(2s)-n-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2r)-2-[(carboxymethyl)amino]-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate and method for its preparing

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino}-3,3-diphenylpropanoyl}-2-pyrrolidine carboxamide maleate of the formula (1): . Also, invention relates to a method for preparing this compound by interaction of free compound of the formula (1) with maleic acid in the presence of organic solvent. This salt can be used as thrombin inhibitor.

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

4 cl, 2 tbl, 13 ex

 

Technical field of invention

This invention relates to a salt of maleic acid (2S)-N-{5[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido following formula (1) and the manner of its reception

Background of the invention

Free compound of formula (1), i.e. the compound without the addition of acid, and its pharmaceutically acceptable salt, hydrate, solvate and isomers are objects lined the publication of the Korea patent No. 2000-047461 and WO 0039124 and can be used effectively as new inhibitors of thrombin.

If the drug does not possess the physical properties required for its development, it can be used several ways to improve them. In particular, in the case of low solubility drugs get salt medicinal product that is a common method of increasing the solubility. Methods of obtaining salts drugs are generally well known (e.g., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, Donald C. Monkhouse et al, 1, 66(1), 1977; and Salt selection for basic drugs, International Journal of Pharmaceutics, Philip L. Gould, 201, 33, 1986).

The physical property of the medicinal product is of great importance for the method of preparation and the development of original drugs and end prep the rata. The drug in solid form may have some advantages, such as ease of handling and storage, control of its quality. In addition, in the process of developing the final product is a medicinal product can be simplified creation of dosage forms and their introduction. The drug in solid form can be roughly divided into crystalline and amorphous forms in accordance with its crystallinity. Some medicines can be obtained in crystalline or amorphous form, while other medicines can only be obtained or in crystalline or amorphous form. Crystalline and amorphous forms can vary greatly in physical and chemical properties. For example, it was reported that some drugs have different solubility and bioavailability depending on the crystalline or amorphous form (e.g., Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Stephen Byrn et al., Pharmaceutical Research, 945, 12(7), 1995). Therefore, for the reasons stated above, the crystallinity of the medicinal product is very important for its production and injection.

Except for certain cases, it is easy to get the drug, possessing a certain crystallinity, in process research and development. The literature is also reported, the crystallinity of drugs can be an important advantage, namely, that at the final stage of obtaining medicines it can be purified by recrystallization, representing a relatively easy way to clean and crystalline drug, physico-chemical properties which can be easily identified, has the advantage even in quality control in the manufacture of the drug (see An integrated approach to the selection of optimal salt form for a new drug candidate, Abu T. M. Serajuddin et al, International Journal of Pharmaceutics, 209, 105, 1994). Thus, when drug get in amorphous form, its crystallization is very important for its development and reception. In addition, because the blurring of the medicinal product makes its receipt and quality control, it is desirable that the drug does not spread. The same applies to the salts of the drugs, and therefore the preferred properties for different synthesized salts are a good solubility, crystallinity and the absence of diffusion.

Some compounds can be difficult to absorb due to the low dissolution rate. To confirm this pre-cook the ROM area of 0.5 cm2and then measure the rate of dissolution in a different environment. Measure astorino amount of time and this value is divided by the area of the disk. The obtained value represents the dissolution rate per unit area. Usually, if this value is equal to 1 mg/min/pH2or more, it is possible to say that the drug problem of the lack of absorption due to the low dissolution rate does not exist. If this value is equal to 0.1 mg/min/pH2or less, you can say that this drug has a problem of absorption due to the low dissolution rate (see Howard C. Ansel, Nicholas G. Popovich amd Loyd V. Allen, 1995, Pharmaceutical Dosage Forms and Drug Delivery Systems, 6-th ed., Williams & Wilkins, pp. 109 and Jens T. Carstensen, 1996, Modern Pharmaceutics: Gilbert S. Banker and Christopher T. Rhodes (Ed.), Drugs and the pharmaceutical sciences, Vol. 72, 3-rd ed., Dekker, pp. 233). Thus, the determination of the dissolution rate per unit area is very important for the prediction of absorption problems that may arise later when testing drugs in vivo. Therefore, the connection having a high dissolution rate per unit area, should be selected as a candidate for drug development.

Brief description of the invention

Applicants conducted a thorough and intensive research among salts synthesized so far, to identify salts drugs having a crystallinity and excellent physical properties, such as very high Rast is almost, the absence of diffusion, a very high dissolution per unit area. In the end it was discovered that the salt of maleic acid drugs is the most appropriate and provides the invention.

