

EFFECT: pharmaceutical composition including claimed compound as active component.

11 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of crystallising N-carbonic anhydride of glutamic acid benzyl ether. The disclosed method includes dissolving N-carbonic anhydride of glutamic acid benzyl ether in a solvent heated to a temperature of 40°C or higher but lower than the boiling point thereof, and the amount of which is 0.5 l or more per mole of N-carbonic anhydride of glutamic acid benzyl ether. A weak solvent is then added in amount of 1.4 l or more per mole of N-carbonic anhydride of glutamic acid benzyl ether at a temperature equal to higher than 40°C, but lower than the boiling point thereof. Further, crystals are precipitated at a temperature equal to higher than 40°C, but lower than the boiling point, and the crystals are cooled to obtain crystalline polymorphs of N-carbonic anhydride of glutamic acid benzyl ether. The solvent which is heated to a temperature of 40°C or higher, but below the boiling point, is ethyl acetate and the weak solvent is an aliphatic hydrocarbon. The invention also relates to crystalline polymorphs of N-carbonic anhydride of glutamic acid benzyl ether obtained using said method.

EFFECT: present method enables to obtain crystalline polymorphs of N-carbonic anhydride of glutamic acid benzyl ether, having high bulk density and excellent storage stability.

5 cl, 5 dwg, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1 where R is hydrogen or a C1-4-alkyl group; R1 means a group selected from the group consisting of structures represented by formulas (Ia), where R2 means hydrogen or a C1-4-alkyl group; R3 means hydrogen, a halogen, CF3, CN or C1-4-alkyl and R4 means hydrogen, a halogen or a C1-4-alkyl; a=0, 1, or 2; b=0, 1, 2 or 3; C=1, 2 or 3, and Ra, Rb, Rc and Rd represent, independently of one another, H or a C1-4-alkyl; X means a C2 aliphatic hydrocarbon bridge optionally containing a double bond or a triple bond or a hetero-atom selected from O and S, or CH(CH2)CH-; Y means hydrogen, a halogen, a C1-4-alkyl, C1-4-alcoxy or C1-4-hydroxyalkyl; Z means a C1-4-aliphatic hydrocarbon bridge optionally containing one double bond and/or one hetero-atom selected from O, S, N and N(CH3), or means a C2-4-aliphatic hydrocarbon bridge fused with a C3-6-cycloalkyl, optionally containing one or more double bonds or with a phenyl ring, or means a C1-4-aliphatic hydrocarbon bridge substituted with a spiro-C3-6-cycloalkyl, optionally containing one or more double bonds; or its pharmaceutically acceptable salt, or a stereoisomer, or a pharmaceutically acceptable salt of the stereoisomer. The compounds according to the invention are obtained due to reductive amination of the benzaldehyde of formula 4 by means of a primary amine R1-NH2, the introduction in the interaction of the obtained secondary amine of formula 2 with ether formyl - or oxocyclohexanecarboxylic acid of formula 3, where X, Y, Z, R1, R, Ra, Rb, Rc, Rd, b and c have the meanings as specified for formula 1, and R' means -CHO or =O, and, optionally, the hydrolysis of the obtained ester of formula 1. The invention also relates to an intermediate compound of formula 2 or a salt thereof. The compound of formula 1 according to the invention is intended for use in the preventive and / or therapeutic treatment of a disease or disorder mediated by CXCR3 receptor as a medicament or as part of a pharmaceutical composition.

EFFECT: cycloalkanecarboxylic acid derivatives as CXCR3 receptor antagonists.

20 cl, 6 tbl, 160 ex

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