Caspase inhibitor prodrugs

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula l where R1 represents CH2CI, CH2F or-C1-2alkyl-R3R4; R3 represents -O-; R4 represents phenyl, where said R4 group is optionally substituted by 0-5 groups J where J represents halogen; R2 represents C6-10aryl; or a group: where Y represents CH, AA2 represents C1-C7alkyl, R8 and R9 represents hydrogen or halogen; or a group: where Y represents CH, AA2 represents C1-C7alkyl, and R6 represents hydrogen, P4 represents -(T)p-R, where T represents -C(O)O-group, R represents C1-C12alkyl, and p is equal to 1; or a group: where A2 represents O, R7 and R8 together with atom whereto attached form a (10-14)members tricyclic unsaturated ring, e.g. carbazole; or a group: where AA2 represents C1-C7alkyl, and R15 represents 2-tert-butylphenyl. The declared compounds are caspase inhibitor prodrugs which under certain conditions can be transformed into biologically active compounds, particularly caspase inhibitors. Also, said invention refers to methods of producing said compounds and to a pharmaceutical composition exhibiting caspase inhibitory action on the basis of the said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can find application in medicine for treating the diseases associated with inflammatory or degenerative conditions.

13 cl, 5 ex

 

The scope of the invention

This invention relates to prodrugs of caspase inhibitors, including furo[3,2-d]oxazoline-5-about the fragment that certain conditions are transformed into biologically active compounds, in particular, caspase inhibitors, and where prodrugs have the formula I, and R1and R2have the meanings defined below.

This invention relates also to methods for data prodrugs of caspase inhibitors.

The invention additionally relates to pharmaceutical compositions comprising these prodrugs, and to their use for the treatment of diseases associated with inflammatory or degenerative conditions.

Background of the invention

Caspase represent the family continplating enzymes that are key mediators in signaling pathways of apoptosis and disassembly of cell structures. The usefulness of caspase inhibitors for the treatment of various painful conditions mammals associated with increased cell apoptosis, demonstrated using peptide inhibitors of the caspase. These inhibitors are useful for the reduction of infarct size and inhibition cardiomyocytes apoptosis after myocardial infarction, reduce the amount of damage and neurological deficit as a result of stroke, SN is the manifestation of post-traumatic apoptosis and neurological deficits in traumatic brain injury, treatment rapid destruction of the liver and improve survival after endotoxic shock.

The use of prodrugs provides desirable characteristics of known drugs, such as increased bioavailability and improved site-specificity. Accordingly, there is a need to prodrugs of caspase inhibitors.

Brief description of the invention

The compounds of this invention and their pharmaceutically acceptable compositions are useful as prodrugs of caspase inhibitors. In some embodiments, the implementation of these prodrugs, including furo[3,2-d]oxazoline-5-about the fragment, in certain conditions, into biologically active compounds, in particular caspase inhibitors. These prodrugs have the formula I or their pharmaceutically acceptable salts, and R1and R2defined below.

These compounds and their pharmaceutically acceptable compositions are useful for the treatment of many painful conditions mammals associated with increased cell apoptosis, including, but not limited to, myocardial infarction, stroke, traumatic brain injury, transient destruction of the liver, endotoxic shock, sepsis, septic shock, chronic hepatitis, pancrea is it.

Detailed description of the invention

This invention provides compounds of formula I:

where R1represents H, R4halogenated, CHN2CH2Cl, CH2F, -CH2OPO(R4)2, -CH2OPO(OR4)2or-C1-2alkyl-R3R4;

R2represents P4-R3-R2, R3-R2or R2fragment of caspase inhibitor;

R3represents-O-, -NH-, -NR4-, -S - or-O(C=O)-;

R4represents a C1-12aliphatic radical, With6-10aryl, (5 to 10)-membered heterocyclyl, (5 to 10)-membered heteroaryl,3-10cycloaliphatic radical, -(C1-6alkyl)-C6-10aryl, -(C1-6alkyl)-((5-10)-membered heteroaryl)- (C1-6alkyl)-((5-10)membered heterocyclyl) or(C1-6alkyl)-C3-10cycloaliphatic radical; where the specified R4group optionally substituted by 0-5 groups J and 0-2 groups J2;

or two R4groups together with the atom to which they are attached, form a (3-8)-membered monocyclic or 8-12)-membered bicyclic ring, optionally substituted by 0-5 groups J and 0-2 groups J2;

J represents a halogen, -OR', -NO2, -CN, -CF3, -OCF3, -R', 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R')2, -SR', -SOR', -SO2R', -SO2N(R') , -SO3R', -C(O)R', -C(O)C(O)R', -C(O)C(O)OR', -C(O)C(O)N(R')2, -C(O)CH2C(O)R', -C(S)R', -C(S)OR', -C(O)OR', -OC(O)R', -C(O)N(R')2, -OC(O)N(R')2, -C(S)N(R')2, -(CH2)0-2NHC(O)R', -N(R')N(R')COR', -N(R')N(R')C(O)OR', -N(R')N(R')CON(R')2, -N(R')SO2R', -N(R')SO2N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')C(S)R', -N(R')C(O)N(R')2, -N(R')C(S)N(R')2, -N(COR')COR', -N(OR')R', -CN, -C(=NR')N(R')2, -C(O)N(OR')R', -C(=NOR')R', -OP(O)(OR')2, -P(O)(R')2, -P(O)(OR')2or-P(O)(H)(OR');

J2is a =NR', =N(OR'), =O or =S;

R' represents H, C1-12aliphatic radical, With6-10aryl, (5 to 10)-membered heterocyclyl, (5 to 10)-membered heteroaryl,3-10cycloaliphatic radical, -(C1-6alkyl)-C6-10aryl, -(C1-6alkyl)-((5-10)-membered heteroaryl)- (C1-6alkyl)-((5-10)membered heterocyclyl) or(C1-6alkyl)-C3-10cycloaliphatic radical;

each R' is independently and optionally substituted by 0-5 substituents selected from H, C1-6of alkyl, CF3, halogen, NO2, OCF3, CN, OH, O(C1-6the alkyl), NH2N(C1-6the alkyl), N(C1-6alkyl)2C(=O)CH3or1-6the alkyl, optionally interrupted by 1 times, the heteroatom selected from O, N and S; where each1-6alkyl is unsubstituted;

unless otherwise stated, any group with suitable valence optionally substituted by 0-5 groups J and 0-2 groups J2.

As used in this about what Isani, the specified interval number of atoms includes any integer. For example, a group having from 1 to 4 atoms that may have 1, 2, 3 or 4 atoms.

As used in this description, the aliphatic group is a hydrocarbon group with a straight, branched or cyclic chain that is completely saturated or partially saturated with 1 or more parts of ninasimone. Unless otherwise specified, aliphatic group has from 1 to 12 carbon atoms. As you can see, alkeline and/or alkyline aliphatic groups have at least 2 carbon atoms. Preferred aliphatic groups are alkyl groups (preferably having from 1 to 6 atoms).

“Cycloalkyl”, “cycloalkenyl” and “cycloaliphatic” groups have from 3 to 10 carbon atoms and are monocyclic or bicyclic fully saturated or partially unsaturated, linear condensed, bridged or spirocyclohexane.

Used in this description, the termaromatic grouporarylrefers to (6-14)-membered ring system that contains at least one aromatic (i.e. fully unsaturated ring. Examples of aromatic rings include, but are not limited to, phenyl, naphthyl, benzimidazole and benzodioxan.