Thus, this invention offers a salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido, represented by the following formula (1):

In another aspect, the present invention proposes a method of obtaining compounds of formula 1, characterized in that the free compound of formula 1 is subjected to interaction with maleic acid in the presence of the alcohol(s) solvent(s).

In another aspect, this invention features a method of obtaining a crystalline form of the compound of formula 1, characterized in that the free compound of formula 1 is subjected to interaction with maleic acid in the presence of the alcohol(s) solvent(s) to obtain the amorphous form of the salt of maleic acid of formula 1, which is then recrystallized.

Brief description of drawings

The drawing shows the powder x-ray diffraction diagram of crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-WPPT is ispropanol}-2-pyrrolidinecarboxamido.

Detailed description of the invention

Detailed description of the present invention are described below.

The compound of formula 1 according to this invention can be obtained by the interaction between the free compounds of formula 1 with maleic acid in the presence of the alcohol(s) solvent(s). Free compound of formula 1 used in the reaction, get it on the method described in laid publishing Korea patent No. 2000-047461 and in WO 0039124. Typically, the solvent(s), (e) must be used in the reaction may be available types of alcohols, which are alcamovia alcohols containing from 1 to 8 carbon atoms, for example, but without limitation only by them, methanol, ethanol, propanol, butanol, isopropanol, octanol, and other, preferably methanol and ethanol, the preferred methanol.

Salt of maleic acid according to this invention receives in amorphous form in accordance with the above-described reaction, but it can also be obtained in crystalline form by recrystallization using a suitable solvent(s). Typically, the solvents that must be used to obtain the amorphous form or recrystallization may be available types of alcohols, which are alcamovia alcohols containing from 1 to 8 carbon atoms, for example, but the ez restrictions only them, methanol, ethanol, propanol, butanol, isopropanol, octanol, etc., preferably methanol and ethanol, the preferred methanol. In addition, solvents which must be used for the recrystallization, in addition to the above as an example, alcohols, can be water and organic solvents such as n-hexane, ethyl acetate, butyl acetate, acetonitrile, chloroform, diethyl ether, acetone and other, and other commonly available solvents. The above free compound can be dissolved or can be dissolved when heated using one or more solvent mixture of these solvents and can be recrystallized. It is established that the specified salt of maleic acid is not blurred even when any relative humidity, the change in mass of salt is relatively small, the rate of dissolution of salt in substantially exceeds the rate of dissolution of the free compounds, as salt of maleic acid was crystallized. These data confirm that the salt of maleic acid is superior to the free connection on the solubility, dissolution and absorption in the gastrointestinal tract.

Because loose coupling can be effectively used as an inhibitor of thrombin, as described in lined with the publication of the Korea patent No. 2000-047461 and in WO 003912, the salt of maleic acid according to this invention is also applicable as a thrombin inhibitor.

Below the invention will be illustrated more in detail with appropriate examples, comparative examples, examples, test. However, it should be understood that these examples are presented as preferred specific embodiments of the present invention and should not be construed as limiting the scope of this invention. Other aspects of this invention will be obvious to the person skilled in the art to which belongs the present invention.

EXAMPLES

Example 1

Obtain the amorphous form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-{(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

Free compound of the formula 1 (1 g) was dissolved in methanol (30 ml) and then to the solution was added water (30 ml). Content was added dropwise equivalent of maleic acid and then the mixture was stirred for one hour. The solvent was removed by distillation under reduced pressure to obtain specified in the header of the amorphous form of the salt of maleic acid (1.1 g, yield 95%).

Example 2

Obtaining a crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxyl who yl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido (1)

Free compound of formula 1 (3 g) was dispersible in methanol (50 ml), content was added 1 M solution of maleic acid in methanol (30 ml) and then the mixture was stirred for 0.5 hour. To the mixture was added acetonitrile (300 ml). The mixture was stirred for 1 hour and then left before the formation of white crystals. The crystals were filtered off, washed with acetonitrile and then dried in vacuum (2.25 g, yield of 61.7%).

Example 3

Obtaining a crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido (2)

Free compound of formula 1 (2.3 g) was dispersible in ethanol (100 ml), content was added 1 M solution of maleic acid in methanol (4.3 ml) and then the mixture was stirred for 0.5 hour. To the mixture was added acetonitrile (500 ml). The mixture was stirred for 1 hour and then left before the formation of white crystals. The crystals were filtered off, washed with acetonitrile and dried in vacuum (1.04 g, yield to 38.3%).

