Caspase inhibitors and use thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

 

This invention relates to the field of medicinal chemistry and relates to compounds and pharmaceutical compositions that inhibit caspase mediating cell apoptosis and inflammation. The invention also relates to methods of producing these compounds. The invention also relates to methods of using compounds and pharmaceutical compositions according to this invention for the treatment of diseases, the development of which involved the activity of the caspase.

Apoptosis, or programmed cell death, is the primary mechanism by which the body removes unwanted cells. Dysregulation of apoptosis or excessive intensity of apoptosis, or the inability to subject him involved in the development of several diseases, such as cancer, acute inflammatory or autoimmune diseases, ischemic diseases, and some neurodegenerative disorders (mostly, see Science, 1998, 281, 1283-1312; Ellis et al., Ann. Rev. Cell Biol., 1991, 7, 663).

Caspase represent a family of enzymes cysteinate, which are key mediators in signaling pathways for apoptosis and destruction of cells (Thornberry, Chem. Biol., 1998, 5, R97-R103). Data signaling pathways vary depending on cell type and stimulus, but it turned out that all of apoptotic paths converge on a common effector path, resulting in the m to the proteolysis of key proteins. Caspase participate in the effector phase signal path and further "upstream"regulation at its initiation. Caspase "upstream"involved in the initiation, activation and, in turn, activate other caspase involved in later phases of apoptosis.

The caspase-1, the first identified caspase, also known as interleukin converting enzyme or ICE. The caspase-1 transforms the precursor interleukin-1β ("pIL-1β) in the active form of prosopalgia through specific cleavage pIL-1β between Asp-116 and Ala-117. In addition to caspase-1 also has eleven other known human caspases, which are all cleaved specifically by aspartam residues. It has been observed that for them also requires stringent conditions, for at least four amino acid residues in the N-end of the cleavage site.

Caspase divided into three groups based on amino acid sequence, which is the preferred or mostly installed. It was shown that in the group of caspases, which include caspase-1, -4, -5 and -13, preferably has a hydrophobic aromatic amino acids at position 4 in the N-end of the cleavage site. In the other group, which include caspase-2, -3 and -7, installed aspartate residues at both positions 1 and 4 in the N-end site cleft is placed and preferably the sequence Asp-Glu-X-Asp. In the third group of caspases, which include caspase 6, 8, 9 and 10, there are a lot of amino acids in the primary sequence recognition, but probably preferably there are the remains of branched, aliphatic side chains, such as valine and leucine in position 4.

Also caspase in groups according to their measurable functions. The first subfamily consists of caspase-1 (ICE), 4, 5, and 13. It was shown that the caspase involved in the processing of cytokines prosopalgia and, therefore, they play an important role in the development of inflammation. The caspase-1, the most studied enzyme of this group activates the precursor of IL-1β by proteolytic cleavage. Therefore, this enzyme plays a key role in the inflammatory response. Also the caspase-1 is involved in the processing of interferon-γ inducing factor (IGIF, also known as IL-18), which stimulates the production of interferon-gamma, a key immunoregulatory, modulating antigen presentation, activation of T cells and cell adhesion.

Other caspase form second and third subfamily. These enzymes are of Central importance in intracellular signaling pathways, leading to apoptosis. One subfamily consists of enzymes involved in the initiating events in the apoptotic path including transd is the Ktsia signals from the plasma membrane. Members of this subfamily include caspase-2, -8, -9 and-10. Another subfamily, consisting of effector caspases-3, -6 and -7, takes part in the final "downstream" rassejannyj events that result in system degradation and cell death by apoptosis. Caspase involved in the "upstream" signal transduction, activate the "downstream" caspase, which then disrupt DNA repair mechanisms, DNA fragment, destroy the cellular cytoskeleton and, finally, fragmenting the cell.

Information about the sequence of four amino acids, mainly available in caspase use to create caspase inhibitors. Were obtained reversible inhibitors based tetrapeptides having the structure CH3CO-[P4]-[P3]-[P2]-CH(R)CH2CO2H, in which P2-P4 represent the optimal amino acid sequence of recognition, and R is an aldehyde, nitrile or ketone has the ability to communicate with the sulfhydryl group of cysteine caspase. Rano and Thornberry, Chem. Biol. 4, 149-155 (1997); Mjalli et al., Bioorg. Med. Chem. Lett. 3, 2689-2692 (1993); Nicholson et al., Nature 376, 37-43 (1995). Were obtained irreversible inhibitors based on similar tetrapeptide sequences of recognition, in which R represents acyloxymethyl-COCH2OCOR'. R' is represented as an example optionally substituted phenyl, such as 2,6-dichlorobenzoate, and the de R is the PINES 2X, where X represents a leaving group such as F or Cl. Thornberry et al., Biochemistry 33, 3934 (1994); Dolle et al., J. Med. Chem. 37, 563-564 (1994).

Was shown the applicability of caspase inhibitors for the treatment of various diseases in mammals associated with increased apoptosis of cells using peptide inhibitors of caspases. For example, in models of mammals, it was shown that caspase inhibitors reduce the size of the area of infarction and inhibit the apoptosis of cardiomyocytes after myocardial infarction, reduce the areas of the lesions and neurological failure as a result of stroke, reduce post-traumatic apoptosis and neurological failure due to brain injury, are effective in the treatment of rapid destruction of the liver and increase survival after endotoxic shock. Yaoita et al., Circulation, 97, 276 (1998); Endres et al., J. Cerebral Blood Flow and Metabolism, 18, 238 (1998); Cheng et al., J. Clin. Invest., 101, 1992 (1998); Yakovlev et al., J. Neuroscience, 17, 7415 (1997); Rodriquez et al., J. Exp. Med., 184, 2067 (1996); Grobmyer et al., Mol. Med., 5, 585 (1999).

Basically the above-described peptide inhibitors are very effective against some of the caspase enzymes. However, their activity is not always reproduced in cell models of apoptosis. In addition, peptide inhibitors, usually characterized by undesirable pharmacological properties, such as poor oral absorbability is doing, low stability and a fast metabolism. Plattner and Norbeck, Drug Discovery Technologies, Clark and Moos, Eds. (Ellis Horwood, Chichester, England, 1990).

Reported the need to improve the pharmacological properties of peptide caspase inhibitors, coworkers peptide inhibitors. Among them reported inhibitors, in which the P3 amino acid was replaced by derivatives of 3-aminopyridine-2-ones and 5-aminopyrimidine-4-ones (U.S. patent 5756466 (Bemis et al.); publication of the PCT application no WO 95/35308 (Bemis et al.); Dolle et al., J. Med. Chem. 39, 2438 (1996); Golec et al. Bioorg. Med. Chem. Lett. 7, 2181 (1997); Semple et al., Would. Med. Chem. Lett. 7, 1337 (1997).

The result is inherent in the peptide inhibitors of the problems is the need for small molecules, the ones caspase inhibitors that are effective, stable, and penetrate through the membrane to effective inhibition of apoptosis in vivo. Such compounds are very suitable for treatment of the above diseases, the development of which play the role of caspase enzymes.

The present invention relates to a compound of the formula I:

in which: R1, R2, R3, R4and R5have the meanings given in the description.

The present invention also relates to pharmaceutical compositions containing a compound of formula I, and methods of using such compounds and compositions for the treatment mediated by caspase is of deseases. The present invention also relates to methods of preparing compounds of formula I.

The present invention relates to a compound of the formula I:

in which:

R1is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, (R6)(H)NC(O)-, R6C(O)C(O)-, R6-, (R6)2NC(O)C(O)-, (R6)(H)NC(O)C(O)- or R6OS(O)C(O)-;

R2represents a hydrogen atom, -CF3, halogen atom, -OR7, -NO2, -OCF3, -CN, or R8;

R3represents a hydrogen atom or (C1-C4)aliphatic group;

R4represents-COOH or-R8;

R5represents-CH2F or-CH2On-2,3,5,6-tetrafluorophenyl;

R6represents (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, (C5-C10)heteroaryl-(C1-C12)aliphatic group, or two R6group associated with a single atom, form together with the atom 3-10-membered aromatic or non-aromatic ring, where the ring is optionally condensed with C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl or (C3-C10)heterocyclyl; where up to 3 aliphatic carbon atoms may shall be substituted by the group selected from O, N, N(R), S, SO and SO2; and where R6substituted by up to 6 substituents, independently selected from R;

R represents a halogen atom, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7, oxo, thioxo, =NR7, =N(OR7), 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)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(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7, -N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2, -N(R7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)OR7, -N(R7)C(O)R7, -N(R7)C(S)R7, -N(R7)C(O)N(R7)2,-N(R7)C(S)N(R7)2, -N(COR7)COR7, -N(OR7R7, -C(=NH)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -OP(O)(OR7)2, -P(O)(R7)2, -P(O)(OR7)2or-P(O)(N)(OR7);

two R7groups together with the atoms to which they are linked, form a 3-10-membered aromatic or nonaromatic ring containing up to 3 heteroatoms, independently selected from N, N(R), O, S, SO and SO22; or

each R7independently chosen from:

the hydrogen atom is,

(C1-C12)aliphatic groups,

(C3-C10)cycloaliphatic group,

(C3-C10)cycloaliphatic-(C1-C12)aliphatic groups,

(C6-C10)aryl-,

(C6-C10)aryl-(C1-C12)aliphatic groups,

(C3-C10)heterocyclyl-,

(C6-C10)heterocyclyl-(C1-C12)aliphatic groups,

(C5-C10)heteroaryl - or

(C5-C10)heteroaryl-(C1-C12)aliphatic groups;

where R7has up to 3 substituents independently selected from J2; and

J2represents a halogen atom, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7, oxo, thioxo, =NR7, =NOR7, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)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(S)R7, -C(S)OR7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7, -N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2,-N(R 7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)or SIG7, -N(R7)C(O)R7, -N(R7)C(S)R7, -N(R7)C(O)N(R7)2,-N(R7)C(S)N(R7)2, -N(COR7)COR7, -N(OR7R7, -CN, -C(=NH)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -OP(O)(OR7)2, -P(O)(R7)2, -P(O)(OR7)2or-P(O)(N)(OR7); and

R8represents (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, - or (C5-C10)-heteroaryl(C1-C12)aliphatic group, where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N, N(R), S, SO and SO2; and where R8optionally substituted with up to 6 substituents, independently selected from R

The present invention also relates to the compound of the formula I:

in which:

R1is R6C(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6C(O)C(O)-, R6-, (R6)2NC(O)C(O)- or R6OS(O)C(O)-;

R2represents a hydrogen atom, -CF3, halogen atom, -OR7, -NO2, -OCF3, -CN, or R8;

R3represents the atom of water is kind or (C1-C4)aliphatic groups;

R4represents-COOH or-R8;

R5represents-CH2F or-CH2On-2,3,5,6-tetrafluorophenyl;

R6represents (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, (C5-C10)heteroaryl-(C1-C12)aliphatic group, or two R6group associated with a single atom, form together with the atom 3-10-membered aromatic or non-aromatic ring, where the ring is optionally condensed with C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl or (C3-C10)heterocyclyl; where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N(H), N(R), S, SO and SO2; and where R6substituted by up to 6 substituents, independently selected from R;

R represents a halogen atom, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7, oxo, thioxo, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)2, -SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)CH2C(O)R7, -C(S)R7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7 , -N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2, -N(R7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)OR7, -N(R7)C(O)R7, -N(R7)C(S)R7, -N(R7)C(O)N(R7)2, -N(R7)C(S)N(R7)2, -N(COR7)COR7, -N(OR7R7, -C(=NH)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -OP(O)(OR7)2, -P(O)(R7)2, -P(O)(OR7)2or-P(O)(N)(OR7);

two R7groups together with the atoms to which they are linked, form a 3-10-membered aromatic or nonaromatic ring containing up to 3 heteroatoms, independently selected from N(H), N(R), O, S, SO and SO2where the ring is optionally condensed with C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl or (C3-C10)heterocyclyl and where any ring has up to 3 substituents independently selected from J2; or

each R7independently chosen from:

the hydrogen atom is,

(C1-C12)aliphatic groups,

(C3-C10)cycloaliphatic group,

(C3-C10)cycloaliphatic-(C1-C12)aliphatic groups,

(C6-C10)aryl-,

(C6-C10)aryl-(C1-C12)aliphatic groups,

(C3-C10)heterocyclyl-,

(C6-C10)heterocyclyl-(C1-C12)aliphatic groups,

(C5-C10)heteroaryl - or

(C5-C10)heteroaryl-(C1-C12)aliphatic groups;

where 7has up to 3 substituents independently selected from J2; and

J2represents a halogen atom, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7, oxo, thioxo, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -SR7, -SOR7, -SO2R7, -SO2N(R7)2, -SO3R7, -C(O)R7, -C(O)C(O)R7, -C(O)CH2C(O)R7, -C(S)R7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2, -OC(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7, -N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2, -N(R7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)OR7, -N(R7)C(O)R7, -N(R7)C(S)R7, -N(R7)C(S)N(R7)2, -N(R7)C(O)N(R7)2, -N(COR7)COR7, -N(OR7R7, -CN, -C(=NH)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -OP(O)(OR7)2, -P(O)(R7)2, -P(O)(OR7)2or-P(O)(N)(OR7); and

R8represents (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, (C5-C10)heteroaryl-(C1-C12)alipate is a mini-group, where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N(H), N(R), S, SO and SO2.

Another variant of implementation of the present invention refers to the compound in which R1is R6C(O)-, R6SO2-, or R6-. In a preferred embodiment, R1is R6C(O)-. In another preferred embodiment, R1is R6SO2-. In another preferred embodiment, R1is R6-.

Another variant of implementation of the present invention refers to the compound in which R1is (R6)2NC(O)- or (R6)OC(O)-. In a preferred embodiment, R1is (R6)2NC(O)-. In another preferred embodiment, R1is (R6)(H)NC(O)-. In another preferred embodiment, R1is (R6)OC(O)-.

In one embodiment of the present invention each R6independently represents (C1-C4)aliphatic group, (C3-C10)cycloaliphatic group, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C6-C10)aryl or (C6-C10)aryl-(C1-C12)aliphatic group (where it should be understood that optional up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N, N(R), S, SO THE SO 2; and where R6optionally substituted with up to 6 substituents, independently selected from R, or R6substituted, as in the description disclosed in any of the embodiments described in the description).

In another embodiment, each R6independently represents H, (C1-C4)aliphatic group or a (C6-C10)aryl, or each R6together with the N atom is (C3-C7)cycloaliphatic group.

In another embodiment, each R6independently represents (C1-C4)aliphatic group, (C5-C10)heteroaryl or (C6-C10)aryl-, where heteroaryl or aryl optionally substituted, or each R6together with the N atom is (C3-C7)cycloaliphatic group.

In another embodiment, each R6independently represents (C1-C4)aliphatic group or a (C6-C10)aryl, where aryl optionally substituted, or each R6together with the N atom is (C3-C7)cycloaliphatic group.

In yet another embodiment, each R6independently represents (C1-C4)aliphatic group, (C3-C7)cycloaliphatic group, (C6-C10)aryl-, (C5-C10)heteroaryl-where heteroaryl or aryl independently and optionally substituted, or each R6together with the N atom is (C3-C7)cycloaliphatic group.

