Method of producing compounds with angiotensin-converting enzyme (ace) inhibitory activity

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing compounds of formula (I) , with ACE inhibitory activity, and to pharmaceutically acceptable salts thereof, in which the carboxyl group of an amino acid of formula (II) is activated with a uronium salt of formula (III) in the presence of an aprotonic solvent, and the activated amino acid is reacted with a corresponding amine from the HR3 family. Substitutes R1-R3, R6-R9, B are given in the formula of invention.

EFFECT: end product with high output and high purity.

17 cl, 1 ex, 1 dwg

 

The scope of the invention

The present invention relates to the field of synthetic organic chemistry and relates to a method of producing compounds having ACE (angiotensinase enzyme) inhibitory activity.

In particular, the present invention relates to a reliable, selective and simple method of obtaining compounds having ACE inhibitory activity.

Prior art

The molecules of most ACE I inhibitors chemically consist of amino acid and deaminations parts. Condensation of these different parts in the final structure flows using mostly common reagents used for the formation of the peptide bond, such as:

the phosgene, diphosgene or triphosgene;

carbonyldiimidazole, chlorthalidone or conidiomata;

dichlorochlordene/1-hydroxybenzotriazole.

Various predecessors ACE inhibitors need different condensing agents for the best reception, good outputs and the corresponding pharmaceutical quality. For example, in SI 9400290 described the synthesis of enalapril with timelimitaction as a condensing agent for the formation of the peptide bond. This reaction gives good results, but requires very strict control of reaction conditions and absolutely anhydrous environment, otherwise provoditsya adverse reactions, for example, the formation of diketopiperazines etc. and the reduction in output.

In another case, described in the patent US 4914214, the synthesis between the (2S,3aS,7aS)-2-carboxyanhydrides, where the carboxyl group is protected with benzyl group, and N-((S)-1-carbethoxy-ISO-butyl)-(S)-alanine with dicyclohexylcarbodiimide/1-hydroxybenzotriazole as a condensing agent used in the process of getting another ACE inhibitor, perindopril. This process gives good results, but requires careful selection due to the formation of dicyclohexylamine as a by-product, which hardly stands out from the reaction mixture. In a later application EP 1279665 describes a method for predecessors of the same perindopril from acid chlorides of the acids with triphosgene. This process gives good results, but requires special attention due to the work with phosgene.

The aim of the present invention to provide compounds with ACE inhibitory activity new and simple way in which ACE inhibitors get high yield and high purity.

A detailed description of the invention

When searching for effective way of getting the ACE I inhibitors it has been unexpectedly discovered that the condensation between the carboxylic acid and amino group of the corresponding amino acids using salts Urania runs quickly, smoothly is pure. The reaction itself is very simple and does not require any special conditions. It is very important that it can very quickly end, for example after 15 min, compared with other processes receiving ACE inhibitors. In addition, the method according to the present invention vasoconstriction and gives highly pure final product without any side products.

The first variant of the present invention is a method of obtaining compounds with ACE inhibitory activity of the formula I:

where R1denotes H, alkyl, phenyl;

R2denotes H, alkyl;

R3means

or

or

or their pharmaceutically acceptor salt,

characterized in that the carboxyl group stereospecific amino acids II:

R2, R2above,

activate salt Urania formula III:

in the presence of an aprotic solvent, and then activated acid into a peptide using the appropriate amine from a number of HR3where R3means:

or

or

Receiving the hydrated so the product can be transferred to the active pharmaceutical form transformations of intermediate products obtained by reaction of removing the protective groups, cleavage of the corresponding esters, neutralization, alkalizing, acidification and, if necessary, obtain a pharmaceutically acceptable salt.

Salt Urania formula

can be selected from the group consisting of:

O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate,

O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium of TETRAPHOSPHATE,

O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate.

The above reagents are known from the literature (G.A.Grant, Synthetic Peptides, Oxford University Press, 1992, 119) as extremely suitable reagents for the synthesis of peptides without adverse reactions isomerization at the chiral centers. These reagents are particularly applicable to the condensation of various amino acids, but were not yet used for receiving ACE inhibitors, which are ones type of molecule.

