Novel bioisosteres of actinonin


FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

 

The present invention relates to new bioisosterism (bioisosterism analogues) actinaria, which is an antibiotic. These new compounds are of interest primarily as inhibitors of metalloproteinases.

Actionin (A) is an antibiotic with antibacterial activity, which is produced by fermentation in the presence of an appropriate strain of actinomycetes (patent US 3240787)

.

Actionin inhibits many enzymes, such as peptidases, metalloproteinases, metalloendopeptidases membranes and ACE (acetylcholinesterase). In one relatively recent publications (.Giglione, .Meinnel, Emerging Therapeutic Targets 5(1), 2001, c.41-57) stated that actionin inhibits peptide-deformylase (PDF).

With regard to the foregoing, the present invention was based on the task to propose new analogues actinaria, which can be synthesized in a simple way. These compounds are of interest primarily to those that are inhibitors of metalloproteinases (primarily peptide-deformylase (PDF)).

The present invention relates accordingly to compounds of formula (I)

,

in which

R1represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cyclol the ilen, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R2represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R3represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R4represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R5represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclohexanes, heteroalicyclic, heterologously, Aracely or heteroalkyl the rest,

R6represents a hydrogen atom, alkyl, alkanniny, alkynylaryl, heteroalkyl, aryl, heteroaryl, cycloalkyl, celtically, heteroalicyclic, heterologously, Aracely or heteroalkyl residue or

two of the residues R1, R2, R3, R4and R6together are a fragment optionally substituted cycloalkyl or geteroseksualbnogo rings and

n denotes 1, 2 or 3,

or pharmaceutically acceptable salts, MES, hydrate or pharmaceutically acceptable compositions of these compounds.

The term "alkyl" refers to saturated hydrocarbon group with a straight or branched chain containing 1-20, preferably 1-12, particularly preferably 1-6, carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, isobutylene, tert-bucilina, n-exilda, 2,2-dimethylbutyl or n-aktiline group.

Under the concepts of "alkenyl" and "quinil" refers to at least partially unsaturated hydrocarbon group, straight or branched chain containing 2 to 20, preferably 2 to 12, particularly preferably 2-6, carbon atoms, for example Attila, allyl, acetylenyl, propargyl, isoprenaline and Gex-2-anilina group. Preferably alkeneamine groups contain one or two (especially preferably one) double bond, and alkyline groups contain one or two (especially preferably one triple bond.

Cu is IU, the term "alkyl", "alkenyl" and "quinil" include groups in which one or more hydrogen atoms replaced with halogen atoms (preferably F or Cl), refers to such groups as 2,2,2-trichlorethylene or triptorelin group.

The term "heteroalkyl" refers to alkyl, Alchemilla or Alchemilla group in which one or more (preferably 1, 2 or 3) carbon atoms are replaced with atoms of oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur, preferably oxygen, sulfur or nitrogen). The concept of "heteroalkyl" includes addition of carboxylic acid or a group - derived carboxylic acids, such as acyl, arylalkyl, alkoxycarbonyl, alloctype, aryloxyalkyl, carboxyaniline or alkoxycarbonylmethyl.

As examples heteroalkyl groups include groups of the following formulas: Ra-O-Ya-, Ra-S-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-NR b)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, in which Rarepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rbrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rcrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, Rdrepresents a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol or2-C6alkylamino group, and Yarepresents a direct link, C1-C6alkylenes,2-C6alkenylamine or2-C6alkynylamino group, each heteroalkyl group contains at least one carbon atom which, and one or more hydrogen atoms may be replaced by fluorine atoms or chlorine. As specific examples heteroalkyl groups can be called methoxy-, triptoreline, ethoxy, h-propyloxy, isopropoxy-, tert-butylacrylate, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino-, dimethylamino-, diethylamino, isopropylethylene, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, simple enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, etoxycarbonyl, N-ethyl-N-methylcarbamoyl and N-methylcarbamoyl. Among other heteroalkyl groups include, for example, nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alternately group.