In the preferred embodiment of this invention R2represents a hydrogen atom, C1-, C2-, C3 - or Salkil-, -CF3, -Cl, -OR7, -NO2, -OCF3or-CN. More preferably, when R2represents a hydrogen atom, C1-alkyl, C2-alkyl or-CF3. More preferably, when R2represents a hydrogen atom or-CF3.

In another preferred embodiment, R3represents ethyl.

In another preferred embodiment, R5represents-CH2On-2,3,5,6-tetrafluorophenyl.

In another preferred embodiment, R5represents-CH2F.

In another preferred embodiment, R8represents (C1-C12)alkyl. More preferably, when R8is (C1-C4)alkyl.

In the preferred embodiment, each R and J2independently represent a halogen atom, -OR7, -OC(O)N(R7)2, -NO2, -CN, -CF3, -OCF3, -R7, oxo, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -C(O)R7, -C(O)C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)N(R7)2or-OC(O)N(R7)2.

In the sense in which they are used in the description, designation of carbon atoms can be specified integer and any intermediate integer. For example, the number of carbon atoms (C1-C4)alkyl is 1, 2, 3 or 4. It should be understood that this designation refers to the total number of atoms is of glared in the appropriate group. For example, (C3-C10)heterocyclyl the total number of carbon atoms and heteroatoms is equal to 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.

In the sense in which this term is used in the description, the aliphatic group include normal and branched group containing the specified number of atoms. If the number of atoms is not specified, the aliphatic group contains from 1 to 12 carbon atoms. It should be understood that alkeneamine and/or alkyline aliphatic groups have at least 2 carbon atoms. Preferred aliphatic groups are alkyl groups (preferably containing from 1 to 6 atoms).

Therefore, unless otherwise indicated, the preferred aliphatic groups in this invention are alkyl groups, and they contain 1, 2, 3, 4, 5 or 6 carbon atoms. More preferred alkyl groups have 1, 2, 3 or 4 carbon atoms. Preferred alkeneamine and/or alkyline groups have 2, 3, 4, 5 or 6 carbon atoms and more preferably 2, 3 or 4 carbon atoms.

Cycloalkyl and cycloalkenyl groups contain from 3 to 10 carbon atoms and are monocyclic or bicyclic, including linearly condensed, connected via a bridge connection or spirocycles. Cycloaliphatic group is preferably cycloalkyl or recloak is Neil. More preferably cycloaliphatic groups are 3-, 4-, 5-, 6 - or 7-membered ring, more preferably are cycloalkenyl rings.

In the sense in which these terms are used in the description, "aromatic group" or "aryl" refers to 6-10-membered ring system that contains at least one aromatic ring. Examples of aromatic rings include phenyl and naphthyl.

In the sense in which this term is used in the description, "heteroaryl" refers to a ring system containing 5-10 members and 1, 2 or 3 heteroatoms independently selected from N, N(R), O, S, SO and SO2where at least one ring is heteroaromatic (e.g., pyridyl, thiophene or thiazole). Preferred heteroaryl groups are 5 - or 6-membered ring containing 1 or 2 heteroatoms. In some embodiments of this invention, more preferred heteroaryl groups are those that contain "=N-group.

Examples of heteroaryl rings include 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, p is ridazine (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, chinoline (for example, 2-chinoline, 3-chinoline, 4-chinoline) and ethenolysis (for example, 1-ethenolysis, 3-ethenolysis or 4-ethenolysis).

In the sense in which this term is used in the description, "heterocycle" refers to a ring system containing 3 to 10 members and 1, 2 or 3 heteroatoms independently selected from N, N(R), O, S, SO and SO2where the ring is not aromatic (for example, piperidine and morpholine). Preferred heterocyclic groups are 5 - or 6-membered ring containing 1 or 2 heteroatoms.

Examples of heterocyclic rings include 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-piperidin the sludge, 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.

Any of these cycloaliphatic, heterocyclic and heteroaryl groups optionally condensed 5 - or 6-membered aryl or heteroaryl ring. In addition, each of any aliphatic group, aryl, cycloaliphatic groups, heteroaryl and heterocyclyl may contain appropriate substituents (preferably up to 5, more preferably up to 3 and more preferably 0 or 1), independently selected from, for example, carbonyl and R Preferred substitutes (including, R and J2represent a halogen atom, -OR7, -NO2, -CF3, -OCF3, -R7, oxo, -OR7, O-benzyl, O-phenyl, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R7)2, -C(O)R7, -OOR7or-C(O)N(R7)2where R7has the meanings given in the description (and preferably represents H, (C1-C6)alkyl or (C2-C6)alkenyl or quinil) with that, (C1-C6)alkyl is preferred). You should understand, is that this definition will include perfluorinated alkyl group.

In embodiments of this invention, where R is the Deputy on the nitrogen atom, the preferred R radicals selected from the group consisting of-R7, -SOR7, -SO2R7, -SO2N(R7)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(S)R7, -C(S)OR7, -C(O)OR7, -C(O)N(R7)2, -C(S)N(R7)2, -(CH2)0-2NHC(O)R7, -N(R7)N(R7)COR7, -N(R7)N(R7)C(O)OR7, -N(R7)N(R7)CON(R7)2, -N(R7)SO2R7, -N(R7)SO2N(R7)2, -N(R7)C(O)OR7, -N(R7)C(O)R7, -N(R7)C(S)R7, -N(R7)C(O)N(R7)2, -N(R7)C(S)N(R7)2, -N(COR7)COR7, -N(OR7R7, -C(=NH)N(R7)2, -C(O)N(OR7R7, -C(=NOR7R7, -OP(O)(OR7)2, -P(O)(R7)2, -P(O)(OR7)2and-P(O)(N)(OR7), where R7has the meanings given in the description (and preferably represents H, (C1-C6)alkyl or (C2-C6)alkenyl and-quinil), with (C1-C6)alkyl is preferred). More preferably, when R is a radical selected from the group consisting of-R7and-C(O)R7.

In the preferred compounds of the present invention, the stereochemistry is the one below:

Any of the embodiments presented in the description, can be combined with the provision of alternative embodiments of the present invention. Specific embodiments of the present invention can be selected from substituents represented by the compounds in table 1.

Compounds of the present invention are inhibitors of caspase broad-spectrum and have enhanced activity compared with the compounds reported that they inhibit apoptosis (see examples 42 and 43).

In a preferred embodiment of the invention this invention relates to the compound of formula Ia or Ib

in which R1, R2, R3and R4have the meanings given in the description in any of the embodiments.

In a more preferred embodiment of the invention the compound of formula I according to the present invention relates to the compound of formula II, selected from table 1 below:

td align="left"> (Et)2N(C=O)-
Table 1
Compounds according to the invention
ExampleR1R2 R3R5
1IU(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
2Et(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
3n-Pr(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
4c-Pr(C=O)NEtCH2O-2,3,5,6-tetrafluorophenyl
5i-Pr(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
6MeOCH2(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
72-Furyl(C=O)-NEtCH2O-2,3,5,6-tetraterpene the l
83-Furyl(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
93-Pyridyl(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
103-Isothiazol(C=O)NEtCH2O-2,3,5,6-tetrafluorophenyl
11Ph(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
12Bn(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
13Me(C=O)-CF3EtCH2O-2,3,5,6-tetrafluorophenyl
14EtNH(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
15NEtCH2O-2,3,5,6-tetrafluorophenyl
16Pyrrolidinyl(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
17MeO(C=O)-NEtCH2O-2,3,5,6-tetrafluorophenyl
18Et(SO2)-NEtCH2O-2,3,5,6-tetrafluorophenyl
19n-Pr(SO2)-NEtCH2O-2,3,5,6-tetrafluorophenyl
20i-Pr(SO2)-NEtCH2O-2,3,5,6-tetrafluorophenyl
21Ph(SO2)-NEtCH2O-2,3,5,6-tetrafluorophenyl
22Et(SO2) CF3EtCH2O-2,3,5,6-tetrafluorophenyl
23Bn(C=O)Hi-PrCH2O-2,3,5,6-tetrafluorophenyl
24Et(SO2)Hi-PrCH2O-2,3,5,6-tetrafluorophenyl
25Et(C=O)HMeCH2F
26Ph(C=O)HMeCH2F
272,6-DiClPh(C=O)HMeCH2F
28Bn(C=O)HMeCH2F
29Et(C=O)HMeCH2F
30 Ph(C=O)HMeCH2F
312,6-DiClPh(C=O)HMeCH2F
322-Pyridyl(C=O)HMeCH2F
33Bn(C=O)HMeCH2F
343-MeBn(C=O)HMeCH2F
35Et(C=O)Hn-PrCH2F
36Et(C=O)Hi-BuCH2F
37Bn(C=O)MeEtCH2F
38The thiazole-2-yl NEtCH2O-2,3,5,6-tetrafluorophenyl
39n-PropylNEtCH2O-2,3,5,6-tetrafluorophenyl

In another embodiment of the invention the present invention relates to pharmaceutical compositions containing:

a) compound of formula I having the values defined in the description, or its pharmaceutically acceptable salt; and

b) a pharmaceutically acceptable carrier, adjuvant or excipient.

The specialist in this area, obviously, it is clear that some compounds in this invention can exist in tautomeric forms or hydrated forms, all such forms of the compounds are within the scope of the invention. Unless otherwise specified, it is assumed that the compounds presented in the description, include all stereochemical forms of the compounds; i.e. R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as mixtures of enantiomers and diastereoisomers of these compounds are within the scope of the invention. Unless otherwise specified, it is assumed that the formulas presented in the description, also include compounds that differ only by the presence of the s one or more enriched isotope of the atom. For example, compounds having the present formula, except for the substitution of a hydrogen atom by deuterium or tritium, or the replacement of a carbon atom on13With or14C-enriched carbon atom, are within the scope of this invention.

Mainly compounds according to this invention can be obtained by methods well known to specialists in this area for similar compounds and the preparative examples that are presented below. For purposes of illustration, are the schemes of reactions I-III synthesis of compounds of the present invention. It should be understood that any protective group, represented in the diagrams, can accordingly be varied with regard to compatibility with other substituents.

In the methods according to the invention can be used with various protective groups (see, for example, T.W.Greene & P.G.M.Wutz, "Protective Groups in Organic Synthesis", 3rdEdition, John Wiley & Sons, Inc. (1999) and earlier editions of this book). Typical functional groups that must be protected, are amines. Any of the amines and other functional groups can be protected by methods known in this field. Compounds, including amines, can be used with or without isolation from the reaction mixtures.

Scheme I (a) EDC/DMAP/HOBt/THF; (b) periodinane dess-Martin; (C) TFA/DCM

The scheme is e reactions I, above, we use the following abbreviations: EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HOBt is 1-hydroxybenzotriazole; THF is tetrahydrofuran; TFA is triperoxonane acid; DCM is dichloromethane; DMAP is 4-dimethylaminopyridine. Acid 1 are combined with aminosterol 2. In this case, the combination is portrayed using EDC/DMAP/HOBt/THF, but you can also use other suitable conditions. Depending on the nature of R4and R5you can use aminoketone instead of amerosport, thus avoiding subsequent stage of oxidation. In the case of formetiketten, where R5is CH2F, aminoplast can be obtained according to the method of Revesz et al., Tetrahedron Lett. 1994, 35, 9693. In the case of tetracarboxylates, where R5represents-CH2On-2,3,5,6-tetrafluorophenyl, amerosport 2 can be obtained by methods similar to that described by Semple et al., Bioorganic and Medicinal Chemistry Letters, 1997, 7, 1337 (reaction scheme II).

Finally, the hydroxyl group in compound 3 are oxidized (for example, periodontal dess-Martin) and the compound obtained is treated according to the nature of R4. For example, if the product I R4represents a carboxylic acid, then R4in compound 3 is preferably an ester, hydrolyzing on horseback the Noi stage scheme of reactions. If this ester is tert-butyl ether (i.e., if R4is CO2tBu), then processing triperoxonane acid provides the acid. The ether is preferably tert-butyl ether, when other substituents in the compound I is compatible with acidic conditions.

If R4the product I is a complex ether, the desired ester can be obtained by esterification of the corresponding acid or obtaining the desired ester group in advance in the connection 2.

Scheme II (a) KF/DMF/ArOH; (b) NaBH4/THF; (C) H2/Pd/C/MeOH

In reaction scheme II, above, uses the following abbreviations: KF represents the potassium fluoride; DMF is N,N-dimethylformamide; ArOH is 2,3,5,6-tetrafluorophenol; THF is tetrahydrofuran; Meon is methanol. Industrial available Bratton 4 (R4=CO2tBu) is subjected to interaction with 2,3,5,6-tetrafluorophenol and potassium fluoride with getting phenoxyethane 5. Then the ketone restore, for example, sodium borohydride to obtain alcohol 6, which hydronaut using, for example, palladium on coal as a catalyst to obtain amerosport 2 (R4=CO2tBu, R5=CH2On-2,3,5,6-tetraphenyl).

Scheme III a) H2Pd/C, MeOH; (b) PhC 2O(CO)Cl/Na2CO3/H2O/THF; (C) (CF3SO2)2O/2,6-lutidine/DCM; (d) NaH/THF; (e) R1 is-Cl/Et3N/DMAP/DCM; (f) TFA/DCM

In reaction scheme III, above, uses the following abbreviations: Z represents benzyloxycarbonylamino group; Meon is methanol; DCM is dichloromethane; TFA is triperoxonane acid; DMAP is 4-dimethylaminopyridine; THF is tetrahydrofuran. Iridocyclitis derivative of I can be obtained in chiral form using a sequence of synthesis presented in reaction scheme III. Source benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid (R2=N) is obtained using the method similar to that described by Warner et al. J. Med. Chem. 1994, 37 (19), 3090-3099. Industrial available (R)-tert-butyl-2-hydroxybutyrate (R3=ethyl) is treated with anhydride triftormetilfullerenov acid and 2,6-lutidine in DCM to obtain the corresponding triflate. The interaction of the triflate with anion benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid (obtained by deprotonation with sodium hydride in THF) gives N-alkilirovanny pyridone. Remove benzyloxycarbonylamino group using hydrogen and palladium on coal gives Amin. Then it is subjected to interaction with the appropriate electrophilic reagent is, the triethylamine and DMAP in DCM. For example, if you want to R1was RC=O (amidon), then you can use the appropriately substituted acid chloride. If you want to R1was RS(=O)2(sulfonamide), then you can use the appropriately substituted sulphonylchloride. If R1is RO (=O) (carbamate), then you can use the appropriately substituted chloroformate. If R1is RN(C=O) (urea), then you can use the appropriately substituted carbamoylated or isocyanate. Accordingly, it is possible to get other R1-group. Then get acid 1 unprotect ether, for example, using triperoxonane acid. Then the acid is combined with aminosterol 2 (reaction scheme 1).