In another embodiment of the present invention the condensation of the acid with the reagent Urania may be adding an organic base such as tertiary amine, from 1.5 to 3 molar excess relative to the reagent, preferably a 2-molar excess. The tertiary amine may be selected from the group consisting of triethylamine, N,N-Diisopropylamine, pyridine, lutidine.

Solvents for this reaction type can be selected from the group consisting of the C chlorinated hydrocarbons, for example methylene chloride, chloroform, cyclic or acyclic hydrocarbons, esters of organic acids, for example, ethyl acetate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or other aprotic solvents such as acetonitrile.

The reaction of formation of the peptide bond is described as follows.

The acid and amine is introduced into the reaction in stoichiometric amounts or in a quantitative ratio from 1.1:1 to 1:1,1 together with the above reagents peptide condensation of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate or tetrafluoroborate in from 1 to 1.5 molar excess in the presence of a tertiary amine in an appropriate solvent. The reaction is carried out in a period of 10-120 minutes, preferably from 10 to 45 min, and most preferably from 15 to 30 minutes, at temperatures from 0 to 40°C, preferably at room temperature, for example at 20-25°C. To the reaction mixture, water is added, and the product produce by the addition of an appropriate solvent in which the product is not soluble. After washing the extracts with water and evaporation of the solvent the product, having the good chemical and optical purity, isolated with high yield (87-95%).

The reaction scheme:

The present invention illustriou is conducted by the following examples, which does not limit the scope of invention:

Example 1: Getting enalaprilat

To the mixture and 2.79 g of 1-((S)-N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine, and 1.15 g of L-Proline in 100 ml of acetonitrile and 5 ml of DMF added 2.9 g of triethylamine and stirring, 3.8 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate. The reaction mixture is then stirred for 30 min at room temperature, add 300 ml of a saturated solution of NaCl and twice extracted with a mixture of 100 ml of ethyl acetate. The combined extracts are washed with a mixture of 70 ml water/1 ml conc. HCl and then 130 ml of water, dried over Na2SO4and evaporated in vacuum at 40°C receives 3,55 g of enalapril.

The intermediate product is dissolved in 100 ml of ethyl acetate, then add a 1.00 g of maleic acid in 50 ml of ethyl acetate. After stirring for 30 min enalaprilat filtered off and dried in vacuum at 40°C, receiving 4, 2 g of the product (85,4%).

Example 2: Obtain benzyl (2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahedron-2-carboxylate (benzyl ether perindopril)

The mixture 855 mg benzyl ester of (2S,3S,7S)-2-carboxyanhydride, 651 mg of N-((S)-1-carbethoxy)-(S)-alanine, 1137 mg O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate and 0.84 ml of triethylamine is stirred in 20 ml of acetonitrile within 30 minutes Add 50 ml of saturated is on NaCl and twice extracted with 35 ml of ethyl acetate. The combined extracts are washed with a mixture of 70 ml water/1 ml conc. HCl and then 130 ml of water, dried over Na2SO4and evaporated in vacuum at 40°C receives 1210 mg (87,7%) of benzyl (2S,3S,7S)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahedron-2-carboxylate (benzyl ether perindopril).

The resulting product is a precursor to receive perindopril or perindopril of albumin, which can be obtained by known literature methods, for example by conversion into the free acid and then pharmaceutically acceptable salt by the known methods described in the patent US 4914214.

Example 3: Getting trandolapril

To 2,79 g (S)-1-(N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine and 1.75 g of (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid in 100 ml of acetonitrile and 5 ml of DMF is first added to 2.9 ml of triethylamine and then with stirring, 3.8 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate and continue stirring the mixture for 30 min at room temperature. Finally, add 300 ml of a saturated solution of NaCl and twice extracted with 100 ml of ethyl acetate. After separation of the product, which is carried out analogously to example 1, the gain of 3.96 g (92) trandolapril.

1. The method of obtaining compounds with ACE inhibitory activity, represented by formula I

and their pharmaceutical is Eski acceptable salts, where R1-R3denote
R1- H, alkyl, phenyl;
R2- H, alkyl, and
R3:

or

or

characterized in that the carboxyl group of the amino acid of formula II

activate salt Urania formula III

in the presence of an aprotic solvent and the activated amino acid is introduced into reaction with a suitable amine of a number of HR3where R3

or
does

or

2. The method according to claim 1, characterized in that the amino acid of formula II using N-((S)-1-carbethoxy)-(S)-alanine.