The term "cycloalkyl" refers to saturated or partially unsaturated (for example, cycloalkenyl) a cyclic group containing one or several cycles (preferably 1 or 2), which form the skeleton containing 3 to 14, preferably 3 to 10 (especially 3, 4, 5, 6 or 7, carbon atoms. The concept of "cycloalkyl" also includes groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2i.e., for example, cyclic ketones such as cyclohex the non 2-cyclohexanone or Cyclopentanone. As other specific cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, Spiro[4,5]deganello, norbornylene, tsiklogeksilnogo, cyclopentenyl, cyclohexadienyl, decolonising, cubanelle, bicyclo[4.3.0]nonalloy, tetralinyl, Cyclopentasiloxane, forceclosing and cyclohex-2-enelow group.

The term "heteroseksualci" means cycloalkyl group of the above in which one or more (preferably 1, 2 or 3) carbon atoms of the cycle are replaced with atoms of oxygen, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Preferably heterocytolysine group contains 1 or 2 cycle 3 to 10 (especially 3, 4, 5, 6 or 7) atoms. The concept of "heteroseksualci" includes, in addition, groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2. As examples of such groups can be called piperidinol, morpholinyl, urotropine, pyrrolidinyloxy, tetrahydrothiophene, tetrahydropyranyloxy, tetrahydrofuryl, oxacyclopropane, azacyclopenta or 2-pyrazolidine group, as well as lactams, lactones, cyclic imides and C is licencie anhydrides.

The term "alkylsilanes" refers to the group that contains, in accordance with the disclosures provided above values as cycloalkyl, and alkyl, alkeline or alkyline group, for example alkylcyclohexane, alkylcyclohexanes, alkenylacyl and alkylcyclohexane group. Preferably alkylcyclohexane group contains cycloalkyl group having one or two cyclic systems, which form the skeleton containing 3 to 10 (especially 3, 4, 5, 6 or 7) carbon atoms and one or two alkyl, alkeline or alkyline group with 1 or 2-6 carbon atoms.

The term "heteroalicyclic" refers alkylcyclohexane group of the above in which one or more (preferably 1, 2 or 3) carbon atoms are replaced with atoms of oxygen, nitrogen, silicon, selenium, phosphorus or sulfur, preferably oxygen, sulfur or nitrogen). Preferably heteroalicyclic group contains 1 or 2 cyclic system of 3 to 10 (especially 3, 4, 5, 6 or 7) atoms and one or two alkyl, alkeline, alkyline or heteroalkyl group with 1 or 2-6 carbon atoms. As examples of such groups may be called alkylchlorosilanes, alkylchlorosilanes, alkenylsilanes, alginolyticus, heteroalicyclic, heteroalkyl heterocyclyl and heterooligomerization, when this cyclic group is saturated or once, twice or three unsaturated.

The term "aryl" (abbreviated Ar) refers to an aromatic group which has one or more cycles and which forms a skeleton containing 6-14, preferably 6-10 (especially 6) carbon atoms. The term "aryl" includes, in addition, groups in which one or more hydrogen atom is replaced by fluorine atoms, chlorine, bromine or iodine or group, HE, SH, NH2or NO2. As examples are phenyl, naftalina, biphenylene, 2-florfenicol, onlinelow, 3-nitroaniline or 4-hydroxyphenyl group.

The term "heteroaryl" refers to an aromatic group which has one or more cycles and which forms a skeleton containing 5-14, preferably 5-10 (especially 5 or 6) atoms of the cycle and one or more (preferably 1, 2, 3, or 4 atoms of oxygen, nitrogen, phosphorus or sulfur (preferably O, S or N). The concept of "heteroaryl" includes, in addition, groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group, HE, SH, NH2or NO2. As such groups include, for example, 4-pyridyloxy, 2-imidazolidinyl, 3-phenylpyrrolidine, thiazolidine, oxazolidine, triazolyl, tetrazol the function, isoxazolidine, indazolinone, indolenine, benzimidazolyl, pyridazinyl, hyalinella, parinello, carbazolyl, criminology, pyramidalnou, 2,3'-biphenylol, 3-pyrazolidine and athinodorou group.