Therefore, another variant of implementation of the present invention relates to a method for obtaining compounds of formula I:

in which R1, R2, R3, R4and R5have the meanings given in the description in any of the embodiments, including:

a) interaction of the compounds of formula (III):

in which:

R9is-NO2, -C(O)OR10, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, R 6N(H)-, (R6)2NC(O)C(O)N(H)- or R6OS(O)C(O)N(H)-;

R10independently represents hydrogen, (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, (C5-C10)heteroaryl-(C1-C12)aliphatic group, where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N(H), N(R), S, SO and SO2; and where R10optionally substituted with up to 6 substituents, independently selected from R; and

R, R2, R3and R6have the meanings given in any of the embodiments of formula (I);

with the compound of the formula (IV):

in which Y is either a carbonyl group or a group; and

R4and R5have the meanings given in any of the embodiments of formula (I);

in the presence of a solvent and under conditions of peptide condensation;

provided that when Y is HE group, the method further includes (b) oxidation of the Oh-group to obtain the compounds of formula (I); and

provided that when R9is-NO2, -C(O)OR10or-CN, the method further includes turning-NO2, -C(O)OR10or-CN, R6C(O)N(H)-, R6 SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)- or R6OS(O)C(O)N(H)-.

Condensation conditions can be any known in the art for education peptidergic links. The preferred combination of conditions are EDC/DMAP/HOBt. The preferred solvent in the above embodiment, is THF.

In a preferred embodiment, the compound of formula (III):

in which R2, R3and R9have the meanings defined in the description;

get the method including:

(C) the interaction of the compounds of formula (V):

in which R, R2, R3and R9have the meanings defined in the description;

in a solvent under conditions suitable to remove the protection.

Conditions for withdrawal of protection will depend on the particular protective group (i.e. R10). For example, if R10represents tert-butyl, the preferred conditions for removing protection will include acid hydrolysis. The preferred acid is TFA. The preferred solvent is DCM. More preferably, when the solvent and hydrolysis conditions include TFA and DCM. If R10represents methyl or ethyl, then the preferred conditions unprotect will be the basics is passed (for example, an aqueous solution of NaOH). If R10is benzyl, then the benzyl group can be removed by hydrogenolysis.

In a preferred embodiment, the compound of formula (V):

in which R2, R3, R9and R10have the meanings defined in the description;

get the method including:

d) the interaction of the compounds of formula (VI):

in which R2and R9have the meanings defined in the description;

with the compound of the formula (VII):

in which X represents a suitable leaving group; and

R3and R10have the meanings defined in the description;

in the presence of a solvent and base.

Preferably X is-I, -Br, -Cl, -OH, alkylsulfonate or arylsulfonate. When X is-HE, the corresponding leaving group can be obtained in situ (for example, in the reaction Mitsunobu). The preferred sulfonates include-O-triftorbyenzola, -O-methanesulfonate, -O-bansilalpet, -O-p-toluensulfonate, -O-m-nitrobenzenesulfonate and-O-p-nitrobenzenesulfonate. Suitable leaving groups suitable in the methods according to this invention, are well known in this field. For example, see "March's Advanced Organic Chemistry, 5thEd., Ed.: Smith M.B. and J. March, John Wiley & Sons, New York (2001).

Can be used on lesofat any solvent, which is compatible with the formation of ions. Preferred solvents include DMF, toluene and THF.

Suitable bases include any that can remove a proton from the hydroxyl group in the compound (V). Such grounds include BuLi, LDA, LHMDS, and NaH. The preferred base is NaH.

Another variant of implementation of the present invention relates to the production of the compounds of formula (VIII):

in which:

R2is-CF3, -Cl, -OR7, -NO2, -OF3, -CN, or R8; and

R3, R8, R9and R10have the meanings defined in the description;

including the state (s) of interaction of the compounds of formula (IX):

R2and R9have the meanings defined in the description;

with the compound of the formula (VII):

in which R3and R10have the meanings defined in the description; and

X represents a leaving group;

in the presence of a solvent and base.

Preferably X is-I, -Br, -Cl, -OH, alkylsulfonate or arylsulfonate. When X is-HE, the corresponding leaving group can be obtained in situ (for example, in the reaction Mitsunobu). The preferred sulfonates include-O-triftorbyenzola, -O-methanesulfonate, -O-bansilalpet, -O-p-toluensulfonate, -O-m-nitrobenzanthrone and-O-p-nitrobenzenesulfonate.

You can use any solvent that is compatible with the formation of anions. Preferred solvents include DMF, toluene and THF. The preferred solvent is THF.

Suitable bases include any that can remove a proton from the hydroxyl group in the compound (V). Such grounds include BuLi, LDA, LHMDS, and NaH. The preferred base is NaH.

Another variant of implementation of the present invention relates to a method for obtaining compounds of formula (I):

R1, R2, R3, R4and R5have the meanings given in any of the embodiments of formula (I), including:

a) interaction of the compounds of formula VI or IX):

in which:

R9is-NO2, -C(O)OR10, -CN, R6C(O)N(H)-, R6OC(O)N(H)-, R6SO2N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)- or R6OS(O)C(O)N(H)-; and

in which R2, R3and R6have the meanings defined in the description;

with the compound of the formula (X):

in which Y is either a carbonyl group or a group; and

R4and R5have the meanings defined in the description;

in the presence of a solvent and in all conditions of condensation, ODA is defined in the description;

provided that when Y is HE group, the method further includes (b) oxidation of the Oh-group to obtain the compounds of formula (I); and

provided that when R9is-NO2, -C(O)OR10or-CN, the method further includes turning-NO2, -C(O)OR10or-CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6C(O)C(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)- or R6OS(O)C(O)N(H)-.

Compounds according to this invention can be tested for their ability to inhibit the release of IL-1β, caspase activity directly or apoptosis. Tests for analysis of each of the activities is known in this field. Selected tests are described below.

If these compositions are pharmaceutically acceptable salts of the compounds according to this invention, the salts are preferably derived from inorganic or organic acids and bases. These acid salts 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-naphthas is insolvent, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate. Basic salts 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 of organic bases, such as salts dicyclohexylamine, N-methyl-D-glucamine, and salts of amino acids such as arginine salt, lysine, and so forth.

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

The compounds used in the compositions and methods according to this invention can also be modified by attaching the appropriate functional groups to enhance selective biological properties. Such modifications are known in this area and include those to increase biological penetration into a specific biological systems is (for example, blood, lymphatic system, Central nervous system), increase the availability of oral introduction, increase solubility to ensure the injection, the metabolism changes and speed changes of the selection.

Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, sautereau substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated fatty acids of vegetable origin, water, salts or electrolytes, such as Protamine sulfate, secondary, acidic sodium phosphate, secondary acid potassium phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium salt of carboxymethylcellulose, polyacrylates, waxes, block copolymers of polyethylene-polyoxypropylene, polyethylene glycol and lanolin.

In a preferred embodiment of the invention the compositions of this invention is prepared for pharmaceutical injection to a mammal, preferably human.

That is their pharmaceutical compositions of the present invention can be administered orally, parenterally, via inhalation spray, topically, rectally, intranasal, buccal, intrawaginalno or via an implanted reservoir. The term "parenteral", in the sense in which it is used in the description, includes subcutaneous, intravenous, intramuscular, intra-articular, nutricentials, intrasternal, intrathecal, intrahepatic, in the lesion and intracranial injection or infusion. Preferably the composition is administered orally or intravenously.

Sterile injectable forms of the compositions of this invention can be aqueous or oil suspension. These suspensions can be formulated according to methods known in this field, 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, acceptable for injecting diluent or solvent, for example in the form of a solution in 1,3-butanediol. Part acceptable carriers or solvents that can be used include water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use sterile, non-volatile oils. For this purpose, the can is to use any soft non-volatile oil, including synthetic mono - or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for injectable drugs, as well as natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylene options. Data oil solutions or suspensions may also contain a diluent alcohol-based long-chain or dispersant, such as carboxymethyl cellulose or similar dispersing means, which is usually used in the manufacture of pharmaceutically acceptable dosage forms including emulsions and suspensions. When preparing dosage forms can also use the commonly used surfactants, such as twins, spiny and other emulsifying agents or substances that increase the bioavailability, which are typically used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms.

The pharmaceutical compositions according to this invention can be administered orally in any acceptable for oral administration the dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use media that are commonly used include lactose and corn the initial starch. Also usually add lubricants such as magnesium stearate. For oral administration in the form of capsules suitable diluents include lactose and dried corn starch. When for oral administration requires the suspension, the active ingredient combined with emulsifiers or suspendresume agents. If you want, you can also add sweeteners, flavorings or dyes.

Alternative pharmaceutical compositions according to this invention can be introduced in the form of suppositories for rectal administration. They can be prepared by mixing the active substance with a suitable, not causing irritation filler, which is solid at room temperature but becomes liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions according to this invention can also be applied topically, especially when the target of treatment includes areas or organs readily accessible for topical application, including diseases of the eye, skin, or the lower parts of the intestinal tract. Suitable compositions for topical application easy to prepare for each of these areas or organs.

Local application h the life of the departments of the intestinal tract can be performed using the compositions for rectal suppository (see above) or in a suitable enema. You can also use transdermal patches for local applications.

For topical applications, the pharmaceutical compositions can be prepared as a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds according to this invention include, but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternative pharmaceutical compositions can be prepared in the form of 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, etilovyj esters wax, clearily alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions can be prepared in the form of micronized suspensions in isotonic, with painted pH sterile saline or preferably, as solutions in isotonic, with painted pH sterile saline solution, with or without a preservative such as benzylalkonium chloride. And ternative for ophthalmic applications, the pharmaceutical compositions can be prepared in the form of ointment, such as vaseline.

The pharmaceutical compositions according to this invention can also be entered in a nasal aerosol or inhalation. Such compositions obtained using methods well known in the field of preparation of pharmaceutical preparations, and can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, substances that promote the absorption to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The above compositions are particularly suitable for therapeutic applications related to mediated IL-1 disease mediated apoptosis disease, inflammatory disease, autoimmune disease, destructive bone disease, a proliferative disease, an infectious disease, a degenerative disease, a disease associated with cell death, or various forms of liver disease. Such diseases include related to rheumatology and autoimmunity, such as rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, grave's disease, severe psevdomatematicheskoe myasthenia gravis, autoimmune neutropenia, autoimmune hemolytic anemia, thrombocytop the Oia, juvenile rheumatoid aritra, gout syndrome behceta, symptoms of still's syndrome activation of macrophages and sarcoidosis; to automobiletechnik syndromes, such as associated with cryopyrin periodic syndromes (including syndrome macl-Wells, familial cold urticaria, chronic infantile neurological cutaneous and articular syndrome (aka. Multisystem inflammatory disease of the newborn), familial Mediterranean fever associated with TNFR1 periodic syndrome (TRAPS), periodic fever syndrome with high levels of IgD (HIDS) and Blau syndrome; dermatological diseases such as psoriasis, atopic dermatitis, scarring, alopecia, acne ordinary and disease; respiratory diseases such as asthma, respiratory distress syndrome, adult cystic fibrosis, emphysema, chronic bronchitis, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis; diseases of internal organs, such as inflammatory peritonitis, inflammatory bowel disease, illness Crohn's, ulcerative colitis, autoimmune gastritis associated with .pylori stomach ulcers and duodenal ulcers, diabetes, pancreatitis, glomerulonephritis, chronic active hepatitis, elementary condition associated with excessive alcohol consumption, kidney disease, polycystic kidney disease, Ojo and, organ apoptosis after burns, hemorrhagic shock, failure of organs (e.g. liver failure, acute renal failure and acute respiratory distress syndrome and endometriosis; it grafts, such as disease graft-versus-host (GVHD) and graft rejection; cancer, such as leukemia and related disorders, myelodysplastic syndrome associated with multiple myeloma bone disease, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma; cardiovascular diseases, such as chronic heart disease, acute heart disease, myocardial infarction, ischemia of myocard, congestive heart disease, atherosclerosis, artificial anastomosis coronary artery (CABG), and acute coronary syndrome; diseases of the Central and peripheral nervous system such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy disease, Prion disease, cerebral ischemia, epilepsy, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis associated with HIV infection encephalitis, brain injury, spinal cord injury, neurological disruption resulting from stroke, diabetes neuropath the I and acute and chronic pain; for ophthalmic diseases, such as uveitis, abnormalities of the retina, diabetic retinopathy, glaucoma and keratitis; to infectious diseases, such as viral disease, sepsis, septic shock, shigellosis, hepatitis b, hepatitis C, hepatitis-G, yellow fever, Dengue fever, Japanese encephalitis, HIV infection, tuberculosis, meningitis, an infection caused by Pseudomonas bacteria, and infection caused by Acinetobacter; and to other violations, such as aging. Compounds and compositions are also suitable for the treatment of complications associated with extracorporeal anastomosis of the coronary artery. The number of connections in the above compositions should be sufficient to cause detective weakening of disease severity or activity of caspase and/or apoptosis of cells defined by any of the tests, known in this field.

In another embodiment of the invention in the composition of this invention can be optionally included another therapeutic agent. These tools include, but are not limited to, thrombolytic agents such as tissue activator of plasminogen and streptokinase. When you use the second tool, the second tool can be entered as a separate dosage form or as part of a single dosage form with the compounds or compositions to nomu invention. Therefore, this invention relates to a combined preparation for simultaneous, separate or sequential use.

Doses of the compounds of protease inhibitors, is described in the description, in the range from about 0.01 to about 100 mg/kg of body weight per day, preferably in the range from about 0.5 to about 75 mg/kg of body weight per day are suitable for monotherapy in the prevention and treatment of diseases associated with the activity of caspase and/or apoptosis.

Typically, the pharmaceutical compositions according to this invention it is necessary to introduce from about 1 to about 5 times per day or alternatively in a continuous infusion. Such introduction can be carried out for long or short-term therapy. The amount of active ingredient which can be combined with carriers, to provide a single dosage form will vary depending upon the host being treated and the particular route of administration. A typical preparation will contain from about 5% to about 95% active compound (wt./wt.). Preferably, such preparations contain from about 20% to about 80% active compound.

When the compositions of this invention contain a combination of compounds of formula (I) and one or more additional therapeutic or prophylactic agents, what about the compound and the additional agent should be present at a dose in the range of about 10 to 100% or more, preferably within about 10 to 80% of the dose normally used for introducing monotherapies.

It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound, the age, body weight, General health, sex, diet, time of administration, rate of excretion, drug combination and the decision of the treating physician and the severity of the particular disease being treated. The number of active ingredients will also depend on the specific compounds and the other therapeutic agent, if present, in the composition.

In a preferred embodiment, the invention relates to a method of treatment of a mammal suffering from one of the above diseases, including the stage of introduction of a given mammal pharmaceutically acceptable composition described above. In this embodiment, if the patient is given another therapeutic agent or an inhibitor of caspase, they can be entered together with the connection according to this invention in a single dosage form or in separate dosage form. With the introduction of a separate dosage form another caspase inhibitor or vehicle can be entered before, at the same time, or after administration of the pharmaceutical preparations is acceptable automatic composition, containing the compound according to this invention.

For a more complete understanding of the present invention are given below preparative and analytical examples. These examples are presented for illustration only and are in no way intended to limit the scope of the invention.