3. The method according to claim 1, characterized in that the amino acid of formula II using 1-((S)-N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine.

4. The method according to claim 1, characterized in that as an amine using L-Proline.

5. The method according to claim 1, characterized in that as an amine using (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid or its ester.

6. The method according to claim 1, characterized in that the quality of the salt Urania use O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate.

7. The method according to claim 1, characterized in that the amino acid of formula II COI is lsout 1-((S)-N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine, as Amina use L-Proline, and as salt Urania - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate.

8. The method according to claim 1, characterized in that the amino acid of formula II using N-((S)-1-carbethoxy)-(S)-alanine, as an amine using (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid or its ester, and the quality of the salt Urania - O-(benzotriazol-1-yl)-N,N,N, N'-tetramethyluronium hexaflurophosphate.

9. The method according to one of claims 1 to 5, characterized in that the condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding an organic base.

10. The method according to one of claims 1 to 5, characterized in that the quality of the salt Urania use O-(benzotriazol-1-yl)-N,N,N, N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding an organic base.

11. The method according to one of claims 1 to 5, characterized in that the condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding triethylamine.

12. The method according to one of claims 1 to 5, characterized in that the quality of the salt Urania use O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania on stateactivity amino acids carried out by adding triethylamine.

13. The method according to claim 1, characterized in that the amino acid of formula II using 1-((S)-N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine, as an amine using L-Proline, and as salt Urania - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding an organic base.

14. The method according to claim 1, characterized in that the amino acid of formula II using 1-((S)-N-(1-(etoxycarbonyl)-3-phenylpropyl)-L-alanine, as an amine using L-Proline, and as salt Urania - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding triethylamine.

15. The method according to claim 1, characterized in that the amino acid of formula II using N-((S)-1-carbethoxy)-(S)-alanine, as an amine using (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid or its ester, and the quality of the salt Urania - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids perform by adding an organic base.

16. The method according to claim 1, characterized in that as amino acids Faure the uly II using N-((S)-1-carbethoxy)-(S)-alanine, as an amine using (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid or its ester, and the quality of the salt Urania - O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate and condensation of amino acids of formula II and salts Urania at the stage of activation of amino acids carried out by adding triethylamine.

17. The method according to PP, 15 or 16, characterized in that the amount of N-((S)-1-carbethoxy)-(S)-alanine and (2S,3R,7S)-octahydro-1H-indole-2-carboxylic acid or its ester is in the ratio of from 1.1:1 to 1:1,1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new indole-alanine derivatives of formula I: , where: R1 is phenyl, naphthyl, where phenyl is substituted with one or two halogen atoms, C1-6 alkyls, C1-6 alkoxy or phenyl C1-6 alkyls; and R2 is H, C1-6 alkyl; in free form, in hydrate form or in form of a pharmaceutically acceptable salt. Formula I compounds exhibit selective agonist activity towards S1P4 receptor, at least ten times more selective towards one or more of S1P1, S1P2, S1P3 or S1P5 receptors.

EFFECT: possibility of using derivatives in a pharmaceutical composition.

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: medicine.

SUBSTANCE: present invention concerns application of new biologically active substances of the general formula of 1 either their racemates, or their optical isomers, or their pharmaceutically comprehensible salts and-or hydrates, and also to a pharmaceutical composition and its use at manufacturing of the medicinal preparations applied to treatment and-or preventive maintenance of diseases, caused by flu viruses. In compounds of the general formula 1, R1 are represented by the substituent to the amino group chosen from unessentially replaced C1-C6alkyl, unessentially replaced aryl or unessentially replaced 5-6 term azaheterocycl, R14 and R24 independently from each other represent the substituent to an amino group chosen from hydrogen, unessentially replaced C1-C6alkyl, unessentially replaced C3-C8cycloalkyl, or R14 and R24, together with atom of nitrogen to which they are bound, form through R14 and R24 unessentially replaced 5-6-term azaheterocycl with 1-3 heteroatoms in a ring and which can be monocyclic or condensed with a benzene ring, or aminoethanamidine; R2 is a substituent chosen from hydrogen, of unessentially replaced mercapto group, unessentially replaced amino group, unessentially replaced hydroxyl represents alkyn; R3 represents the lowest alkyl; R5 the substituent to the cyclic system chosen from hydrogen, atom of halogen, cyano group, unessentially replaced aryl or unessentially replaced 5-6-term heterocycl represents, the containing 1-2 heteroatoms chosen from nitrogen, oxygen or sulphur and which can be monocyclic or condensed with a benzene ring.