The term "aralkyl" refers to the group that contains, in accordance with the disclosures provided above values as aryl and alkyl, alkeline, alkyline and/or cycloalkyl group, for example arylalkyl, arylalkyl, arylalkylamine, arylcyclohexylamine, arylcyclohexylamine, alkylalcohol and alkylaminocarbonyl group. More specifically include, for example, such aralkyl as toluene, xylene, mesitylene, styrene, benzylchloride, o-vtortola, 1H-inden, tetralin, dihydronaphthalene, indanan, vinylcyclopentane, cumene, cyclohexylphenol, fluoren and indan. Preferably kalkilya group contains one or two aromatic cyclic system (1 or 2 cycles) with 6-10 carbon atoms and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms and/or one cycloalkyl group with 5 or 6 carbon atoms in the loop.

The term "heteroalkyl" means kalkilya group of the above in which one or more (preferably 1, 2, 3, or 4) carbon atoms are replaced with atoms of oxygen, nitrogen, silicon, selenium, is asfora, boron or sulfur, preferably oxygen, sulfur or nitrogen), i.e. the mean of the group which, in accordance with the disclosures provided above values contain aryl, respectively, heteroaryl, and alkyl, alkeline, alkyline, and/or heteroalkyl, and/or cycloalkyl, and/or heterocytolysine group. Preferably heteroalkyl group contains one or two aromatic cyclic system (1 or 2 cycles) with 5 or 6-10 carbon atoms and one or two alkyl, alkeline and/or alkyline group with 1 or 2-6 carbon atoms and/or one cycloalkyl group with 5 or 6 carbon atoms in the cycle, with 1, 2, 3 or 4 of these carbon atoms is replaced by oxygen atoms, sulfur or nitrogen.

As examples arylheteroacetic, analgeticalkie, allgemeingultige, arrangementvalentine, arrangedelementcollection, arylaminomethylidene, arrangementvalentine, heteroallyl, heteroarylboronic, heteroallyl, heterooligomerization, heteroalicyclic, heteroarylboronic, heterooligomerization, heterooligomerization, heteroresistance, heterooligomerization, heterooligomerization, heteroaromatic alkylcyclobutanones and heterooligomerization group, when this cyclic group is saturated or once, twice or three unsaturated. More specifically include, for example, tetrahydroisoquinoline, benzoyloxy, 2 - or 3-ethylindole, 4-methylpyridine, 2-, 3 - or 4-metoksifenilny, 4-ethoxyphenyl and 2-, 3 - or 4-carboxypenicillins group.

The concept of "cycloalkyl", "heteroseksualci", "alkylsilanes", "heteroalicyclic", "aryl", "heteroaryl", "aralkyl and heteroaryl" include groups in which one or more hydrogen atoms in these groups are replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2.

The term "optionally substituted" refers to groups in which one or more hydrogen atoms replaced by fluorine atoms, chlorine, bromine or iodine or group IT, =O, SH, =S, NH2, =NH or NO2. This concept includes, among this group, which is substituted by unsubstituted C1-C6alkyl, C2-C6alkenylamine,2-C6alkenylamine, C1-C6heteroalkyl,3-C10cycloalkenyl,2-C9heteroseksualnymi,6-C10aryl, C1-C9heteroaryl, C7-C12Uralkalij or2-C11heteroalkyl groups.

The compounds of formula (I) is based schemes and their replacement can contain one or more chiral centers. Accordingly the scope of the present invention included as all pure enantiomers and all pure diastereoisomers and mixtures thereof in any ratio to each other. In addition, the scope of the present invention also includes all CIS - and TRANS-isomers of compounds of General formula (I), as well as mixtures thereof. In addition, the scope of the present invention includes all tautomeric forms of the compounds of formula (I).

Preferred are those compounds of formula (I)in which R1represents a hydrogen atom.

Preferred further those compounds of formula (I)in which R2represents a hydrogen atom.