Used in the data is the description of the term “heteroaryl” refers to a ring system, having from 5 to 14 members and 1, 2 or 3 heteroatoms independently selected from N, NR', O, S, SO and SO2,where at least one heteroaromatic ring is fully unsaturated ring containing up to 4 heteroatoms selected from O, N and S; for example, pyridyl, thiophene or thiazole).

Used in this description, the term “heterocycle” refers to a ring system having 3 to 10 members and 1, 2 or 3 heteroatoms independently selected from N, NR', O, S, SO and SO2where neither one ring is aromatic (e.g., piperidine and morpholine).

Further examples of heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuran, benzothiophene, indolyl (e.g., 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazole, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinol, pyrazinyl, 1,3,5-triazinyl, hin is linil (for example, 2-chinoline, 3-chinoline, 4-chinoline) and ethenolysis (for example, 1-ethenolysis, 3-ethenolysis or 4-ethenolysis).

Additional examples of heterocyclic rings include, but are not limited to, 3-1H-benzimidazole-2-it, 3-(1-alkyl)benzimidazole-2-it, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydrofuranyl, 2-morpholino, 3 morpholino, 4-morpholino, 2-thiomorpholine, 3 thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydropyranyl, tetrahydroisoquinoline, benzothiophen, benzodithiol and 1,3-dihydroimidazole-2-it.

In some embodiments of the invention the alkyl or aliphatic chain may be optionally interrupted by another atom or group. This means that the methylene link is alkyl or aliphatic chain optionally substituted specified by another atom or group. Examples of such atoms or groups include, but are not limited to, -NR', -O-, -S-, CO2, -OC(O)-, -C(O)CO-, -C(O)-, -C(O)NR'-, -C(=N-CN), -R CO-, -NR'r C(O)O-, -SO2NR'-, -NR'r SO2-, -NR'r C(O)NR-, -OC(O)NR'-, -NR'r SO2NR-, -SO - or-SO2-, where R' is defined in this specification. Unless otherwise specified, the optional substitution form a chemically stable compound. An optional interrupt can take place inside the chain, and at either end of the chain; i.e. as in the connection point and/or at the end of the chain. Two optional substitution may also be related to each other within the chain, until it leads to a chemically stable compound. If not stated otherwise, in the case where the substitution or interruption occurs at the end of the chain, replacing the atom associated with the N on the end of the chain. For example, if the group-CH2CH2CH3was optionally interrupted by-O-, the resulting compound may be-och2CH3, -CH2Och3or-CH2CH2HE.

The termprotecting or protective group”,used in this description, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In some embodiments, the implementation of the protective group has one or more, or preferably all, of the following characteristics: (a) selectively reacts with a good solution to obtaining a protected substrate that is stable to the reactions occurring in one or not is how many other reactive sites ;and b) able to be selectively removed in good yield by reagents that do not affect the regenerated functional group. Typical protective groups are described in detail in the work of Greene, T.W., Wuts, P. G. Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the contents of which are fully incorporated in the description by reference. The term “nitrogen protecting group”, as used herein, refers to agents that are used to temporarily block one or more desired reactive nitrogen sites in a multifunctional compound. Preferred nitrogen protecting groups also have characteristics that are listed as examples above, and some typical nitrogen protecting groups are also described in detail in Chapter 7 in the work of Greene, T.W., Wuts, P. G “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the contents of which are fully incorporated in the description by reference.

Each of the above aliphatic, aryl, cycloaliphatic, heteroaryl and heterocyclyl group may be optionally substituted by appropriate substituents (preferably up to 5, more preferably up to 3 and more preferably 0 or 1).

Described here, the term “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted who first.” Usually the term “substituted”, precedes him, the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified exactly Deputy. Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted by more than one Deputy, selected from a specified group, the Deputy may be either the same or different in each position.

Combinations of substituents, proposed by the present invention are preferably those that result in the formation of a stable or chemically possible connections. The term “stable(s)”as used herein, refers to compounds that are essentially unchanged when exposed to conditions enabling them to obtain, detection, and preferably their separation, purification, and use for one or more of the purposes disclosed in this description. In some embodiments of the invention a stable compound or chemically feasible compound is a compound that essentially does not change during storage at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least weeks.

Unless otherwise stated, the preferred substituents in the aliphatic, aryl, cycloaliphatic, heteroaryl or heterocyclyl group selected from a halogen, OR', -NO2, -CF3, -OCF3, -R', oxo, -OR', -O-benzyl, -O-phenyl, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R')2, -C(O)R', -COOR', and-CON(R')2where R' is defined in this specification (and is preferably H, C1-6alkyl, C2-6alkenyl or2-6quinil, and most preferred is From1-6alkyl). It should be clear that this definition includes perfluorinated alkyl group.

In some embodiments of the invention the preferred substituents at the nitrogen atom selected from the group consisting of-R7, -SOR7, -SO2R7, -SO2(NR7)2, -SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)C(O)OR7, -C(O)C(O)N(R7)2, -C(O)CH2C(O)R7, -C(O)OR7, -C(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7, -C(=NR7)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -P(O)(R7)2, -P(O)(or SIG7)2and-P(O)(H)(OR7), where R7defined in this specification.

In other embodiments, the implementation of the nitrogen substituents are H, R7, R7, S(O)2R7or-CO2R7. Another option is the implementation of the substituents of the nitrogen are R 7or-C(O)R7.

A qualified specialist in the art should be obvious that some compounds of the present invention may exist in tautomeric forms or hydrated forms, and all such forms of the compounds covered by the scope of the invention. Unless otherwise noted, it is also understood that the structure shown in this description, include all stereochemical forms of the structure; i.e., R and S configurations for each asymmetric center. Therefore, the scope of the invention covered by a single stereochemical isomers as well as enantiomeric and diastereomeric mixture of these compounds.

Unless otherwise noted, it is also understood that the structures depicted herein, include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the scope of this invention covers compounds having presented the structure, except for the replacement of a carbon by a deuterium or tritium, or the replacement of13With or17C-enriched carbon.

The compounds of this invention can be obtained by any method, including conventional synthetic methods known to experts in the art for analogous compounds. For illustration purposes, provided the following CX the mA synthesis of compounds of the present invention.

Use the following abbreviations:

TFAA - triperoxonane anhydride

EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

DCM - dichloromethane

1H-NMR proton nuclear magnetic resonance

19F-NMR fluorine nuclear magnetic resonance

13C-NMR - carbon nuclear magnetic resonance

IHMS - liquid chromatography/mass spectroscopy

Scheme I

Scheme I shows the formation of compounds of formula I. the compounds of formula I can be obtained by treating the compounds of formula II using an activating agent on the basis of a carboxylic acid and a suitable solvent, such as DCM (dichloromethane). Examples of activating agents on the basis of the carboxylic acid include, but are not limited to, TFAA, acetic anhydride, EDC and anhydrides of carboxylic acids.Professionals in this field should be obvious that TFAA can be replaced by any reagent used to activate carboxylic acids. Professionals in this field should also be obvious that the DCM can be replaced by other suitable organic solvents.

As is clear qualified practitioners, some stages of the method can be performed in separate stages orin situ. For example, if the method of the present invention includes removing the protection and p is the following reaction amine, these stages can be performed Paladino or in the form of a one stage procedure.

The remains of chiral aspartic acid, such as certain of the compounds of formula II, to form enantiomerically pure products when exposed to the conditions described in scheme I. the Remains of racemic aspartic acid, such as some other compounds of formula II, to form a mixture of SYN-isomers.

