Enzyme inhibiting compounds

FIELD: chemistry.

SUBSTANCE: invention relates to α',β'-epoxides of peptides of formulae (III) and (IV) which inhibit chymotrypsin-like activity of 20S proteasome.

EFFECT: increased effectiveness of the compounds.

19 cl, 29 ex

 

The technical field

This invention relates to compounds and methods for inhibition of enzymes. In particular, the invention relates to therapeutic methods based on the inhibition of enzymes.

The level of technology

In eukaryotes protein degradation is mainly mediated pathway of ubiquitin, in which proteins that are targeted for destruction, with the subsequent ligation with the polypeptide of 76 amino acid ubiquitin. Targeted, ubiquitinated proteins then serve as substrates for the 26S proteasome, a multicatalytic protease that cleaves proteins into short peptides by the actions of its three major proteolytic activities. Having the main function in the intracellular metabolism of protein-mediated proteasome degradation also plays a key role in many processes, such as the presentation of major histocompatibility complex (MHC) class I, apoptosis, cell division and activation of NF-κB.

20S proteasome is a 700 kDa complex multicatalytic proteases cylindrical shape, containing 28 subunits arranged in four rings, which plays an important role in the regulation of cell growth, the presentation of major histocompatibility complex (MHC) class I, apoptosis, processing of antigens, activation of NF-κB and transduction proposal the positive signals. In yeast and other eukaryotes 7 different α subunits form the outer ring, and 7 different β subunits make up the inner ring. Subunit α serve as binding sites for the 19S (PA700) and 11S (PA28) regulatory complexes, as well as a physical barrier to internal proteolytic cavity formed by two rings of β subunits. Thus,in vivothe proteasome, is believed to exist in the form of particles 26S ("26S proteasome"). Experimentsin vivoshowed that you can easily find the relationship between inhibition shaped 20S proteasome and inhibition of the 26S proteasome. Cleavage N-terminal proposedvalue β subunit during formation of the particle releases the N-terminal threonine residues that serve as catalytic nucleophiles. Subunit, responsible for the catalytic activity of the proteasome, thus, contain N-terminal nucleophilic residue, and these subunits belong to the family of hydrolases with N-terminal nucleophilic group (Ntn) (where N-terminal nucleophilic residue is, for example, Cys, Ser, Thr, and other nucleophilic groups). This family includes, for example, penicillin-G-acylase (PGA), penicillin-V-acylase (PVA), glutamine-FCF-amidotransferase (GAT) and bacterial glucosylceramidase. In addition to the common expressiom the m subunits β, higher vertebrates have three induced by γ-interferon β subunit (LMP7, LMP2 and MECL1), which replaces their normal corresponding parts, X, Y, and Z, respectively, thus changing the catalytic activity of the proteasome. Using a variety of peptide substrates three main proteolytic activity were determined for 20S proteasome in eukaryotes: chymotrypsin-like activity (CT-L), at which fission occurs after large hydrophobic residues; trypsin-like activity (T-L), in which there is a cleavage after basic residues, and peptidylglutamyl-peptideatlas activity (PGPH), in which there is a cleavage after acidic residues. The proteasome is also credited with two additional less studied activity: activity BrAAP at which fission occurs after the branched chain amino acids, and the activity of SNAAP at which fission occurs after a small neutral amino acids. In the main proteolytic activity of the proteasome, apparently, contribute different catalytic sites, as inhibitors, point mutations in the β subunits and replacement induced by γ-interferon β subunits modify these activities to varying degrees.

There are several examples of small molecules that are used for Inga is investing proteasome activity; however, these compounds, mainly, lack of specificity, stability, or activity required for the study and use of the role of the proteasome at the cellular and molecular level. Therefore, the synthesis of low molecular weight inhibitor(s) with high specificity to the binding site of, with improved stability and solubility and increased activity necessary to carry out the study of the role of the proteasome at the cellular and molecular level.

The invention

The invention relates to a class of molecules known as α',β'-epoxy peptides and α',β'-aziridine peptides. Assume that the original molecules are effectively irreversibly and selectively contacted by hydrolases containing N-terminal nucleophilic group (Ntn), and can specifically inhibit certain enzymes with multiple catalytic activity.

Earlier it was suggested that the proteasome only remove denatured proteins and proteins with incorrect styling, and now found that the proteasome form a proteolytic system, which regulates the levels of a variety of intracellular proteins through their degradation-dependent signals way. Therefore, there is great interest in the detection reagents that can specifically change actively the ti proteasome and other Ntn hydrolases and, thus, be used as probes to study the role of these enzymes in biological processes. Here described, synthesized and tested compounds that act on Ntn hydrolases. Described and claimed epoxides peptides and aziridine peptides, which may be very selectively and irreversibly inhibit the specific activity of the proteasome.

Unlike some other inhibitors on the basis of the peptides described here epoxides peptides and aziridine peptides, as expected, not significantly inhibit neproseyannye protease, such as trypsin, chymotrypsin, cathepsin, papain and calpain, at concentrations up to 50 μm. At higher concentrations can be observed inhibition, but would be expected that it will be competitive and not irreversible, if simply inhibitor competes with the substrate. Also expect new peptide epoxides and aziridines peptides inhibit the activation of NF-κB and stabilize the levels of p53 in cell culture. In addition, these compounds are expected to possess anti-inflammatory activity. Thus, these compounds may represent a unique molecular probes that have the versitility to study the function of the enzyme Ntn under normal biological and pathological processes.

In one aspect invented the e refers to inhibitors, includes a three-membered ring containing a heteroatom. Such inhibitors can inhibit the catalytic activity of enzymes hydrolases with N-terminal nucleophilic group (e.g., 20S proteasome or 26S proteasome), if these inhibitors are present in concentrations below approximately 50 microns. Relative to the 20S proteasome, specific inhibitors hydrolases inhibit chymotrypsin-like activity of the 20S proteasome, when the inhibitor is present at concentrations below about 5 microns, and does not inhibit trypsin-like activity or PGPH activity of the 20S proteasome, when present at concentrations below about 5 microns. Nucleoside hydrolases can represent, for example, α',β'-epoxyketone or α',β'-aziridine, and the peptide can be tetrapeptide. The peptide may include branched or linear side chains, such as hydrogen, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl, C1-6-aralkyl, C1-6-alkylamide, C1-6-alkylamino, C1-6-carboxylic acid, C1-6-ether carboxylic acid, C1-6-alkylthiol or C1-6-alkylthiomethyl, for example isobutyl, 1-naphthyl, phenylethyl and 2-phenylethyl. the α'-Carbon of α',β'-epoxyketone or α',β'-aziridination can be a chiral carbon atom, such as carbon in the configuration (R) or β as is and are defined here.

In another aspect the invention relates to pharmaceutical compositions comprising pharmaceutically acceptable carrier and a pharmaceutically effective amount of an inhibitor of hydrolases, which among other things improves the symptoms of neurodegenerative diseases (such as Alzheimer's disease), a condition that causes muscle wasting, cancer, chronic infectious diseases, fever, inactivity, muscle denervation, nerve is affected, starvation and associated with the immune system of the state.

In another aspect the invention relates to anti-inflammatory compositions.

In another aspect the invention relates to any of the following ways: inhibiting or reducing HIV infection in a patient; impact on the level of expression of a viral gene in a patient; changes multiple antigenic peptides produced by the proteasome in the body; determine whether regulated proteolytic activity of certain of Ntn hydrolases cellular process, developmental or physiological process or production in the body; the treatment of Alzheimer's disease in the patient; decreasing the rate of degradation of muscle proteins in a cell; reducing the rate of intracellular protein degradation in a cell; reducing the rate of degradation of p53 protein in the cell; inhibiting the growth associated with p53 cancers in patie the same; inhibition of antigen presentation in a cell; suppress the patient's immune system; inhibition of the degradation of IκB-α in the body; reducing the content of NF-κB in a cell, muscle, organ, or patient; effects on cyclin-dependent cycles of eukaryotic cells; the treatment of proliferative diseases; impact on dependent proteasome regulation of oncogenic proteins in the cell; treatment of tumor growth in a patient; treatment is associated with p53 apoptosis in a patient; and screening of proteins, processed by hydrolases with N-terminal nucleophilic group in the cell. Each of these methods includes the introduction or contacting an effective amount of the composition containing the described inhibitors hydrolases, the patient, in a cell, tissue, organ or organism.

Other characteristics and advantages of the invention will become apparent from the following detailed description and from the claims.

Detailed description of the invention

The invention relates to compositions, applicable as inhibitors of the enzyme. Song data, mainly applicable to the inhibition of enzymes containing a nucleophilic group on the N-end. For example, the activity of enzymes or subunits of enzymes containing N-terminal amino acids with nucleophilic groups in their side chains, such as threonine, with the Rin or cysteine, you can successfully inhibit described here inhibitors of the enzyme. The activity of enzymes or subunits of enzymes containing diaminotoluene nucleophilic group at their N-ends, such as, for example, protective groups or hydrocarbons, can also be successfully inhibit described here inhibitors of the enzyme.

Despite the fact that it is not linked to any particular theory of the process, I believe that this N-terminal nucleophilic group Ntn form covalent adducts with epoxy functional group described here inhibitors of the enzyme. For example, in the β5 subunit/Pre2 20S proteasome N-terminal threonine is considered irreversibly forms morpholinyl or piperazinovogo adduct by the reaction with the epoxide or aziridine peptide, such as described below. This adduct formation would entail splitting with opening of the epoxide cycle or aziridine.

Options for implementation, including such groups associated with the α'-carbon, the stereochemical configuration of the α'-carbon (carbon, which forms part epoxy or aziridine rings) can be either (R) or (S). The invention is based in part on structural and functional information described here, which involves the following preferred stereochemical configuration. It should be noted that preferred the additional compound may contain a large number of stereocenters, marked as vzaimoprityazhenie top-bottom (or β-α, where β, as depicted here, is above the plane of the page) or as (R)-(S) (i.e. it is not required that each stereocenter in connection meet the established preference). In some preferred embodiments, the implementation of the stereochemistry of the α'-carbon is a (R), then there is an atom X is at location β or above the plane of the molecule.

With regard to stereochemistry, the rules of Cahn-Ingold-Prelog to determine the absolute stereochemistry are the following. These rules are described, for example, inOrganic Chemistry, Fox and Whitesell; Jones and Bartlett Publishers, Boston, MA (1994); Section 5-6, pp 177-178, a section of which is thus incorporated here by reference. The peptides may contain a repeating structure of the main chain with side chains radiating from the link in the main chain. In General, each link in the main chain contains a side chain associated with it, although in some cases the side chain represents a hydrogen atom. In other embodiments, the implementation not every link in the main chain contains related side chain. Peptides used to obtain peptide epoxides or aziridines peptide, have two or more links of the main chain. In some embodiments, implementation, applicable for inhibition chymotrypsin-like activity (CT-L) of the proteasome, etc which has from two to eight links of the main chain, in some embodiments, the implementation for the inhibition of CT-L is from two to six links of the main chain.

Side chains extending from the links of the main chain may include natural aliphatic or aromatic side chains of amino acids, such as hydrogen (glycine), methyl (alanine), isopropyl (valine), sec-butyl (isoleucine), isobutyl (leucine), phenylmethyl (phenylalanine), and a side chain, which is the amino acid Proline. The side chain may also be branched or linear aliphatic or aromatic groups such as ethyl, n-propyl, n-butyl, tert-butyl and aryl-substituted derivatives such as 1-phenylethyl, 2-phenylethyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like compounds. Aryl groups may optionally be substituted branched or linear C1-6-alkyl groups or substituted alkyl groups, acetyl and the like, or optionally aryl groups or substituted aryl groups such as benzoyl and the like. Heteroaryl groups can also be used as substituents of the side chains. Heteroaryl groups include nitrogen-, oxygen - and sulfur-containing aryl group, such as thienyl, benzothiazyl, naftotiekis, thianthrene, furyl, pyranyl, isobenzo is Anil, chromanol, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, purinol, chinosol and the like.

In some embodiments, the implementation of polar or charged residues can be introduced into the peptide epoxides or aziridines peptides. For example, you can enter naturally occurring amino acids, such as hydroxy-group containing (Thr, Tyr, Ser) or sulfur-containing (Met, Cys)and non-essential amino acids, such as taurine, carnitine, citrulline, cystine, ornithine, norleucine and others. You can also type not found in the nature of the substituents of the side chains with charged or polar groups such as, for example, the chain C1-6-alkyl or C6-12-aryl group with one or more hydroxy-, alkoxy - short-chain, sulfide, thio-, carboxyl, ether, phospho-, amido and amino groups, or such substituents, substituted by one or more halogen atoms. In some preferred embodiments, implementation, there is at least one aryl group present in the side chain of the peptide part.

In some embodiments, the implementation of the links of the main chain are amide links [-NH-CHR-C(=O)-], where R represents a side chain. Such designation does not exclude naturally occurring amino acid Proline, or other non-naturally occurring cyclic secondary AMI is ocelote, which well-known experts in this field.

In other embodiments, implementation of the links of the main chain are N-alkylated amide links (for example, N-methyl and the like), olefinic counterparts (in which one or more amide linkages replaced with olefinic bond), analogs of tetrazole (in which the ring tetrazole gives CIS-configuration of the main chain) or combinations of such linkages in the main chain. In some embodiments, the implementation of the α-carbon of amino acids modified by the introduction of α-alkyl substituent, for example aminoadamantane acid. In some additional embodiments, the implementation side chains locally modified, for example, ΔE- or ΔZ-dihydromorphinone, which contains a double bond between the α and β atoms of the side chain, or, for example, ΔEor cyclopropene ΔZ-a modification that has cyclopropyl group between α and β atoms of the side chain. In yet some additional embodiments, implementation, using amino acid group, you can use D-amino acids. Additional implementation may include the cyclization of the side chain to the main chain, the formation of a disulfide bond, the formation of lactam, asosiasi and other modifications discussed in the book "Peptides and Mimics, Design of Conformationally Constrained" by Hruby and Boteju, in "Molecular Biology and Bitechnology: A Comprehensive Desk Reference", ed. Robert A. Meyers, VCH Publishers (1995), pp. 658-664, which, therefore, included here as a reference.

One aspect of the invention relates to compounds having the structure of formula (I)or their pharmaceutically acceptable salts.

where each A is independently selected from C=O, C=S and SO2preferably C=O;

each B is independently selected from C=O, C=S and SO2preferably C=O;

D is absent or represents a C1-8-alkyl;

G is selected from O, NH and N-C1-6-alkyl;

K is absent or is selected from C=O, C=S and SO2preferably K is absent or represents C=O;

L is absent or selected from C=O, C=S and SO2preferably L is absent or represents C=O;

M is absent or represents a C1-8-alkyl;

Q is absent or selected from O, NH and N-C1-6-alkyl, preferably Q is absent, represents O or NH, most preferably Q is absent;

X is selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

each V is independently absent or selected from O, S, NH and N-C1-6-alkyl, preferably V is absent or represents O;

W is absent or independently selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

Y is absent or selected from O, NH, N-C1-6-alkyl, S, SO, SO2, CHOR10and CHCO 2R10;

each Z is independently selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

R1, R2, R3and R4each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl, C1-6-aralkyl and R14DVKOC1-3-alkyl-, where at least one of R1and R3is an R14DVKOC1-3-alkyl-;

R5represents N(R6)LQR7;

R6selected from hydrogen, OH, and C1-6-alkyl, preferably represents C1-6-alkyl;

R7is a further chain of amino acids, hydrogen, a protective group, aryl or heteroaryl, any of which is optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C1-5-alkyl; or R7selected from C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, C1-6-aralkyl, C1-6-heteroalkyl, R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C1-8-alkyl-, MZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-, (R10)2N-C1-8-alkyl-, (R10)3N+-C1-8-alkyl-, heterocyclyl, carbocyclic-, 11SO2C1-8-alkyl and R11SO2NH; or

R6and R7taken together, represent a C1-6-alkyl-Y-C1-6-alkyl, C1-6-alkyl-ZA-C1-6-alkyl, A-C1-6-alkyl-ZA-C1-6-alkyl, A-C1-6-alkyl-or A C1-6-alkyl-A, preferably C1-2-alkyl-Y-C1-2-alkyl, C1-2-alkyl-ZA-C1-2-alkyl, And-C1-2-alkyl-ZA-C1-2-alkyl, A-C1-3-alkyl-or A C1-4-alkyl-A, with the formation of the cycle, preferably R6represent hydrogen and R7represents a C1-6-alkyl;

R8and R9independently selected from hydrogen, metal cation, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl, preferably from hydrogen, metal cation, and C1-6-alkyl, or R8and R9taken together, represent a C1-6-alkyl, with the formation of the loop;

each R10independently selected from hydrogen and C1-6-alkyl, preferably of C1-6-alkyl;

each R11independently selected from hydrogen, OR10C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl;

R14selected from hydrogen, (R15O)(R16O)P(=O)W-, R15GB-, heterocyclyl-, (R17) 2N-, (R17)3N+-, R17SO2GBG - and R15GBC1-8-alkyl-, where C1-8-alkyl optionally substituted by OH, C1-8-W (optionally substituted by halogen, preferably by fluorine, aryl, heteroaryl, carbocyclic, heterocyclyl and C1-6-aralkyl, preferably at least one R14that is different from hydrogen;

R15and R16independently selected from hydrogen, metal cation, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl, preferably from hydrogen, metal cation, and C1-6-alkyl, or R15and R16taken together, represent a C1-6-alkyl, with the education cycle; and

each R17independently selected from hydrogen, OR10C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl;

provided that R6represents H; L represents C=O and Q absent, R7is not hydrogen, C1-6-alkyl or substituted or unsubstituted aryl or heteroaryl and

D, G, V, K and W are chosen so that there are no ties Oh, N-O, S-N or S-O.