It preferred are those compounds of formula (I)in which n denotes 1.

Preferred are further those compounds of formula (I)in which R3represents a hydrogen atom.

In addition to these, the preferred are those compounds of formula (I)in which R6represents a hydrogen atom.

As examples of pharmaceutically acceptable salts of compounds of formula (I) include salts formed with physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and salts formed with organic acids such as methanesulfonate acid, n-toluensulfonate acid, lactic acid, m is Ravina acid, acetic acid, triperoxonane acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. The compounds of formula (I) can be subjected to solvation, primarily hydration. Hydration can occur, for example, in the process of producing compounds of the formula (I) or due to the hygroscopicity of these initially containing no water connections.

The pharmaceutical compositions according to the invention contain at least one compound of formula (I) as active ingredient and optionally carriers and/or excipients.

Prodrugs (see, for example, R.B.Silverman, Medizinische Chemie, published by VCH Weinheim, 1995, Chapter 8, c.361 and forth), which are also the object of the present invention contain a compound of the formula (I) or (II) and at least one pharmacologically acceptable protective group, tsepliaeva under physiological conditions, for example the hydroxy-group, alkoxygroup, aralkylated, acyl group, or alloctype, such as, for example, methoxy group, ethoxypropan, benzyloxy, acetyl group or acetyloxy.

Application in therapeutics compounds of formula I, their pharmacologically acceptable salts, respectively, solvate and hydrate, as well as compositions and pharmaceutical compositions, is also the object of this image is to be placed.

The use of these active ingredients for obtaining a drug intended for the prevention and/or treatment of diseases, especially diseases mediated by the activity of the enzyme PDF is also an object of the present invention. In principle, the compounds of formula (I), including the application of known and acceptable modifications are introduced into the organism, either individually or in conjunction with any other therapeutic agent. While you can enter them in different ways and, in particular, orally, such as tablets, coated tablets, pills, semi-solid substances, soft or hard capsules, solutions, emulsions or suspensions, parenteral, for example, in the form of solution for injection, rectally as a suppository, by inhalation, for example, in the form of powdered or spray, transdermal or nasal. For the manufacture of such tablets, pills, semi-solid compositions, coated tablets, dragées and hard gelatin capsules intended for therapeutic purposes, the product is mixed with used drugs pharmacologically inert, inorganic or organic carriers, for example, lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, dried skimmed say the com etc. For the manufacture of soft capsules may be used in drug carriers, such as vegetable oils, refined petroleum, animal or synthetic oils, wax, fat and polyhydric alcohols. For the preparation of liquid solutions and syrups may be used in drug carriers, such as water, alcohols, aqueous salt solutions, aqueous dextrose, polyols, glycerine, vegetable oil, refined petroleum, animal or synthetic oils. For suppositories may be used in drug carriers, such as vegetable oils, blown oil refining, animal or synthetic oils, wax, fat and polyhydric alcohols. For aerosol compositions can be applied compressed gases suitable for this purpose, for example oxygen, nitrogen or carbon dioxide. In a composition intended for application in the pharmaceutical industry funds may also contain additional substances, such as preservatives, stabilizers, emulsifiers, flavorings, flavoring agents, salts for modifying the osmotic pressure, buffers, additives to obtain the relevant shell and antioxidants.

The compounds of formula (I) can be obtained by the mechanism of three-component reaction IGO (see, for example, A.Dömling, I.Ug, Angew. Chem. 112, 2000, c.3300-3344) with subsequent conversion of ester used in hydroxamic acid:

Examples

General methods

1 mmol of isonitrile (II), 1 mmol of carbonyl compound (III) and 1 mmol derived amino acids (IV) are dissolved in 5 ml of methanol and within 24 hours was stirred at room temperature. If necessary, the reaction can be carried out in the presence of a catalyst, such as n-toluensulfonate acid or BF3·Et2O. Then added 10 equivalents of hydroxylamine (50%in N2About) and stirring is continued for 12 hours After removal of the solvent of the protective group (if any) otscheplaut and finally the desired product is distilled through GHUR (liquid chromatography high resolution).