In some embodiments of the invention the above methods described herein (e.g., diagrams, examples and accompanying description).

One variant implementation of the invention provides a method of obtaining the compounds of formula I

where R1and R2defined in this description;

includes treatment of compounds of formula II:

where R1and R2defined in this description;

the activating agent on the basis of a carboxylic acid and a suitable solvent, with the formation of compounds of formula I. In some embodiments, the implementation of the activating agent on the basis of a carboxylic acid selected from TFAA, acetic anhydride or EDC. In some embodiments, the implementation of the activating agent on the basis of the carboxylic acid is TFAA.

The compounds used in the compositions and methods of this izopet the tion, can also be modified by attaching the appropriate functional groups to enhance selective biological properties. Such modifications are known in this area and include modifications which increase biological penetration into a given biological system (e.g., blood, lymphatic system, Central nervous system), increase oral availability, increase solubility, allowing administration by injection, alter metabolism and alter rate of excretion.

For example, the carboxylic acid group in the compound of the present invention can be derivational, for example, ester. Preferred esters are esters derived from:

unbranched or branched C1-6of alkyl, alkenyl or quinil, where the alkyl, alkenyl or quinil optionally substituted C6-10the aryl, CF3, Cl, F, OMe, OEt, OCF3CN or NMe2;

With1-6cycloalkyl, in which 1-2 carbon atoms in cycloalkyl optionally replaced by groups-O -, or-NR9-.

The compounds of this invention having a carbonyl group can be similarly derivationally in the form of, for example, acetal, Catala, oxime (=NR9), hydrazine (=NN(R9)2), thioacetal or thioketal.

The corresponding derivatives of amines is swesty in this area and are also covered by the scope of the invention.

Some of the above derivatives include protective groups known to skilled practitioners (see, for example, by T.W. Greene, & P.G.M. Wuts, “Protective Groups in Organic Synthesis”, 3ndEdition, John Wiley & Sons, Inc. (1999)). As obviously skilled practitioners understand, these protective groups can also be used in the methods of the present invention.

The compounds of this invention can be analyzed for their ability to inhibit apoptosis, the release of IL-1β or directly the activity of the caspase. Analyses for each of the types of activity known in the art. However, as is clear from qualified professionals, proletarienne compound of this invention should be active only in those analyses where Proletarskiy fragment will be chipped off, usually in the analysis ofin vivo.

The compounds of this invention can be tested using techniques such as described in WO 99/47545 and WO 2004/106304, the contents of which are included in the description by reference.

In the art fragments R2specifically referred to in the form of P2, R3or R4slice or website. Data Rxthe terms are references to amino acid sequence adjacent to the site of cleavage of aspartyl specific Casanova substrate. P1refers to bartelemy the remainder of the substrate, depoisited induced by caspase cleavage in the natural substrate. In the design of new ones inhibitors of caspase designation Pxoften kept as to show which part of the amino acid sequence is replaced with ones of the fragment. Used in this description, the term “P4-R3-R2”, “P3-R2or R2” or fragment corresponds to amino acid sequences described above, or to chemical fragment, known to replace this sequence for the purpose Casanova substrate.

Examples R4-R3-R2, R3-R2or R2fragments, which are the ones described in U.S. patent 5919790 (Allen et al.); 5874424 (Batchelor et al.); 5847135 (Bemis et al.); 5843904 (Bemis et al.); 5756466 (Bemis et al.); 5716929 (Bemis et al.); 5656627 (Bemis et al.); in the international application WO 99/36426 (Warner-Lambert); Dolle et al., J. Med. Chem., 40, 1941 (1997); international applications WO 98/10778 (Idun); WO 98/11109 (Idun); WO 98/11129 (Idun) and WO 98/16502 (Warner-Lambert), all of which are included in the description by reference.

According to one variant of implementation of the present invention, R4-R3-R2, R3-R2or R2fragment of caspase inhibitor is optionally substituted group selected from C6-10aryl, (5 to 10)-membered heteroaryl, and one of the structures shown in table 1:

Table 1
P4-R 3-R2-R3-R2or R2group

where n is 0-3;

each R3and R4is an independently -(T)p-R;

T represents-CO-, -C(O)O-, -C(O)C(O)-, -C(O)C(O)O-, C(O)NR7-, -C(O)NR7NR7-, -C(O)C(O)NR7-, -SO2NR 7- or-SO2-;

p is 0 or 1;

R represents H, C1-12aliphatic group5-10aryl, (5 to 10)-membered heterocyclyl, (5 to 10)-membered heteroaryl,3-10cycloaliphatic group, -(C1-6alkyl)-C6-10aryl, -(C1-6alkyl)-((5-10)-membered heteroaryl)- (C1-6alkyl)-((5-10)membered heterocyclyl)- (C1-6alkyl)-benzo(C3-10cycloalkyl) or(C1-6alkyl)-C3-10cycloaliphatic group;

each AA, AA2and AA3represents independently amino acid side chain;

X represents-N-, -O-, -S-, -SO-, -SO2-, -CHF-, -CF2-, -C(R11)2-, -C=O or C=NOR11-;

X2-X1represents-N(R11)-C(R11)-, -C(R11)2-C(R11)-, -C(R11)2-N-, -N=C-, -C(R11)=N, -C(R11)=C-, -C(=O)-N - or-C(=O)-C(R11)-;

And2represents O, S or H2;

Y represents N or CR8;

Ar represents optionally substituted C6-10aryl or optionally substituted (5 to 10)-membered heteroaryl;

L is an R7, (CH2)nR7, COR7, CO2R7, SO2R7, CON(R7)2or SO2N(R7)2;

G1and G3independently selected from N or C;

G2is a valence bond, O, S, N or C;

Ring W contains 0 - double bond and optionally condensed with a saturated or unsaturated (5-7)-membered ring, containing 0-3 heteroatoms;

Ring a represents a (3-8)-membered monocyclic, (8-12)-membered bicyclic or (10-14)-membered tricyclic heterocyclyl, which is either saturated or unsaturated and which contains 1-6 heteroatoms selected from O, N and S;

The ring is a (5-7)-membered heterocyclyl containing 1-4 nitrogen atom;

The ring is a condensed6-10aryl or (5 to 10)-membered heteroaryl ring;

Ring D is a (3-8)-membered monocyclic, (8-12)-membered bicyclic or (10-14)-membered tricyclic heterocyclyl, which is either saturated or unsaturated and which contains 1-6 heteroatoms selected from O, N and S;

Ring Z is a 6-membered aryl, (5-7)-membered heteroaryl,3-7cycloaliphatic radical, or (5-7)-membered heterocyclyl;

R5represents H, halogen, CN, C1-12alkyl, NH2, -NH(C1-12alkyl), -NH(C1-12alkyl)2HE, -O(C1-12alkyl), -O(phenyl), C1-12halogenated, -O(C1-12halogenated)6-10aryl, -(C1-6alkyl)-C6-10aryl, -C(O)(C1-12alkyl), -C(O)HE, -C(O)O(C1-12alkyl), -NHC(O)(C1-12alkyl), -N(C1-12alkyl)C(O)(C1-12alkyl), SO2NH2, -S(O)2(C1-12alkyl) or-S(O)2O(C1-12alkyl);

R6represents H R 7or (C1-12alkyl)-(C=O)R7;