Suitable N-terminal protective group known in the field of peptide synthesis include tert-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (trityl) and trichlorocyanuric (Troc) and the like. The use of various N-protecting groups, for example benzyloxycarbonyl group or tert-butoxycarbonyl group (Boc), various condensing agents, for example, dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-gidroksibenzotriazola (HATU), carbonyldiimidazole or monohydrate 1-oxybisethanol (HOBT) and different cleavage conditions: for example, triperoxonane acid (TFA), HCl in dioxane, the hydrogenation of Pd-C in organic solvents (such as methanol or ethyl acetate), Tris-triptorelin boron, brazian, and reaction in solution with isolation and purification of intermediate products is well known in the field of peptide synthesis and applies equally to obtain the considered compounds.

In some embodiments, the implementation of R1, R2, R3and R4each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl, C1-6-aralkyl and R14DVKOC1-3-alkyl-, where at least one of R1and R3is an R14DVKOC1-3-alkyl-. In preferred embodiments, the implementation of one of R1and R3represents a C1-6-aralkyl and the another is an R 14DVKOC1-3is alkyl and R2and R4independently represents a C1-6-alkyl. In the most preferred implementation of one of R1and R3is a 2-phenylethyl or phenylmethyl and the other is an R14DVKOCH2and R14DVKO(CH3)CH-, and both R2and R4are isobutyl.

In some embodiments, the implementation of each R11independently selected from hydrogen, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl.

In some embodiments, the implementation of each R17independently selected from hydrogen, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl.

In some embodiments, the implementation of L and Q are absent, and R7selected from hydrogen, more chains of amino acids, C1-6-acyl protective groups, aryl, heteroaryl, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, C1-6-aralkyl and C1-6-heteroalkyl. In some such embodiments, the implementation of R6represents a C1-6-alkyl and R7selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments implementing the Tulane L represents the SO 2, Q is absent and R7selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R7selected from methyl and phenyl.

In some embodiments, the implementation of L is a C=O and R7selected from the

C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, C1-6-aralkyl, heteroaryl and C1-6-heteroalkyl, R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C1-8-alkyl-, MZAZ-C1-8-alkyl-, (R10)2N-C1-8-alkyl-, (R10)3N+-C1-8-alkyl-, heterocyclyl, carbocyclic-, R11SO2C1-8-alkyl and R11SO2NH-. In some embodiments, the implementation of L represents C=O, Q is absent and R7represents H.

In some embodiments, the implementation of R6represents a C1-6-alkyl, R7represents a C1-6-alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R7represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent and R7PR is dstanley a C 1-6-aralkyl. In some such embodiments, the implementation of R7selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R6represents a C1-6-alkyl and R7represents aryl. In some such embodiments, the implementation of R7represents a substituted or unsubstituted phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O and R7represents (CH2)ncarbocyclic. In some such embodiments, the implementation of R7is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and A are C=O, Q is absent, Z are O and R7selected from R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl - and MZAZ-C1-8-alkyl-. In some such embodiments, the implementation of R7represents MZAZ-C1-8-alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl or N(R12)(R13), where R12and R13that is Satya together represents a C1-6-alkyl-Y-C1-6-alkyl, preferably C1-3-alkyl-Y-C1-3-alkyl, with the formation of the loop.

In some preferred embodiments, the implementation of L represents C=O, Q is absent and R7selected from (R8O)(R9O)P(=O)O-C1-8-alkyl-, (R10)2N-C1-8-alkyl, (R10)3N+(CH2)nand heterocyclyl-M-. In some such embodiments, the implementation of R7represents a C1-8the N(R10)2or-C1-8the N+(R10)3where R10represents a C1-6-alkyl. In some other such embodiments, the implementation of R7represents heterocyclyl-where heterocyclyl selected from morpholino group, piperidino group, piperazino group and pyrrolidino group.

In some embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7selected from C1-6-alkyl, cycloalkyl-M, C1-6-aralkyl and C1-6-heteroalkyl. In other embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-alkyl, where C1-6-alkyl selected their methyl, ethyl and isopropyl. In additional embodiments, the implementation of L represents C=O, R6/sup> represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-aralkyl where aralkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-heteroalkyl where heteroalkyl represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent or represents C=O and R6and R7taken together, represent a C1-6-alkyl-Y-C1-6-alkyl, C1-6-alkyl-ZA-C1-6-alkyl or C1-6-alkyl-And, with the formation of the loop. In some preferred embodiments, the implementation of L represents C=O, Q and Y are absent, and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation of the L and Q are absent, and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation L represents C=O, Q is absent, Y is selected from NH and N-C1-6-alkyl and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation L represents C=O, Y is absent and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-Ala is L. In another preferred implementation of L and A are C=O and R6and R7taken together, represent a C1-2-alkyl-ZA-C1-2-alkyl. In another preferred implementation of L and A are C=O and R6and R7taken together, represent a C2-3-alkyl-A.

In some embodiments, the implementation of R14represents (R15O)(R16O)P(=O)W-. In some such embodiments, the implementation of D, V, K and W are absent. In other such embodiments, the implementation of V and K are absent, D is a C1-8-alkyl, and W represents O. In some such embodiments, the implementation of D represents C1-8-alkyl, K is a C=O and V and W represent O.

In some embodiments, the implementation of R14is an R15GB-. In preferred embodiments, the implementation of B represents C=O, G represents O, D represents C1-8-alkyl, V is O and K represents the C=O.

In some embodiments, the implementation of R14represents heterocyclyl-. In preferred such embodiments, the implementation of D represents C1-8-alkyl. In some such embodiments, the implementation of the V represents O, K represents C=O and heterocyclyl is oxadiazolyl. In other such embodiments, assests is of V is absent, K is absent or represents C=O and heterocyclyl represents N(R18)(R19), where R18and R19taken together, represent the J-T-J, J-WB-J or B-J-T-J, T is absent or is selected from O, NR17, S, SO, SO2, CHOR17, CHCO2R15, C=O, CF2and CHF and J is absent or represents a C1-3-alkyl.

In some embodiments, the implementation of R14represents (R17)2N - or (R17)3N+and preferably V is absent. In preferred such embodiments, the implementation of D represents C1-8-alkyl and K is absent or is C=O. In some embodiments, implement, where V is absent and R14represents (R17)2N-, D is absent, K is absent or represents C=O, preferably K is a C=O.

In some embodiments, the implementation of R14is an R17SO2GBG-. In preferred such embodiments, the implementation of B represents C=O, D, V and K are absent and G is a NH or NC1-6-alkyl.

In some embodiments, the implementation of R14is an R15GBC1-8-alkyl. In preferred embodiments, the implementation of B represents C=O, G represents O and group C1-8-alkyl optionally substituted by OH, C1-8the alkyl (optional samisen the m halogen, preferably fluorine), C1-8-W, aryl, heteroaryl, carbocyclic, heterocyclyl and C1-6-aralkyl. In some such embodiments, the implementation of group C1-8-alkyl is an unsubstituted, mono - or disubstituted by C1-alkyl.

In some embodiments, the implementation of the compounds of formula I has the following stereochemical configuration:

In preferred embodiments, the implementation of the inhibitor has the structure of formula II or its pharmaceutically acceptable salt

where each A is independently selected from C=O, C=S and SO2preferably C=O;

each B is independently selected from C=O, C=S and SO2preferably C=O;

D is absent or represents a C1-8-alkyl;

G is selected from O, NH and N-C1-6-alkyl;

K is absent or is selected from C=O, C=S and SO2preferably K is absent or represents C=O;

L is absent or selected from C=O, C=S and SO2preferably L is absent or represents C=O;

M is absent or represents a C1-8-alkyl;

Q is absent or selected from O, NH and N-C1-6-alkyl, preferably Q is absent, represents O or NH, most preferably Q is absent or represents O;

X is selected from O, S, NH and N-C1-6-alkyl, preferably provided which allows a;

each V is independently absent or selected from O, S, NH and N-C1-6-alkyl, preferably V is absent or represents O;

W is absent or independently selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

Y is absent or selected from O, NH, N-C1-6-alkyl, S, SO, SO2, CHOR10and CHCO2R10;

each Z is independently selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

R1and R3each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl, C1-6-aralkyl and R14DVKOC1-3-alkyl-, where at least one of R1and R3is an R14DVKOC1-3-alkyl-;

R5represents N(R6)LQR7;

R6selected from hydrogen, OH, and C1-6-alkyl, preferably represents C1-6-alkyl;

R7is a further chain of amino acids, hydrogen, a protective group, aryl or heteroaryl, any of which is optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C1-5-alkyl, or R7selected from C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, C1-6-aralkyl, C1-6-heteroalkyl, R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ- 1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C1-8-alkyl-, MZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-, (R10)2N-C1-8-alkyl-, (R10)3N+-C1-8-alkyl-, heterocyclyl, carbocyclic-, R11SO2C1-8-alkyl and R11SO2NH or

R6and R7taken together, represent a C1-6-alkyl-Y-C1-6-alkyl, C1-6-alkyl-ZA-C1-6-alkyl, A-C1-6-alkyl-ZA-C1-6-alkyl, A-C1-6-alkyl-or A C1-6-alkyl-A, preferably C1-2-alkyl-Y-C1-2-alkyl, C1-2-alkyl-ZA-C1-2-alkyl, And-C1-2-alkyl-ZA-C1-2-alkyl, A-C1-3-alkyl-or A C1-4-alkyl-A, with the formation of the loop;

R8and R9independently selected from hydrogen, metal cation, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl, preferably from hydrogen, metal cation, and C1-6-alkyl, or R8and R9taken together, represent a C1-6-alkyl, with the formation of the loop;

each R10independently selected from hydrogen and C1-6-alkyl, preferably of C1-6-alkyl and

each R11independently selected from hydrogen, OR10C1-6-alkyl, C1-6-alkenyl, C 1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl;

R14selected from hydrogen, (R15O)(R16O)P(=O)W-, R15GB-, heterocyclyl-, (R17)2N-, (R17)3N+-, R17SO2GBG - and R15GBC1-8-alkyl, where the group C1-8-alkyl optionally substituted by OH, C1-8-W (optionally substituted by halogen, preferably by fluorine, aryl, heteroaryl, carbocyclic, heterocyclyl and C1-6-aralkyl, preferably at least one R14that is different from hydrogen;

R15and R16independently selected from hydrogen, metal cation, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl, preferably from hydrogen, metal cation, and C1-6-alkyl, or R15and R16taken together, represent a C1-6-alkyl, with the formation of the loop;

each R17independently selected from hydrogen, OR10C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl;

provided that R6represents H; L represents C=O and Q absent, R7is not hydrogen, C1-6-alkyl is m or substituted or unsubstituted aryl or heteroaryl, and

D, G, V, K and W are chosen so that there are no ties Oh, N-O, S-N or S-O.

In some embodiments, the implementation of R1and R3each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl, C1-6-aralkyl and R14DVKOC1-3-alkyl-, where at least one of R1and R3is an R14DVKOC1-3-alkyl. In preferred embodiments, the implementation of one of R1and R3represents a C1-6-aralkyl and the other is an R14DVKOC1-3-alkyl-. In the most preferred implementation of one of R1and R3is a 2-phenylethyl or phenylmethyl and the other is an R14DVKOCH2or R14DVKO(CH3)CH-.

In some embodiments, the implementation of each R11independently selected from hydrogen, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl.

In some embodiments, the implementation of each R17independently selected from hydrogen, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, carbocycle, heterocyclyl, aryl, heteroaryl, C1-6-aralkyl and C1-6-heteroalkyl.

In some embodiments, the implementation of L and Q are absent, and R7selected from hydrogen, EXT is niceley chain amino acids, C1-6-acyl protective groups, aryl, heteroaryl, C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, C1-6-aralkyl and C1-6-heteroalkyl. In some such embodiments, the implementation of R6represents a C1-6-alkyl and R7selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

In other embodiments, the implementation of L represents the SO2, Q is absent and R7selected from C1-6of alkyl and aryl. In some such embodiments, the implementation of R7selected from methyl and phenyl.

In some embodiments, the implementation of L is a C=O and R7selected from C1-6-alkyl, C1-6-alkenyl, C1-6-quinil, aryl, C1-6-aralkyl, heteroaryl and C1-6-heteroalkyl, R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C1-8-alkyl-, MZAZ-C1-8-alkyl-, (R10)2N-C1-8-alkyl-, (R10)3N+-C1-8-alkyl-, heterocyclyl, carbocyclic-, R11SO2C1-8-alkyl and R11SO2NH-. In some embodiments, the implementation of L represents C=O, Q is absent and R7the submitted is an H.

In some embodiments, the implementation of R6represents a C1-6-alkyl, R7represents a C1-6-alkyl, Q is absent and L is a C=O. In some such embodiments, the implementation of R7represents ethyl, isopropyl, 2,2,2-triptorelin or 2-(methylsulphonyl)ethyl.

In other embodiments, the implementation of L represents C=O, Q is absent and R7represents a C1-6-aralkyl. In some such embodiments, the implementation of R7selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl and (4-forfinal)bromide.

In other embodiments, the implementation of L represents C=O, Q is absent, R6represents a C1-6-alkyl and R7represents aryl. In some such embodiments, the implementation of R7represents a substituted or unsubstituted phenyl.

In some embodiments, the implementation of L represents C=O, Q is absent or represents O and R7represents (CH2)ncarbocyclic. In some such embodiments, the implementation of R7is cyclopropyl or cyclohexyl.

In some embodiments, the implementation of L and A are C=O, Q is absent, Z are O and R7selected from R8ZA-C1-8-alkyl-, R11Z-C1-8-alkyl-, R8ZA-C1-8-alkyl-ZAZ-C 1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-ZAZ-C1-8-alkyl-, (R8O)(R9O)P(=O)O-C1-8-alkyl-Z-C1-8-alkyl - and MZAZ-C1-8-alkyl. In some such embodiments, the implementation of R7represents MZAZ-C1-8-alkyl-, where heterocyclyl represents a substituted or unsubstituted oxadiazolyl or N(R12)(R13), where R12and R13taken together, represent a C1-6-alkyl-Y-C1-6-alkyl, preferably C1-3-alkyl-Y-C1-3-alkyl, with the formation of the loop.

In some preferred embodiments, the implementation of L represents C=O, Q is absent and R7selected from (R8O)(R9O)P(=O)O-C1-8-alkyl, (R10)2N-C1-8-alkyl-, (R10)3N+(CH2)nand heterocyclyl-. In some such embodiments, the implementation of R7represents a C1-8the N(R10)2or-C1-8the N+(R10)3where R10represents a C1-6-alkyl. In some other such embodiments, the implementation of R7represents heterocyclyl-where heterocyclyl selected from morpholino group, piperidino group, piperazino group and pyrrolidino group.

In some embodiments, the implementation of L represents C=O, R6represents a C-6 -alkyl, Q is selected from O and NH and R7selected from C1-6-alkyl, cycloalkyl, C1-6-aralkyl and C1-6-heteroalkyl. In other embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-alkyl, where C1-6-alkyl selected their methyl, ethyl and isopropyl. In additional embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-aralkyl where aralkyl represents phenylmethyl. In other embodiments, the implementation of L represents C=O, R6represents a C1-6-alkyl, Q is selected from O and NH and R7represents a C1-6-heteroalkyl where heteroalkyl represents (4-pyridyl)methyl.