On this General technique has also received the following compounds, the characteristics of which were determined using GHUR-MS, respectively IHMS-CHLOE.

img src="https://img.russianpatents.com/1044/10445331-s.jpg" height="45" width="67" />

1. The compounds of formula (I)
,
in which
R1represents a hydrogen atom,
R2represents a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenolic balance, where the heteroatom pre which is a sulfur,
R3represents a hydrogen atom,
R4is a (C1-C6)alkyl residue, (C3-C7)cycloalkenyl the rest,
R5represents a
(C1-C6)alkyl residue, optionally substituted geteroseksualnoe group containing one cycle with 6 atoms, where 2 of these atoms represent oxygen and nitrogen heteroaryl group containing one cycle with 5 atoms, where 1 of these atoms represent sulfur, phenyl, optionally substituted CF3, halogen, a group of the formula Ra-O-CO-Ya-where Rais a (C1-C6)alkyl group, a hydrogen atom, a Yais a (C1-C6)alkyl group, (C3-C7)cycloalkyl group;
a group of the formula Ra-N(Rb)-CO-Ya-where Yais a (C1-C6)alkyl group, optionally substituted by phenyl, (C1-C6)alkylphenyl, Rbrepresents a hydrogen atom, Rais a (C3-C7)cycloalkyl group, (C1-C6)alkyl group, substituted phenyl, optionally substituted with halogen, heteroalkyl group having one aromatic cyclic system with 6 carbon atoms and one cycloalkyl group with 5 atoms in the cycle, when this 2 of these atoms represent oxygen, heteroaryl group containing one cycle with 6 atoms, in which 1 of these atoms is a nitrogen, geteroseksualnoe group containing 1 cycle 5 atoms, where 1 of these atoms represent oxygen;
a group of the formula Ra-CO-Yawhere Yais a (C1-C6)alkyl group, Rarepresents geterotsyklicescoe group containing one cycle with 6 atoms, where 2 of these atoms represent nitrogen, substituted (C1-C6)alkyl group, substituted heteroalkyl group containing one aromatic cyclic system with 6 carbon atoms and one cycloalkyl group with 5 atoms in the cycle, with 2 of these atoms represent oxygen;
aracelio group containing one aromatic system with 6 carbon atoms and one cycloalkyl group with 6 carbon atoms in the cycle;
R6represents a hydrogen atom;
n denotes 1, 2 or 3;
or pharmaceutically acceptable salts of such compounds.

2. Compounds according to claim 1, in which R2represents a hydrogen atom.

3. Compounds according to claim 1 or 2, in which n denotes 1.

4. Pharmaceutical composition having activity inhibitor peptideatlas (PDF), which contains as active ingredient a compound according to one of claims 1 to 3, and pharmaceutically pickup is acceptable carriers and/or excipients.

5. The use of compounds according to one of claims 1 to 3 as an inhibitor of peptideatlas (PDF).

6. The use of the pharmaceutical composition according to claim 4 for inhibiting peptideatlas (PDF).

7. The use of compounds according to one of claims 1 to 3 for the manufacture of drugs having inhibitory activity against peptideatlas (PDF).

8. The use of the pharmaceutical composition according to claim 4 for the manufacture of drugs having inhibitory activity against peptideatlas (PDF).



 

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20 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described is compound representing 2,5-disubstituted 3-mercaptopentanic acid of formula (I) or its pharmaceutically acceptable salt, where R' represents phenyl, possibly substituted, naphtyl, pyridinyl, 1,2,3,4-tetrahydropyrimidine-2,4-dion-yl, substituted with C1-4alkyl, or tetrahydrothienyl; R2 represents aminopyridinyl, aminothiazolyl or 3-azabicyclo[3.2.1]octyl; R3 represents C1-4alkoxy, possibly substituted with phenyl (substituted with halogen) or pyridinyl; NR5R6 or N-bonded 5- or 6-member heterocyclic ring representing pyrrolidinyl, piperidinyl or piperazinyl ring, non-substituted or monosubstituted, or condensed with benzene ring, which is possibly substituted with C1-4alkoxy; R4 represents N-bonded pyrrolidinyl ring, monosubstituted with C1-4alkyl, which is substituted with NHphenyl; R5 and R6 independently represent hydrogen, C1-4alkyl, possibly substituted, or C2-4alkenyl; and method of obtaining it.