R7represents H, C1-12aliphatic group6-10aryl, (5 to 10)-membered heterocyclyl, (5 to 10)-membered heteroaryl,3-10cycloaliphatic group, -(C1-6alkyl)-C6-10aryl, -(C1-6alkyl)-((5-10)-membered heteroaryl)- (C1-6alkyl)-((5-10)membered heterocyclyl)- (C1-6alkyl)-benzo(C3-10cycloalkyl) or(C1-6alkyl)-C3-10cycloaliphatic group;

or R6and R7taken together with the atom(s)to which at any time they are attached, form a (3-8)-membered monocyclic, (8-12)-membered bicyclic or (10-14)-membered tricyclic ring which is either saturated or unsaturated and which contains 0-6 heteroatoms selected from O, N and S;

R8represents H, CF3, halogen, NO2, OCF3CN, OR7or R7;

R9represents H, CF3, halogen, OCF3, SR11CN, C6-10aryl, C5-10heteroaryl, -O(phenyl) or-S-(phenyl);

R10represents a C1-6alkyl, optionally interrupted by heteroatoms in the amount of up to 2, selected from O, N or S;

R11and R12represent, each independently, H or C1-6alkyl;

or R11and R12taken together with the atoms to which they are attached, form a (5-7)-membered ring, optionally teramae to 3 heteroatoms, selected from O, N or S;

R13represents H, C1-6aliphatic group, F2, JV, C6-10aryl, or R13attached to Ar with the formation of unsaturated or partially saturated 5 to 6-membered ring having 0-2 heteroatoms, which fused with Ar;

R14represents R, OR7or N(R7)2;

R15is an R7, NR7, OR7or 2-tert-butylphenyl;

R16represents H, R7-(C1-6alkyl)-NR6R7-(C1-6alkyl)-OR7-(C1-6alkyl)-NHCOR7-(C1-6alkyl)NC(=NH)NH2-(C1-6alkyl)-NH2R7-(C1-6alkyl)-SR7-(C1-6alkyl)-OR7-(C1-6alkyl)-cycloalkyl; or two R16taken together, constitute (3-6)-membered carbocycle;

R17and R18represent, each independently, H, C1-6aliphatic group6-14aryl or (5-14)-membered heteroaryl; or R17and R18taken together with the atom(s)to which at any time they are attached, form a (3-7)-membered heterocyclyl with 1 heteroatom selected from O, N or S;

R19represents a C6-10aryl, -(C1-6alkyl)-C6-10aryl, C3-10cycloalkyl or benzoannelirovannykh3-10cycloalkyl;

or R19and AA2together with the carbon atoms to which they are attached is, form a ring A.

In other embodiments of this invention R1selected from H, R4, halogenoalkane, CHN2CH2Cl, CH2F, -CH2OR4, -CH2SR4, -CH2O(C=O)R4, -CH2OPO(R4)2, -CH2OPO(or SIG4)2CH2Other4or CH2N(R4)2.

In still other embodiments of this invention R1selected from H, C1-6of alkyl,

In other embodiments, implementation of R1selected from-CH2On-2,3,5,6-tetrafluorophenyl, -CH2O-tryptophanyl, CH2F or-CH2O-tetrafluorophenyl.

In one embodiment, R1represents

In another embodiment, R1represents

In some embodiments, the implementation of p is 0. In other embodiments, the implementation of p is 1.

In some embodiments of this invention, T represents-CO-, -NH-, -C(O)O-, -C(O)C(O)-, -SO2-. In some embodiments, the implementation of T represents-CO - or SO2-. In some embodiments, the implementation of T represents-CO-.

In some embodiments, the implementation of R represents H, C1-12aliphatic group6-10aryl, (5 to 10)-clenn the th heteroaryl or 3-10heterocyclyl. In some embodiments, the implementation of R represents a C6-10aryl or (5 to 10)-membered heteroaryl. In some embodiments, the implementation of R represents naphthyl, phenyl or ethanolic.

In some embodiments of this invention, T represents-CO - and R represents a C6-10aryl or (5 to 10)-membered heteroaryl.

In some embodiments, the implementation of T represents-CO - and R represents a phenyl, optionally substituted in position 3 or 5 halogen or1-3the alkyl and optionally substituted in position 4 groups NH2, -N(O)CH3, OH or OCH3.

In some embodiments, the implementation of the AA, AA2and AA3represent, each independently, a group, are seamlessly integrated in the S2 sub-unit of the caspase. In some embodiments, the implementation of the AA, AA2and AA3represent, each independently, N or C1-10aliphatic group. In some embodiments, the implementation of the AA, AA2and AA3represent, each independently, With1-7alkyl. In some embodiments, the implementation1-7alkyl optionally substituted with halogen, HE, SMe, -C(=O)OH or phenyl.

In some embodiments, implementation And2represents O or S. In some embodiments, implementation And2represents O. In other vari is ntah implementation And 2represents S.

According to other variants of implementation, the ring And selected from the

orwhere n is 0-3.

In some embodiments, the implementation of the ring And substituted 0-3 groups J and 0-1 bands J2.

In some embodiments, the implementation of the ring And is substituted by =O, halogen, C1-4the alkyl or C1-4alkoxy.

According to one variant of implementation, R6and R7together with the atom or atoms to which they are attached, form a ring selected from indole, isoindole, indoline, indazole, purine, dihydropyrimidine, benzimidazole, benzothiazole, imidazole, imidazoline, thiazole, pyrrole, pyrrolidone, pyrroline, pyrazole, pyrazoline, pyrazolidine, triazole, piperidine, research, thiomorpholine, pyrazine, piperazine, carbazole, fenotiazina, phenoxazine, phenanthridine, dihydropteridine, acridine, dihydrouridine, hemolysin, heatline, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, cinnoline, dihydroindolone, phenazine, dihydrophenazine, cinoxacin, dihydroquinoxaline, phthalazine, 1,8-naphthiridine, dihydronaphthalene, tetrahydronaphthalene, pteridine, hinoklidina, β-carboline, pyrido[7,3-b]indole, 2,3,9-diazafluoren, 9-thia-2,10-disant the price, 3,6,9-diazafluoren and thieno-[3,2-b]pyrrole.

According to another variant implementation, R6and R7together with the atom or carbon atoms to which they are attached, form a ring selected from the

In some embodiments, the implementation of the ring formed by R6, R7and the atom or atoms to which they are attached, a substituted 0-3 groups J and 0-1 bands J2.

In some embodiments, the implementation of R9represents H, CF3, halogen, OCF3, SR11CN, C6-10aryl, C5-10heteroaryl, -O(phenyl) or-S-(phenyl); where specified phenyl group optionally substituted by 1-3 groups J, where J is a halogen, CH3, CF3, JV, OCH3, OCF3or N(R')2.

In some embodiments, the implementation of Ar represents a C6-10aryl group. In some embodiments, the implementation of the Ar is a phenyl ring. In some embodiments, the implementation of Ar is optionally replaced with 0-3 groups J and 0-1 bands J2. In some embodiments, the implementation of Ar optionally substituted by 1-3 groups selected from halogen, CH3, CF3, JV, OCH3, OCF3and NR11R12.

According to one variant of implementation, Z represents

In some embodiments, the implementation of Z C is substituted 0-3 groups J and 0-1 bands J 2.

In some embodiments, the implementation of the G1, G2and G3represent C. In some embodiments, the implementation of the ring W contains two double bonds and forms Spiridonova ring.

In some embodiments, the implementation of the variables are as described in the connections table 2.

In some embodiments, the implementation of the prodrug inhibitor of caspase selected from the prodrugs are shown in table 2:

Although the above patterns show only one possible stereoisomer of the compound, the invention covers all possibleSYN-stereoisomers of each connection. By means of example compound I-2 as shown below on the left is oneSYN-stereoisomer. AnotherShin-isomer, shown at right, is also part of this invention.