In some embodiments, the implementation of L is absent or represents C=O and R6and R7taken together, represent a C1-6-alkyl-Y-C1-6-alkyl, C1-6-alkyl-ZA-C1-6-alkyl or C1-6-alkyl-And, with the formation of the loop. In some preferred embodiments, the implementation of L represents C=O, Q and Y are absent, and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation of the L and Q are absent, and R6and R7taken together, PR is astavliaut a C 1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation L represents C=O, Q is absent, Y is selected from NH and N-C1-6-alkyl and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation L represents C=O, Y is absent and R6and R7taken together, represent a C1-3-alkyl-Y-C1-3-alkyl. In another preferred implementation of L and A are C=O and R6and R7taken together, represent a C1-2-alkyl-ZA-C1-2-alkyl. In another preferred implementation of L and A are C=O and R6and R7taken together, represent a C2-3-alkyl-A.

In some embodiments, the implementation of R14represents (R15O)(R16O)P(=O)W-. In some such embodiments, the implementation of D, V, K and W are absent. In other such embodiments, the implementation of V and K are absent, D is a C1-8-alkyl, and W represents O. In some such embodiments, the implementation of D represents C1-8-alkyl, K is a C=O and V and W represent O.

In some embodiments, the implementation of R14is an R15GB-. In preferred embodiments, the implementation of B represents C=O, G represents O, D represents C1-8-alkyl,V is O and K represents the C=O.

In some embodiments, the implementation of R14represents heterocyclyl-. In preferred such embodiments, the implementation of D represents C1-8-alkyl. In some such embodiments, the implementation of the V represents O, K represents C=O and heterocyclyl is oxadiazolyl. In other such embodiments, the realization of V is absent, K is absent or represents C=O and heterocyclyl represents N(R18)(R19), where R18and R19taken together, represent the J-T-J, J-WB-J or B-J-T-J, T is absent or is selected from O, NR17, S, SO, SO2, CHOR17, CHCO2R15, C=O, CF2and CHF and J is absent or represents a C1-3-alkyl.

In some embodiments, the implementation of R14represents (R17)2N - or (R17)3N+and preferably V is absent. In preferred such embodiments, the implementation of D represents C1-8-alkyl and K is absent or is C=O. In some embodiments, implement, where V is absent and R14represents (R17)2N-, D is absent, K is absent or represents C=O, preferably K is a C=O.

In some embodiments, the implementation of R14is an R17SO2GBG-. In preferred such embodiments enjoyment at represents C=O, D, V and K are absent and G is a NH or NC1-6-alkyl.

In some embodiments, the implementation of R14is an R15GBC1-8-alkyl. In preferred embodiments, the implementation of B represents C=O, G represents O and group C1-8-alkyl optionally substituted by OH, C1-8the alkyl (optionally substituted with halogen, preferably fluorine), C1-8-W, aryl, heteroaryl, carbocyclic, heterocyclyl and C1-6-aralkyl. In some such embodiments, the implementation of group C1-8-alkyl is an unsubstituted, mono - or disubstituted by C1-alkyl.

Another aspect of the invention relates to compounds having the structure of formula (III) or formula (IV), or their pharmaceutically acceptable salts

where each Ar independently represents an aromatic or heteroaromatic group, optionally substituted from 1 to 4 substituents;

L is absent or selected from C=O, C=S and SO2preferably is a SO2or C=O;

X is selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

Y is absent or selected from C=O and SO2;

Z is absent or represents a C1-6-alkyl;

R1, R2and R3each independently selected from C1-6-alkyl, C1-6-hydrox is the alkyl, C1-6-alkoxyalkyl, aryl and C1-6-aralkyl, any of which is optionally substituted by one or more of amide, amine substituents, carboxylic acid (or its salt), ester (including C1-6-alkilany ether, C1-5-alkilany ether and arrowy ether), tilenum or thioester deputies;

R4represents N(R5)L-Z-R6;

R5selected from hydrogen, OH, and C1-6-aralkyl-Y and C1-6-alkyl-Y preferably represents hydrogen;

R6selected from hydrogen, OR7C1-6-alkenyl, Ar-Y-, carbocycle and heterocycle; and

R7and R8independently selected from hydrogen, C1-6-alkyl and C1-6-aralkyl, preferably represent hydrogen.

In some embodiments, the implementation of L is selected from C=O, C=S and SO2preferably is a SO2or C=O.

In some embodiments, the implementation of R5selected from hydrogen, OH, C1-6-aralkyl and C1-6-alkyl, preferably represents hydrogen.

In some embodiments, the implementation of R6selected from hydrogen, C1-6-alkenyl, Ar-Y-, carbocycle and heterocycle.

In some embodiments, implementation of the X represents O and R1, R2and R3each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl and C1-6-aralkyl. Pre is respectful of such options, implementation of R 1and R3independently represents a C1-6-alkyl and R2represents a C1-6-aralkyl. In preferred such embodiments, the implementation of R1and R3both are isobutyl and R2represents phenylmethyl.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2, R6is an Ar-Y -, and each Ar is independently selected from phenyl, indolyl, benzofuran, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some such embodiments, the implementation of the Ar, you can replace the Ar-Q-, where Q is selected from a direct link, -O -, and C1-6-alkyl. In some other such embodiments, the implementation, where Z represents a C1-6-alkyl, Z could be replaced preferably Ar, such as phenyl.

In some embodiments, the implementation of R5represents hydrogen, Z is absent, L is a C=O or SO2and R6selected from Ar-Y or heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected from romanillos, romanillos, morpholinos and piperidino group. In some other preferred embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuran, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and so podobno is.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2Z is absent and R6represents a C1-6alkenyl, where C1-6alkenyl represents a substituted vinyl group, where Deputy preferably represents aryl or heteroaryl group, more preferably phenyl group, optionally substituted by 1-4 substituents.

In some embodiments, the implementation of R7and R8independently selected from hydrogen and C1-6-alkyl. In some such preferred embodiments, the implementation of R7and R8independently selected from hydrogen and methyl. In more preferred embodiments, the implementation as R7and R8represent hydrogen.

In some embodiments, the implementation of the compounds of formula (III) or formula (IV) has the following stereochemical configuration

In preferred embodiments, the implementation of the inhibitor has the structure of formula (V) or formula (VI) or its pharmaceutically acceptable salt

where each Ar independently represents an aromatic or heteroaromatic group, optionally substituted by 1-4 substituents;

L is absent or selected from C=O, C=S and SO2preferably represents the FDS is th SO 2or C=O;

X is selected from O, S, NH and N-C1-6-alkyl, preferably represents O;

Y is absent or selected from C=O and SO2;

Z is absent or represents a C1-6-alkyl;

R1and R3each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, aryl and C1-6-aralkyl, any of which is optionally substituted by one or more of amide, amine substituents, carboxylic acid (or its salt), ester (including C1-6-alkilany ether and arrowy ether), tilenum or thioester deputies;

R4represents N(R5)L-Z-R6;

R5selected from hydrogen, OH, and C1-6-aralkyl-Y and C1-6-alkyl-Y preferably represents hydrogen;

R6selected from hydrogen, OR7C1-6-alkenyl, Ar-Y-, carbocycle and heterocycle; and

R7and R8independently selected from hydrogen, C1-6-alkyl and C1-6-aralkyl, preferably represent hydrogen.

In some embodiments, the implementation of L is selected from C=O, C=S and SO2preferably is a SO2or C=O.

In some embodiments, the implementation of R5selected from hydrogen, OH, C1-6-aralkyl and C1-6-alkyl, preferably represents hydrogen.

In some embodiments, the implementation of R6in the bran from hydrogen, C1-6-alkenyl, Ar-Y-, carbocycle and heterocycle.

In some embodiments, implementation of the X represents O and R1and R3each independently selected from C1-6-alkyl, C1-6-hydroxyalkyl and C1-6-aralkyl. In such preferred embodiments, the implementation of R1and R3independently represents a C1-6-alkyl. In preferred such embodiments, the implementation of R1and R3are isobutyl.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2and R6is an Ar-Y, each Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like. In some such embodiments, the implementation of the Ar, you can replace the Ar-Q-, where Q is selected from a direct link, -O -, and C1-6-alkyl. In some other such embodiments, the implementation, where Z represents C1-6-alkyl, Z could be replaced, for example, preferably Ar, more preferably phenyl.

In some embodiments, the implementation of R5represents hydrogen, Z is absent, L is a C=O or SO2and R6selected from Ar-Y or heterocyclyl. In certain preferred such embodiments, the implementation heterocyclyl selected from romanillos, romanillos, morpholino the th and piperidino group. In some other preferred embodiments, the implementation of Ar is selected from phenyl, indolyl, benzofuranyl, naphthyl, chinoline, chinolone, teinila, pyridyl, pirila and the like.

In some embodiments, the implementation of R5represents hydrogen, L represents C=O or SO2Z is absent and R6represents a C1-6alkenyl, where C1-6alkenyl represents a substituted vinyl group, where Deputy preferably represents an aryl or heteroaryl group, more preferably Deputy represents a phenyl group, optionally substituted from one to four substituents.

In some embodiments, the implementation of R7and R8independently selected from hydrogen and C1-6-alkyl. In some such preferred embodiments, the implementation of R7and R8independently selected from hydrogen and methyl. In preferred such embodiments, the implementation as R7and R8represent hydrogen.

In some embodiments, the implementation of the-L-Z-R6selected from the

One aspect of the invention relates to a medical device containing the composition described herein, which contains the inhibitor having the structure of any of formulas is I through VI. In one embodiment, the composition is contained in a medical device. In some embodiments, the medical device is a gel containing polymer matrix or ceramic matrix and the inhibitor. The specified polymer may be either of natural origin or synthetic. In another implementation of the specified gel is used as a depot preparation, adhesive, suture material, barrier or insulating substance.

Another aspect of the invention relates to a medical device containing a substrate with a surface, where the inhibitor having the structure of any of formulas I through VI. In one embodiment, the inhibitor is directly placed into a medical device. In another embodiment, the coating is placed in such a way that the coating contains a polymer matrix or ceramic matrix with dispersed or dissolved therein an inhibitor having the structure of any of formulas I through VI.

In one embodiment, the medical device is a coronary, cerebrovascular, or peripheral biliary stent. In more detail, the stent of the present invention is a expanding stent. When applied to the surface of the matrix containing the inhibitor having the structure of any of formulas I through VI, m is the Trix is flexible to adapt to the compressed and expanded state such expanding stent. In another embodiment of this invention, the stent includes at least a portion which is insertable or implantable into the patient, where the plot has a surface which is adapted to effects on the tissue of the body, and where at least a portion of the surface is coated with an inhibitor having a structure of any of formulas I to VI, or a floor, the support matrix containing the inhibitor having the structure of any of formulas I through VI, distributed or dissolved in it. An example of a suitable stent described in U.S. patent No. 4733665, which is fully incorporated here by reference.

In another embodiment, the medical device according to the present invention is a surgical instrument, such as a vascular prosthesis, intraluminal device, surgical insulating material or vascular substrate. In more detail, the medical device according to the present invention is a catheter, implantable passage for vascular access, Central venous catheter, arterial catheter, vascular grafts, intra-aortic balloon counterpulsation, suture material, ventricular auxiliary pump containing medicine partition, plaster, vascular cuff, extra/perivascular substrate, a filter for CROs and or filter, adapted for deployment in a blood vessel, coated with an inhibitor having a structure of any of formulas I through VI, either directly or through a matrix containing the inhibitor having the structure of any of formulas I through VI.

In some embodiments, the implementation of the intraluminal device is coated with an inhibitor having a structure of any of formulas I to VI or a coating containing a biologically devoid of immunogenic properties of the matrix and distributed in the polymer inhibitor having the structure of any of formulas I through VI, with the specified device has an internal surface and an external surface having a coating on at least part of the inner surface of the outer surface or on both parts.

In some embodiments, the medical device can be used to prevent restenosis after angioplasty. The medical device can also be used to treat various diseases and conditions, providing localized introduction of an inhibitor having the structure of any of formulas I through VI. Such diseases and conditions include restenosis, inflammation, rheumatoid arthritis, tissue damage due to inflammation, hyperproliferative disease, severe or arthritic psoriasis, a disease that causes we acnee exhaustion, chronic infectious diseases, abnormal immune response, status, caused by rupture easily damaged atherosclerotic plaques, disorders associated with ischemic conditions, and viral infection and proliferation. Examples of diseases and conditions that respond to treatment, including the use of covered drug medical devices of the present invention include atherosclerosis, acute coronary syndrome, Alzheimer's disease, cancer, fever, muscle inactivity (atrophy, denervation, occlusion of blood vessels, stroke, HIV infection, nerve damage, kidney failure, associated with acidosis, and liver failure. See, for example, Goldberg, U.S. patent No. 5340736.

The term "Cx-y-alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including alkyl groups with a linear chain alkyl group, branched chain, containing from x to y carbon atoms in the chain, including halogenoalkane groups such as trifluoromethyl and 2,2,2 - triptorelin etc. C0-alkyl denotes hydrogen, where the group is in the limit position, if the connection is internal. The terms "C2-yalkenyl" and "C2-y-quinil" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution of sunnym above alcelam, but that contain at least one double or triple bond, respectively.

The term "alkoxy" denotes an alkyl group containing attached to it oxygen. Typical representatives of alkoxygroup include methoxy, ethoxy-, propoxy-, tert-butoxypropan and the like. "Plain air" consists of two hydrocarbon covalently associated with oxygen. Accordingly, the Deputy of alkyl, which is involved in the formation of such Olkiluoto ether, represents or similar alkoxygroup.

The term "C1-6-alkoxyalkyl" represents C1-6is an alkyl group substituted by alkoxygroup, thereby forming a simple ether.

Used herein, the term "C1-6-aralkyl" represents C1-6is an alkyl group, substituted aryl group.

The terms "amine" and "amino" are adopted in this area and is designated as unsubstituted and substituted amines and their salts, for example, fragments of which can be represented by the General formula:

where R9, R10and R10'each independently represents hydrogen, alkyl, alkenyl, -(CH2)m-R8or R9and R10taken together with the N atom to which they are attached, constitute a heterocycle containing 4 to 8 atoms in the ring structure; R8represents aryl, cyclea the keel, cycloalkenyl, heterocyclyl or polycyclic and m represents zero or an integer from 1 to 8. In preferred embodiments, the implementation of only one of R9or R10can be a carbonyl, e.g., R9, R10and the nitrogen together do not form an imide. In even more preferred embodiments, the implementation of R9and R10(and optionally R10'each independently represents hydrogen, alkyl, alkenyl, -(CH2)m-R8. In some embodiments, implementation of the amino group is a primary, indicating that the protonated form has the pKa≥7,00.

The term "amide" and "amido-" accepted in the field as aminosilane CARBONYLS and include a fragment which can be represented in the General formula:

where R9, R10represent substituents as described above. Preferred embodiments of the amide does not include imides which may be unstable.

Used herein, the term "aryl" includes 5-, 6 - and 7-membered substituted or unsubstituted adnakolava aromatic group in which each atom in the ring is a carbon. The term "aryl" also includes polycyclic ring systems in which two or more carbons are common to two adjoining rings, where at m is re, one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like.

Used herein, the term "carbocycle" and "carbocyclic" denotes a non-aromatic substituted or unsubstituted ring in which each atom in the ring is a carbon. The term "carbocycle" and "carbocyclic" also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two adjoining rings, where at least one ring is carbocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocyclyl.

The term "carbonyl" is known in this field and includes such fragments, which can be represented General formula:

where X is a bond or represents an oxygen or sulfur and R11represents hydrogen, alkyl, alkenyl, -(CH2)m-R8or a pharmaceutically acceptable salt, R11'represents hydrogen, alkyl, alkenyl, -(CH2)m-R8where m and R8JW is Auda same as explained above.

In those cases, when X is oxygen and R11or R11'is not hydrogen, the formula represents an "ester". In those cases, when X is oxygen and R11is hydrogen, the formula represents a "carboxylic acid".

Used herein, the term "enzyme" can be any partially or fully the protein molecule, which carries out a chemical reaction by the catalytic method. Such enzymes may be native enzymes, enzymes merge, proenzymes, apparments, denaturirovannyj enzymes, farnesiani enzymes, ubiquitination enzymes, enzymes, acylated fatty acids, geranyl-geranylgeranyl enzymes, GPI-linked enzymes associated with lipid enzymes, prenisolone enzymes, naturally occurring or artificially produced mutant enzymes, enzymes with modifications of the side chains or main chain enzymes containing a leader sequence, and the enzyme, in complex with a non-protein substance, such as proteoglycans and proteoliposome. Enzymes can be obtained by any means, including natural expression, expression from the promoter, cloning, various methods for the synthesis of peptides in rest the re and on the solid phase and such ways, well-known experts in this field.