EFFECT: obtaining compounds inhibiting carboxypeptidase and which can be used in prevention and treatment of diseases in which inhibiting carboxypeptidase is useful.

7 cl, 1 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compound of crystalline polymorphous bisulfate form with antagonistic effect on thrombin receptors, displaying x-ray refraction in powder, almost identical to picture in Figure 1, or displaying differential scanning calorimetry diagram almost identical to picture in Figure 3, and presented by compound 2 formula: Compound 2. Additionally invention concerns method of obtaining compound 2.

EFFECT: claimed pharmaceutical composition including polymorphous bisulfate form and at least one solvent or carrier, and application of polymorphous form of compound 2 in treatment of various physiological disorders, such as thrombosis.

16 cl, 3 dwg, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or their pharmaceutically acceptable salts: , where R1 is selected out of C3-10cycloalkyl-C1-6alkyl, tetrahydropyranyl-C1-6alkyl and tetrahydropyranyl, where the C3-10cycloalkyl-C1-6alkyl, tetrahydropyranyl -C1-6alkyl and tetrahydropyranyl used in definition of R1 are possibly substituted by one or more group selected out of halogen, methyl and ethyl; R2 is C1-10alkyl, where the C1-10alkyl used in definition of R2 is optionally substituted by one or more group selected out of methyl, ethyl; R3 is selected out of -H, C1-10alkyl, C2-10alkenyl, pyrrolidinyl, morpholinyl, piperidinyl, pyrrolidinyl-ethyl, morpholinyl-ethyl, piperidinyl-ethyl and , possibly substituted by one or more group selected out of C1-6alkyl, amino, C1-6alkoxy; or R3 is 2-aminoethoxy-ethyl or (2-hydroxyethyl)amino-ethyl; each of R8 and R9 is C1-10alkyl; and R4 is selected out of -H and C1-10alkyl. Invention also concerns compounds selected out of the group, application of compounds for any of claim points 1-5, pharmaceutical composition, and method of obtaining compounds of the formula I.

EFFECT: obtaining new bioactive compounds with agonistic effect selective in respect of CB1 receptors.

11 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed method of producing (+)duloxetine or its acid-additive salt, including (i) isolation of racemic (±)duloxetine with chiral acid thus producing chiral acid salt and (+)duloxetine, essentially free from (-)duloxetine; and (ii) if desired, transformation of the salt produced at the stage (i) into free base or other acid-additive salt if reasonable. Additionally, method of producing (+)duloxetine or its acid-additive salt can include intermediate process stage that is O-alkylilation enabled with the base or phase-transfer catalyst added.

EFFECT: specified method allows for production of receive enantiomer-pure (+)duloxetine.