In some embodiments, the implementation of the compounds of this invention include compounds I-1 and I-2, represent a mixture of twoSYN-isomers.

In other embodiments, the communication of the present invention, including the compounds I-3, I-4 and I-5 are enantiomerically pureSYN-isomers that have the molecular structures shown in t the blitz above.

According to another variant implementation, the present invention provides a pharmaceutical composition which includes:

a) compound of the invention, as defined herein, or its pharmaceutically acceptable salt; and

b) a pharmaceutically acceptable carrier, adjuvant or binder.

If the pharmaceutically acceptable salts of the compounds of the present invention used in these compositions, these salts are preferably derived from inorganic or organic acids and bases. Among such salts of acids include the following: acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, fumarate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate. Salts of the bases include ammonium salts, alkali metal salts, such as salts of sodium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, N-is ethyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc.

Also, the basic nitrogen-containing groups can be quaternity such agents as lower alkylhalogenide, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; diallylsulfide, such as dimethyl, diethyl, dibutil and dimycolate, halides, long-chain, such as decyl, lauryl, myristyl and sterilgarda, bromides and iodides, aralkylated, such as benzyl and phenetermine and others. Thus obtained water - or oil-soluble or dispersible products.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion-exchange substances, aluminum, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride a mixture of saturated fatty acids from vegetable oil, water, salts or electrolytes, such as preteenslut, secondary, acidic sodium phosphate, secondary acid potassium phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, substance on the basis of cellulose, polyethylene glycol, carboxymethylcellulose sodium, polyacrylates, waxes, block polymers of polyethylene, polio is DIPROPYLENE, the polyethylene glycol and lanolin.

According to a preferred variant implementation of the compositions of the present invention formulated into formulations for pharmaceutical injection mammals, preferably humans.

Such pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasal, buccal, vaginally or via an implanted reservoir. The term “parenteral”as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, nutricentials, vnutrigrudne, vnutrikojnuu, intrahepatic, intranidus and vnutribronhialno injection or infusion technique. Preferably, the composition is administered orally or intravenously.

Sterile injectable forms of the compositions of this invention may be aqueous or oily suspension. These suspensions can be formulated according to known art techniques using suitable dispersing or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among acceptable is sitela and solvents, which can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use sterile, fixed oils. For this purpose, can be used in any mixed fixed oils, including synthetic mono - or di-glycerides. When receiving injectable drugs useful fatty acids such as oleic acid and its glyceride derivatives, and natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene options. Data oil solutions or suspensions may also contain long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are usually used in the preparation of pharmaceutically acceptable dosage form, including emulsions and suspensions. For the purposes of recipes you can also use other commonly used surfactants, such as twins, spiny and other emulsifying agents or amplifiers bioavailability, which is usually used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms.

The pharmaceutical compositions of this invention can be is about to be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Usually also add lubricating agents such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When oral administration is required aqueous suspensions of the active ingredient is combined with emulsifying and suspenders agents. If desired, can also be added some sweetening, flavoring or aromatic or tinted agents.

Alternatively, the pharmaceutical compositions of this invention can be introduced in the form of suppositories for rectal administration. They can be prepared by mixing the agent with a suitable not irritating excipient, which is solid at room temperature, but liquid at the rectal temperature and will therefore melt in the rectum, releasing the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention can also enter topically, especially when the target of treatment includes areas or organs readily susceptible to the local application, on the tea eye diseases, the skin or the lower intestine. Suitable formulations for topical application easily prepare for each of these areas or organs.

Topical application for the lower intestine may be effective in the rectal suppositories (see above) or in a suitable composition for enemas. You can also use topically-transdermal patches.

For local applications, the pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated as a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carrier materials include, but are not limited to, mineral oil, monostearate sorbitan, Polysorbate 60, citylove esters wax, Cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical is oppozitsii can be prepared in formulations in the form of micronized suspensions in isotonic, sterile saline solution with a defined pH or, preferably, as solutions in isotonic, sterile saline solution with a defined pH, or a preserving agent such as chloride benzylamine, or without it. Alternatively, for ophthalmic applications, the pharmaceutical compositions can be prepared in formulations in the form of ointment, such as vaseline.

The pharmaceutical compositions of this invention can also be entered using a nasal aerosol or inhalation. Such compositions are prepared in accordance with techniques well known in the field of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to increase the bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The above-described compounds and compositions are particularly useful for therapeutic applications related to IL-1-mediated disease, an apoptosis-mediated disease, inflammatory disease, autoimmune disease, destructive bone violation, proliferative disorders, infectious diseases (e.g., bacterial infections, preferably, eye infections), finally the operational diseases, disease associated with cell death, disease associated with excessive alcohol consumption, mediated by virus disease, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, respiratory distress syndrome of adults, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic Hashimoto's, grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, angiosclerosis gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, disease, graft-versus-host rejection of transplantable organs, apoptosis bodies after burns, osteoporosis, leukemias and related disorders, myelodysplastic syndrome, multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi sarcoma, diffuse myeloma, haemorrhagic shock, sepsis, septic shock, burns, shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy disease, disease caused by prions, cerebral ischemia, epilepsy, fits or seizures, Mika dialno ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, of bypass graft of coronary artery, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain damage, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, various forms of liver disease, renal disease, politicheskoi kidney disease, H. pylorus is preserved-associated gastric and duodenal ulcer, HIV infection, tuberculosis, meningitis, toxic epidermal necrolysis, hand, foot and automobiletechnik disease (sometimes called automobiletechnik febrile syndromes) and identical syndromes, such as syndrome Muckle Wales (MWS), familial cold urticaria (FCU), familial Mediterranean fever (FMF), chronic infantile neurological cutaneous and articular syndrome (CINCAS), also known as the Initial Neonatal Multisystem Inflammatory disease (NOMID), TNFR1-associated periodic syndrome (TRAPS) and Hyper-IgD periodic fever syndrome (HIDS). The connection of the composition is also useful in the treatment of complications associated with bypass grafts to coronary arteries. Compounds and compositions are also useful for decreasing IGIF or IFN-γ production. Compounds and compositions are also useful in immunotherapy, such as cancer treatment. It should be understood that the treatment of the disease involves reducing the severity of disease, cure disease and maintain a stable or controlled condition with the disease.

Compounds and compositions can also be used in the methods of preservation of cells. These methods would be useful for the conservation of organs, in particular, organs intended for transplantation or blood products.

According to another variant implementation of the compositions of this invention may additionally include another therapeutic agent (i.e. one or more additional assets). These tools include, but are not limited to, thrombolytic agents such as tissue plasminogen activator and streptokinase. When to use an additional tool, it can be entered either as a separate dosage form or as part of a single dosage form with the compounds or compositions of the present invention.

The number of compounds present in the compositions of this invention must be sufficient to cause a noticeable reduction in the severity of illness or Akti is caspase activity and/or cell apoptosis, measured using any of the assays known in this field.

For monotherapy useful are the dose levels of from about 0.01 to about 50 or about 100 mg/kg of body weight per day, preferably from 0.5 to about 75 mg/kg of body weight per day and most preferably from about 1 to about 25 or about 50 mg/kg of body weight per day of the compounds as the active ingredient.