Examples

Example 1

(S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Method a:

Tert-butyl ether (S)-2-(3-benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)butyric acid

To a cooled (0°C.) solution of (R)-tert-butylhydroxyanisole (1,03 g, to 6.43 mmol) in dichloromethane (25 ml) was slowly added 2,6-lutidine (1,38 g, 12.9 mmol) and then anhydride triftormetilfullerenov acid (3,45 g, 12.2 mmol). The resulting mixture was stirred at 0°C for 1 h, and then distributed between tert-butylmethylamine ether (150 ml) and aqueous solution of 1M HCl (30 ml). The organic layer was washed with saturated salt solution (30 ml), dried (sodium sulfate), filtered and concentrated to obtain triflate in the form of a light brown oil.

To a solution of benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid (P.Warner et al., J. Med. Chem., 37, 19, 1994, 3090-3099) (1.73 g, 7,07 mmol) in dry THF (60 ml) was added sodium hydride (60% on sparse, 257 mg, to 6.43 mmol) and the solution was stirred at room temperature for 45 minutes, the Reaction mixture was slowly transferred via cannula into a solution of triflate prepared above, in THF (3 ml). The reaction mixture was stirred at room temperature for 90 min and extinguished aqueous solution of ammonium chloride (10 ml). A large part of the solvent is evaporated and the residue was distributed between EtOAc and saturated aqueous NH4Cl. The organic layer was washed with saturated salt solution (30 ml), dried (MgSO4), filtered and evaporated. The residue was purified flash chromatography (mixture of 10% ethyl acetate/hexane) to obtain the specified title compound as a colourless oil (2,48 g, 100%);1H NMR (400 MHz,

CDCl3) δ to 0.92 (3H, t), of 1.45 (9H, s), of 1.94 (1H, m), of 2.25 (1H, m), 5,23 (2H, s), vs. 5.47 (1H, DD), 6,32 (1H, t), 7,01 (1H, d), 7,32-the 7.43 (5H, m), 7,92 (1H, s), of 8.06 (1H, userd).

Method:

Tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid

To a solution of tert-butyl methyl ether (S)-2-(3-benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)butyric acid (2,48 g, to 6.43 mmol) in a mixture of Meon (15 ml) and EtOAc (15 ml) was added 10% Pd/C (250 mg). The mixture was degirolami and stirred at room temperature for 90 min in an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through a short pad of silica gel, which is ZAT is washed Meon. The combined filtrates were evaporated under reduced pressure to obtain specified in the title compounds as white solids (1,62 g, 100%);1H NMR (400 MHz, CDCl3) δ of 0.91 (3H, t), of 1.44 (9H, s), at 1.91 (1H, m), of 2.21 (1H, m), 4,24 (2H, users), of 5.50 (1H, DD), 6,11 (1H, t), 6,53 (1H, d), 6,77 (1H, d).

The method:

Tert-butyl ether (S)-2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)butyric acid

To a cooled (0°C.) solution of tert-butyl methyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid (500 mg, to 1.98 mmol) in dichloromethane (5 ml) was added triethylamine (220 mg, 2,18 mmol) followed by the addition of acetic anhydride (202 mg, to 1.98 mmol). The reaction mixture was stirred at room temperature for 12 h and then was distributed between EtOAc and aqueous 1M HCl solution. The organic layer was washed saturated aqueous NaHCO3saturated salt solution (30 ml), dried (MgSO4), filtered and evaporated. The residue was purified flash chromatography (mixture of 40% ethyl acetate/hexane) to obtain the specified title compound as a colourless oil (569 mg, 97%);1H NMR (400 MHz, CDCl3) δ of 0.87 (3H, t), of 1.40 (9H, s), at 1.91 (1H, m)to 2.13 (3H, s), 2,19 (1H, m), 5,38 (1H, DD), of 6.26 (1H, t), of 6.99 (1H, d), with 8.33 (1H, d), 8,43 (1H, users).

The way D:

(S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)butyric acid

The solution required the-butyl ether (S)-2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)butyric acid (569 mg, of 1.93 mmol) in dichloromethane (5 ml) was cooled to 0°C. was Added triperoxonane acid (5 ml) and the resulting mixture was allowed to warm to room temperature and was stirred for 2 hours Then the mixture was concentrated under reduced pressure and the residue was again dissolved in dichloromethane. This manipulation was repeated several times to remove excess triperoxonane acid. The obtained solid is suspended in diethyl ether, filtered and again washed with diethyl ether. Then the solid was dried to constant weight in a vacuum. This gave specified in title product as a white solid (327 mg, 71%);1H NMR (400 MHz, d6-DMSO) δ 0,78 (3H, t), 2,02-2,17 (5H, m), to 4.98 (1H, DD), of 6.29 (1H, t), 7,35 (1H, d), 8,21 (1H, d), of 9.30 (1H, s), 13,07 (1H, users).

Method E:

Tert-butyl ether (S,S)-3-[2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-hydroxy-5-(2,3,5,6-tetraterpenes)pentanol acid

Stir a mixture of (S)-2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)butyric acid (100 mg, 0.42 mmol), tert-butyl ester 3-amino-5-(2,3,5,6-tetraterpenes)-4-hydroxypentanal acid (163 mg, 0,462 mmol), HOBt (62 mg, 0,462 mmol), DMAP (56 mg, 0,462 mmol) and THF (5 ml) was cooled to 0°C. then was added EDC (89 mg, 0,462 mmol). The mixture was allowed to warm to room temperature over 16 h, then concentrated under pony is hinnon pressure. The residue was purified flash chromatography (mixture of 50-50% ethyl acetate/hexane) to obtain the specified title compound as a white foam (221 mg, 92%);1H NMR (400 MHz, CDCl3) δ 0.88 to 0,93 (3H, m), 1,37-1,38 (D, 2C), 1,86 is 1.96 (1H, m), 2,15 was 2.25 (4H, m), 2,55-a 2.71 (2H, m), 3,70 with 4.64 (5H, m), 5,30 of 5.39 (1H, m), 6,30 to 6.35 (1H, m), 6.75 in-6,86 (1H, m), 7,17-7,31 (2H, m), 8,31-of 8.47 (2H, m).

The way F:

Tert-butyl ether (S,S)-3-[2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid

Mix a solution of tert-butyl methyl ether (S,S)-3-[2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-hydroxy-5-(2,3,5,6-tetraterpenes)pentanol acid (221 mg, 0,385 mmol) in anhydrous DCM (10 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)one (212 mg, 0.5 mmol) at 0°C. the resulting mixture was stirred at 0°C within 2 h, diluted with ethyl acetate, then poured into a mixture of saturated aqueous solution of sodium bicarbonate saturated aqueous solution of sodium thiosulfate and 1:1. The organic layer was removed and the aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated. The residue was purified flash chromatography (mixture of 50-50% ethyl acetate/hexane) to obtain the specified title compound as a white solid (187 mg, 85%);1H NMR (400 MHz, CDCl3) δ of 0.93 (3H,t), of 1.36 (3H, s), of 1.95 (1H, m), of 2.21 (3H, in), 2.25 (1H, m), 2,73 (2H, DD), 2,89 (1H, DD), 4,91 (1H, m), 5,04-5,17 (2H, m), vs. 5.47 (1H, m), 6,34 (1H, t), to 6.80 (1H, m), 7,19 (1H, m), 7,68 (1H, d), at 8.36-to 8.41 (2H, m,).

The way G:

(S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

A solution of tert-butyl methyl ether (S,S)-3-[2-(3-acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid (187 mg, 0,327 mmol) in dichloromethane (5 ml) was cooled to 0°C. was Added triperoxonane acid (5 ml) and the resulting mixture was allowed to warm to room temperature and was stirred for 2 hours Then the mixture was concentrated under reduced pressure and the residue was again dissolved in dichloromethane. This manipulation was repeated several times to remove excess triperoxonane acid. The obtained solid is suspended in diethyl ether, filtered and again washed with diethyl ether. Then the solid was dried to constant weight in a vacuum. This gave specified in title product as a white solid (138 mg, 82%);1H NMR (400 MHz, d6-DMSO) δ 0,78 (3H, t), 1,87 and 2.13 (5H, m), 2,56-2,78 (2H, m), to 4.62 (1H, m), 5,18-of 5.29 (2H, m), of 5.40 (1H, m), 6,28 (1H, t), 7,37 (1H, d), 7,53-7,66 (1H, m), 8.17-a 8,21 (1H, m), of 8.92 (1H, d), of 9.21 (1H, s), 12,51 (1H, users);19F NMR (376 MHz,d6-DMSO, with the junction between protons) δ -156,9, -141,1; M+N 516,2, M-N 514,2.

Por what measures 2

(S,S)-4-Oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid anhydride and propionic acid according to methods C-G; white solid; IR-spectrum (solid) 1584, 1642, 1662, 1717, 1749 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,78 (3H, t), was 1.04 (3H, t), 1,88-2,11 (2H, m), 2,43 (2H, HF), 2,59 (1H, d), a 2.75 (1H, DD), br4.61 (1H, m), 5,18-of 5.29 (2H, DD), of 5.40 (1H, m), of 6.29 (1H, t), 7,37 (1H, d), 7,58 (1H, m), by 8.22 (1H, d), 8,91 (1H, d), the remaining 9.08 (1H, s), 12,50 (1H, users);19F NMR (376 MHz,d6-DMSO, with the junction between protons) δ -140,6, -140,8, -141,1, -156,8, -157,0; M+N 530,2, M-N consists 528.3.

Example 3

(S,S)-3-[2-(3-Butylimino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and butyrylcholine on how C-G; beige solid; IR-spectrum (solid) 1659, 1645, 1509, 1490 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,76-0,80 (3H, m)to 0.88 (3H, t), 1,53 is 1.58 (2H, m), 1,88-of 1.93 (1H, m), 2,01-of 2.09 (1H, m), 2,37-to 2.41 (2H, m), 2,59 (1H, DD), 2,70-of 2.81 (1H, m), 4,59-4,63 (1H, m), 5,20-a 5.25 (2H, m), 5,38-of 5.50 (1H, 2 × m)that was 7.36-7,38 (1H, m), 7,55-to 7.61 (1H, m), 8,21-8,23 (1H, m), 8,61-of 8.92 (1H, 3 × d), 9,06-9,10 (1H, m), 12,49 (1H, users);19F NMR (376 MHz,d6-DMSO, with the junction between protons) δ -140,6, -141,1, -156,, -157,0; M+N TO 544.3, M-N USD 542.3.

Example 4

(S,S)-3-{2-[3-(Cyclopropanecarbonyl)-2-oxo-2H-pyridin-1-yl]bucillamine}-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and cyclopropanecarbonitrile on how C-G; white solid;1H NMR (400 MHz, d6-DMSO) δ 0.74 and-0,82 (7H, m)of 1.93 (1H, m)2,07 (1H, m), 2,17 (1H, m), 2,59 (1H, d), a 2.75 (1H, DD), to 4.62 (1H, m), 5,19-and 5.30 (2H, DD), 5,41 (1H, m), 6,27 (1H, t), 7,37 (1H, d), EUR 7.57 (1H, m), 8,17 (1H, d), 8,92 (1H, d), 9,49 (1H, s), 12,51 (1H, users); M+H 542,2, M-H 540,3.

Example 5

(S,S)-3-[2-(3-Isobutylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and isobutyramide on how C-G; white solid; IR-spectrum (solid) 1664, 1517, 1491 cm-1;1H NMR (400 MHz, d6-DMSO) δ 1,75-of 1.85 (3H, m)of 1.05 (6H, d), 1,9-2,1 (2H, m), 2,6-2,9 (3H, m), 4,55-to 4.62 (1H, m), 5,2 to 5.35 (2H, m), 5,4-5,43 (1H, m), and 6.25 (1H, t), 7,4 was 7.45 (1H, m), and 7.6 to 7.7 (1H, m), 8,2-8,24 (1H, m), 8,8-9,0 (2H, m); M+H to 544.3, M-H USD 542.3.

Example 6

(S,S)-3-{2-[3-(2-Methoxyethylamine-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-what iridin-1-yl)butyric acid and methoxyacetanilide on how C-G; pink solid;1H NMR (400 MHz, d6-DMSO) δ 0,75-0,80 (3H, m), 1,88-of 1.97 (1H, m), 2,02-2,10 (1H, m), 2,56-2,63 (1H, m), 2,72-and 2.79 (1H, m), 3,37 is 3.40 (3H, m), 4,00-a 4.03 (2H, m), 4.53-in-the 4.65 (1H, m), 5,13-5,46 (3H, m), 6,32 to 6.35 (1H, m), 7,39 was 7.45 (1H, m), 7,51-7,66 (1H, m), 8,21 compared to 8.26 (1H, m), 8,92-8,98 (1H, m), 9,12-9,17 (1H, m), 12,51 (1H, users); M+H 546,2, M-H 544,2.

Example 7

(S,S)-3-(2-{3-[(Furan-2-carbonyl)amino]-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and 2-frailcare on how C-G; white solid;1H NMR (400 MHz, d6-DMSO) δ 0,81 (3H, m), of 1.95 (1H, m), is 2.09 (1H, m)2,60 (1H, DD), 2,77 (1H, DD), br4.61 (1H, m), 5,19-of 5.29 (2H, m), 5,42 (1H, m), to 6.39 (1H, t), 6,74 (1H, m), 7,30 (1H, m), 7,46-7,58 (2H, m), 7,95 (1H, m), 8,27 (1H, d), 8,98 (1H, d), 9,16 (1H, s), 12,50 (1H, users); M+H 568,3, M-H 566,3.

Example 8

(S,S)-3-(2-{3-[(Furan-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}butyramide]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and 3-frailcare on how C-G; not quite white solid; IR-spectrum (solid) 1748, 1711, 1663, 1640, 1583, 1517, 1488 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,80 (3H, m), 1,90-of 2.20 (2H, m), 2,60-2,90 (2H, m)and 4.65 (1H, m), 5,10-the ceiling of 5.60 (3H, m), 6,40 (1H, t), to 6.95 (1H, m), 7,40-the 7.65 (2H, m), a 7.85 (1H, s), to 8.20 (1H, m), and 8.50 (1H, m), 8,90-9,20 (2H,m); 19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,0, -156,8; M+H 568,2, M-H 566,3.

Example 9

(S,S)-4-Oxo-3-(2-{2-oxo-3-[(pyridine-3-carbonyl)amino]-2H-pyridine-1-yl}bucillamine)-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and 3-pyridinecarboxamide on how C-G (allocated in the form of the TFA salt); yellow solid; IR-spectrum (solid) 1745, 1678, 1650, 1517, 1488;1H NMR (400 MHz, d6-DMSO) δ 0,80 (3H, m), 1,90-of 2.30 (2H, m), 2,50-2,90 (2H, m)and 4.65 (1H, m), 5,10-5,65 (3H, m), of 6.45 (1H, t), 7,40-7,80 (3H, m), 8,10-to 8.40 (2H, m), cent to 8.85 (1H, s), 8,90-9,20 (2H, m), 9,65 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,0, -156,8; M+H 579,2, M-N 577,3.