17 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new derivative of cyclic amine or its salts with the following formula (I): (where symbols stand for the following: A: 5-8-member cyclic amine, which may contain a double bond, a bridged structure and may contain substitutes R7-R11 in the ring, or -NH2, -NH(inferior alkyl), -N(inferior alkyl)2 or ) morpholin-1-yl; ring B: benzole, thiophene, furane, pyrrole, 5-7-member cycloalkane or 5-7-member cycloalkene; X1: a bond or inferior alkylene; X2: -(CR12R13)n-, -N(R14)-, -N(R14)CO-, -CON(R14)-, -CO-, -CH(OH)-, -N(R14)- (CR12R13)n-, (CR12R13)n-N(R14)-, -CON(R14)-(CR12R13)n-, -n(R14)CO-(CR12R13)n-, -(CR12R13)n-N(R14)CO-, -(CR12R13)n-CON(R14)-, -CO-(CR12R13)n- or -(CR12R13)n-CO-; Y1: -OH, -O-inferior alkyl, NH2 or -N3; R1 and R2: are identical or different and stand for a halogen atom, inferior alkyl or inferior alkylene-OH; R3-R6: are identical or different and stand for a hydrogen atom, a halogen atom, inferior alkyl, inferior alkenyl, inferior alkynyl, -O-inferior alkyl, -OH, -NH2, -NH(inferior alkyl), -N(inferior alkyl)2, -NH-CO- inferior alkyl, -N(inferior alkyl)-CO- inferior alkyl, -CN-, -NO2, -CF3, -O-inferior alkylene-OH, -inferior alkylene-OH, -inferior alkylene-halogen, -inferior alkylene-O-inferior alkyl, -CO-5-8-member cyclic amine, -COOH-inferior alkyl, -COO-inferior alkylene-aryl, pyridine, thiophene, -inferior alkylene-morpholine, aryl, which may contain a substitute: -O-inferior alkyl or -CF3; R7: hydrogen atom, inferior alkyl, -inferior alkylene-aryl or -inferior alkylene-pyridine: R7 is substitute on the nitrogen atom of the cyclic amine; R8-R14: are identical or different and stand for a hydrogen atom or inferior alkyl; n: is an integer, equal to 1, 2 or 3; where R5 and R6, R4 and R5 or R3 and R4 can form an inferior alkylene together, -O-inferior alkylene-O-, -O-inferior alkylene-, -inferior alkylene-O-, -C(R15)=C(R16)-O-, -O-C(R15)=C(R16)-, -C(R15)=C(R16)-C(R17)=C(R18)-; R3 and Y1 together can form -O-inferior alkylene-O- or -inferior alkylene-O-; R1 and Y1 together can form -inferior alkylene-O-; and Y1 and a branch on - X1-A together can form -O- or -O-inferior alkylene; R15-R18 stand for a hydrogen atom, under the condition that, 6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol is not included in the group of compounds). The invention also pertains to a derivative of cyclic amine or its salts with formula (II), to a derivative of cyclic amine or its salts with formula (III), to pharmaceutical composition, as well as their use.

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on these compounds, with antagonist effect on NMDA receptors NMDA.

7 cl, 160 ex, 45 tbl

FIELD: chemistry.

SUBSTANCE: method of enantiomeric obtaining aminoalcohols of formula I in which R1, R2 and n have values given in invention formula, lies in enantioselective hydration of aminoketones in presence of non-racemic catalyst, representing complex of transitive metal, which contains one or more metals and its salts, selected from group, including rhodium, iridium, ruthenium and palladium, in which transitive metal forms complex with chiral diphosphine ligand A.

EFFECT: improvement of synthesis of aminoalcohols, which are acceptable as precursors for obtaining anti-depressants.

11 cl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

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

10 cl, 493 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

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

9 cl, 89 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to compound of formula (I) in which m represents integer number, equal 1 or 2; R1 represents group, selected, in particular from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, naphtyl, chinolinyl, isochinolinyl, benzisoxazolyl, tienopyridinyl, said group is possibly substituted with one or several groups of R3, similar or different from each other or by group R4, R2 represents group of general formula CHR5CONHR6, R3 represents halogen atom or one of the following groups: piano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-trifluoralkyl, C1-6-trifluoralkoxy, benzyloxy, phenyloxy, R4 represents group, selected, in particular from phenyl, benzofuranyl, naphtyl; one orseveral groups R4 can by substituted with one or several groups R3, similar or different from each other; R5 represents hydrogen atom or C1-3-akyl group; R6 represents hydrogen atom or alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl -C1-3-alkylene group; as base, salts of binding of acid, hydrate or solvate. Also invention relates to method of obtaining compound of formula I, its use as medicine and to based on it pharmacological composition.

EFFECT: novel derivatives of 1-pyperazine and 1-homopyperazincarboxilates, useful for prevention or treatment of pathology, in which endogen cannabinoids and/or any other substrates, metabolised by ferment FAAH, participate.

12 cl, 3 tbl, 11 ex

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