Typically, the compound or composition of the present invention will type about from one to 5 times per day or alternatively, as a continuous infusion. This introduction can be used as a chronic or acute therapy. The amount of active ingredient which can be combined with the materials of the carrier to produce a single dosage form will depend upon the exposed treatment of the subject and the particular route of administration. A typical preparation will contain from about 5% to about 95% active compound (wt./wt.). Preferred preparations contain from about 20% to about 80% active compound.

If the compositions of this invention include the combination of the compounds of this invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dose levels from about 10% to about 100% and is more preferably from about 10% to about 80% of the dose, conventionally administered in monotherapy.

After improvement of the condition of the patient, if necessary, you can enter a maintenance dose of a compound, composition or combination of this invention. Subsequently, the dosage or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which the improved condition is retained after the symptoms alleviated to the desired level, and the treatment should be discontinued. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

Obviously it is clear to the skilled practice, in some cases, may be necessary to lower or higher doses than the doses above. It should be understood that a specific dosage and treatment regimens for any particular patient will depend on many factors, including the activity of specific connections in use, the age, body weight, General health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of a particular disease, prone patients being treated with disease, and the opinion of the attending physician. The number of active ingredients will also depend on the specific compounds and the other therapeutic agent, if present, in the composition.

In predpochtitel the om embodiment, the invention provides a method of treatment of a patient, preferably a mammal suffering from one of the above-mentioned diseases, including the stage of introduction of a given patient the compound or pharmaceutically acceptable composition described above. In this embodiment, if the patient is given another therapeutic agent or a caspase inhibitor, it can be delivered together with the compound of the present invention in the form of a single dosage form or in separate dosage forms. When it is administered as separate dosage forms, another inhibitor of caspase or means you can enter up to, simultaneously with or after the introduction of a pharmaceutically acceptable composition comprising a compound of this invention.

The compounds of this invention can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable funds, including the connection of the present invention and a carrier suitable for coating specified implantable means. In another aspect of the present invention includes implantable means that the applied coating composition, comprising the compound of the present invention and is of the l, suitable for covering the specified implantable tools.

Another aspect of the invention relates to a method for inhibiting caspase activity in a biological sample, and this method comprises contacting a specified biological sample with the compound of the formulaIor a composition comprising the specified connection. The term “biological sample”, as used herein, includes, without limitation, cell cultures and their extracts; material for biopsy obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Inhibition of caspase activity in a biological sample is useful for a variety of purposes that are known to specialists in this field. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological samples and biological tests.

The compounds of this invention are useful in the methods of preservation of cells, which may be necessary for organ transplantation or for the preservation or protection of blood products. It was reported about similar types of use of caspase inhibitors [Schierle et al., Nature Medicine, 5, 97 (1999)]. The method includes processing cells or tissues that are subject to preservation solution, including Inga is for caspase. The amount of inhibitor of caspase, which will depend upon the effectiveness of the inhibitor for a given cell type and the length of time required to protect cells from apoptotic cell death.

Out of touch with any theory, it is believed that cyclic acetylene connection applicants are prodrugs. Namely, furo[3,2-d]oxazoline-5-he splitin vivoor in appropriate conditions (e.g., plasma) to obtain the derivative of aspartic acid, which is an active connection.

In order to more fully understand this invention, represented by the following preparative examples and examples of tests. These examples are only for illustration purposes and should not be construed as limiting the scope of the invention in any way.

Example 1

1-(3a-vermeil-5-oxo-3a,5,6,6a-tetrahydrofuro[3,2-d]oxazol-2-yl)-2-methylpropionyl ether (S)-carbazole-9-carboxylic acid (Ι-1)

Method a:

Triperoxonane anhydride (128 μl, 0,907 mmol, 2.0 EQ.) was added to a solution of 1-(1-carboxymethyl-3-fluoro-2-oxopropylidene)-2-methylpropionic ether (S)-carbazole-9-carboxylic acid (200 mg, 0,752 mmol, 1.0 EQ.) in anhydrous dichloromethane (2 ml) in a nitrogen atmosphere at ambient temperature. After 1 hour the reaction mixture was diluted with anhydrous of dihormati the Ohm (10 ml), added Tris-(2-amino-ethyl)amine-polystyrene resin (0,907 g of 3.07 mmol, 6,8 EQ.) and the reaction mixture was stirred additionally for one hour. The resin was removed by filtration and the filtrate was concentrated in vacuo and triturated with dichloromethane and petroleum ether, getting mentioned in the title compound as a white solid (170 mg, 73%);1H-NMR (700 MHz, CDCl3) δ 1,16-of 1.27 (6H, m), 2,79 is 2.55 (1H, m), 2,90 (1H, DD), of 3.07 (1H, DD), to 7.67-a 7.92 (3H, m), 5,61 (1H, DD), 7,72 (1H, t), 7,52 (1H, t), 8,02 (1H, d), of 8.37 (1H, d); M+H 725,5.

Example 2

3a-Vermeil-2-naphthalene-1-yl-6,6a-dihydro-3aH-furo[3,2-d]oxazol-5-he (Ι-2)

Was obtained from 5-fluoro-3-[(naphthalene-1-carbonyl)amino]-7-oxopentanoic acid according to method A (270 mg, 93%); white solid;1H-NMR (700 MHz, CDCl3) δ 3,10 (1H, d), 3,20 (1H, DD), a 7.85 (1H, DD), of 7.97 (1H, DD), is 5.18 (1H, d), 7,53-of 7.60 (2H, m), to 7.67 (1H, t), to 7.93 (1H, d), of 8.06 (1H, d), 8,17 (1H, d), 9,17 (1H, d);13C-NMR (101 MHz, CDCl3, steamed proton) δ 35,7, 69,9, 80,7, 82,2, 125,0, 126,3, 126,9, 128,7, 129,2, 130,7, 131,3, 137,0, 137,1, 173,0;19F-NMR (376 MHz, CDCl3, steamed proton) δ -232,5; M+H 286,7.

Example 3

(S,S,S)-7-Chloro-2-{1-[5-oxo-3A-(2,3,5,6-tetracarboxylate)-3a,5,6,6a-tetrahydrofuro[3,2-d]oxazol-2-yl]propyl}-2Hisoquinoline-1-he (Ι-3)

Received from (S)-3-[2-(7-chloro-1-oxo-1H-isoquinoline-2-yl)Butylimino]-7-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid according to method A (122 mg, 63%); white solid which second substance; IR (solid) 1795, 1659, 1616, 1586, 1509, 1785, 1093, 939, 827 cm-1;1H-NMR (700 MHz, CDCl3) δ and 0.98 (3H, t), 1,99-2,05 (1H, m), 2,25-of 2.30 (1H, m), 2,92 (1H, d)and 3.15 (1H, DD), to 7.59 (2H, DD), to 7.99 (1H, d), of 5.92-5,95 (1H, m), of 6.66 (1H, d), 6.87 in-6,89 (1H, m), 7,01-7,03 (1H, m), 7,78 (1H, d), a 7.62 (1H, DD), 8,72 (1H, USD);13C-NMR (101 MHz, CDCl3, steamed proton) δ 9,3, 23,6, 33,6, 51,8, 67,7, 72,0, 100,0 (t), 105,7, 111,7, 126,0, 126,7, 126,8, 127,0, 132,28, 132,7, 139,5 (DD), 175,3 (DD), 160,2, 163,9, RUB 171.1;19F-NMR (376 MHz, CDCl3, steamed proton) δ -170,21 (kV), -170,37 (kV), -158,10 (kV), -158,60 (kV); M+H 525,2, M-H 523,2.