Used herein, the term "C1-6-heteroalkyl" represents C1-6is an alkyl group, substituted heteroaryl group.

The term "heteroaryl" includes substituted or unsubstituted aromatic 5-7 membered ring structures, more preferably 5-6-membered cycles, whose ring structures include one to four heteroatoms. The term "heteroaryl" also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two adjoining rings, where at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazin, pyridazine, pyrimidine and the like.

Used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, phosphorus and sulphur.

The term "heterocyclyl" or "heterocyclic group" means a substituted or unsubstituted non-aromatic 3-10-membered ring structure is ture, more preferably 3-7-membered cycles, whose ring structures include one to four heteroatoms. The term "heterocyclyl" or "heterocyclic group" also includes polycyclic ring systems containing two or more cyclic rings in which two or more carbons are common to two adjoining rings, where at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocyclyl. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term "C1-6-hydroxyalkyl" represents C1-6is an alkyl group substituted by a hydroxy-group.

Used herein, the term "inhibitor" is meant to describe a compound that blocks or reduces the activity of the enzyme (for example, inhibition of proteolytic cleavage of the standard fluorogenic peptide substrate, such as suc-LLVY-AMC, Box-LRR-AMC and Z-LLE-AMC, inhibition of the different catalytic activities of the 20S proteasome). The inhibitor may act according to the type of competitive, noncompetitive, or uncompetitive inhibition. The inhibitor can bind reversibly or irreversibly, and therefore the term includes soy is inane, are suicide substrates of the enzyme. The inhibitor may modify one or more plots in the active centre or near the active site of the enzyme, or it may cause a conformational change somewhere in another part of the enzyme.

Used herein, the term "peptide" includes not only standard amide bond with the standard α-substituents, but also widely used peptidomimetics, other modified communication is not occurring side chains and modification of the side chains, as described in detail below.

The terms "politikil" or "polycyclic" refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocyclyl), in which two or more carbons are common to two adjoining rings, such as rings are condensed ring. Each of the rings polycycle may be substituted or unsubstituted.

The term "prevention" is known in this area and when used in relation to the state, such as a local recurrence (e.g., pain), a disease such as cancer, symptom, such as heart failure or any other medical condition, is well understood in this area and includes the introduction of a composition which reduces the frequency of occurrence or hold the AET the onset of symptoms of the medical condition of the patient relative to the patient, do not take the composition. Thus, prevention of cancer includes, for example, reducing the number of detected cancers in a population of patients receiving prophylactic treatment, relative to not receiving treatment control population, and/or delay the appearance of detectable cancerous tumors in treated populations compared with non-treated control population, and/or delay the appearance of detectable cancerous tumors in treated populations compared with non-treated control population, for example, by a statistically and/or clinically significant amount. Prevention of infection includes, for example, reducing the number of diagnosis of infection receiving treatment population compared with non-treated control population and/or delay the onset of symptoms of infection in treated populations compared with non-treated control population. Prevent pain includes, for example, reduction in force, or in the alternative delay, the sensation of pain experienced by patients receiving treatment population compared with non-treated control population.

The term "prodrug" includes compounds which, under physiological conditions transform is implemented in therapeutically active funds. The standard way to get prodrugs should include the selected fragments, which units are hydrolyzed under physiological conditions to allow one to find the desired molecule. In other embodiments, implementation of the prodrug transform through the enzymatic activity of the host body of the animal.

The term "prophylactic or therapeutic treatment known in the field and includes introduction to the body-the owner of one or more essential nutrients. If the substance is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host body of the animal), then the treatment is prophylactic (i.e., it protects the body of the host from the development of an undesirable condition), whereas, if the composition is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate or stabilize an existing undesirable condition or side effects).

Used herein, the term "proteasome" includes immuno - and constitutive proteasome.

The term "substituted" refers to fragments having substituents replacing a hydrogen on one or more carbon atoms in the main chain. It is clear that the terms "replacement" and "substituted" include implicit is slowie, that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable connection, which, for example, does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, and so forth. Used herein, the term "substituted", as it implies, includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and linear, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents may constitute one or more and same or different substituents for the relevant organic compounds. For purposes of this invention, heretofore such as nitrogen may have hydrogen substituents and/or any permissible substituents described here, the organic compounds which satisfy the valencies of the heteroatoms. Substituents may include, for example, halogen, hydroxyl, a carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), a thiocarbonyl (such as a complex tiefer, thioacetal or thioformate), CNS, phosphoryl, phosphate, phosphonate, phosphinate, amino-, amido-, amidinov, Eminova, qi is but, nitro, azido-, sulfhydryl, alkylthio-, sulphate, sulphonate, sulfamoyl, sulfonamide-, sulfonylurea, heterocyclyl, kalkilya, or an aromatic or heteroaromatic fragments. Specialists in this field will be clear that the groups substituted on the hydrocarbon chain, if appropriate, can be overridden.

"Therapeutically effective amount" of a compound in terms of treatment refers to the amount of compound(s) in the product that, when introduced as part of the required schemas dosage (to a mammal, preferably a human) alleviates a symptom, facilitates a condition, or slows the emergence of disease conditions according to clinically acceptable standards for disorders or conditions that must be cured, or for cosmetic purposes, for example, with a reasonable ratio of benefit/risk, applicable to any medical treatment.

The term "thioether" refers to an alkyl group as described above that contains sulfur attached to it a fragment. In preferred embodiments, the implementation of "tiefer" presents-S-alkyl. Typical representatives of the thioester groups include methylthio, ethylthiourea and the like.

Used herein, the term "treat" or "treatment" includes alteration, reduction or relief of symptoms is s, clinical symptoms and underlying pathology of the condition by improving or stabilizing the patient's condition.

The selectivity in respect of the 20S proteasome

Described here inhibitors of the enzyme is useful, in particular, because they inhibit the activity of the 20S proteasome. Additionally, in contrast to other inhibitors of the 20S proteasome, the described connection of vysokoselektivnye against 20S proteasome compared to other ProcessName enzymes. That is, the compounds according to the invention show selectivity for 20S proteasome in comparison with other proteases, such as cathepsins, calpini, papain, chymotrypsin, trypsin, tripeptidylpeptidase II. Selectivity of inhibitors of the enzyme against 20S proteasome is that, at concentrations below approximately 50 microns inhibitors of the enzyme have shown inhibition of the catalytic activity of the 20S proteasome, without showing at the same time inhibiting the catalytic activity of other proteases, such as cathepsins, calpini, papain, chymotrypsin, trypsin, tripeptidylpeptidase II. In preferred embodiments, the implementation of inhibitors of the enzyme have shown inhibition of the catalytic activity of the 20S proteasome at concentrations below about 10 microns, without showing at the same time inhibiting the catalytic activity of the other is rateas at these concentrations. In even more preferred embodiments, the implementation of inhibitors of the enzyme have shown inhibition of the catalytic activity of the 20S proteasome at concentrations below about 1 μm, without showing at the same time inhibiting the catalytic activity of other proteases in such concentrations. Study of enzyme kinetics is described in the patent application U.S. serial number 09/569748, example 2, and Stein et al., Biochem. (1996), 35, 3899-3908.

Selectivity for chymotrypsin-like activity

Certain embodiments of described herein inhibiting the enzyme connections next applicable, because they can effectively and selectively inhibit chymotrypsin-like activity of the 20S proteasome compared to the trypsin-like and PGPH activity. Chymotrypsin-like activity of the 20S proteasome is characterized by the cleavage of the peptides in the immediate vicinity of large hydrophobic residues. In particular, chymotrypsin-like activity of Ntn-hydrolases can be determined by splitting the standard substrate. Examples of such substrates are known in this field. For example, you can use a derived lateralisation. Study of enzyme kinetics is described in the patent application U.S. serial number 09/569748, example 2, and Stein et al., Biochem. (1996), 35, 3899-3908.

Inhibitors f is rment

Biological consequences of inhibiting the proteasome extensive. At the cellular level reported on the accumulation polyubiquitinated proteins, morphological changes of cells and apoptosis after treatment of cells with different inhibitors of the proteasome. Inhibition of the proteasome is also offered as a possible anticancer therapeutic strategy. The fact that Apoksiomen was originally discovered by screening for antitumor activity, allows to evaluate the proteasome as a target for cancer chemotherapy. Accordingly, these compounds are applicable for the treatment of cancer. Inhibition of the proteasome is also associated with activation of inhibition of NF-κ and stabilization of p53 levels. Thus, the compounds according to the invention can also be used to inhibit the activation of NF-κ and stabilize the levels of p53 in cell culture. Because NF-κ is a key regulator of inflammation, it is an attractive target for anti-inflammatory therapeutic effects. Thus, the compounds according to the invention can be used to treat conditions associated with chronic inflammation, including as non-limiting examples of COPD, psoriasis, bronchitis, emphysema and cystic fibrosis.

Described compounds can be used to Le the surveillance state mediated directly proteolytic function of the proteasome, such as muscle wasting, or indirectly mediated via proteins which are processed by the proteasome, such as NF-κ. The proteasome is involved in the rapid removal and post-translational processing of proteins (e.g. enzymes)involved in cellular regulation (for example, cell cycle, transcription of genes and metabolic pathways), intercellular contacts and immune responses (e.g., presentation of antigen). Specific examples discussed below include β-amyloid protein and regulatory proteins, such as collini, TGF-β and the transcription factor NF-κ.

Another implementation of the invention is the use of compounds described herein for the treatment of neurodegenerative diseases and conditions, including as non-limiting examples of stroke, ischemic damage to the nervous system, neural trauma (e.g., concussion, spinal cord injury, and traumatic damage to the nervous system), multiple sclerosis and other immune-mediated neuropathies (e.g., Guillain-Barre syndrome and its variants, acute motor axonal neuropathy, acute inflammatory demyelinizing the polyneuropathy, and Fisher syndrome), dementia complex HIV/AIDS, axonomy, diabetic neuropathy, the disease Parks is Sona, Huntington's disease, multiple sclerosis, bacterial, parasitic, fungal and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, dementia Taurus Levi, dementia of the frontal lobe, such as the disease Peak, subcortical dementia (such as paralysis Huntington or progressive supranuclear palsy), syndrome of focal cortical atrophy (such as primary aphasia), metabolic-toxic dementia (such as chronic hypothyroidism or B12-deficiency) and dementia caused by infection (such as syphilis or chronic meningitis).

Alzheimer's disease is characterized by extracellular deposits of β-amyloid protein (β-AP) in the form of senile plaques in the cerebral vessels. β-AP is a fragment of 39 to 42 amino acids, derived from the amyloid precursor protein (APP). Known, at least three isoforms of APP (695, 751 and 770 amino acids). Alternative splicing of the mRNA leads to isoforms; normal processing affects the part of the sequence of β-AP, thus preventing the emergence of β-AP. I believe that the abnormal processing of the protein by the proteasome contributes to the abundance of β-AP in the brain in Alzheimer's disease. ARR-processrule enzyme in rats contains approximately ten different subunits (22 kDa, 32 kDa). Subjedinica 25 kDa contains N-terminal is the selected X-Gln-Asn-Pro-Met-X-Thr-Gly-Thr-Ser, which is identical to the β-subunit of human macrofauna (Kojima, S. et al., Fed. Eur. Biochem. Soc., (1992) 304: 57-60). ARR-processrule enzyme cleaves the bond Gln15-Lys16in the presence of calcium ion, the enzyme also cleaves the bond Met-1-Asp1and communications Asp1-Ala2to remove extracellular domain of β-AP.

One variant of implementation, therefore, is a method of treating Alzheimer's disease, covering the introduction to the patient an effective amount of the compound (e.g., pharmaceutical compositions)described herein. This treatment includes a reduction in the rate of formation of plaques of β-AP, reducing the rate of formation of β-AP and the reduction of clinical signs of Alzheimer's disease.

Other embodiment of the invention related to cachexia and diseases that cause muscle exhaustion. Proteasome involved in the degradation of many proteins in maturing the reticulocytes and growing fibroblasts. In cells deprived of insulin or serum, the rate of proteolysis almost doubled. Inhibition of the proteasome reduces proteolysis, thus reducing the loss of muscle protein, and nitrogen load on the kidneys or liver. The inhibitors according to the invention is applicable to the treatment of conditions such as cancer, chronic infectious diseases, fever, muscle inactivity (atrophy), denervation, nerve damage,starvation, renal failure associated with acidosis, diabetes and liver failure. See, for example, Goldberg, U.S. patent No. 5340736. Embodiments of the invention therefore encompasses methods of reducing the rate of muscle protein degradation in a cell; reducing the rate of intracellular protein degradation; reduce the rate of degradation of p53 protein in the cell and inhibiting growth-related p53 cancers. Each of these methods includes the contact cells (in vivoorin vitrofor example, muscles of the patient with an effective amount of the compounds described herein (e.g., pharmaceutical compositions).

Fibrosis represents an excessive and persistent formation of scar tissue resulting from a hyperproliferative growth of fibroblasts, and it is associated with activation of the transmission signals of TGF-β. Fibrosis is extensive deposition of extracellular matrix and may be within virtually any tissue or among several different tissues. Typically, the level of intracellular signaling protein (Smad), which activates the transcription of genes required for stimulation of TGF-β is regulated by the activity of the proteasome (Xu et al., 2000). However, increased degradation of the signal components of the TGF-β was observed in cancers and other hyperproliferative conditions. Thus, some implementation izopet the deposits relate to a method of treatment of hyperproliferative conditions, such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, atresia of bile ducts, congestive heart failure, scleroderma, radiation-induced fibrosis, and pulmonary fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease, sarcoidosis, interscalene pulmonary disease and acquired pulmonary disorders). The treatment of burns victims often complicated by fibrosis, thus, an additional variant embodiment of the invention is a local and systematic introduction inhibitors for the treatment of burns. Wound closure after surgery is often associated with disfiguring scars, which can be prevented by inhibition of fibrosis. Thus, in some embodiments implementing the invention relates to a method of preventing or reducing scarring.

Another protein, processed by the proteasome, is NF-κ, a member of protein family Rel. The Rel family of transcription proteins activators can be divided into two groups. For the first group required proteolytic processing, and it includes p50 (NF-κ 1, 105 kDa) and p52 (NF-κ2, 100 kDa). For the second group does not require proteolytic processing, and it includes p65 (RelA, Rel (c-Rel and RelB). As Homo-and heterodimer can razovyutsya members of the Rel-semesta; NF-κ, for example, represents heterodimer p50-p65. After phosphorylation and ubiquitination Iκ and p105 two proteins are being degraded and are processed to obtain the active NF-κ, which moves from the cytoplasm into the nucleus. Ubiquitination p105 also processed purified proteasomes (Palombella et al., Cell (1994) 78: 773-785). Active NF-κ forms stereospecific enhancer complex with other transcription activators and, for example, HMG I (Y), which induces selective expression of a particular gene.

NF-κ regulates genes involved in immune and inflammatory response and mitotic phenomena. For example, NF-κ required for gene expression of the light chain κ immunoglobulin gene α-chain of the receptor for IL-2 gene major histocompatibility complex class I a large number of cytokine genes encoding, for example, IL-2, IL-6, granulocyte colony-stimulating factor and IFN-β (Palombella et al., Cell (1994) 78: 773-785). Some embodiment of the invention encompass methods of influence on the expression level of IL-2, MHC-I, IL-6, TNFα, IFN-β or any of the other previously mentioned proteins, each of which method comprises administration to the patient effective amounts of compounds described herein. Complexes, including p50, are quick mediators of acute inflammation and immune response (Thanos, D. and Maniatis, T., Cell (1995) 80: 529-532).

NF-κ is also involved in the expression the AI adhesion genes cells, which encode E-selectin, P-selectin, ICAM, and VCAM-1 (Collins, T., Lab. Invest. (1993) 68:499-508). One variant of the invention is a method of inhibiting adhesion of cells (e.g., of cell adhesion mediated by E-slection, P-selectin, ICAM or VCAM-1), covering the interaction of a cell with (or introduction to the patient an effective amount of the compounds described herein (or pharmaceutical compositions).