Example 10

(S,S)-3-(2-{3-[(Isothiazol-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}bucillamine)-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and 3-isothiazolinone on how C-G; pink solid; IR-spectrum (solid) 1678, 1649, 1516, 1493 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.85 (3H, m), 1.85 to 2,30 (2H, m), 2,50-2,90 (2H, m), 4,20-4,70 (1H, 2m), 5,10-the ceiling of 5.60 (3H, m), of 6.45 (1H, t), 7,40-of 7.70 (2H, m), 7,95 (1H, m), 8,40 (1H, d), 8,95 is 9.15 (1H, 2m), of 9.30 (1H, d), 10,00 (1H, 2s);19F NMR (376 MHz, d6-DMSO, with interchange of protons) is -141,0, -156,9; M+H 585,1, M-N 583,2.

Example 11

(S,S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and benzoyl chloride according to methods C-G; pink solid; IR-spectrum (solid) 1645, 1509, 1490 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0.79, which is of 0.85 (3H, m), 1,95 of 1.99 (1H, m), 2.06 to-2,10 (1H, m)2,60 (1H, DD), 2,77 (1H, DD), 4,59-4,63 (1H, m), 5.25-inch (2H, m), 5,42-of 5.55 (1H, m), 6,38-6.42 per (1H, m), 7,51 to 7.62 (5H, m), 7,89-to $ 7.91 (2H, m), 8,27-8,31 (1H, m), 8,69-8,99 (1H, m), 9.28 are (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -140,6, -141,0, -156,9, -157,0; M+H 578,2, M-H 576,2.

Example 12

(S,S)-4-Oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and phenylacetylglutamine on how C-G; pink solid; IR-spectrum (solid) 1659, 1635, 1519 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.77 (3H, t), 1.85 to a 1.96 (1H, m), 2,03-2,07 (1H, m), 2,59 (1H, DD), 2.71 to 2,77 (1H, m), with 3.79 (2H, s), br4.61-of 4.66 (1H, m), 5,16-of 5.29 (2H, m), 5,35-5,44 (1H, m), 6,28 (1H, t), 7.24 to 7,39 (6N, m), 7,52-to 7.67 (1H, m), 8,19-8,21 (1H, m), 8,61-of 8.92 (1H, m), 9.28 are (1H, users);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -140,6, -141,0, -156,90, -157,0; M+H 592,2, M-H 590,2.

When is EP 13

(S,S)-3-[2-(3-Acetylamino-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from benzyl ether (2-oxo-5-trifluoromethyl-1,2-dihydropyridines-3-yl)carbamino acid according to methods a-G; white solid; IR-spectrum (solid) 1659, 1514 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.79 (3H, t), 2,07 is 2.33 (5H, m), 2,59-and 2.79 (2H, m), 4,59-4,63 (1H, m), 5,18-of 5.29 (2H, m), 5,41-of 5.45 (1H, m), 7,55 to 7.62 (1H, m), 7,89 (1H, s), to 8.41-8,43 (1H, m), 9,04 (1H, d), being 9.61-9,63 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -61,4, -140,7, -141,1, -156,8-156,9, -157,02, -157,1; M+N 584,2, M-N 582,2.

Example 14

(S,S)-3-{2-[3-(3-Ethylurea)-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and utilizationof on how C-G; pink solid; IR-spectrum (solid) 1664, 1645, 1550, 1493, 1208 cm-1;1H NMR (400 MHz, d6-DMSO) δ to 0.80 (3H, t), of 1.05 (3H, t), 1,80-2,20 (2H, m), 2,50-to 2.85 (2H, m)and 3.15 (2H, m)and 4.65 (1H, m), 5.25-inch (2H, DD), of 5.40 (1H, m), and 6.25 (1H, t), to 7.15 (1H, s), 7,25 (1H, d), 7,60 (1H, m), with 8.05 (1H, m), 8,20 (1H, s), of 8.95 (1H, d);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,1, -156,9; M+N 545,2, M-N 543,2.

Example 15

(S,S)-3-{2-[3-(3,3-Diethylurea)-2-oxo-2H-pyridin-1-yl]bucillamine}-4-oxo-5-(2,3,5,6-t is triftorperasin)pentane acid

Method N:

To a cooled (0°C.) solution of tert-butyl methyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid (400 mg, to 1.59 mmol) in dichloromethane (3 ml) was added triethylamine (0,254 ml, 1.82 mmol). This solution was added dropwise to a solution of diphosgene (0,11 ml of 0.91 mmol) in dichloroethane (7 ml) at 0°C for 10 min. the Reaction mixture was stirred at room temperature for 90 min and then was distributed between EtOAc and aqueous 1M HCl solution. The organic layer was washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated to obtain isocyanate in the form of a brown oil.

To a cooled (0°C.) solution of the isocyanate obtained above (244 mg, of 0.79 mmol), in dichloroethane (4 ml) was added triethylamine (0,122 ml, 0.87 mmol) followed by the addition of diethylamine (0,082 ml of 0.79 mmol). The reaction mixture was stirred at room temperature for 3 h and then was distributed between EtOAc and aqueous 1M HCl solution. The organic layer was washed with a saturated solution of salt, dried (MgSO4), filtered and evaporated to obtain a brown oily residue, which was purified column flash chromatography (mixture of 50% ethyl acetate/hexane) to obtain dieselmachine in the form of a colorless oil.

This intermediate compound used in the sequence is eacci, described in methods D-G, obtaining specified in the connection header; pink solid; IR-spectrum (solid) 1640, 1512, 1213 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,75-0,95 (3H, m), 1,10-1,40 (6H, m), 1,90 was 2.25 (2H, m), 2,60-2,90 (2H, m), 3,30-to 3.50 (4H, m), and 4.75 (1H, m), 5,10-the ceiling of 5.60 (3H, m), 6.35mm (1H, t), 7,30 (1H, m), of 7.75 (1H, m), 7,80 (1H, m), with 8.05 (1H, m), 8,95-9,05 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,0, -156,9; M+N 573,3, M-N 571,2.

Example 16

(S,S)-4-Oxo-3-(2-{2-oxo-3-[(pyrrolidin-1-carbonyl]amino-2H-pyridine-1-yl}bucillamine)-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and pyrrolidine on how H, D-G; pink solid; IR-spectrum (solid) 1650, 1593, 1512, 1489, 1208 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,80 (3H, m), 1,80-2,20 (6H, m), 2,60-2,90 (2H, m), 3,30-to 3.50 (4H, m), 4,60-of 4.75 (1H, m), 5,10-5,50 (3H, m), 6,30 (1H, t), 7,35 (1H, m), 7,50 to 7.75 (2H, m), 8,00 (1H, m), cent to 8.85-8,95 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,1, -156,9; M+N 571,3, M-N 569,3.

Example 17

(S,S)-3-[2-[3-Methoxycarbonylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and methylchloroform on how C-G; pink t is ardoe substance; IR-spectrum (solid) 1644, 1661, 1709 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,81 (3H, m), of 1.95 (1H, m), is 2.09 (1H, m), 2,50 are 2.98 (2H, m), 3,70 (3H, s), 4,20-of 5.50 (4H, m), of 6.31 (1H, m), 7,40 (1H, m), to 7.59 (1H, m), 7,82 (1H, m), to 8.20 (1H, s), 8,55-9,00 (1H, d);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -140,6, -141,0, -141,1, -156,80, -156,9, -157,0, -157,1; M+N 532,3, M-N us $ 530, 3.

Example 18

(S,S)-3-[2-[3-Ethanolamine-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and acanaloniidae on how C-G; pink solid;1H NMR (400 MHz, d6-DMSO) δ 0,74-of 0.82 (3H, m), 1,17-1,25 (3H, m), 1.85 to 2,10 (2H, m), 2,54-and 2.79 (2H, m), 3,09 is 3.15 (2H, m), 4,58-and 4.68 (1H, m), 5,13 is 5.38 (2H, m), 6,26 of 6.31 (1H, m), 7,34-7,38 (1H, m), 7,51-7,73 (2H, m), 8,72-8,76 (1H, m), 8,89-8,97 (1H, m), 12,51 (1H, users); M+H 566,2, M-H 564,2.

Example 19

(S,S)-4-Oxo-3-{2-[2-oxo-3-(propane-1-sulfonylamino)-2H-pyridine-1-yl]bucillamine}-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and propanesulfinamide on how C-G; pink solid;1H NMR (400 MHz, d6-DMSO) δ 0,74-of 0.82 (3H, m), from 0.88 to 0.94 (3H, m), 1,63-of 1.74 (2H, m), 1.85 to 2,10 (2H, m), 2,56-and 2.79 (2H, m), 3,06-3,13 (2H, m), 4,58-and 4.68 (1H, m), 5,13-of 5.40 (2H, m), 6,26 of 6.31 (1H, m), 7,34-7,37 (1H, m), 7,50 to 7.62 (2H, m), 8,71 is 8.75 (1H,m), 8,90-8,97 (1H, m), of 12.53 (1H, users); M+H 580,3, M-N 578,3.

Example 20

(S,S)-4-Oxo-3-{2-[2-oxo-3-(propane-2-sulfonylamino)-2H-pyridine-1-yl]bucillamine}-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and isopropylacetanilide using methods similar to P-G; pink solid; IR-spectrum (solid) 1645, 1518 cm-1;1H NMR (400 MHz, d6-DMSO) δ a 1.7-1.8 (3H, m), 1.18 to 1,25 (6H, m), 1.85 to 2.05 is (2H, m), 2,55-2,8 (2H, m), 3,2 and 3.3 (1H, m), to 4.52-to 4.62 (1H, m), 5,15-5,32 (3H, m), 5,4-5,43 (1H, m), and 6.25 (1H, t), 7,3-to 7.35 (1H, m), 7,45 and 7.6 (2H, m), 8.6 out of 8.7 (1H, m), 8,9-9,0 (1H, m); M+H 580,2, M-N 578,2.

Example 21

(S,S)-3-[2-(3-Benzosulfimide-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from tert-butyl ether (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)butyric acid and benzosulfimide on how C-G; pink solid;1H NMR (400 MHz, d6-DMSO) δ 0,55-0,66 (3H, m), 1,72-of 1.84 (1H, m), 1,91 is 2.01 (1H, m), 2,53-2,61 (1H, m), 2,68 was 2.76 (1H, m), 4,54-4,63 (1H, m), 5,06-5,32 (2H, m), of 6.20 and 6.25 (1H, m), 6,98-7,86 (9H, m), 8,84-of 8.90 (1H, m), 9,40-to 9.45 (1H, m), 12,51 (1H, users); M+H 614,1, M-H 612,1.

Example 22

(S,S)-3-[2-(3-Ethanolamine-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from benzyl ether (2-oxo-5-trifluoromethyl-1,2-dihydropyridines-3-yl)carbamino acid according to methods a-G; not quite white solid; IR-spectrum (solid) 1664, 1519 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,78-of 0.87 (3H, m), 1,18-of 1.23 (3H, m), 1,99 with 2.14 (2H, m), 2,55 is 2.80 (2H, m), 3,19-of 3.25 (2H, m), 4,54-of 4.66 (1H, m), 5,20-and 5.30 (2H, m), 5,35-of 5.45 (1H, m), 7,47 (1H, m), 7,55-7,71 (1H, m), 8,01 (1H, s), 9,05 (1H, m), 9,31 (1H, s);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -63,11, -139,6, -157,1, -157,2; M+N 634,1, M-N 632,1.

Example 23

(S,S)-3-[3-Methyl-2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid according to methods a-G; pink solid; IR-spectrum (solid) 1644, 1683, 1740, 1791 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.6 (3H, m), and 1.0 (3H, m), 2,2-2,3 (1H, m), of 2.5-3.0 (2H, m), of 3.7-3.8 (2H, m), a 4.1 and 5.4 (4H, m), 6,2-6,3 (1H, m), 7,2-7,4 (5H, m), of 7.5 to 7.7 (2H, m), of 8.1 to 8.2 (1H, m), of 8.7 to 9.2 (2H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -140,6, -141,0, -156,8, -157,0, -157,2; M+N 606,3, M-N 604,3.

Example 24

(S,S)-3-[2-(3-Ethanolamine-2-oxo-2H-pyridin-1-yl)-3-methylbutylamine]-4-oxo-5-(2,3,5,6-tetraterpenes)pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid in which the means A-G; not quite white solid; IR-spectrum (solid) 1595, 1646, 1682, 1742, 1789 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.7 (3H, m), 0.9 to 1.0 (3H, m), 1,2 (3H, m), 2,3 (1H, m), of 2.6-3.0 (2H, m), 3,1 (2H, m), a 4.1 and 5.4 (4H, m), and 6.3 (1H, m), and 7.3 (1H, m), of 7.5 to 7.7 (2H, m), of 8.7 to 9.2 (2H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -140,6, -141,0, -156,7, -157,0, -157,1; M+N 580,2, M-N 578,3.

Example 25

(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)propionamido]pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1643, 1658, 1711, 1740 cm-1;1H NMR (400 MHz, d6-DMSO) δ 1,0-1,2 (3H, m), is 1.4-1.6 (3H, m), 2,4-3,2 (4H, m), 4,2-4,6 (1,5H, m), 5,0-5,6 (2,5H, m), and 6.3 (1H, m), and 7.3 (1H, m), and 8.2 (1H, m), of 8.3 to 8.8 (1H, m), and 9.1 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,8, -226,9, -230,6, -231,4, -232,7, -232,8; M+N 370,4, M-N 368,3.

Example 26

(S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)propionamido]-5-fluoro-4-oxopentanoic acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1523,/p>

1644 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 1.6 (3H, m), of 2.5-3.2 (2H, m), 4,2-4,7 (1,5H, m), 5,0-5,6 (2,5H, m), 6,4 (1H, m), 7,4-7,6 (3H, m), 7,9 (2H, m), and 8.3 (1H, m), 8,5-8,9 (1H, m), and 9.3 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,8, -230,4, -231,3, -232,8, -232,9; M+N 418,3, M-N 416,3.

Example 27

(S)-3-{2-[3-(2,6-Dichloraniline)-2-oxo-2H-pyridin-1-yl]propionamide}-5-fluoro-4-oxopentanoic acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1521,

1646 cm-1;1H NMR (400 MHz, d6-DMSO) δ a 1.5-1.6 (3H, m), of 2.5-3.2 (2H, m), 4,2-4,7 (1,5H, m), 5,0-5,5 (2,5H, m), 6,3-6,4 (1H, m), between 7.4 to 7.5 (3H, m), and 8.3 (1H, m), 8,5-8,9 (1H, m), 10,2 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,8, -230,6, -231,4, -232,8, -232,9; M+N 486,3, M-N 484,3.

Example 28

(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)propionamido]pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1524,2, 1652,4 cm-1;1H NMR (400 MHz, d6-DMSO) δ 1,5 (3H, m), of 2.5-3.2 (2H, m, 3,8 (2H, m), 4,2-4,7 (1,5H, m), 5,0-5,5 (2,5H, m), and 6.3 (1H, m) , 7,2-7,4 (6H, m), and 8.2 (1H, m), 8,4-8,9 (1H, m), and 9.3 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,8, -230,6, -231,5, -232,8, -232,9; M+N 432,3, M-N 430,3.