Example 4

Obtaining a crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido (3)

Free compound of formula 1 (3.9 g) was dissolved in isopropanol (100 ml), the solution was added to the 1 M solution of maleic acid in methanol (7.2 ml) and then the mixture was stirred for 0.5 hour. To the reaction mixture was added acetonitrile (500 ml). The mixture was stirred for one hour and left to obtain white crystals. The crystals were filtered off, washed with acetonitrile and then dried in vacuum (3.3 grams, the output 72,8%).

Example 5

Recrystallization of the amorphous form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

The amorphous form of a salt of maleic acid (1 g)obtained in example 1 was dissolved in methanol (20 ml). Then the content was added acetonitrile (80 ml) and the solution was passed before the formation of white crystals. After filtration the crystals were washed with acetonitrile and dried in vacuum (of 0.62 g, yield 62%).

Example test 1

The study of the crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido powder x-ray

40 mg of crystalline form of the salt of maleic acid, obtained in example 2, a thin layer was applied on the sample holder and was investigated using powder x-ray diffraction in accordance with the following conditions. The study was performed on the apparatus Rigaku Geigeflex D/max-III C at 35 kV, 20 mA. Scanning speed (2θ) $ 5/min, the time selection is Rob: 0,03 sec, scan mode: continuous, Cu-target (Ni filter).

The result is a powder x-ray is shown in the drawing, the position of the peaks shown on this drawing are listed in the table. 1.

Table 1

Peaks of the powder x-ray diffraction salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido
Peak
6,149
6,754
12,254
13,261
13,91
14,345
16,661
17,577
17,966
18,506
19,592
20,368
21,082
22,445
23,198
23,701
24,364
24,897
26,171
26,601
2,127
28,16
28,76
29,292
30,212
31,077
31,559
32
34,005

Sample test 2

Study of the absorption of moisture and hydrated amorphous form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

After 40 mg of the amorphous form of the salt of maleic acid, obtained in example 1, a thin layer was applied to a chemical beaker, the sample was moistened due to absorption by keeping at each relative humidity equal to 33%, 57%, 64%, 75% and 93%for two or more days and its condition recorded. To obtain the value of each relative humidity above and are given in table 2, were prepared saturated aqueous solutions of salt, put them in a desiccator, which was closed.

Table 2
Relative humidity 33%MgCl2a saturated aqueous solution
Relative humidity 57%
Relative wet who here 64% NaNO2a saturated aqueous solution
Relative humidity 75%NaCl saturated aqueous solution
Relative humidity 93%KNO3a saturated aqueous solution

The amorphous form of the salt of maleic acid-free connection hardened at a relative humidity of 75% and swam at a relative humidity of 93%.

Example test 3

Study of the absorption of moisture and dehydration of crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

100 mg of crystalline form of the salt of maleic acid, obtained in example 2, a thin layer was applied to a chemical glass and then kept at each relative humidity 33%, 57%, 64%, 75% and 93% for two or more days to absorb moisture. Next, we measured the change in mass of a sample, recording its condition. To obtain values of relative humidity above and are given in table 2 of example test 2, was prepared saturated aqueous solutions of salt, put them in a desiccator, which was closed.

Mass characterizing the absorption of moisture, increased by 1,4%, 3,0%, 4,3%, 4,1% and 6.7% in relation to the initial mass forms at a relative humidity of 33%, 57%, 64, 75% and 93%, respectively, similarly to the changed mass characterizing dehydration in relation to moisture absorption. In contrast to amorphous form, crystalline form of the salt of maleic acid do not bleed even at a relative humidity of 93%.

Example test 4

The study of the crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carbomer)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido powder x-ray during absorption of moisture and dehydration

40 mg salt of maleic acid, obtained in example 2, a thin layer was applied on the sample holder. Then the sample was dried under vacuum in the presence of P2About5then the sample was kept for moisture absorption for two or more days at a relative humidity (each) 33%, 53%, 64%, 75% and 93%, respectively, were performed on sample studies powder x-ray according to the conditions specified in the example test 1, for observation of changes in crystalline form during moisture absorption. At lower relative humidity, the same study was repeated to study the change of crystal form during dehydration. For the above values of relative humidity are given in table 2 of example test 2, was prepared saturated wagnerstr salts and put them in a desiccator, which was closed. The powder x-ray diffraction diagram of crystalline form of the salt of maleic acid showed no changes during absorption of moisture and dehydration.

Example test 5

Study of the dissolution rate per unit area for the crystalline form of the salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

200 mg of crystalline form of the salt of maleic acid, obtained in example 2 was placed in a form. Under pressure got the disk area of 0.5 cm2this disc was added to each of the buffer solutions (600 ml) with a pH of 3.8 and 7.4 for testing dissolution. Periodically selected portion of a solution and measured its concentration to determine the dissolution rate per unit area. The dissolution rate per unit area salt of maleic acid was 11.8 mg/min/pH2at pH 3.8 and 1.7 mg/min/cm2at pH 7.4.