Ischemic condition and reperfusion damage lead to hypoxia, a condition in which there is a failure coming into the body tissues of oxygen. This condition causes increased degradation of Iκ-Bα, thereby leading to activation of NF-κB (Koong et al., 1994). It was demonstrated that the severity of the damage, leading to hypoxia, can be reduced with the introduction of proteasome inhibitor (Gao et al., 2000; Bao et al., 2001; Pye et al., 2003). Therefore, some embodiments of the invention relate to a method of treatment of ischemic or reperfusion injury comprising the administration to a patient in need of such treatment, an effective amount of compounds described herein. Examples of such conditions or lesions as non-limiting examples include acute coronary syndrome (easily damaged atherosclerotic plaques), occlusive lesion of the arteries (cardiac, cerebral and peripheral arterial and vascular occlusion), atherosclerosis (coronary atherosclerosis, coronary artery disease), heart attacks, heart failure, pancreatitis, myocardial hypertrophy, stenosis and restenosis.

NF-κB also specifically binds to HIV enhancer/promoter. When compared with mac239 Nef regulatory protein of HIV Nef pbj14 differs by two amino acids in the region, which controls the binding of the protein kinase. Suppose that the protein kinase transmits a signal on the phosphorylation of IκB, causing degradation of IκB through the path of the ubiquitin-proteasome. After degradation, NF-κB is released into the nucleus, thus increasing the transcription of HIV (Cohen, J., Science (1995) 267: 960). Two variants of the invention provide a method for inhibiting or reducing HIV infection in a patient and the method of reducing the level of expression of a viral gene, each of which method comprises administration to the patient effective amounts of compounds described herein.

Excessive production induced by lipopolysaccharide (LPS), cytokines, such as TNFα, as I believe, is the Central process associated with septic shock. In addition, it is generally accepted that the first stage in the activation of cells LPS is a LPS binding to specific membrane receptors. α - and β-Subunit complex of the 20S proteasome were identified as LPS binding protein, suggesting that inducyruemaya LPS transduction may represent an important therapeutic target for the treatment and prevention of sepsis (Qureshi, N. et al., J. Immun. (2003) 171: 1515-1525). In some embodiments, the implementation therefore compounds according to the invention can be used for inhibition of TNFα in order to prevent and/or treat septic shock.

When intracellular proteolysis formation of small peptides for presentation to T lymphocytes to induce mediated MHC class I immune response. The immune system protects against autologous cells that are infected with a virus or have undergone oncogenic transformation. One implementation is a method of inhibiting antigen presentation in a cell, covering the effects on the cell described in this connection. The connection according to the invention can be used to treat associated with the immune response conditions, such as allergies, asthma, rejection of organ/tissue (graft versus host) and autoimmune diseases, including as non-limiting examples erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease). Thus, additional implementation is a method of suppressing the immune system of the patient (for example, inhibition of transplant rejection, allergies, autoimmune diseases and asthma), including introduction to patient effective if the ESCWA described here the connection.

Another optional implementation is a way to change the diversity of antigenic peptides produced by the proteasome or other Ntn with multicatalytic activity. For example, if the PGPH activity of 20S proteasome selectively inhibit, then the other number of antigenic peptides will be produced by the proteasome and presented to MHC molecules on the cell surface, which was producirovanie and would be either no inhibition of any enzyme, or, for example, when the selective inhibition chymotrypsin-like activity of the proteasome.

Some inhibitors of the proteasome block as the degradation and processing ubiquitination NF-κBin vitroandin vivo. The proteasome inhibitors also block the degradation of IκB-α and activation of NF-κB (Palombella, et al. Cell (1994) 78: 773-785; Traenckner et al., EMBO J. (1994) 13: 5433-5441). One variant of the invention is a method of inhibiting the degradation of IκB-α, covering the effects on the cell described in this connection. Additional exercise is a way of reducing the cellular content of NF-κB in a cell, muscle, organ or organism, including the effects on the cell, muscle, organ or organism of the patient described in this connection.

Other eukaryotic transcription factors that PR is Teoreticheskie processing, include the main transcription factor TFIIA, auxiliary protein of herpes simplex virus VP16 (factor host cell), protein induced by virus regulatory factor 2 and IFN protein 1, binding membrane-bound regulatory element Sterol.

Other embodiments of the invention are methods of cyclin-dependent cycles of eukaryotic cells, covering the effects on the cell (in vitroorin vivo) described in this connection. Cycline represent proteins involved in controlling the cell cycle. Proteasome involved in the degradation of tsiklonov. Examples of tsiklonov include mitotic cycline, cycline G1 and cyclin b Degradation tsiklonov allows the cell to go from one stage of the cell cycle (e.g., mitosis) and enter into another (e.g., division). I believe that all cycline associated with p34.sup.cdc2 protein kinase or related kinases. The positioning signal for proteolysis localized in the amino acid 42-RAALGNISEN-50 (Boxing destruction). There is evidence that cyclin turns into a form amenable to the action of ubiquitinate, or what specific cyclina ligase is activated during mitosis (Ciechanover, A., Cell (1994) 79:13-21). Inhibition of the proteasome inhibits the degradation cyclina and, consequently, inhibits cell proliferation, e.g. the R, associated with cyclin cancers (Kumatori et al., Proc. Natl. Acad. Sci. USA (1990) 87: 7071-7075). One variant of the invention is a method of treating a proliferative disease of the patient (e.g., cancer, psoriasis or restenosis), including introduction to the patient effective amounts of compounds described herein. The invention also includes a method of treatment associated with cyclin inflammation in a patient, comprising the administration to the patient therapeutically effective amounts of compounds described herein.

Additional embodiments of the invention are methods of influence on the dependent proteasome regulation of oncogenic proteins and methods of treating or inhibiting the growth of cancers, each method includes effects on the cell (in vivofor example, on the patient, orin vitro) described in this connection. Proteins E6 derived from HPV-16 and HPV-18, stimulate ATP - and ubiquitin conjugation and degradation of p53 in untreated lysates reticulocytes. Recessive oncogene p53 has been shown to accumulate in not allowing for the development of the temperature in cell lines with mutated thermostable E1. Increased levels of p53 can lead to apoptosis. Examples of proto-oncogenic proteins, degradiruem system of ubiquitin include c-Mos, c-Fos and c-Jun. One option assests the Deposit is a method of treatment associated with p53 apoptosis, includes introduction to the patient therapeutically effective amounts of compounds described herein.

In another embodiment, the described connections applicable for the treatment of parasitic infections, such as infections caused by protozoa parasites. The data proteasome parasites believed to be involved primarily in the differentiation of cells and replication activity (Paugam et al., Trends Parasitol. 2003, 19(2): 55-59). In addition, the kinds of entameba been shown to lose their ability to encapsulating the effects of proteasome inhibitors (Gonzales, et al., Arch. Med. Res. 1997, 28, Spec No: 139-140). In some such embodiments, the implementation of the described compounds applicable for the treatment of parasitic infections in humans caused by protozoa parasites selected from Plasmodium species (including P. falciparum, P. vivax, P. Malariae and P. ovale, which cause malaria), Trypanosoma species (including T. cruzi, which causes Chagas disease, and T. Brucei, which causes African sleeping sickness), Leishmania species (including L. amazonensis, L. donovani, L. infantum, L. Mexicana, and so on), Pneumocystis carinii (simplest, which is known to cause pneumonia in patients with AIDS and other immunosuppressive diseases), Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens and Giardia lamblia. In some embodiments, the implementation of the described compounds applicable for the treatment of parasitic infections in animals and large ro is Togo cattle, caused by protozoa parasites selected from Plasmodium hermani, Cryptosporidium species, Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa. Other compounds applicable as proteasome inhibitors in the treatment caused by parasites diseases described in WO 98/10779, which is fully included here.

In some embodiments, the implementation of the described compounds irreversibly inhibit the proteasome activity in the parasites. This irreversible inhibition, as has been shown, causes the enzyme without restoring red blood cells and white blood cells. In some such embodiments, the implementation of the long half-life of blood cells can provide prolonged protection as therapy against re-exposure to parasites. In some embodiments, the implementation of the long half-life of blood cells can provide prolonged protection as chemoprophylaxis future infections.

It was also demonstrated that inhibitors that are associated with the 20S proteasome, stimulate bone formation in organ cultures of bone. In addition, when these inhibitors were systematically injected into mice, some inhibitors of the proteasome resulted in the increase of bone volume and rate of bone formation more than 70% (Garrett, I.R. et al. , J. Clin. Invest. (2003) 111: 1771-1782), assuming the trail is therefore the ubiquitin-proteasome apparatus regulates the differentiation of osteoblasts and bone formation. Therefore, the described compounds can be used to treat and/or prevent the development of diseases associated with bone loss, such as osteoporosis.

Bone is an excellent source of factors that have the ability to stimulate bone cells. Thus, extracts of bovine bone contain not only structural proteins that are responsible for maintaining the structural integrity of the bones, but also for biologically active growth factors bone, which can stimulate proliferation of bone cells. Among these latter factors is a recently described family, called bone morphogenetic proteins (BMP). All these growth factors also affect other types of cells as well as bone cells, covering Hardy, M.H., et al.,Trans Genet(1992) 8: 55-61, which describes the evidence that bone morphogenetic proteins (BMP) differently expressed in the hair follicles in the development process. Harris, S.E., et al.,J Bone Miner Res(1994) 9: 855-863, describe the effect of TGFβ on the expression of BMP-2 and other substances in bone cells. The expression of BMP-2 in Mature follicles takes place during maturation and after a period of cell proliferation (Hardy, et al. (1992, above). Thus, connection is obreteniyu can also be used to stimulate the growth of hair follicles.

In conclusion, the described compounds are also applicable as a diagnostic means (e.g., in diagnostic kits or for use in clinical laboratories) for screening proteins (e.g. enzymes, transcription factors), processed by the Ntn hydrolases, including the proteasome. The described compounds are also used as reagents for studies of specific binding subunit X/MB 1, or α-chain and inhibition associated proteolytic activity. For example, one can determine the activity (and specific inhibitors of other subunits of the proteasome.

Most cellular proteins undergo proteolytic processing during maturation or activation. Described here inhibitors of the enzyme can be used to determine whether regulated cellular process, developmental or physiological process or the products of proteolytic activity specific hydrolases Ntn. One such method includes receiving body, preparation of intact cells or cell extract; effects on the body, the preparation of cells or cell extracts described in this connection; the impact on the affected connection body, the preparation of cells or cell extract signal and the monitoring of process or product. Visokoefektivnih compounds described here allows rapid and precise removal of or involvement Ntn (for example, 20S proteasome) in a particular cellular process, developmental or physiological process.

Introduction

Obtained, as described herein, the compounds can be entered in different types depending on the disorder that must be treated, and the age, condition and body weight of the patient, as is well known in this field. For example, in cases where the compound is administered orally, they can be prepared in the form of tablets, capsules, granules, powders or syrups, or parenteral administration can be prepared by injection (intravenous, intramuscular or subcutaneous), drugs for drip infusion or suppositories. For insertion through the mucous membrane of the eyes can be prepared in the form of eye drops or eye ointments. The data of the dosage form can be prepared in a common manner, and, if necessary, the active ingredient can be mixed with any conventional additive or excipient such as a binder, baking powder, grease, modifier drugs, solubilizers tool, suspensionusual agent, emulsifying agent, tool coating, cyclodextrin and/or a buffer. Although the dosage will vary depending on symptoms, age and body weight of the patient, nature and severity of the offense, which is necessary to cure or prevent the ü its development, the method of administration and the form of the medicinal product, in the General case for the adult recommended daily dosage of from 0.01 to 2000 mg of the compound, and can be entered as a single dose or in divided doses. The number of active component that can be combined with the substance of the medium in order to obtain a formulation for a single dose, in General, will constitute such an amount of a compound that has a therapeutic effect.

The precise time of administration and/or the number of connections that will lead to the most efficient results regarding the effectiveness of treatment for this patient will depend upon the activity, pharmacokinetics and bioavailability of a particular compound, physiological condition of the patient (including age, gender, type of disease and stage, General physical condition, responsiveness of a given dosage and type of treatment), the route of administration and so forth. However, the above recommendations can be used as the basis for precise adjustment of the treatment, for example, determining the optimal time and/or quantity for the introduction, which will not require more than an ordinary experimentation, consisting of control over the patient and the selection of dosage and/or timing.

Used here, the phrase "pharmaceutically acceptable" seat is no such ligands, substances, compositions and/or dosage forms which are, from a medical point of view, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable ratio of benefit/risk.

Used here, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or interporous substance. Each carrier must be "acceptable" in the sense that it must be compatible with other ingredients of the drug and should not be harmful to the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include : (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch, and substituted and unsubstituted β-cyclodextrin; (3) cellulose, and its derivatives, such as carboxymethylcellulose sodium, ethylcellulose and cellulose acetate; (4) powdered tragakant; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and wax for suppositories; (9 oil, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive m the words, corn oil and soybean oil; (10) glycols, such as propylene glycols; (11) polyols of the type of glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buferiruemoi tools, such as magnesium hydroxide and a hydroxide of alumia; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution and (21) other non-toxic compatible substances used in pharmaceutical preparations. In some embodiments, the implementation of the pharmaceutical compositions of the present invention are pyrogen free and no, that is not cause significant temperature increase with the introduction of the patient.

The term "pharmaceutically acceptable salt" refers to relatively non-toxic additive salts of inorganic and organic acid inhibitor(s). Such salts can be obtainedin situduring the final selection or purification of the inhibitor(s), separately subjecting the purified inhibitor(s) in the form of its free base reaction with a suitable organic or inorganic acid, and separating the thus formed salt. Typical examples of salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, t is spending, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate, laurilsulfate salts, amino acids, and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

In other cases, the inhibitors that are applicable in the methods of the present invention may contain one or more acidic functional groups and, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic additive salts of inorganic and organic bases of the inhibitor(s). Such salts can in a similar way to get thein situduring the final selection or purification of the inhibitor(s), separately subjecting the reaction of the purified inhibitor(s) in its free acid form with a suitable organic or inorganic base, such as hydroxide, carbonate or bicarbonate pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical examples of bases or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Typical examples of organic amines, applicable for the formation of additive salts of bases include ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al.,above).

Wetting means, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coverage tools, sweetening, flavoring and aromatic additives, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include : (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) soluble in oil; antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like, and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Preparations suitable for oral administration may be in the form of capsules, sachets, pills, tablets, candies (using a flavored basis, usually sucrose and gum Arabic or tragakant), powders, granules or in the form of a solution or suspension in aqueous or non-aqueous liquid, or as fluid is th emulsion of the type oil-in-water or water-in-oil or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerol or sucrose and gum Arabic) and/or liquid for mouth rinses, and the like, and each contains a predetermined quantity of inhibitor(s) as an active ingredient. The composition can also enter bolus, electuary or paste.

In solid dosage forms for oral administration (capsules, tablets, pills, pills, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and/or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polivinilpirolidon, sucrose and/or gum Arabic; (3) humectants, such as glycerol; (4) dezintegriruetsja tools, such as agar-agar, calcium carbonate, potato starch or starch from tapioca, alginic acid, certain silicates and sodium carbonate; (5) solutions inhibiting means, such as paraffin; (6) absorption accelerators, such as Quaternary ammonium compounds; (7) wetting means, so is e as, for example, acetyloxy alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring tools. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain bothersome funds. Solid compositions of a similar type can also be used as fillers in soft and completely filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The tablet can be manufactured by extrusion or molding, optionally with one or more additional ingredients. Molded tablets can be made using binder (for example, gelatin or hypromellose), a lubricating substance, inert thinner, preservative, raising agent (e.g. sodium starch glycolate, or perekrestnotochny carboxymethylcellulose sodium), surface-active or dispersing agent. Injection molded tablets can be made, molding in a suitable device, the powder mixture of the inhibitor(s), moistened with an inert liquid thinner.

Tablets and the other is e solid dosage forms, such as pills, capsules, pills and granules, may optionally be manufactured with grooves or with coatings and shells, such as intersolubility coatings and other coatings well known in the field of pharmaceutical preparations. They can also be manufactured so as to provide slow or controlled release of the active ingredient, using, for example, hypromellose in different proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized, for example, by filtration through a retaining bacteria filter or adding a sterilizing agent in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. Such compositions may also optionally contain opalescent components and may belong to the compositions, which release only the active component(s) or preferably only in a certain part of the gastrointestinal tract, optionally, a prolonged way. Examples of embedded compositions that can be used include polymeric substances and waxes. The active ingredient can also be encapsulated in the form of microcapsules, if this target is obratno, with one or more of the above fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert thinners, usually used in this field, such as, for example, water or other solvents, solubilizing means and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, oil cake germ, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, polyethylene glycols and esters of fatty acids and sorbitan and mixtures thereof.