Example 29

(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)Butylimino]pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1644, 1585, 1518, 1214 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.8 to 0.9 (3H, m)of 1.05 (3H, t), 1,9-2,1 (2H, m), of 2.4-2.5 (2H, m), 2,6-2,95 (2H, m), 4,2-4,5(2H, m), 5,1-5,5 (3H, m), 6,3 to 6.35 (1H, m), 7,4 was 7.45 (1H, m), 8,2-of 8.25 (1H, m), 8,8-8,9 (1H, m), 9,1-to 9.15 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -232,6; M+N 384,3, M-N 382,3.

Example 30

(S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)propionamido]-5-fluoro-4-oxopentanoic acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1643, 1522, 1204 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,75-0,85 (3H, m), 1,9-2,2 (2H, m), 2,6-2,9 (2H, m), 4,3-4,7 (2H, m), of 5.1 to 5.6 (2H, m), 6,4-6,5 (1H, m), 7.5 to a 7.85 (4H, m), of 7.9 to 8.0 (1H, m), 3-8,4 (1H, m), cent to 8.85-8,95 (1H, m), a 9.35 (1H, s); M+H 432,3, M-H 430,3.

Example 31

(S)-3-{2-[3-(2,6-Dichloraniline)-2-oxo-2H-pyridin-1-yl)Butylimino}-5-fluoro-4-oxopentanoic acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; white solid; IR-spectrum (solid) 1682, 1645, 1580, 1516, 1216 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.8 to 0.9 (3H, m), 1,9-2,1 (2H, m), from 2.6 to 2.85 (2H, m), 4,4-4,7 (2H, m), 5,1-5,5 (2H, m), 6,4-6,5 (1H, m), and 7.5 and 7.6 (4H, m), 8,33 is 8.38 (1H, m), cent to 8.85-8,95 (1H, m), 9,15-a 9.25 (1H, s), M+H 500,3, M-H 498,3.

Example 32

(S)-5-fluoro-4-oxo-3-[2-{2-oxo-3-[(pyridine-2-carbonyl)amino]-2H-pyridine-1-yl}bucillamine)pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; cream solid; IR-spectrum (solid) 1685, 1644, 1521 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,81 is 0.86 (3H, m), 1,90-2,05 (1H, m), 2.06 to 2,19 (1H, m), 2,54-2,90 (2H, m), 4,58-4,72 (1H, m), 5,07-5,31 (2H, m), 5,42-to 5.57 (1H, m), 6,40-6,44 (1H, m), 7,47-7,49 (1H, m), 6,68-7,72 (1H, m), 8,09-8,11 (1H, m), 8,18 (1H, d), 8,45-of 8.47 (1H, m), 8,73 is 8.75 (1H, m), 8,87 (1H, DD), a 10.74 (1H, s), 12,45 (1H, users);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,8, -230,4, -230,6, -231,0, -232,5, -232,6, -232,8, -232,9; M+N 433,4, The-N 431,4.

Example 33

(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid; IR-spectrum (solid) 1644, 1672, 1742, 1785 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.7-0.8 (3H, m), 1.8-to 2.2 (2H, m), of 2.5-3.2 (2H, m), 3,8 (2H, s), 4,2-4,7 (2H, m), 5,1-5,5 (2H, m), and 6.3 (1H, m), 7,2-7,4 (6H, m), and 8.2 (1H, m), 8,5-or 9.4 (2H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,7, -230,4, -231,2, -232,6, -232,6; M+N 446,3, M-N 444,3.

Example 34

(S)-5-fluoro-4-oxo-3-{2-[2-oxo-3-(2-m-tolylacetylene)-2H-pyridine-1-yl)Butylimino}pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; brownish-yellow solid; IR-spectrum (solid) 1644, 1678 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.7-0.8(3H, m), 1.8-to 2.2 (2H, m), 2,3 (3H, s), of 2.5-3.2 (2H, m), of 3.7-3.8 (2H, s), 4,2-5,5 (4H, m), and 6.3 (1H, m), 7,0 is 7.3 (4H, m), and 7.4 (1H, m), and 8.2 (1H, m), 8,5-8,9 (1H, m), and 9.2 and 9.3 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,7, -230,4, -231,2, -232,6, -232,7; M+H 460,3, M-H 459,4.

Example 35

(S)-5-fluoro-4-oxo-3-[2-(-oxo-3-propionamido-2H-pyridine-1-yl)pentanediamine}pentane acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; white solid;1H NMR (400 MHz, d6-DMSO) δ 0,85-0,95 (3H, m), to 1.0-1.1 (3H, m), 1,1-1,17 (2H, m), 1,9-2,0 (2H, m), of 2.4-2.5 (2H, m), 2,6-2,90 (2H, m), 4,5 with 4.65 (1H, m), 5,1-5,5 (3H, m), 6,3 to 6.35 (1H, m), 7,4-the 7.43 (1H, m), 8,2-8,23 (1H, m), 8,8-8,9 (1H, m), 9,05 and 9.1 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -232,6; M+H 398,4, M-N 396,4.

Example 36

(S)-5-fluoro-3-[4-methyl-2-(2-oxo-3-propionamido-2H-pyridine-1-yl)pentanediamine]-4-oxopentanoic acid

Was obtained from benzyl ether (2-oxo-1,2-dihydropyridines-3-yl)carbamino acid tert-butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; pink solid;1H NMR (400 MHz, d6-DMSO) δ of 0.85 (6H, m)of 1.05 (3H, t), of 1.30 (1H, m), 1.70 to 2,10 (2H, 2 × m), 2,30-of 3.00 (4H, m), 4,60-4,80 (1H, m), of 5.05-of 5.40 (2H, m), the 5.65 (1H, m), 6.35mm (1H, m), 7,45 (1H, m), of 8.25 (1H, m), of 8.95 (1H, m), 9,15 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -232,5; M+H 412,3.

Example 37

(S)-5-fluoro-3-[2-(5-methyl-2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-4-oxopentanoic acid

Was obtained from benzyl ether (5-methyl-2-oxo-1,2-dihydropyridines-3-yl)carbamino acid butyl ester 3-amino-5-fluoro-4-hydroxypentanal acid according to methods a-G; yellow solid; IR-spectrum (solid) 1654, 1741, 1785 cm-1;1H NMR (400 MHz, d6-DMSO) δ of 0.7-0.8 (3H, m), 1.8-to 2.2 (5H, m), of 2.5-3.2 (2H, m), 3,8 (2H, s), 4,2-5,5 (4H, m)and 7.1 to 7.4 (6N, m)and 8.1 (1H, m), 8,4-8,9 (1H, m), 9,2-or 9.4 (1H, m);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -226,7, -226,7, -227,5, -230,5, -231,3, -232,6, -232,6, -233,4; M+H 460,4, M-H 458,4.

Example 38

(S,S)-4-Oxo-{2-[2-oxo-3-(thiazol-2-ylamino)-2H-pyridine-1-yl)Butylimino}-5-(2,3,5,6-tetraterpenes)pentane acid

The way I:

3-(Thiazol-2-ylamino)-1H-pyridine-2-he

To a solution of 3-amino-1H-pyridine-2-she (2.0 g, to 18.7 mmol) in water (2 ml) was added 15% aqueous HCl (10 ml, 18 mmol) followed by the addition of ammonium thiocyanate (1.5 g, 18 mmol) and the mixture was heated to boiling under reflux for 2 hours While cooling the intermediate thiourea was deposited in the form of red-brown solid. The mixture was filtered and the solid washed with water (5 ml). To a solution of thiourea (1.3 g, 7.7 mmol) in EtOH (20 ml) and water (5 ml) was added chloroacetaldehyde (2.3 ml, 16.4 mmol) and the mixture was heated to boiling under reflux for 4 hours Under cooling and the mixture was diluted with EtOAc (30 ml) and washed with 10% solution of NaHCO3and a saturated solution of salt. The organic phase was dried over MgSO4and concentrated in vacuum. The residue was purified to lodochnoy flash chromatography (100% EtOAc) obtaining specified in the title compounds as a pale green solid (1,43 g, 40%);1H NMR (400 MHz, CDCl3) δ 1,6 (1H, s), of 6.45 (1H, t), of 6.75 (1H, s), 7,05-7,10 (1H, m), 7,40-7,42 (1H, m), 8,35 to 8.5 (2H, m); M+H 194,1, M-N USD 192.1.

This intermediate compound used in the sequence of reactions described in methods a and B-G to obtain example 38 as a white solid; IR-spectrum (solid) 1648, 1593, 1517, 1490 cm-1;1H NMR (400 MHz, d6-DMSO) δ 0,75-0,85 (3H, t), 1,9-2,2 (2H, m), 2,6-2,8 (2H, m), 4,6-4,7 (1H, m), 5,2-5,3 (2H, m), 5,35-of 5.45 (1H, m), 6,3 to 6.35 (1H, m), of 6.96-6,98 (1H, m), 7,2-7,3 (2H, m), 7.5 to the 7.65 (1H, m), 8.4 to 8,43 (1H, m), 8,8-8,9 (1H, 2 × d), 9,9 (1H, users), and 12.5 (1H, users);19F NMR (376 MHz, d6-DMSO, with the junction between protons) δ -141,0, -156,9; M+N 557,2, M-N 555,2.

Example 39

(S,S)-4-Oxo-3-[2-(2-oxo-3-propylamino-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentane acid

The way J:

Tert-butyl ether (S)-2-[3-(benzyloxycarbonylamino)-2-oxo-2H-pyridin-1-yl]butyric acid

To a solution of tert-butyl methyl ether (S)-2-(3-benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)butyric acid (100 mg, 0.26 mmol) in anhydrous DMF (3 ml) was added NaH (60% dispersion, 10 mg, 0.26 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes was Added dropwise propyliodide (30 μl, 0.31 mmol) and the reaction mixture was stirred at ambient temperature overnight. See the camping was concentrated in vacuo to solids and distributed between EtOAc (10 ml) and water (10 ml). The organic layer was separated, dried over MgSO4and concentrated in vacuum. The residue was purified column flash chromatography (mixture of 30% EtOAc/hexane) obtaining specified in the title compounds as a pale green solid (1,43 g, 40%);1H NMR (400 MHz, CDCl3) δ 0,85-0,95 (6H, m)of 1.35 (9H, s), 1,55-1,65 (2H, m), 1.85 to 1,95 (1H, m), 2,20-of 2.27 (1H, m), 3,6-3,7 (2H, m), 5,15-5,2 (2H, m), 5,5-5,6 (1H, m), and 6.25 (1H, t), 7,25 was 7.45 (7H, m); M+H 429,4.

This intermediate compound used in the sequence of reactions described in methods C-G, and, finally, subjected to hydrogenolysis as described in the method, the obtaining of example 39 in the form of not-quite-white solid; IR-spectrum (solid) 1581, 1517, 1489, 938 cm-1;1H NMR (400 MHz, d6-DMSO) δ to 0.80 (3H, t), and 0.9 (3H, t), 1,5-1,6 (2H, m), 1,8-of 2.05 (2H, m), 2,5-2,7 (2H, m), of 2.9-3.0 (2H, m), 4,6-4,7 (1H, m), of 5.1 and 5.4 (3H, m), 6,1-6,2 (2H, m), 6,85-6,9 (1H, m), 7.5 to the 7.65 (1H, m), 8,7-of 8.90 (1H, 3 × d), and 12.5 (1H, users); M+H 516,2, M-H 514,2.

Example 40

Enzymatic tests

Tests on inhibition of caspase splitting fluorogenic substrate under the action of purified recombinant human caspase-1, -3 or-8. Tests carried out basically as described Garcia-Calvo et al. (J. Biol. Chem. 273 (1998), 32608-32613) c by using a substrate specific for each enzyme. A substrate for caspase-1 is acetyl-Tyr-Val-Ala-Asp-amino-4-methylcoumarin. A substrate for caspase-3 and -8 is what I acetyl-Asp-Glu-Val-Asp-amino-4-methylcoumarin. Both substrate known in this field.

The observed rate of inactivation of the enzyme at a certain concentration of inhibitor, kobsexpected in the processing of data by the equation obtained Thornberry et al. (Biochemistry 33 (1994), 3943-3939) using a computer program for nonlinear analysis of least squares (PRISM 2,0; GraphPad software). To obtain the rate constants of the second order, kinact, build a dependency graph of values of kobsagainst the corresponding concentrations of the inhibitor and then counted values of kinactcomputer analysis of linear regression.

The above method was determined by the inhibition of the activity of caspases-1, -3 or -8 for selected compounds of this invention. Connection 1-39 inhibited caspase-1 when the value of kinact>200000 (M-1s-1), caspase-3 when the value of kinact>50000 (kinact(M-1s-1) and caspase-8 when the value of kinact>50000 (kinact(M-1s-1).

Example 41

Inhibition of the secretion of IL-1β from whole blood

Vegetariano human blood was obtained from healthy donors was diluted 1:2 in PBS. To 500 µl of the diluted blood was added 50 ml of pre-diluted test compounds in RPMI medium and 10 ml of LPS (final concentration in the Cup 5 ng/ml) (LPS, Serotype 0111:B4, Sigma L3012). After stimulation for 18 h supernatant with whom Bireli and analyzed the concentration of IL-1β by using the appropriate set for production by ELISA (R& D systems).

Table 2 below presents data on the inhibition of the secretion of IL-1β from human whole blood for the selected compounds according to this invention, in the individual definition of the above methods.

Example 42

Induced by hypoxia apoptosis of rat cortical neurons

Cortical neurons were isolated from embryos of Wistar rats (E17) using a modified method of Rogers et al. 1997, Brain Res. Bulletin, 44: 131. Briefly, in aseptic conditions identified cortex of 15-20-day-old embryos of Wistar rats. The cell suspension was prepared by grinding of the cerebral cortex and their digestion by papain. Cells were washed inhibitor ovomucoid enzyme and Dnazol and I were sown covered with poly-D-lysine tablets with DMEM high glucose containing 10% heat inactivated processing fetal calf serum, L-glutamine, penicillin and streptomycin. The output neurons was 10×7 on the embryo, and 80-90% of them were viable when assessing staining Trifanova blue.

Neurons were cultured in complete medium at 37°C in a normal atmosphere for 48 h before conducting experiments with hypoxia. To play hypoxia normal cell medium was replaced with medium containing no serum depletion kislorodnyi incubated in an atmosphere of 95% N 2/5% CO2during different periods of time. Compounds were dissolved in DMSO at a concentration of 100 mm and then diluted in medium and added into the culture, starting from time = 0. The level of apoptosis was determined using the set for the production of ELISA for detection of cell death (Roche), which can be used to detect DNA fragmentation. The tablets were analyzed at 405 nm. Controls consisted of cells cultured under aerobic conditions in a medium containing serum (+ serum)and cells cultured under aerobic conditions in a medium without serum (serum).

Table 3 presents the results of determining the activity of selected compounds of this invention tested individually in the test-induced hypoxia apoptosis of rat cortical neurons.