Comparative example 1

Getting dihydrochloride salt

Above the original compound (3 g) was added 6 N HCl (90 ml), the mixture was stirred for 4 h (controlling the termination of the reaction by HPLC). Then the solution was concentrated under reduced pressure, was added 2-propanol (0 ml) and the mixture was stirred for 10 min when heated, haven't got a clean solution. The solution was cooled to room temperature, then it slowly under stirring was added 30 ml of hexane. The obtained white substance was filtered, washed with hexane and dried in nitrogen atmosphere. Received dihydrochloride salt had amorphous form, when you try it recrystallization of the crystalline form was not received.

Comparative example 2

Study of the dissolution rate per unit area of the free compound (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido

Experience similar to that specified in example test 5 was conducted for the free compounds of formula 1. The dissolution rate per unit area specified free connection was 1.3 mg/min/pH2at pH 3.8 and 0.3 mg/min/cm2at pH 7.4.

Comparative example test 1

The method described in example trial 2, used for amorphous dihydrochloride obtained in comparative example 1. Based on observations of changes of salt at each value of relative humidity found that this salt is spread at a relative humidity of 75%. The result contrasts with the result of example test 3 in which the salt of maleic acid according to this the invention do not bleed even at a relative humidity of 93%. Therefore, we can conclude that the salt of maleic acid is the best among the salts of various acids.

Industrial applicability

From the comparison of the values obtained in example tests 5 and in comparative example 2, it follows that the salt of maleic acid showed the dissolution rate per unit area far greater than for the free connection even at neutral pH and at pH 3.8. In particular, as confirmed by the examples in tests 2, 3 and 4, the crystalline form of the salt of maleic acid in this invention has excellent properties such as a slight change in the process of absorption of moisture and dehydration, and lack of diffusion at a relative humidity of 93%. Consequently, salt of maleic acid is most applicable as a thrombin inhibitor.

1. Salt of maleic acid (2S)-N-{5-[amino(imino)methyl]-2-thienyl}methyl-1-{(2R)-2-[(carboxymethyl)amino]-3,3-diphenylpropane}-2-pyrrolidinecarboxamido represented by formula 1

2. The method of obtaining the compounds of formula 1 according to claim 1, characterized in that the free compound of formula 1 according to claim 1 is subjected to interaction with maleic acid in the presence of the alcohol(s) solvent(s).

3. A method of obtaining a crystalline form of the compound of formula 1 according to claim 1, characterized t is m, that free compound of formula 1 according to claim 1 is subjected to interaction with maleic acid in the presence of the alcohol(s) solvent(s) to obtain the amorphous form of the salt of maleic acid of formula 1 and subsequent recrystallization.

4. The method according to claim 2 or 3, wherein the alcohol(s) solvent(s) is(are) one or more solvents selected from the group comprising methanol, ethanol, propanol, butanol, isopropanol and octanol.



 

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SUBSTANCE: invention relates to novel trifluoromethylpyrrole carboxamides of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, cyano-group or (C1-C6)-alkylcarbonyl; A means the group of the formula:

, or wherein R3 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyl-(C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C4)-alkyl-(C4-C7)-cycloalkenyl, phenyl, naphthyl or phenoxy-group, or substituted phenyl, or substituted phenoxy-group wherein substituted represent 1-3 groups taken independently among an order comprising halogen atom, (C1-C4)_alkyl, (C1-C4)-alkoxy-, cyano-group, (C1-C4)-alkylcarbonyl, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-, methylenedioxy-, difluoromethylenedioxy-group or phenyl; R4 means hydrogen, halogen atom or (C1-C4)-alkyl; each among R5, R6 and R7 means (C1-C6)-alkyl. Compounds of the formula (I) are used for control of phytopathogen organisms or for prophylaxis in damaging cultured plants by these organisms.

EFFECT: valuable properties of compounds.

10 cl, 3 tbl, 1 sch, 12 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thienyl(amino)sulfonylureas of formula I ,

wherein A represents nitrogen or methane; Q represents direct bond or imino; R1 represents fluorine, chlorine, bromine, unsubstituted C1-C4-alkyl, C1-C4-alkoxyl optionally substituted with halogen, unsubstituted C1-C4-alkylthio, or di(C1-C4-alkyl)amino; R2 represents hydrogen or C1-C4-alkyl. Compounds of present invention are useful as herbicide agents.

EFFECT: new compounds with herbicide activity.

5 cl, 11 tbl, 5 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

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