In addition to the inert thinners compositions for oral administration can also include adjuvants such as wetting means, emulsifying and suspendresume tools, sweetening, gives taste, coloring, otdushivayut and preservatives.

Suspensions, in addition to the active inhibitor(s) contain suspendresume means, such as, for example, ethoxylated isostearoyl alcohol, polyoxyethylene esters of sorbitol and sorbitan, microcrystal the ical pulp, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

Preparations for rectal or vaginal injection can be a suppository, which can be made by mixing one or more inhibitor(s) with one or more suitable non-irritating fillers or carriers comprising, for example, cocoa butter, polyethylene glycol, wax suppositories or a salicylate, and which is solid at room temperature, but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active agent.

Drugs that are suitable for vaginal administration, also include pessaries, tampons, creams, gels, pastes, foams or drugs in the form of a spray containing such carriers as are known in this area are appropriate.

Dosage forms for local or transdermal injection of inhibitor(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

Ointments, pastes, creams and gels in addition to the inhibitor(s) may contain fillers such as animal and vegetable fats, is of asle, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays in addition to the inhibitor(s) may contain fillers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powders based on polyamides or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

The inhibitor(s) alternatively, the injected spray. This is done by preparing an aqueous aerosol, liposomal preparation or solid particles containing the composition. You can use non-aqueous suspension (for example, fluorocarbon propellant). Ultrasonic nebulizers are preferred as they minimize the impact on the tool shear layers, which can lead to degradation of the connection.

Typically, water spray get preparing an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements for a particular composition, but typically include nonionic surfactants (tween, pluronic, ether with bitana, lecithin, crematory), pharmaceutically acceptable co-solvents, such as glycols, non-toxic proteins, such as serum albumin, oleic acid, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are usually prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlled delivery of the inhibitor(s) in the body. Such dosage forms can be prepared by dissolving or dispersive agent in an appropriate environment. The absorption accelerators can also be used to increase intake of inhibitor(s) on the skin. The rate of such flux can be controlled either through controlling the speed of the membrane, or dispersive inhibitor(s) in a polymer matrix or gel.

Pharmaceutical compositions of this invention suitable for parenteral administration contain one or more inhibitor(s) in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be turned into sterile injectable solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostatic, solutions that give drugs the the ATU isotonicity the blood of the intended recipient, or suspendresume or thickening means.

Examples of suitable aqueous and nonaqueous carriers which can be used in the pharmaceutical compositions according to the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as etiloleat. The proper fluidity can be maintained, for example, with substances of the coating, such as lecithin, maintaining the required particle size in the case of dispersions, and by using surface-active substances.

These compositions may also contain adjuvants such as preservatives, wetting means, emulsifying dispersing means and tools. Prevention of the action of microorganisms can be ensured by the addition of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It is also desirable to add to the composition supports toychest tools, such as sugars, sodium chloride, and the like. In addition, prolonged absorption of the injectable pharmaceutical form can be called by the addition of agents which delay absorption such as aluminum monostearate and gelatin.

In some the older cases, to prolong the effect of the drug, it is necessary to slow down the absorption of the drug by subcutaneous or intramuscular injection. For example, slow the absorption of parenteral input form of the drug is carried out by dissolving or suspending the drug in an oil medium.

Injectable pharmaceutical form prolonged action receive, forming microencapsulating the matrices with inhibitor(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug and polymer and the nature of the particular polymer used, you can control the rate of release of the drug. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injectable long-acting drugs also get through the drug in liposomes or microemulsions that are compatible with the tissue of the body.

Drugs drugs can be administered orally, parenterally, topically or rectally. They, of course, give the forms appropriate for each route of administration. For example, they are administered in the form of tablets or capsules, injection, inhalation, eye lotion, ointment, suppository, injection; topically in the form of lotion or ointment; and rectal by suppositories. Prefer the Ino oral administration.

Used herein, the phrases "parenteral administration" and "enter parenteral" refers to the route of administration other than enteral and local administration, usually by injection, and without limitation include intravenous, intramuscular, intraarterial, intrathecal, intracapsular, lower eyelid, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, under the cuticle, intra-articular, podkapsulnaya, podporchennuyu, vnutrismennyh and epigastric injection and infusion.

Used here, the phrase "system introduction, injected systemically", "peripheral introduction" and "enter perifericheskie" refers to the introduction of the ligand, drug or other substance by the way, except for direct injection into the Central nervous system, such that the drug is introduced into the system of the patient and, therefore, he is subject to metabolism and other like processes, for example, subcutaneous administration.

These inhibitors can enter to man and other animals for the treatment of any appropriate manner of administration, including oral, nasal as, for example, by a spray, rectally, intrawaginalno, parenteral, intracisternally and topically, as by powders, ointments or drops, including buccal and sublingual.

Regardless of the way in which edenia inhibitor(s), which can be used in a suitable hydrated form, and/or pharmaceutical compositions according to the present invention are pharmaceutically acceptable dosage forms by using common methods known to experts in this field.

Actual dosage levels of active ingredients in the pharmaceutical composition according to this invention can be modified in order to obtain an amount of active ingredient which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration, without being toxic to the patient.

The concentration of the described compounds in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the input connections, the pharmacokinetic characteristics of the compound(s) and method of administration. In General the compositions of this invention can be provided in an aqueous solution containing about 0.1-10% wt./about. described here are the links among other substances for parenteral administration. Typical dose ranges are in the range of from about 0.01 to about 50 mg/kg of body weight per day, with the introduction in 1-4 divided doses. Each divided dose may contain the same or different compounds according to the invention. Dosiro is and will be an effective amount depending on several factors, including the General health of the patient and the drug and route of administration selected connection(s).

Another aspect of the invention relates to combination therapies, where one or more different therapeutic agents administered with an inhibitor of the proteasome. Such combination therapy can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

In some embodiments, the implementation of the connection according to the invention is administered together with one or more other inhibitor(s) of the proteasome.

In some embodiments, the implementation of the connection according to the invention is administered in conjunction with chemotherapy drug. Suitable chemotherapeutic drug may include natural products such as Vinca alkaloids (i.e. vinblastine, vincristine and vinorelbine), paclitaxel, epileptogenesis (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubitsin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systematically metabolizes L-asparagine and destroys cells that lack the ability to synthesize their own asparagine); antiplatelet means; antiproliferative/antimitoticescoy alkylating with whom estva, such as nitrogen mustard (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamine (hexamethylmelamine, thiotepa), alkylated sulfonates (busulfan), nitrosoanatabine (carmustin (BCNU) and analogs, streptozocin), triazin-dacarbazine (DTIC); antiproliferative/antimitoticescoe antimetabolites, such as analogs of folic acid (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, tioguanin, pentostatin and 2-chloromethoxypropyl); aromatase inhibitors (anastrozole, exemestane and letrozole); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutetimid; hormones (i.e. estrogen) and hormone agonists, such as agonists of lutropin-releasing hormone (LHRH) analogues (goserelin, leuprolide, and triptorelin). Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine or any analog or derivative variant of the foregoing.

In some embodiments, the implementation of the connection according to the invention is administered in conjunction with the steroid. Suitable steroids can include as non-limiting examples 21-acetoxyphenyl, alclometasone, algestone, amcinonide, beclomet is he, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortisol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, flashcart, fluchloralin, flumetazon, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluoropharma, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, farmacita, halcinonide, halobetasol propionate, halobetasol, hydrocortisone, loteprednol etabonate, mazipredon, Madison, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednesol, prednisone, rimexolone, tixocortol, triamcinolone, triamcinolone, triamcinolone, triaminoguanidine and their salts and/or derivatives.

In some embodiments, the implementation of the connection according to the invention is administered in conjunction with immunotherapy agent. Appropriate immunotherapy can include as non-limiting examples of cyclosporine, thalidomide, and monoclonal antibodies. Monoclonal antibodies can be either simple or conjugated, such as rituximab, tositumomab, alemtuzumab, epratuzumab, ibric tomb tiuxetan, gemtuzumab ozogamicin, bevacizumab, cetuximab, erlotinib and trastuzumab.

EXAMPLES

Scheme 1: synthesis of example 1

Synthesis of ((A)

To a solution of the hydrochloride of the methyl ester of phenylalanine (2,31 mmol, 0.5 g) in 25 ml DMF was added pyrazinecarboxamide acid (2,31 mmol, 0.28 g), DIEA (9,24 mmol, 1.19 g, 1,61 ml) and HOBT (3,70 mmol, 0.50 g) and the solution was cooled to 0ºC. To the cooled solution in several portions was added PyBOP (3,70 mmol, 1,93 g) and the mixture was removed from the bath with ice and gave it to warm to room temperature with stirring in an argon atmosphere for 6 hours. The mixture was diluted with saturated saline solution (50 ml) and was extracted with EtOAc (5×15 ml). The organic layers were combined, washed with H2O (2×15 ml) and saturated saline (2×15 ml) and dried over MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography to obtain (A) (0.64 g).

Synthesis of (B)

To the suspension (A) (1,03 mmol, 0,298 g) in 15 ml of MeOH, cooled to 0ºC was added LiOH (10,31 mmol, 0,247 g), dissolved in 5 ml of H2O. After 4 hours at 0 reaction was suppressed 20 ml of saturated NH4Cl and pH of the reaction mixture was brought to 2 with 1 N. HCl. Volatiles were removed under reduced pressure and the solids were collected by filtration to get the ü (B) (0,200 g).

Synthesis of compound1

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.08 mmol) in MeCN (2 ml) was added (B) (0.08 mmol, 0,021 g), DIEA (0,320 mmol, by 0.055 ml) and HOBT (0,128 mmol, of 0.017 g). The mixture was cooled to 0ºC in a bath with ice and several portions was added BOP (0,128 mmol, 0,057 g). The mixture was stirred at 5ºC in an argon atmosphere overnight. Then the reaction mixture was diluted with H2O (15 ml) and was extragonadal EtOAc (3×5 ml). The organic layers were combined, washed with water (2×5 ml), saturated NaHCO3(2×5 ml) and saturated saline (2×5 ml), and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography to obtain1(0,017 g).

Scheme 2: synthesis according to example 2

Synthesis of (D)

To a solution of NBOC leucine (40.0 mmol, 9,25 g) and serine methyl ester (40.0 mmol, from 6.22 g) in 400 ml DMF was added HOBT (64,0 mmol, 8.65 g) and DIEA (160,0 mmol, 20,68 g, 28 ml). The mixture was cooled to 0ºC in a bath with ice and several portions over five minutes was added BOP (64,0 mmol, 28,30 g). The mixture was placed in an argon atmosphere and was stirred overnight. The reaction mixture was diluted with saturated brine (1000 ml) and was extracted with EtOAc (6×200 ml). The organic layers were combined, washed with water (10×100 ml) and saline races is a thief (3×200 ml) and dried over MgSO 4. MgSO4was removed by filtration and the volatiles removed under reduced pressure to obtain (D) (13,65 g).

Synthesis of (E)

To a solution of imidazole (99,3 mmol, 6,76 g) in DMF (330 ml) was added TBDPSCl (49,64 mmol, 13,65 g) and the mixture was stirred for 15 minutes in an argon atmosphere. Added the compound (D) (33,10 mmol, 11,0 g) and the mixture was stirred over night. The mixture was diluted with saturated brine (750 ml) and was extracted with EtOAc (6×200 ml). The organic layers were combined, washed with H2O (3×300 ml) and saturated saline (2×200 ml) and dried over MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography, obtaining (E) (13,78 g).

Synthesis of (F)

To 50 ml and cooled to 0 solution of 80% TFA/DCM was added (E) (of 12.26 mmol, 7.0 g). The solution was stirred and allowed him to warm to room temperature over 2 hours Volatiles were removed under reduced pressure. To the oil was added BocNHhPhe (of 12.26 mmol, 3.42 g), 125 ml of DMF, HOBT (19,62 mmol, 2.65 g) and DIEA (49,04 mmol, 6,34 g, 8.5 ml). The mixture was cooled to 0ºC in a bath with ice and several portions over five minutes was added BOP (19,62 mmol, 8,67 g). The reaction mixture was placed under argon and allowed it to warm to room temperature over night. The reaction mixture was diluted with DCM in the amount of 100 ml and poured into 60 ml of H 2O. the Organic layers were separated and washed with H2O (1×100 ml), saturated NaHCO3(1×100 ml) and saturated brine (1×100 ml) and dried over MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure to obtain (F) (8,14 g).

Synthesis of (G)

To a solution of (F) (1.6 mmol, 1.0 g) in DCM (10 ml) at 0ºC in a bath with ice was slowly added a solution of 20% TFA/DCM (20 ml). The solution was slowly heated to room temperature and was stirred overnight. Volatiles were removed in vacuum and the residue was diluted with DCM and evaporated (3×). The oil obtained was placed in a high vacuum for 2 h to obtain (G).

Synthesis of (H)

To a solution of intermediate product (G) (1.6 mmol) in pyridine (10 ml) at 0ºC in a bath with ice was slowly added acetic anhydride (10 ml). The resulting solution was heated to room temperature and was stirred overnight. Volatiles were removed in vacuum and the residue was diluted with DCM and evaporated. The obtained solid was dissolved in hot EtOH (20 ml) and slowly poured into ice (200 ml). The solids were collected by filtration and dried in the air, receiving (H) (0,735 g, 1.3 mmol).

Synthesis (I)

To a solution of targetrate pyridinium (109 mmol, 2.2 g) in THF (10 ml) and pyridine (5.7 ml) was slowly added (H) (0.36 mmol, 0.20 g). The resulting solution was stirred for 2.5 h and then extinguished ment is authorized by the addition of saturated NaHCO 3(10 ml). The mixture was extracted with EtOAc (3x10 ml) and the organic layers were combined, washed with H2O (3×10 ml) and saturated saline (10 ml) and dried over MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure to obtain (I) (0.22 mmol, 0,095 g).

Synthesis of (J)

For the heterogeneous solution (I) (0.12 mmol, 0,050 g) in MeOH (1.5 ml) and H2O (0.5 ml) at 0ºC was added dropwise a solution of LiOH (1.0 mmol, 0,024 g) in H2O (0.25 ml). The resulting solution was slowly heated to room temperature and was stirred overnight. The reaction mixture was diluted with saturated NH4Cl (10 ml) and poured into ice (10 ml) and the pH of the solution was brought to a value of 2 1 N. HCl. The resulting solution was extracted with EtOAc (3×15 ml) and the organic layers were combined, washed with H2O (1×10 ml) and saturated brine (1×10 ml) and dried over MgSO4, MgSO4was removed by filtration and the volatiles removed under reduced pressure, to obtain a semi-solid substance. Semi-solid substance was placed in a high vacuum for 2 hours to obtain (J) (0,023 g, 0.05 mmol).

Synthesis of compound2

To mix the solution (C) (see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (15 mg, 0,19 mmol) in DMF (2 ml) was added (J) (0.05 mmol, 0.02 g), DIEA (0.02 mmol, 0,033 ml) and HOBT (0.02 mmol, 0,010 g). The mixture was cooled to 0ºC in a bath with ice and added in several portions BOP (0,07 is mol, 0.035 g). The mixture was stirred at 5ºC in an argon atmosphere overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4.MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain2(3.6 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <500 nm.

Scheme 3: synthesis according to example 3

Synthesis of (K)

To the resin Fmoc-Phe-Wang (4.0 mmol, 5.0 g) was added to a mixture of 20% piperidine/DMF (50 ml). The heterogeneous mixture was shaken for 20 minutes, filtered and the resin washed with DMF (100 ml), MeOH (100 ml) and DCM (100 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to obtain (K).

Synthesis of (L)

To a mixture of (K) (4.0 mmol) and DMF (40 ml) was added in order Fmoc-Leu-OH (7.9 mmol, 2,82 g), DIEA (13.3 mmol, 2,23 ml) and HOBT (8,10 mmol, 1.24 g). To the above mixture was slowly added BOP (7,98 mmol, of 3.53 g) was dissolved in DMF (40 ml). The reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (150 ml), MeOH (150 ml), DCM (150 ml) and dried in air to obtain (L).

Synthesis of (M)

To (L) (4.0 mmol) was added to a mixture of 20% piperidine/DMF (50 ml). The heterogeneous mixture was shaken for 20 minutes. The solution was filtered and the resin washed with DMF (100 ml), MeOH (100 ml) and DCM (100 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to receive (M).

Synthesis of (N)

To (M) (0.10 mmol, 0,130 g) was added THF (2 ml), DIEA (0.40 mmol, of 0.08 ml) and benzoyl chloride (0.34 mmol, 0.04 ml). The resulting mixture was shaken for 30 minutes. The reaction mixture was filtered and the resin washed with DMF (20 ml), water (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air to obtain (N).