Example 4

Methyl ether (S,S,S)-2-oxo-1-{1-[5-oxo-3A-(2,3,5,6-tetracarboxylate)-3a,5,6,6a-tetrahydrofuro[3,2-d]oxazol-2-yl]propyl}-1,2-dihydropyridines-3-yl)carbamino acid (Ι-4)

Was obtained from (S,S)-3-[2-(3-methoxycarbonylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-7-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid according to method A (38 mg, 80%); white solid; IR (solid) 1803, 1726, 1677, 1603, 1516, 1790, 1209, 1091, 937 cm-1;1H-NMR (700 MHz, CDCl3) δ of 0.96 (3H, t), 1,97-2,03 (1H, m), 2,22-2,03 (1H, m), 2,90 (1H, DD), 3,17 (1H, DD), of 3.80 (3H, s), to 7.59 (2H, DD), of 7.97 (1H, d), 5,79-of 5.82 (1H, m), of 6.31 (1H, t), 6,83-6,91 (2H, m), 7,79 (1H, USS), 8,02 (1H, USD);13C-NMR (101 MHz, CDCl3, steamed proton) δ 10,7, 27,9, 37,7, 52,8, 57,3, 68,6, 73,3, 101,3 (t), 107,7, 112,6, 120,1, 125,7, 129,9, 157,7, 157,5, 167,7, 172,2;19F-NMR (376 MHz, CDCl3, steamed proton) δ -138,95 (kV), -157,33 (a); MHz To 517.7, M-H 512,3.

Example 5

(S,S,S)-N-(2-tert-Butylphenyl)-N'-{1-[5-OK what about-3A-(2,3,5,6-tetracarboxylate)-3a,5,6,6a-tetrahydrofuro[3,2-d]oxazol-2-yl]ethyl}oxalate (Ι-5)

Was obtained from (S,S)-3-{2-[(2-tert-butylphenylmethyl)amino]propionamide}-7-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid according to method A (159 mg, 65%); white solid; IR (solid) 1808, 1675, 1518, 1793, 1779, 1100, 971, 760 cm-1;1H-NMR (700 MHz, CDCl3) δ 1.77 in (9H, s), was 1.58 (3H, d), 2,90 (1H, USD), 3,12-3,19 (1H, m), 7,58-of 7.69 (2H, m), 7,80-7,86 (1H, m), 7,98 (1H, t), 6.87 in-6,93 (1H, m), 7,20 (1H, t), 7,28-to 7.32 (1H, m), of 7.75 (1H, d), 8,03 (1H, d), of 8.06 (1H, OSS), to 9.57 (1H, USD);13C-NMR (101 MHz, CDCl3, steamed proton) δ 18,6, 18,7, 31,0, 37,7, 37,8, 77,7, 77,5, 68,3, 68,5, 73,2, 73,7, 101,3, 101,6, 113,1, 127,3, 126,5, 127,1, 127,7, 137,7, 160,3;19F-NMR (376 MHz, CDCl3, steamed proton) δ -138,90 (DQC), -157,22 (DQC); M+H is 552.5 M-H 550,7.

1. The compound of formula I:

where R1represents CH2Cl, CH2F or-C1-2alkyl-R3R4;
R3represents-O-;
R4represents phenyl, where the specified R4group optionally substituted by 0-5 group J, where J is a halogen;
R2represents a C6-10aryl; or a group:

where Y represents CH,
AA2represents a C1-C7alkyl, and
R8and R9represents hydrogen or halogen;
or group:

where Y represents CH,
AA2represents a C1-C7alkyl, R6represents hydrogen,
R4represents a -(T)p-R, where T represents-C(O)O-group, R
represents a C1-C12alkyl and p is 1;
or group:

where a2represents O,
R7and R8together with the atom to which they are attached, form a (10-14)membered tricyclic unsaturated ring, for example, carbazole;
or group:

where AA2represents a C1-C7alkyl, and
R15is a 2-tert-butylphenyl.

2. The compound according to claim 1, in which R1selected from

3. The compound according to claim 2, in which R1represents a

4. The compound according to claim 2, in which R1represents a

5. The compound according to claim 1, selected from the following compounds:

6. Pharmaceutical composition having inhibitory activity against caspase, including:
a) a compound according to any one of claims 1 to 5; and
b) a pharmaceutically acceptable carrier, adjuvant or excipient.

7. A method of treating disease in a patient, where the disease is osteoarthritis, pancreatitis, respiratory distress syndrome, adult rheumatoid arthritis, systemsource erythematosus, chronic active hepatitis, angiosclerosis myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, disease graft-versus-host rejection of transplantable organs, sepsis, septic shock, cerebral ischemia, myocardial ischemia, myocardial infarction, atherosclerosis, amyotrophic lateral sclerosis, multiple sclerosis, neurological damage due to stroke, traumatic brain injury, hepatitis-B, hepatitis-C, hepatitis-G, liver disease, renal disease, complications associated with bypass graft coronary artery, including the stage of introduction of a given patient the compound according to any one of claims 1 to 5, or a pharmaceutical composition 6.

8. The method of inhibition mediated by caspase function in a patient, comprising the stage of introduction of a given patient the compound according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6.

9. The way to reduce IGIF or IFN-γ production in a patient, comprising the stage of introduction of a given patient the compound according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 6.

10. The method of preservation of cells, including stage washing of the cells with a composition based on compounds according to any one of claims 1 to 5.

11. The method according to claim 10, in which these cells are:
a) the organization is, intended for transplantation; or
b) the product of blood.

12. The method of obtaining the compounds of formula I

where R1and R2have the values defined in any one of claims 1 to 4, comprising processing the compounds of formula II:

where R1and R2have the values defined in any one of claims 1 to 4;
the activating agent on the basis of a carboxylic acid and a suitable solvent, with the formation of compounds of formula I.

13. The method according to item 12, in which the activating agent on the basis of the carboxylic acid is triperoxonane anhydride (TFAA).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to 11b-(het)aryl-2,3,6,11b-tetrahydrooxazolo[2',3':2,1]pyrrolo [3,4-b]quinolin-5,11-diones with general formula 1 R1=Ar, Het; R2=H, Alk, OAlk, halogen; R3 - H, Alk, OAlk, halogen; R4=H, Alk, OAlk, halogen and to a synthesis method which involves reacting initial 3-(het)aroyl-4-oxo-1,4-dihydro-2-quinolincarboxylate with monoethanolamine in ratio 1:1 in methanol, ethanol, tetrahydrofuran, toluene, dioxane while heating in the presence or absence of acetic acid for 2-24 hours (control using thin-layer chromatography).

EFFECT: formula 1 compounds have potential for use as low-toxicity substances with biological activity, for example antimicrobial, antiviral and anticonvulsant; method of producing formula 1 compounds is easy to implement, safe, does not require special conditions, allows for obtaining substances which can not be produced using other methods.