Example 43

Test anti-Fas-induced apoptosis

Cellular apoptosis can be induced by binding of Fas-ligand (FasL) with its receptor, CD95 (Fas). CD95 is one of the close family of receptors, known as death receptors that can trigger apoptosis in cells through the activation of a cascade of enzyme caspase. The process is initiated by the binding molecules adapter FADD/MORT-1 c cytoplasmic domain of the complex CD95 receptor-ligand. Then the caspase-8 binds to FADD and AK is EVERETTE, initiating a cascade of events involving the activation of downstream" of caspases and subsequent cell apoptosis. Apoptosis can also be induced in cells expressing CD95, for example in cell lines cell lymphoma Jurkat E6.1 T, using antibodies, but not FasL binding of CD95 cell surface. Anti-Fas-induced apoptosis is also triggered by the activation of caspase-8. This provides the basis for cellular test for screening compounds inhibiting mediated by caspase-8 apoptosis.

The course experience

Cells Jurkat E6.1 were cultured in complete medium consisting of RPMI-1640 (Sigma No.) + 10% fetal calf serum (Gibco BRL No. 10099-141) + 2 mm L-glutamine (Sigma # G-7513). Cells were harvested in the logarithmic growth phase. 100 ml of cell titer 5-C5cells/ml was transferred into a sterile centrifuge Falcon tubes with a capacity of 50 ml and centrifuged for 5 min at 100×g at room temperature. The supernatant was removed and combined cellular precipitation, obtained after centrifugation, resuspendable in 25 ml of complete medium. Determined the number of cells and brought the full density medium to 2×106cells/ml

The test compound was dissolved in dimethyl sulfoxide (DMSO) (Sigma # D-2650) with a 100 mm stock solution. It was diluted to 400 μm in complete medium, and then was preparing a series of dilutions in 96-lonodn the m tablet before you make the tablet for setting the test cell.

100 μl of cell suspension (2×106) were introduced into each well of a sterile 96-well round-bottom advance of the tablet (Costar No. 3790). 50 μl of a solution of the compound at the appropriate dilution and 50 μl of anti-Fas antibodies, clone CH-11 (Upstate, Cat No. 1544675) with a final concentration of 10 ng/ml was added to the wells. Control wells consisted of minus antibodies and negative connection, but contained a serial dilution of DMSO as a control for the solvent. The plates were incubated for 16-18 h at 37°C in an atmosphere of 5% CO2and 95% humidity.

Apoptosis of cells was assessed by quantification of DNA fragmentation using the set for a production of "test for detection of cell death" produced by Roche Diagnostics, No. 1544675. After incubation for 16-18 h analytical plates were centrifuged at 100×g at room temperature for 5 minutes, 150 μl of supernatant was removed and replaced by 150 μl of fresh complete medium. Then the cells were collected and added into each well 200 μl of a buffer for lysis available in the analytical set. The cells were washed to ensure complete lysis and incubated for 30 min at 4°C. Then the plates were centrifuged at 1900×g for 10 min and supernatant was diluted 1:20 in the given buffer for incubation. Then 100 μl of this solution was analyzed according to the manufacturer's instructions, pritave is passed to the set. After 20 min was determined by optical density (OD405 nm after making the final of the substrate on the reader SPECTRAmax Plus plate (Molecular Devices). Build a graph of values OD405 nm on the concentration of the compounds was calculated IC50 values for compounds using curve SOFTmax Pro (Molecular Devices) using the option from the four options.

Selected compounds were analyzed in this test, and it was shown that they inhibit Fas-induced apoptosis of Jurkat cells with values IC50in the range from 0.001 μm to 0.15 μm.

Despite the fact that the applicants have described a number of embodiments of the present invention, it is obvious, it is clear that their main examples can be modified by providing other embodiments, using the compounds and methods according to this invention. Therefore, it is clear that the scope of the present invention will largely be determined by the attached claims rather than specific implementation options that were presented in the example above.

1. The compound of formula I:

in which R1is R6CO)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-;
R2represents a hydrogen atom, -CF3or R8;
R3represents a hydrogen atom or (C1-C4)aliphatic group;
R4is-COOH;
R5represents-CH2F or-CH2O-2,3,5,6-tetrafluorophenyl;
R6represents (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and R6substituted by up to 6 substituents, independently selected from R;
R represents a halogen atom, -OR7and R7;
R7represents (C1-C6)aliphatic group,
R8represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group.

2. The compound according to claim 1:

in which:
R1is R6C(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-or (R6)2NC(O)C(O);
R2represents a hydrogen atom, -CF3or R8;
R3represents a hydrogen atom or (C1-C4)aliphatic groups;
R4is-COOH;
R5represents-CH2F or-CH2O-2,3,5,6-tetrafluorophenyl;
R6represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, and where R6substituted by up to 6 substituents, independently selected from R;
R represents a halogen atom, -OR7or-R7;
where R7represents (C1-C6)aliphatic group; and
R8represents (C1-C12)aliphatic the forge - or (C3-C10)cycloaliphatic group.

3. The compound according to claim 1, in which R5represents-CH2O-2,3,5,6-tetrafluorophenyl.

4. The compound according to claim 2, in which R5represents-CH2O-2,3,5,6-tetrafluorophenyl.

5. The compound according to claim 1, in which R5represents-CH2F.

6. The compound according to claim 2, in which R5represents-CH2F.

7. The compound according to claim 1, in which R1is R6C(O)-.

8. The compound according to claim 1, in which R1is R6SO2-.

9. The compound according to claim 1, in which R1is R6-.

10. The compound according to claim 1, in which R1is (R6)2NC(O)-.

11. The compound according to claim 1, in which R1is (R6)(H)NC(O)-.

12. The compound according to claim 1, in which R1is (R6)OC(O)-.

13. The connection according to one of claims 1 to 12, in which R6represents (C1-C4)aliphatic group, (C3-C10)cycloaliphatic group, (C3-C10)heterocyclyl, (C6-C10)aryl-; and R6optionally substituted.

14. The connection according to one of claims 1 to 12, in which R6represents (C1-C4)aliphatic group or a (C6-C10)aryl-, where aryl optionally substituted.

15. The connection according to one of claims 1 to 12, in which R6represents (C1-C4)aliphatic group or a (C6-C10)aryl-, where aryl optionally substituted.

16. The connection according to one of claims 1 to 12, in which the aliphatic group is (C1-C4)alkyl-./p>

17. The connection according to one of claims 1 to 12, in which R2represents a hydrogen atom, CF3or CH3.

18. The connection 17 in which R2represents a hydrogen atom or CF3.

19. The connection according to one of claims 1 to 12, in which R3represents (C1-C4)alkyl-.

20. The connection according to claim 19, in which R3represents ethyl.

21. A compound selected from
(S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Butylimino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-{2-[3-(Cyclopropanecarbonyl)-2-oxo-2H-pyridin-1-yl]bucillamine}-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Isobutylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-{2-[3-(2-Methoxyethylamine-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-(2-{3-[(Furan-2-carbonyl)amino]-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-(2-{3-[(Furan-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}butyramide]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-(2-{2-oxo-3-[(pyridine-3-arbonyl)amino]-2H-pyridine-1-yl}bucillamine)-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-(2-{3-[(Isothiazol-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}bucillamine)-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Acetylamino-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-{2-[3-(3-Ethylurea)-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-{2-[3-(3,3-Diethylurea)-2-oxo-2H-pyridin-1-yl]bucillamine}-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-(2-{2-oxo-3-[(pyrrolidin-1-carbonyl]amino-2H-pyridine-1-yl}bucillamine)-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-[3-Methoxycarbonylamino-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-[3-Ethanolamine-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-{2-[2-oxo-3-(propane-1-sulfonylamino)-2H-pyridine-1-yl]bucillamine}-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Benzosulfimide-2-oxo-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Ethanolamine-2-oxo-trifluoromethyl-2H-pyridin-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[3-Methyl-2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-3-[2-(3-Ethanolamine-2-oxo-2H-pyridin-1-yl)-3-methylbutylamine]-4-oxo-5-(2,3,5,6-tetraterpenes)pentanol acid
(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)propionamido]pentanol acid
(S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)propionamido]-5-fluoro-4-oxopentanoic acid
(S)-3-{2-[3-(2,6-Dichloraniline)-2-oxo-2H-pyridin-1-yl]propionamide}-5-fluoro-4-oxopentanoic acid
(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)propionamido]pentanol acid
(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)Butylimino] pentanol acid
(S)-3-[2-(3-Benzoylamino-2-oxo-2H-pyridin-1-yl)propionamido]-5-fluoro-4-oxopentanoic acid
(S)-3-{2-[3-(2,6-Dichloraniline)-2-oxo-2H-pyridin-1-yl)Butylimino}-5-fluoro-4-oxopentanoic acid
(S)-5-fluoro-4-oxo-3-[2-{2-oxo-3-[(pyridine-2-carbonyl)amino]-2H-pyridine-1-yl} bucillamine)pentanol acid
(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino] pentanol acid
(S)-5-fluoro-4-oxo-3-{2-[2-oxo-3-(2-m-tolylacetylene)-2H-pyridine-1-yl)Butylimino}pentanol acid
(S)-5-fluoro-4-oxo-3-[2-(2-oxo-3-propionamido-2H-pyridine-1-yl)pentanediamine}pentanol acid
(S)-5-fluoro-3-[4-methyl-2-(2-oxo-propionamido-2H-pyridine-1-yl)pentanediamine]-4-oxopentanoic acid
(S)-5-fluoro-3-[2-(5-methyl-2-oxo-3-phenylacetylamino-2H-pyridine-1-yl)Butylimino]-4-oxopentanoic acid
(S,S)-4-Oxo-{2-[2-oxo-3-(thiazol-2-ylamino)-2H-pyridine-1-yl)Butylimino}-5-(2,3,5,6-tetraterpenes)pentanol acid
(S,S)-4-Oxo-3-[2-(2-oxo-3-propylamino-2H-pyridine-1-yl)Butylimino]-5-(2,3,5,6-tetraterpenes)pentanol acid.

22. Pharmaceutical composition having caspase-inhibitory activity containing:
a) a compound according to one of claims 1 to 21; and
b) a pharmaceutically acceptable carrier, adjuvant or excipient.

23. The method of treatment mediated IL-1 disease mediated apoptosis diseases, inflammatory diseases, autoimmune diseases, destructive bone diseases, proliferative diseases, infectious diseases, degenerative diseases, diseases associated with cell death, viral disease, or liver disease in a patient, comprising the administration to a patient a therapeutically effective amount of a compound according to one of claims 1 to 21 or a pharmaceutical composition according to item 22.

24. A method of treating rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, psoriasis, respiratory distress syndrome of adults, inflammatory bowel disease, Crohn's disease, pancreatitis, glomerulonephritis, chronic active hepatitis, diseases of transportation shall antat against the owner, transplant rejection, myocardial infarction, myocardial ischemia, atherosclerosis, cerebral ischemia, amyotrophic lateral sclerosis, multiple sclerosis, brain injury, neurological damage due to stroke, sepsis, septic shock, hepatitis b, hepatitis C, hepatitis G, liver disease, kidney disease, complications associated with vascular shunt in a patient, comprising the administration to a patient a therapeutically effective amount of a compound according to one of claims 1 to 21 or a pharmaceutical composition according to item 22.

25. The method according to paragraph 24, in which the disease is osteoarthritis, pancreatitis, asthma, respiratory distress syndrome of adults, rheumatoid arthritis, systemic lupus erythematosus, thrombocytopenia, chronic active hepatitis, inflammatory bowel disease, Crohn's disease, psoriasis, disease graft-versus-host, sepsis, septic shock, cerebral ischemia, myocardial ischemia or neurological disruption resulting from a stroke.

26. The method according to paragraph 24, in which the disease is a complication associated with artificial anastomosis of the coronary artery.

27. The method of inhibition mediated by caspase function in a patient, comprising the administration to a patient a therapeutically effective amount of a compound according to one of claims 1 to 21 or pharmaceuticalcompanies on p.22.

28. The way to reduce production IGIF or IFN-β in a patient, comprising the administration to a patient a therapeutically effective amount of a compound according to one of claims 1 to 21 or a pharmaceutical composition according to item 22.

29. The method of preservation of cells, where the method includes a step of storing cells in a bath in a solution of compounds according to one of claims 1 to 21.

30. The method according to clause 29, where these cells are located in the
(a) the authority designated for transplant; or
b) the product of blood.

31. The method of obtaining the compounds of formula (I):

R1is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-;
R2represents a hydrogen atom, -CF3or R8;
R3represents a hydrogen atom or (C1-C4)aliphatic group;
R4is-COOH;
R5represents-CH2F or-CH2O-2,3,5,6-tetrafluorophenyl;
R6represents (C1-C12)aliphatic group or -(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and R6substituted by up to 6 substituents, independently selected from R;
R represents a halogen atom, -OR7or R7;
R7represents (C1-C6)aliphatic group;
R8represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group, including:
(a) interaction is soedineniya formula (III):

in which
R9is-NO2, -C(O)OR10, -CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)-;
R10independently represents a hydrogen atom, (C1-C12)aliphatic-(C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, (C5-C10)heteroaryl-(C1-C12)aliphatic group, where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N(H), N(R), S, SO and SO2; and where R10optionally substituted with up to 6 substituents, independently selected from R; and
R, R2, R3and R6have the meanings defined above;
with the compound of the formula (IV):

in which Y is either a carbonyl group or-group; and R4and R5have the meanings defined above;
in the presence of a solvent and condensation;
provided that when Y is HE group, the method further includes (b) oxidation of the Oh-group to obtain the compounds of formula (I); and
provided that when R9is-NO2, -C(O)OR10or-CN, the method further includes turning-NO2 , -C(O)OR10or-CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)-.

32. The method according to p, in which the compound of formula (III):

where R2represents a hydrogen atom, -CF3or R8;
R3represents a hydrogen atom or (C1-C4)aliphatic group;
R9is-NO2, -C(O)OR10, -CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)-;
R6represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and R6substituted by up to 6 substituents, independently selected from R;
R represents a halogen atom, -OR7or R7;
where R7represents (C1-C6)aliphatic group, and
R8represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group,
get way, including
the interaction of the compounds of formula (V):

in which R10independently represents a hydrogen atom, (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, (C5-C10)heteroaryl-, (C3-C10)cycloaliphatic-(C1-C12)aliphatic group, (C6-C10)aryl-(C1-C12)aliphatic group, (C3-C10)heterocyclyl-(C1-C12)aliphatic group, - (C5-C10)heteroaryl-(C1-C12)aliphatic group, where up to 3 aliphatic carbon atoms may be substituted by a group selected from O, N, N(R), S, SO and SO2;
R, R2, R3and R9have the meanings defined above;
agent for removing the protective groups (deprotonate agent) in a solvent under conditions suitable for removing the protective group.

33. The method according to p, in which the compound of formula (V):

in which R2, R3, R9and R10have the meanings defined in p;
get the method including:
the interaction of the compounds of formula (VI):

in which R2and R9have the meanings defined in p;
with the compound of the formula (VII):

in which X represents a suitable leaving group; and
R3and R10have the meanings defined above;
in the presence of a solvent and base.