Synthesis of (About)

K (N) (0.10 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). The mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure and the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to get (About).

Synthesis of compound3

To mix the solution (C) (see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (19 mg, 0.11 mmol) in MeCN (2 ml) was added (O) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated Sol is the best solution, and dried over anhydrous MgSO 4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixtures of EtOAc/hexane as eluent to obtain3(13,8 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 4: synthesis of case 4

Synthesis of (P)

To the intermediate product (K) (0.10 mmol, 0,130 g) was added THF (2 ml), DIEA (0.40 mmol, of 0.08 ml) and benzoyl chloride (0.34 mmol, 0.04 ml). The resulting mixture was shaken for 30 minutes. The reaction mixture was filtered and the resin washed with DMF (20 ml), water (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air to obtain (P).

Synthesis of (Q)

To (P) was added 50% TFA/DCM (2 ml) and shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure and the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to obtain (Q).

Synthesis of compound4

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (19 mg, 0.11 mmol) in MeCN (2 ml) was added (Q) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g). Then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and extra is believed EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified by the method of flash chromatography using 20 to 40% mixtures of EtOAc/hexane as eluent to obtain4(12.7mm mg).

Scheme 5: synthesis example 5

Synthesis of (R)

K (K) (0.10 mmol, 0,130 g) was added THF (2 ml), DIEA (0.40 mmol, of 0.08 ml) and 2-thiophenesulfonyl (0.34 mmol, 0,064 g). The resulting mixture was shaken for 30 minutes. Then the reaction mixture was filtered and the resin washed with DMF (20 ml), water (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air to obtain (R).

Synthesis of (S)

K (R) (0.10 mmol) was added 50% TFA/DCM (2 ml) and shaken for 20 minutes (the resin was purple). Then the reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure and the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times, to obtain (S).

Synthesis of compound5

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (S) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature for overnight is. Then the reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain5(13.1 mg).

Scheme 6: synthesis example 6

Synthesis of (T)

K (K) (0.8 mmol, 1.0 g) was added DMF (20 ml), Fmoc - isonipecotic acid (2.8 mmol, 0,320 g), DIEA (4.8 mmol, 0,445 ml), HOBT (0.9 mmol, 0,140 g), and BOP (1.0 mmol, 0,450 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (150 ml), MeOH (150 ml) and DCM (150 ml) and dried in air to obtain (T).

Synthesis of (U)

K (T) (0.8 mmol, 1.0 g) was added to a mixture of 20% piperidine/DMF (30 ml) and the heterogeneous mixture was shaken for 20 minutes. The mixture was filtered and the resin washed with DMF (150 ml), MeOH (150 ml) and DCM (150 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to obtain (U).

Synthesis of (V)

(U) (0.10 mmol, 0,130 g) was added THF (2 ml), DIEA (0.40 mmol, of 0.08 ml) and 2-thiophenesulfonyl (0.34 mmol, 0,064 g) and the resulting mixture was shaken for 30 minutes. Rea is operating and the mixture was filtered and the resin washed with DMF (20 ml), water (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air to obtain (V).

Synthesis of (W)

To (V) (0.10 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). Then the reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to obtain (W).

Synthesis of compound6

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (19 mg, 0.11 mmol) in MeCN (2 ml) was added (W) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain6(7.4 mg).

Scheme 7: synthesis example 7

Synthesis of (X)

To (M) (0.8 mmol, 1.0 g) was added DMF (20 ml), Fmoc-isonipecotic acid (2.8 mmol, 0,320 g), DIEA (4.8 mmol, 0,445 ml), HOBT (0.9 mmol, 0,140g) and BOP (1.0 mmol, 0,450 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (150 ml), MeOH (150 ml) and DCM (150 ml) and dried in air to obtain (X).

Synthesis of (Y)

K (X) (0.8 mmol, 1.0 g) was added 20% piperidine/DMF (30 ml) and the resulting heterogeneous mixture was shaken for 20 minutes. The solution was filtered and the resin washed with DMF (150 ml), MeOH (150 ml) and DCM (150 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to obtain (Y).

Synthesis of (Z)

K (Y) (0.10 mmol, 0,130 g) was added THF (2 ml), DIEA (0.40 mmol, of 0.08 ml) and 2-thiophenesulfonyl (0.34 mmol, 0,064 g) and the resulting mixture was shaken for 30 minutes. The reaction mixture was filtered and the resin washed with DMF (20 ml), water (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air to obtain (Z).

Synthesis of (AA)

K (Z) (0.10 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to get (AA).

Synthesis of compound7

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (AA) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain7(18.2 mg). IC50CT-L 20S <500 nm, IC50CT-L cells <500 nm.

Scheme 8: synthesis example 8

Synthesis of (BB)

To (M) (0.12 mmol, 0,100 g) was added DMF (2 ml), 3-(p-tolyl)propionic acid (0.09 mmol, 0.015 g), DIEA (0,17 mmol, 0,029 ml), HOBT (0.11 mmol, 0,016 g), and BOP (0.11 mmol, 0,051 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (15 ml), MeOH (15 ml) and DCM (15 ml) and dried in air to obtain (BB).

Synthesis of (CC)

(BB) (0.12 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to obtain (CC).

Synthesis of compound8

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, , 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (CC) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3saturated saline solution and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain8(3.9 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 9: synthesis example 9

Synthesis of (DD)

To a solution of Fmoc-Phe(4-F)-OH (2.4 mmol, 1.0 g) in DCM (20 ml) was added MeIm (6.7 mmol, 0,370 ml). When the solution became homogeneous, add MSNT (2.9 mmol, 0,870 g). When MSNT were dissolved, the reaction mixture was added to the Wang resin (0.8 mmol, 1.0 g) and the resulting solution was shaken for 45 minutes. The resin was filtered and washed with DMF (50 ml), MeOH (50 ml) and DCM (50 ml). The resulting resin was dried in air to obtain (DD).

Synthesis of (EE)

To (DD) (0.40 mmol, 0.5 g) was added 20% piperidine/DMF (10 ml) and the resulting heterogeneous solution was shaken for 20 minutes. The mixture was filtered, the resin washed the DMF (20 ml), MeOH (20 ml) and DCM (20 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to obtain (EE).

Synthesis of (FF)

K (EE) (0.40 mmol) was added DMF (20 ml), Fmoc-Leu-OH (0.40 mmol, 0,143 g), DIEA (1.6 mmol, 0,12 ml), HOBT (0.64 mmol, 0,062 mg) and BOP (0.64 mmol, 0,178 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (40 ml), MeOH (40 ml) and DCM (40 ml) and dried in air to obtain (FF).

Synthesis of (GG)

(FF) (0.08 mmol, 0.10 g) was added 20% piperidine/DMF (2 ml) and the resulting heterogeneous solution was shaken for 20 minutes. The solution was filtered, the resin washed with DMF (10 ml), MeOH (10 ml) and DCM (10 ml) and dried in air. The resin was subjected to the above reaction conditions for the second time, to obtain (GG).

Synthesis of (HH)

(GG) (0.08 mmol) was added DMF (20 ml), Fmoc-hPhe-OH (0.40 mmol, 0,143 g), DIEA (1.6 mmol, 0,12 ml), HOBT (0.64 mmol, 0,062 mg) and BOP (0.64 mmol, 0,178 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (40 ml), MeOH (40 ml) and DCM (40 ml) and dried in air to obtain (HH).

Synthesis of (II)

(HH) (0.08 mmol) was added 20% piperidine/DMF (2 ml) and the resulting heterogeneous solution was shaken for 20 minutes. The solution was filtered and the resin washed with DMF (10 ml), MeOH (10 ml) and DCM (10 ml) and dried in air. The resin was subjected to the above reaction conditions vtoro the time to obtain (II).

Synthesis of (JJ)

To (II) (0.08 mmol) was added DMF (2 ml), 4-morpholinothio acid (0.10 mmol, 0.015 g), DIEA (0,17 mmol, 0,029 ml), HOBT (0.11 mmol, 0,016 g), and BOP (0.11 mmol, 0,051 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (15 ml), MeOH (15 ml) and DCM (15 ml) and dried in air to obtain (JJ).

Synthesis of (KK)

For (JJ) (0.08 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to get (KK).

Synthesis of compound9

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (KK) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40%, see the si EtOAc/hexane as eluent, to get9(7.7 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 10: synthesis example 10

Synthesis of (LL)

K (K) (0.12 mmol, 0,100 g) was added DMF (2 ml), 4-morpholinothio acid (0.12 mmol, 0,018 g), DIEA (0,17 mmol, 0,029 ml), HOBT (0.11 mmol, 0,016 g), and BOP (0.11 mmol, 0,051 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered, the resin washed with DMF (15 ml), MeOH (15 ml) and DCM (15 ml) and dried in air to obtain (LL).

Synthesis of (MM)

To (LL) (0.12 mmol) was added 50% TFA/DCM (2 ml) and the mixture was shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to obtain (MM).

Synthesis of compound10

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (MM) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3and saturated saline and dried over anhydrous MgSO4. MgSO4delete filtrat is her and volatile substances were removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain10(14 mg).

Scheme 11: synthesis example 11

Synthesis of (NN)

K (K) (0.12 mmol, 0,100 g) was added DMF (2 ml), biphenyl-4-carboxylic acid (0.12 mmol, 0.025 g), DIEA (0,17 mmol, 0,029 ml), HOBT (0.11 mmol, 0,016 g), and BOP (0.11 mmol, 0,051 g) and the reaction mixture was shaken overnight. The reaction mixture was filtered and the resin washed with DMF (15 ml), MeOH (15 ml) and DCM (15 ml) and dried in air to obtain (NN).

Synthesis of (OO)

(NN) (0.12 mmol) was added 50% TFA/DCM (2 ml) and shaken for 20 minutes (the resin was purple). The reaction mixture was filtered and the resin washed with DCM (10 ml). Volatiles were removed under reduced pressure, the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times to obtain (PO).

Synthesis of compound11

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (0.11 mmol, 0,019 g) in MeCN (2 ml) was added (OO) (0.1 mmol), DIEA (2.9 mmol, 0.5 ml), HOBT (0.2 mmol, to 0.032 g), and BOP (0.23 mmol, 0,103 g) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated brine (15 ml) and was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3saturated salt solution and visas the Wali over anhydrous MgSO 4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. The crude substance was purified flash chromatography using 20 to 40% mixture of EtOAc/hexane as eluent to obtain11(7.4 mg).

Scheme 12: synthesis examples 12, 13 and 14

Synthesis of (PP)

To a solution of Nboc leucine (85,67 mmol, 19,81 g, 1.0 EQ.) and benzyl ester of phenylalanine (85,67 mmol, 25,0 g, 1.0 EQ.) in 900 ml of MeCN was added DIEA (342,68 mmol, 44,29 g, 60 ml, 4.0 EQ.) and the mixture was cooled to 0ºC in a bath with ice. To the mixture was added HOBT (137,08 mmol, holds 18.52 g, 1.6 EQ.), followed by PyBOP (137,08 mmol, 71,33 g, 1.6 EQ.), which was added in several portions over five minutes. The reaction mixture was placed in an argon atmosphere and was stirred overnight. Volatiles were removed under reduced pressure and the remaining substance was transferred to a 500 ml EtOAc and washed with saturated NaHCO3H2O and saturated saline and dried over anhydrous MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure to obtain (PP) (37,3 g).

Synthesis of (QQ)

Connection (PP) (4,27 mmol, 2.0 g) was dissolved in MeOH/EtOAc (1:1, 40 ml) was added Pd-C (5%, 800 mg). The mixture was stirred at room temperature under a pressure of 1 atmosphere of hydrogen for 2 hours and then filtered through celite and concentrate the has demonstrated, to get (QQ).

Synthesis of compound12

To mix the solution (C) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] (6.0 mmol, 1.8 g, 1.4 EQ.) in DMF (50 ml) was added (QQ) (4,27 mmol, 2.0 g, 1 EQ.), DIEA (0.02 mol, 3.5 ml, 4 EQ.) and then HOBT (32 mmol, 4.3 g, 1.6 EQ.). The mixture was cooled to 0ºC in a bath with ice and several portions was added PyBOP (32 mmol, 16.6 g, 1.6 EQ.). The mixture was stirred at 5ºC in nitrogen atmosphere overnight. The reaction mixture was diluted with saturated NaCl and was extracted with EtOAc. The organic layer was washed with water and saturated saline and dried over anhydrous MgSO4, filtered and concentrated to an oil, which was purified with flash chromatography to obtain12(0.50 g).

Synthesis of compound13

Connection12(0.046 mmol, 24.5 mg) was mixed with TFA/DCM (80%) and was stirred at room temperature for one hour, during which time the mixture was concentrated, and it was placed in a high vacuum for 2 hours, getting13.

Synthesis of compound14

To a solution of DCM (10 ml) and13added 3-thiophenesulfonyl (by 0.055 mmol, 0,012 g, 1.2 EQ.) and TEA (0,184 mmol, was 0.026 ml, 4.0 EQ.). The mixture was stirred at room temperature for 2 h and then concentrated to a dry substance. The residue was placed in EtOAc, washed with water and saturated saline and dried over anhydrous MgSO4was filtered and koncentrirane and to oil, which was purified preparative HPLC to obtain14(1 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 13: synthesis example 15

Synthesis of compound15

To a solution of DCM (2 ml) and13(0,092 mmol) was added phenylisocyanate (0.14 mmol, of 0.015 ml, 1.5 EQ.) and DIEA (0.276 mmol, 0,050 ml, 3 EQ.) and the mixture was stirred at room temperature overnight. The crude mixture was then concentrated to a dry substance and the residue was placed in EtOAc. The organic layers were washed with water and saturated saline and dried over anhydrous MgSO4, filtered and concentrated to an oil, which was purified preparative HPLC to obtain15(2.8 mg).

Scheme 14: synthesis example 16

Synthesis of compound16

To a solution of DCM (2 ml) and 13 (0,07 mmol) was added 4-methoxyphenylacetylene (0.1 mmol, of 0.015 ml, 1.5 EQ.) and DIEA (0.21 mmol, 0,040 ml, 3 EQ.) and the mixture was stirred at room temperature overnight. The crude substance was concentrated to a dry substance and the residue was placed in EtOAc. The organic layer was washed with water and saturated saline and dried over anhydrous MgSO4, filtered and concentrated to an oil, which was purified with flash chromatography to obtain16(2 mg). IC50CT-L 20S <50 nm, IC50CTL cells < 50 nm.

Scheme 15: synthesis example 17

Synthesis of compound17

To a solution of DCM (2 ml) and13(0,092 mmol) was added 4-methoxyphenylacetylene (0.14 mmol, 0,018 ml, 1.5 EQ.) and DIEA (0.276 mmol, 0,050 ml, 3 EQ.) and the mixture was stirred at room temperature overnight. The crude substance was concentrated to a dry substance and the residue was placed in EtOAc. The organic layer was washed with water and saturated saline, dried over anhydrous MgSO4, filtered and concentrated to an oil, which was purified with flash chromatography to obtain 17 (2.5 mg). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 16: synthesis example 18

Synthesis of compound18

To a solution of THF (15 ml) and13(1.4 mmol) at 0ºC was added 4-morpholinothio acid (1,79 mmol, is 0.260 g), HOBT (1.92 mmol, is 0.260 g), HBTU (1,72 mmol, 0,656 g) and DIEA (of 11.45 mmol, 2.0 ml), the mixture was stirred and allowed it to warm to room temperature over night. The reaction solution was diluted with saturated NaHCO3(15 ml) and layers were separated. The aqueous layer was extracted with EtOAc (3×5 ml), organic layers were combined, washed with H2O (1×15 ml) and saturated brine (1×15 ml) and dried over MgSO4. MgSO4was removed by filtration and the volatiles removed under reduced pressure. N the purified substance was purified flash chromatography, to get18(0,423 g). IC50CT-L 20S <50 nm, IC50CT-L cells <50 nm.

Scheme 17: synthesis example 19

Synthesis of (RR)

To a solution of2(1 mmol) and DIEA (1.5 mmol) in dry CH2Cl2(100 ml) at 0ºC was added dropwise a solution of dibenzylpiperazine (1 mmol) in dichloromethane (10 ml). The reaction mixture was fully stirred at room temperature, washed with cold 1 N. HCl and then saturated saline, dried over MgSO4, filtered and evaporated to obtain (RR).