2 cl, 10 ex

The invention relates to new compounds of the formula (I) in which R1represents a group of formula (Ia) or (IB), in which either R7represents an optionally protected hydroxy-group, alloctype, halogen, -OR10where R10represents lower alkyl, optionally protected-O(CH2)mHE, where m = 2 to 4, or-ОСОNН2and R7ais hydrogen, or R7and R7atogether represent oxoprop, R8represents a hydroxy or methoxy group, and R9- hydroxy - or alloctype; R2- hydrogen, alloctype or optionally protected hydroxy-group, and between the two carbon atoms connected by the dotted line, there is a simple or a double bond; R3is methyl, ethyl, n-propyl or allyl; or R4represents hydrogen or a hydroxy-group, and R4ais hydrogen, or R4and R4atogether represent oxoprop; or R5represents a hydroxy-group, and R5ais hydrogen, or R5and R5atogether represent oxoprop; and a represents a group of formula-CH(OR6)-CH2-(CH2)nor-CH= CH-(CH2)n- associated with carbon atom (CH2

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles of general formula: where R=H (a); CH3 (b); OCH3 (c); CI (d) which can be used as biologically active substances, fluorescent materials and for synthesis of phthalocyanines. The method involves synthesis of substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles through a reaction which takes place in two steps, where at the first step 4-bromo-5-nitrophthalonitrile reacts with sodium salts of substituted 3-phenylpropanoates in molar ratio 1:2, respectively, at temperature 19…25°C for 12-20 hours in dimethyl formamide (DMF) solution, after which the reaction mass is diluted with tenfold excess water with T=0…25°C. The released resinous residue is extracted with dichloromethane, thoroughly washed with water and chromatographed on silica gel. The eluent (solvent) is evaporated. The residue of the intermediate product is filtered and re-crystallised from alcohol. At the second step of the method, tin dichloride solution in concentrated hydrochloric acid is mixed with the solution of the obtained intermediate product in ethyl alcohol in molar ratio 3.5-4.5:1, respectively, at temperature 30...50°C and reaction time of 1-2 hours, after which the reaction mixture is diluted with tenfold excess water with T=0…25°C, and the precipitate is filtered and re-crystallised from alcohol.

EFFECT: obtaining novel heterocyclic dicyano-derivatives of benzoxazines.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (5H-pyrazolo[1,5-c][1,3]benzoxazin-5-yl)phenylmethanone derivatives (I), useful as HIV viral replication inhibitors, as well as pharmaceutical compositions, use thereof as medicinal agents.

EFFECT: disclosed compounds are meant for preventing or treating HIV infection and treating AIDS.

7 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I and to their physiologically compatible salts. In general formula I , X denotes identical or different groups =C(-R)- or =N-, wherein at least one =C(-R-)- is substituted by =N-; Y is -O-; R denotes identical or different hydrogen, halogen, (C1-C6)-alkyl; R1 denoes (C4-C16-alkyl, (C1-C4)-alkylene-(C6-C10)-aryl, (C1-C4)-alkylene-(C3-C12)-cycloalkyl, (C9-C10)-bicyclic ring, wherein the aryl can be singly or multiply substituted with (C1-C6)-alkyl; R2 denotes hydrogen; or R1 and R2 together with the nitrogen atom which it is bonded form a monocyclic, saturated 6-member ring in which separate members of the ring system can be substituted with -CHR4-; R4 denotes (C1-C6)-alkyl. The invention also relates to a pharmaceutical composition having inhibiting action on endothelial lipase (EL) and containing one or more compounds of formula I, to use of the disclosed compounds to prepare a medicinal agent and to methods of producing compounds of formula I.

EFFECT: high effectiveness of derivatives.

11 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzoxazines

in which substitute R1 denotes a hydrocarbyl residue having 1-3000 carbon atoms, and substitutes R2, R3, R4 and R5 independently denote hydrogen atoms, hydroxyl groups or hydrocarbyl residues, having 1-3000 carbon atoms, respectively, and in which substitutes R3 and R4 or R4 and R5 with a partial structure -O-CH2-NR7-CH2-, bonded to the benzene ring, can also form a second tetrahydrooxazine ring, where R7 denotes hydrocarbyl residues having 1-3000 carbon atoms, provided that at least one of substitutes R1, R2, R3, R4, R5 or R7 are polyisobutenyl, having 3000 carbon atoms and the rest of the substitutes from the group R1, R2, R3, R4, R5 or R7, if they denote hydrocarbyl residues, have 1-20 carbon atoms, respectively, as anti-oxidants for stabilising mineral oil and fuel products against the effect of light, oxygen and heat. The invention also describes jet fuel and jet fuel additive concentrate containing tetrahydrobenzoxazine of formula (I).

EFFECT: preparation of stabilisers having improved stabilisation of nonliving organic material, particularly jet fuel against the effect of light, oxygen and heat.

9 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for treating cardiovascular and cerebrovascular diseases. A method of preparing a therapeutic composition for treating cardiovascular and cerebrovascular diseases that involves selection of scorpion, centipede, eupolyphaga or steleophaga, leech, cicadas, ginseng root, prepared incense, peony root, sweet and white sandal wood, boras camphor and Ziziphi spinosae seeds according to the preset amounts, preparation of crude therapeutic extracts of said initial materials, agitation of the prepared extracts. A product of the therapeutic composition for treating cardiovascular and cerebrovascular diseases. A method of preparing the therapeutic insect extracts for treating cardiovascular and cerebrovascular diseases. The therapeutic insect extracts for treating cardiovascular and cerebrovascular diseases.

EFFECT: agents are effective for treating cardiovascular and cerebrovascular diseases.

11 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmacy and deals with novel antiarrhythmic medication based on compound of heterocyclic series, 2H-1-benzopyran-2-on derivative, namely - 4-methyl-7,7'-ethylenedioxy-2H-1-dibenzopyran-2,2'-dione of formula 1.

EFFECT: compound possesses high antiarrhythmic activity.

4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of beta-hydroxybutyrate or its salts in combination with other active substance or combination of active substances, selected from group, given in the invention formula, for preparation of medication, which possesses cytoprotective activity, including neuroprotective, cardioprotective, anti-ischemic, antihypoxic, antistress and adaptogenic activities, medication and method of prevention, relief and treatment by means of said medication. Demonstrated is synergic of medication components as cytoprotector in urgent states as it possesses complex impact on key links of pathogenesis of said diseases.

EFFECT: elaboration of medication which possesses cytoprotective activity.

24 cl, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to therapy and deals with application of organic compound -rennin inhibitor aliskiren for treatment and prevention of type 2 diabetes and kidney disease. For this purpose aliskiren is introduced in efficient amount as monotherapy.

EFFECT: invention ensures efficient treatment and prevention of said diseases due to aliskiren ability to increase sensitivity of tissues to insulin and reduce proteinuria.

5 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and medicine, namely to obtaining orally decomposing powder of cilostazol. For this purpose into pharmaceutical preparation included are from 10% wt to 20% wt of cilostazol and from 70% to 79.5% wt of mannitol.

EFFECT: creation of cilostazol preparation, easily decomposing in oral cavity and not requiring taking water with it.

13 cl, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: extremity ischemia is modelled by removing a portion of a great vessel, including with simultaneous additional modelling of nitrogen oxide (NO) deficiency by intraperitoneal introduction of a NO synthesis blocker N-nitro-L-arginine of methyl ester (L-NAME) 25 mg/kg daily for 7 days. In both cases, the ischemia is corrected by subcutaneous introduction of recombinant erythropoein 50 IU/kg for the first, third and fifth days of experiment.

EFFECT: effective ischemia treatment in experiment ensured by improved extremity microcirculation.

1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology, and deals with treatment of patients with neuropathic and neuroischemic forms of "diabetic foot" syndrome. For this purpose at the first stage on both extremities injection of 0.25% Novocain is made in dose 50.0 ml into fascial compartment of common paroneal nerve in distal direction to upper musculo-peroneal canal. After 1-2 days as the second stage injections of 0.125% Novocain solution in amount 50.0 ml are repeated in turns into each extremity with interval 3-5 days, course containing 5-6 injections.

EFFECT: elaborated doses and mode of Novocain introduction provide possibility to preserve foot due to stopping purulent inflammation with absence of side effects.

1 ex

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