34. The method of obtaining the compounds of formula (I):

in which R1is R6C(O)-, HC(O)-, R6SO2, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-;
R2represents a hydrogen atom, -CF3or R8;
R3represents a hydrogen atom or (C1-C4)aliphatic group;
R4is-COOH;
R5represents-CH2F or-CH2O-2,3,5,6-tetrafluorophenyl;
Rsup> 6represents (C1-C12)aliphatic group, (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-, and where R6substituted by up to 6 substituents, independently selected from R;
R represents a halogen atom, -OR7or-R7;
R7represents (C1-C6)aliphatic group;
R8represents (C1-C12)aliphatic -, or (C3-C10)cycloaliphatic group, including:
a) interaction of the compounds of formula (III):

in which R9is-NO2, -C(O)OR10, -CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)N(H)-, R6N(H)-, (R6)2NC(O)C(O)N(H)-; and
R2, R10and R6have the meanings defined above;
with the compound of the formula (X):

in which Y is either a carbonyl group or-group; and R3, R4and R5have the meanings defined above;
in the presence of a solvent and under conditions of condensation;
provided that when Y is HE group, the method further includes (b) oxidation of the Oh-group to obtain the compounds of formula (I); and
provided that when R9is-NO2, -C(O)OR10or-CN, the method further includes turning-NO2, -C(O)OR10or-CN, R6C(O)N(H)-, R6SO2N(H)-, R6OC(O)N(H)-, (R6)2NC(O)NH)-, R6N(H)-, (R6)2NC(O)C(O)N(H)-.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention can be used for treating or preventing diseases and conditions, mediated by peroxisome proliferator activated gamma receptor (PPARγ). In formula (I) W represents a COOH group or -COOC-C1-C4alkyl; Y represents NH; Z represents S or O; X represents O; R1-R6 each independently represents a hydrogen atom or substitute, chosen from a group consisting of: C1-C4-alkyl, thienyl or phenyl, where phenyl is optionally substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, a halogen atom; -NO2 and -CN; A represents C1-C4-alkyl, -N(C1-C4-alkyl)-CO-C3-C7-cycloalkyl, aryl, chosen from a group consisting of phenyl, naphthyl, or heteroaryl, chosen from a group consisting of oxazolyl, isoxazolyl, thienyl, pyridyl, thiazolyl, thiadiazolyl, benzo[b]thienyl, imidazolyl, indolyl and carbazolyl, where aryl and heteroaryl are substituted or not substituted with one or more substitutes, independently chosen from a group consisting of C1-C4-alkyl, C1-C4-alkoxy, phenyl and a halogen atom; and n is an integer from 0 to 4. The invention also relates to a pharmaceutical composition, containing the invented compound as an active component, use of the compounds to make a medicinal agent, and method of treatment.

EFFECT: obtaining new biologically active compounds.

22 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invented compounds have inhibitory activity towards protein kinase. In formula 1a m lies between 0 and 1, R1 is chosen from a group which includes hydrogen, methyl, isopropyl, imidazolylpropyl, piperazinylpropyl, pyridinyl, diethylaminopropyl, hydroxyethyl, pyrimidinyl, morpholinopropyl, phenyl, cyclopropyl, morpholinoethyl, benzyl and morpholino, where any of pyridinyl, imidazolyl, piperazinyl or pyrimidinyl in R1 are optionally substituted with 1-3 radicals, independently chosen from a group, which includes methyl, methylamine, dimethylaminomethyl, cycloproylamine, hydroxyethylamine, diethylaminopropylamine, pyrrolydinylmethyl, morpholino, morpholinomethyl, piperazinylmethyl and piperazinyl, where any of morpholino and piperazinyl in R1 are optionally further substituted with a radical, chosen from a group which includes methyl, hydroxyethyl and ethyl, R2, R3 and R5 each represents hydrogen, R4 represents methyl, L is chosen from a group which includes -NR5C(O)- and -C(O)NR5-, R10 represents trifluoromethyl, and R11 is chosen from a group which includes halogen, morpholinomethyl, piperazinyl, optionally substituted with a methyl, ethyl or hydroxyethyl group; piperazinylmethyl, optionally substituted with a methyl or ethyl group, imidazolyl, optionally substituted with methyl, pyrrolidinylmethoxy and piperidinyl, optionally substituted with a hydroxy group.

EFFECT: more effective treatment.

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invented compounds have antagonist properties towards CB1 receptors. In formula (I) , R1 is a lower alkoxy, (lower alkyl amino)-(lower alkoxy) or -N(Ra)Rb; Ra is hydrogen, lower alkyl, carbamoyl-(lower alkyl), hydroxy-(lower alkyl), dihydroxy-(lower alkyl), lower alkynyl, lower alkoxy, (lower alkoxy)-(lower alkyl), di-(lower alkylamino)-(lower alkyl), C3-6cycloalkyl; or Ra is a phenyl-(lower alkyl) group, where the phenyl fragment can be optionally mono-substituted, independently, by lower alkyl, lower alkoxy or halogen; or Ra is a 5- or 6-member heteroaromatic ring system, containing one or two nitrogen atoms in the ring, where the said heteroaromatic ring system is bonded to the remaining part of the molecule by lower alkylene; or Ra is a 5-, 6- or 7-member saturated heterocyclic ring system, containing one nitrogen heteroatom, where the said heterocyclic ring system is optionally mono-substituted by lower alkyl; Rb is hydrogen, lower alkyl or (lower alkoxy)-(lower alkyl); or Ra and Rb together with a nitrogen atom to which they are bonded, for a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring system, optionally containing an extra heteroatom, which is chosen from nitrogen, oxygen or sulphur, where the said heterocyclic ring system is optionally mono- or disubstituted, independently, by lower alkyl, hydroxy group, hydroxy-(lower alkyl), lower alkoxy, (lower alkoxy)-(lower alkyl) group, cyano group, halogen, phenyl and/or benzyl; R2 is hydrogen or lower alkyl; R3 is phenyl, mono- or disubstituted, independently, by lower alkoxy, halogen, or perfluoro-(low alkoxy) group; and R4 is phenyl, which is mono- or disubstituted with a halogen.

EFFECT: new compounds have useful biological properties.

18 cl, 195 ex

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention is related to compounds of formula (II) as inhibitor of leukotriene A4-hydrolase (LTA4H) and their enantiomers, racemic compounds and pharmaceutically acceptable salts, and also to treatment methods, method inhibition and pharmaceutical composition on their basis. In general formula (II) , X is selected from group that consists of O and S; Y is selected from group that consists of CH2 and O; R4 represents H; R6 represents H or F; and R2' is determined as R2, and R3' is determined as R3, as follows: R2 and R3, each, is independently selected from group that consists of A) H, C1-7alkyl, C3-7cycloalkyl, where each of substitutes of A) is independently substituted with 0 or 1 RQ, and each of mentioned RQ is substitute at carbon, which is distanced from nitrogen at least by one carbon atom; alternatively, R2 and R3, taken together with nitrogen, to which they are connected, create heterocyclic ring, which contains at least one heteroatom, which is specified nitrogen of connection, and specified heterocyclic ring is selected from group that consists of i) (4-7)-member heterocyclic ring HetRb, where specified (4-7)-member heterocyclic ring HetRb has single heteroatom, which is specified nitrogen of connection, and 0, 1 or 2 are substituted by substitutes at the same or different substituted atoms, at that specified substitutes are selected from group that consists of -RY, -C(O)RY, -C0-4alkylCO2RY, -C0-4alkylC(O)NRYRZ, -C0-4alkylNRYC(O)Rz, -C0-4alkylNRYC(O)CH2ORY, -C0-4alkylNRYCO2RY, -C0-4alkylNRYC(O)NRYRz, -C0-4alkylNRyC(S)NRyRz, -NRyC(O)CO2Ry, -C0-4alkylNRwSO2RY, tetrazol-5-yl, -C0-4alkylN(RY)(SO2)NRYRY, -C0-4alkylN(RY)(SO2)NRYCO2RY, ii) (5-7)-member heterocyclic ring HetRc, where specified (5-7)-member heterocyclic ring has single additional heteroatom distanced from specified nitrogen of connection at least by one carbon atom, thereat the specified additional heteroatom is selected from group that consists of O, S(=O)0-2 and >NRM, and where mentioned (5-7)-member heterocyclic ring HetRc has 0 or 1 carbonyl group; iv) one of 2,8-diazaspyro[4.5]decan-1-on-8-yl, 4-{[(2-tret- butoxycarbonylaminocyclobutancarbonyl)amino]methyl}-piperidine-1-yl, 4-{[(2-aminocyclobutancarbonyl)amino]methyl}piperidine-1-yl, tret-butyl ether of 3,9-diazaspyro [5.5]undecan-3-carbonic acid-9-yl; where RK is selected from group that consists of H, -C1-4alkyl, each not necessarily substituted by 1 substitute RN; RM is selected from group that consists of -SO2RY, -C(O)RY, -C(O)C1-4alkylORY, each not necessarily substituted by 1 substitute RN; RN is selected from group that consists of OH, NH2, CF3; RQ is selected from group that consists of -C0-4alkylRAr', -C0-4alkylCO2RY, -C0-4alkylNRYRz, -C0-4alkylNRYCORY, -C0-4alkylNRyCONRyRz; Rw is selected from group that consists of RY and -C3-7cycloalkyl; RY is selected from group that consists of H, -C1-4alkyl, -C0-4alkylRAr and -C0-4alkylRAr', each not necessarily substituted by 1 substitute RN; Rz is selected from group that consists of RY, -C1-2alkylCO2RY; RAr represents fragment connected via carbon atom, and specified fragment is selected from phenyl, pyridyl; RAr' represents (5-6)-member cyclic ring, having 1 or 2 heteroatoms selected from group that consists of O, N and >NRY, having 0 unsaturated connections, having 0 or 1 carbonyl group, where each atom, when allows for valency, in every of mentioned cyclic rings is independently substituted by 0 or 1 RK; provided that (a) specified R2' and R3', moreover, satisfy the following requirements: (e1): specified R2' and R3', both, are not H, when Y represents O and X represents S; (e3): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperazine group, when X represents O and Y is one of O and CH2; (e4): specified R2' and R3', taken together with nitrogen, with which they are connected, do not create piperidine group, which is mono-substituted by 6-member cyclic group, when X represents O and Y is one of O and CH2; and (e5): specified R2' and R3', taken together with nitrogen, with which they are connected, create neither substituted piperidine group or substituted piperazine group, where specified substituted piperidine group or specified substituted piperazine group is substituted in position 4 by substitute XG, at that specified XG has structure , where n=0, 1, and when ne=1, then XL represents C1-6alkyl, OSG represents O or S, and XR1 and XR2, taken together with nitrogen, with which they are connected, create one of piperidine group, piperazine group, morpholine group, thiomorpholine group and pyrrolidine group, or each of XR1 and XR2, taken independently, represent one of H, C1-6alkyl, aryl, aralkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, heteroalkyl, heteroaryl-C1-6alkyl, heterocycloalkyl and heterocycloalkyl-C1-6alkyl; where aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl may be not necessarily substituted by one or several substitutes, independently selected from halogen, hydroxy, C1-6alkyl, C1-6alkoxy, halogenated C1-6alkyl, halogenated C1-6alkoxy, nitro, cyano, amino, C1-4alkylamino, di(C1-4alkyl)amino, heteroaryl or heterocycloalkyl; and (b) further provided that when X represents S and Y represents O, then one of R2' and R3' is not XCG, while the other represents C1-6alkyl, where XCG represents group , where HC16 represents one of H, C1-6alkyl, halogenC1-6alkyl, allyl and C1-6alcoxymethyl, and GO represents group connected to carbon atom, which has substitute =0, creating amido group with nitrogen, with which all mentioned GO group is connected.

EFFECT: compounds may find application for treatment and prevention of diseases mediated by LTA4H, for instance, asthma, chronic obstructive lung disease, atherosclerosis, rheumatoid arthritis, disseminated sclerosis, inflammatory disease of bowels and psoriasis.

39 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: medicine.

SUBSTANCE: invention refers to salt N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide, particularly bismaleate N,2-dimetyl-6-[7-(2-morpholinoethoxy)chinoline-4-iloxy]benzofuran-3-carboxamide with antitumor activity.

EFFECT: cancer treatment availability.

11 cl, 35 dwg, 9 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention 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: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new coumarin derivatives and their carboxamides, with general formula (I) , where R3 is chosen from a group consisting of H, carboxyl, alkyloxycarbonyl, 5'-(phenyloxadiazol-2')-yl, 5'-(pyridyl-4"-oxadiazol-2')-yl, , CONHR9, where R9 is chosen from a group consisting of fatty acids C2-C8, benzoxamido, isonicotinamido, unsubstituted, or mono-, or polysubstituted phenyl, in which the substitute can be hydroxy, C1-C8-alkoxy, CF3, carboxyl, alkyloxycarbonyl, OCH2CO2H, NO2, halogen, SO3H, SO2NHR11, where R11 is chosen from a group consisting of hydrogen, amidino, 2"-thizolyl, 3"-(511-methylisooxazolyl), 2"-pyrimidinyl, 2"-(4",6"-dimethylpyrimidinyl), 4"-(5",6"-dimethoxypyrimidinyl); R4 is chosen from a group consisting of hydrogen, CONHR10, where R10 is chosen from a group consisting of C2-C8 fatty acids, unsubstituted phenyl; R5 is chosen from a group consisting of H, C1-C4 alkyl; R6 is chosen from a group consisting of H, C1-C12-alkyl, halogen, NO2, CONHR13, where R13 is substituted phenyl; R7 is chosen from a group consisting of H, hydroxyl, C1-C4alkyl or alkoxyl, carboxyalkyleneoxyl, OCH2CONHR14, where R14 is chosen from a group consisting of unsubstituted, mono-, or polysubstituted phenyl, in which the substitute can be hydroxyl, OCH3, CF3, CO2H, CO2C2H5, NO2; R8 is chosen from a group consisting of H, C1-C4-alkyl or alkoxyl, NO2; under the condition that, when R3, R5 and R6 are H, and R7 is OH, R4 and R7 are not groups, chosen from H, C1-C6-alkyl or C1-C6-alkoxy. The invention also relates to pharmaceutical compositions based on formula I compounds and their use as medicinal preparations for protecting kidneys, for curing hypertonia, cardio-cerebrovascular diseases, non-achrestic diabetes, tumours, precancerous diseases and oedema.

EFFECT: enhanced effectiveness of the composition and treatment method.

17 cl, 6 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention is related to new compound - 1-((3-pyridylcarbonyl)aminomethyl)-1-cyclohexane acetic acid of formula I and its pharmaceutically acceptable salts, which display nootropic, anticonvulsive, anxiolytic properties and may find application as neurotropic drug. Compound I is produced by condensation of alkyl ether of 3-pyridine-carbonic acid with salt 1-(aminomethyl)cyclohexane acetic acid, normally, in organic dissolvent at dissolvent boiling temperature with further treatment with mineral or organic acid, if required.

EFFECT: in order to produce salt of compound I, it is treated usually with oxide hydrate or oxide of alkaline or alkali-earth metal.

5 cl, 8 tbl, 5 ex

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