Synthesis (SS)

Solution (RR) (1 mmol) and liquid 20% Pd(OH)2/C (100 mg; catalyst Perlman) in EtOAc (10 ml) was subjected to the full hydrogenation at atmospheric pressure and room temperature. The reaction mixture was filtered through celite and evaporated to obtain the desired compound (SS). This substance is so selected that can be used as is or in the next stage, or to test in any study.

Synthesis of compound19

Connection (SS) (1 mmol) was diluted in MeOH (5 ml) and was treated with a standardized solution of 1.00 N. NaOH (2.00 mmol) in H2O (2 ml). The solution was stirred for 2 hours and liofilizirovanny to get19.

Scheme 18: synthesis of for example 20

Synthesis of (UU)

To a solution of the (TT) (1 mmol) [poluchenogo standard methods of peptide synthesis in solution], benzyl solution of threonine (1 mmol) and DIEA (2.5 mmol) in dry CH2Cl2(100 ml) was added HBTU (2.5 mmol). The reaction mixture was fully stirred at room temperature, washed with cold 1 N. HCl and water, dried over MgSO4, filtered and evaporated to get (UU).

Synthesis of (VV)

To the compound (UU) (1 mmol) in dry CH2Cl2(100 ml) was added TBDPSCl (1 mmol) and imidazole (1.2 mmol). The reaction mixture was fully stirred at room temperature, washed with cold 1 N. HCl and water, dried over MgSO4, filtered and evaporated to obtain (VV).

Synthesis of (WW)

Solution (VV) (1 mmol) and 10% Pd/C (100 mg) in MeOH (10 ml) was subjected to the full hydrogenation at atmospheric pressure and room temperature. The reaction mixture was filtered through celite and evaporated to obtain (WW).

Synthesis of (XX)

To a solution of (WW) (1 mmol) and E (1 mmol) [see Bioorg. Med. Chem. Letter 1999, 9, 2283-88] in DMF (10 ml) was added HOBT (1,60 mmol) and DIEA (4 mmol). The mixture was cooled to 0ºC and within a few minutes was added BOP (1,60 mmol). The resulting solution was heated to room temperature and was stirred overnight. The reaction mixture was diluted with saturated saline solution and was extracted with EtOAc. The combined organic layer was extracted with H2O and saturated saline solution, dried over MgSO4and evaporated to p in order to obtain (XX).

Synthesis of compound20

To a solution of (XX) (1 mmol) in THF (100 ml) at room temperature was slowly added TBAF (1 mmol) and the resulting mixture was fully stirred. Evaporation and chromatography of the resulting sludge was received20.

Scheme 19: synthesis example 21

Synthesis of (CCC)

The target connection receive essentially after the procedure of turning2in (RR), except that the20used instead of2.

Synthesis of (DDD)

The target connection receive essentially after the procedure transformation (RR) (SS), except that (CCC) is used instead of (RR).

Synthesis of compound 21

The target connection receive essentially after the procedure transformation (SS) in19except that (DDD) is used instead of (SS).

Scheme 20:withinches in example 22

Synthesis of (EEE)

[Cm. J. Med. Chem. 1999, 42(16), 3094-3100.] To a solution of dibenzylpiperazine (1 mmol) [U.S. patent 6204257] in anhydrous acetonitrile in argon was added connection to2(1 mmol) and 1,2,2,6,6-pentamethylpiperidin (1.2 mmol), followed by full stirring at 70ºC. Then the solvent was removed in vacuum to obtain (EEE).

Synthesis of (FFF)

The target connection receive essentially after the procedure transformation (RR) (SS), except that (EE) is used instead of (RR).

Synthesis of compound22

The target connection receive essentially after the procedure transformation (SS) in19except that (FFF) is used instead of (SS).

Scheme 21: synthesis example 23

Synthesis of (GGG)

(See Pharmaceutical Research, 1993,10(9), 1350-55.) To a solution of (UU) (1 mmol) and proton sponge (1 mmol) in dry CH2Cl2(10 ml) at 0ºC was added dropwise a solution of chlormethiazole ether Harborview acid (1 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature overnight, washed with cold 1 N. HCl and water, dried over MgSO4, filtered and evaporated to obtain (GGG).

Synthesis of (HHH)

Solution (GGG) (1 mmol) and dibenzylamine silver (1.5 mmol) in dry benzene (10 ml) was boiled under reflux overnight. The reaction mixture was cooled, filtered, washed with a saturated solution of Na2CO3, dried over MgSO4and evaporated to get (HHH).

Synthesis of (III)

To a solution of (HHH) (1 mmol) in 3:1 MeOH/H2O (20 ml) at 0ºC was added dropwise a solution of LiOH (5 mmol) in H2O (2.5 ml). The reaction mixture was placed in an argon and kept at 5ºC during the night. The reaction was suppressed at 0ºC addition of saturated NH4Cl (50 ml) and diluted with cold water (150 ml). The pH was brought to 2 at 0ºC cold 6 N. HCl is obtained solids were collected by vacuum filtration, to obtain (III).

Synthesis of (JJJ)

The target connection receive essentially after the procedure transformation (WW) (XX), except that (III) is used instead of (WW).

Synthesis of (KKK)

The target connection receive essentially after the procedure transformation (RR) (SS), except that (JJJ) is used instead of (RR).

Synthesis of compound23

The target connection receive essentially after the procedure transformation (SS) in19except that (KKK) is used instead of (SS).

Scheme 22: synthesis example 24

Synthesis of (LLL)

The target compound (III) receive essentially after the procedure of turning2in (RR), replacing the connection2connection (YY) [obtained by standard methods of peptide synthesis in solution] and the acid chloride dibenzylamino acid to the acid chloride Chloroacetic acid.

Synthesis of (MMM)

To a solution of (LLL) (1 mmol) in DMF (10 ml) at room temperature under argon was added Cs2CO3(1 mmol)then was added piperidine (1 mmol). Stirring is continued until, until the reaction has ended. Then the mixture was poured into a saturated saline solution and washed with EtOAc. EtOAc was dried over MgSO4, filtered and evaporated under reduced pressure to obtain compound (MMM).

Synthesis of (NNN)

The target connection is ucaut essentially after the procedure transformation (VV) (WW), except that (MMM) is used instead of (VV).

Synthesis of compound24

The target connection receive essentially after the procedure transformation (WW) (XX), except that (NNN) is used instead of (WW).

Scheme 23: synthesis example 25

Synthesis of (LLC)

The target connection receive essentially after the procedure of turning2in (RR), except that (YY) is used instead of2and tert-butylbromide used instead of the acid chloride dibenzylamino acid.

Synthesis of (PPP)

The target connection receive essentially after the procedure transformation (VV) (WW), except that (LLC) is used instead of (VV).

Synthesis of (QQQ)

The target connection receive essentially after the procedure transformation (WW) (XX), except that (PPP) is used instead of (WW).

Synthesis of compound25

Processing (QQQ) (1 mmol) with neat TFA (10 ml) at 0ºC was accompanied by the evaporation of TFA under reduced pressure, see Bioorg. Med. Chem. Letter 1999, 9, 2283-88]to get25.

Scheme 24: synthesis example 26

Synthesis of (RRR)

To a solution of (UU) (1 mmol) in anhydrous DMF (10 ml) at room temperature was carefully added NaH (1 mmol). After stirring for 0.5 h the mixture was treated with 1,3-dibromopropane (1.2 mmol) and the reaction is ionic mixture was stirred until completion of the reaction. The solution is then carefully extinguished by the addition of saturated NH4Cl (1 ml), then poured the mixture into cold saturated salt solution (10 ml). The resulting mixture was washed CH2Cl2, dried over MgSO4was filtered and the solvent evaporated under reduced pressure to obtain (RRR).

Synthesis (SSS)

To a solution of (RRR) (1 mmol) in anhydrous DMF (10 ml) at room temperature under argon was added Cs2CO3(1 mmol)then was added N-methylpiperazine (1 mmol). Stirring is continued until, until the reaction has ended. Then the mixture was poured into a saturated saline solution and washed with EtOAc. EtOAc was dried over MgSO4, filtered and evaporated under reduced pressure to obtain compound (SSS).

Synthesis of (TTT)

The target connection receive essentially after the procedure transformation (VV) (WW), except that (SSS) is used instead of (VV).

Synthesis of compound26

The target connection receive essentially after the procedure transformation (WW) (XX), except that (TTT) is used instead of (WW).

Scheme 25: synthesis example 27

Synthesis of (VVV)

The target connection receive essentially after the procedure transformation (TT) (UU), except that N-acetylserine used instead of (TT) and (UUU) [received the standard SPO is Obama synthesis of peptides in solution] is used instead of benzyl ester of serine.

Synthesis of (WWW)

The target connection receive essentially after the procedure transformation (UU) (VV), except that (VVV) is used instead of (UU).

Synthesis of (XXX)

The target connection receive essentially after the procedure transformation (VV) (WW), except that (WWW) is used instead of (VV).

Synthesis of (YYY)

The target connection receive essentially after the procedure transformation (WW) (XX), except that (XXX) is used instead of (WW).

Synthesis of compound27

The target connection receive essentially after the procedure transformation (XX) in20except that (YYY) is used instead of (XX).

Scheme 26: synthesis example 28

Synthesis of (ZZZ)

The target connection receive essentially after the procedure of turning2in (RR), except that the27used instead of2.

Synthesis of (AAAA)

The target connection receive essentially after the procedure transformation (RR) (SS), except that (ZZZ) is used instead of (RR).

Synthesis of compound28

The target connection receive essentially after the procedure transformation (SS) in19except that (AAAA) is used instead of (SS).

Scheme 27: synthesis according to example 29

Synthesis of (BBBB)

The target connection get essentially the pic is e procedure transformation (YY) (LLL), except that (VVV) is used instead of (SS).

Synthesis of (CCCC)

The target connection receive essentially after the procedure transformation (LLL) (MMM), except that (BBBB) is used instead of (LLL) and morpholine is used instead of piperidine.

Synthesis of (DDDD)

The target connection receive essentially after the procedure transformation (MMM) in (NNN), except that (CCCC) is used instead (MMM).

Synthesis of compound29

Connection (WW) receive essentially after the procedure transformation (WW) (XX), except that (DDDD) is used instead of (WW).

Equivalents

Specialists in this field will know or be able to identify, using no more than ordinary experimentation, many equivalents of the compounds described herein and methods of their use. It is assumed that such equivalents are included in the scope of the present invention and protected in accordance with the following claims.

All quoted above links and publications hereby incorporated here by reference.

1. The compound having the structure of formula (III), or its pharmaceutically acceptable salt

where L is selected from C=O and SO2;
X represents O;
Z is absent or represents a C1-6-alkyl;
R1and R3both are C1-6-alkyl;
R2PR is dstanley a C 1-6-aralkyl;
R4represents N(R5)L-Z-R6;
R5represents hydrogen;
R6selected from Ar and heterocyclyl, which represents a non-aromatic 3-7 membered ring containing up to two heteroatoms selected from nitrogen and oxygen, and optionally substituted by thienylmethyl;
where Ar represents a phenyl, optionally substituted stands, or heteroaryl, which represents a 5-6-membered ring containing a sulfur atom, and
R7and R8both represent hydrogen.

2. The compound according to claim 1, in which R1and R3both are isobutyl and R2represents phenylmethyl.

3. The compound according to claim 2, in which R6is an Ar.

4. The compound according to claim 3, in which each Ar is independently selected from phenyl and tanila.

5. The compound according to claim 3, in which Z represents a C1-6-alkyl.

6. The compound according to claim 2, in which Z is absent.

7. The connection according to claim 6, in which R6is an Ar and Ar is selected from phenyl and tanila.

8. The compound having the structure of formula (IV), or its pharmaceutically acceptable salt

where L is selected from C=O and SO2;
X represents O;
Z is absent or represents a C1-6-alkyl;
R2and R3each independently selected from C1-6-alkyl and C1-6 -aralkyl;
R4represents N(R5)L-Z-R6;
R5represents hydrogen;
R6selected from Ar and heterocyclyl, which represents a non-aromatic 3-7 membered ring containing up to two heteroatoms selected from nitrogen and oxygen, and optionally substituted by thienylmethyl;
where Ar represents a phenyl, biphenyl or heteroaryl, which represents a 5-6-membered aromatic ring containing up to two heteroatoms selected from nitrogen and sulfur, and R7and R8both represent hydrogen.

9. The connection of claim 8, in which R3represents a C1-6-alkyl and R2represents a C1-6-aralkyl.

10. The connection according to claim 9, in which R3represents isobutyl and R2represents phenylmethyl.

11. The connection of claim 10, in which R6is an Ar.

12. The connection of claim 10, in which each Ar is independently selected from phenyl and tanila.

13. Connection by claim 11, in which Z represents a C1-6-alkyl.

14. The connection of claim 10, in which Z is absent.

15. The connection 14, in which R6is an Ar and Ar is selected from phenyl and tanila.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of Formula II and to methods of immune response suppression, e.g. by inhibition of indirect MHC type II of T-cells activation. Compounds under invention can be applied to treatment or prevention of derangements, such as rheumatoid arthritis and/or multiple sclerosis.

EFFECT: production of compounds which can be used for immune response suppression.

25 cl, 19 dwg, 4 tbl, 22 ex

FIELD: pharmaceutical chemistry, chemistry of peptides, hormones.

SUBSTANCE: invention relates to a method for preparing analogs of adrenocorticotropic hormone (ACTH) (4-10) possessing neurotropic activity. Method for preparing analogs of adrenocorticotropic hormone (ACTH), a sequence (4-10), of the general formula (I): A-Glu-His-Phe-Pro-Gly-Pro-OH (I) wherein A means hydrogen atom (H), Met, Met(O), Lys, Ser, Trp, Ala, Gly, Thr is carried out by liquid-phase method by step-by-step splicing peptide chain beginning from C-terminal protected tetrapeptide of the formula: H-Phe-Pro-Gly-Pro-OH (II) wherein X means a protective group and using corresponding fully protected amino acids in activated form followed by removal of protective groups at each step and purification of the end product by liquid chromatography. Method provides simplifying the process and to enhance the yield of the end product.

EFFECT: improved preparing method.

5 cl, 1 tbl, 5 ex

FIELD: biotechnology, medicine, oncology.

SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.

EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: medicine, chemistry of peptides, amino acids.

SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).

EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.

4 cl, 16 tbl, 9 ex

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

The invention relates to novel soluble synthetic polimersvarka the anthracyclines, exhibiting antitumor activity, to a method of receiving and containing pharmaceutical compositions

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: medicine; pharmacology.

SUBSTANCE: offered are compositions of formula 1 , where PG represents hydrogen or formyl group. R1 and R2 together with nitrogen atom to which they are attached, form heterocycle chosen from piperidine or morpholine and their pharmaceutically acceptable salts.

EFFECT: high haemostatic activity.

8 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes heterocyclic compounds represented by the general formula (I): and possessing elastase-inhibitory activity, and intermediate compounds for synthesis of such compounds. In the formula (I) R1 represents heterocyclic group represented by the formula (II): wherein A represents presence or absence of benzene ring; X represents oxygen atom, sulfur atom or -NH; Y represents nitrogen atom or -CH. Indicated heterocyclic group can be substituted with 1-3 substitutes that can be similar or different and they are chosen from group consisting of lower alkyl, lower alkoxy group and phenyl that can be optionally substituted with halogen-containing lower alkyl, lower alkoxy group or halogen atom; each among R2 and R3 represents hydrogen atom or hydroxyl, or R2 and R3 can be combined to form oxo group under condition that both are not hydrogen atoms.

EFFECT: valuable biochemical property of compounds.

8 cl, 7 tbl

FIELD: medicine, biochemistry.

SUBSTANCE: invention describes compounds that inhibit function of NS3-protease encoded by hepatitis C virus.

EFFECT: valuable medicinal properties of inhibitors.

6 cl, 2 tbl, 472 ex

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to derivatives of 2-hydroxytetrahydrofurane , of general formula (I) , which possess ability to inhibit calpaines and/or ability to catch active oxygen forms and can be used to obtain medication, intended for inhibiting calpaines and/or lipid peroxidation.

EFFECT: medications possess higher efficiency.

9 cl, 64 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 and R2 are chosen independently from (C1-C4)-alkyl; R3 represents hydrogen atom or hydroxy-group; R4 represents (C1-C4)-alkyl; R5 represents hydroxy-group, or to its pharmaceutically acceptable salts, esters or amides. Also, invention relates to using these compounds as inhibitors of bile acids transfer in ileum for treatment of hyperlipemia. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions comprising thereof.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 2 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group
Up!