EFFECT: invention provides increase of efficiency of a composition and a method of treatment.

11 cl, 1 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to method of producing compounds of formula VII: and intermediate compounds for producing said compounds. Values of Y, R1, R2, R3, R4, R5, X, n are given in paragraph 1 of the formula.

EFFECT: increased efficiency of the method of producing said compounds.

24 cl, 2 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of obtaining N-(N'-substituted glycyl)-2-cyanopyrrolidine with formulae IA and IB; (IA) or (IG), where R' is hydroxyl, C1-7alkoxy group, C1-8alkanoyloxy group or R"'R""N-C(O)O-, where R"' and R"" are independently C1-7alkyl or phenyl, which is not substituted or substituted with a substitute, chosen from C1-7alkyl, C1-7alkoxy group, halogen and trifluoromethyl, and where R'" additionally represents hydrogen; or R' and R" are independently C1-7-alkyl; in form of a free base or acid addition salt, involving (a) reaction of formula (V) compound, where X1 and X3 independently represent a halogen; X2 is a halogen, OH, O-C(=O)-CH2X3, -O-SO2-(C1-8)alkyl or -O-SO2-(aryl), with L- prolineamide in the presence of dimethylformamide, subsequent reaction (b) of the obtained compound with halogen (halogenalkylene)dialkylammonium as a dehydrating agent, without extraction of the obtained compound, subsequent reaction (c) of the obtained compound with the corresponding amine with formula (VI), without extraction of the obtained compound, in the presence of a base H2NR (VI), where R is substituted adamantyl, described above, and (d) extraction of the obtained compound in form of a free base or acid addition salt.

EFFECT: method allows for obtaining desired product without extraction of toxic intermediate compounds.

3 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: medicine, hematology, organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel peptidylarginals of the formula (I): Xaa-Xbb-Arg-H wherein Xaa means residue of alpha-substituted carbonic acid of the formula (II): Q-CH(R)-CO wherein Q means (C1-C3)-alkyloxycarbonylamino-group, methylamino-group or hydroxyl group; R means (C7-C9)-cycloalkylmethyl group or (C5-C7)-cycloalkyl group; Xbb means residue of L-proline or L- azethidine-2-carboxylic acid, and its additive acid salts formed by organic or inorganic acid. Intermediate compounds are described also. Compounds of the formula (I) possess the inhibitory effect on free thrombin, thrombin bound with a clot, Xa factor, plasmin and plasminogen activators that allows their using in pharmaceutical composition in treatment of a patient suffering from disseminated intravascular coagulation syndrome.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to new (N-substitutes glycyl)-2-cyanopyrrolidines of formula I , wherein R is adamantly, substituted in 3- and/or 5-site with one or more substituents, selected from group including C1-C10-alkyl, OR1 (R1 is C1-C10-alkyl, C1-C8-alkanoyl, -CO-NR4R5, wherein R4 and R5 are independently from one another hydrogen, cyclohexyl, C1-C10-alkyl, phenyl optionally substituted with C1-C10-alkyl or C1-C10-alkoxy), in free form or in form of acid additive salt. Claimed compounds inhibit dipeptidyl-peptidase IV (DPP-IV) activity and useful in pharmaceutical composition for treatment of conditions mediated by DPP-IV, such as insulin-independent diabetes mellitus and obesity.

EFFECT: new pharmaceutical compounds inhibiting dipeptidyl-peptidase IV.

5 cl, 1 dwg, 4 tbl, 12 ex

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