Inhibition of proteasome 26s and 20s by indanone

 

(57) Abstract:

The invention relates to the field of medicine. A method of treatment of mammals with impaired cell proliferation, immune system disorders and infectious diseases, which consists in introducing a therapeutically effective amount of the compounds of formula (I). Suggested songs based on them. The method does not have undesired Toxicological effects, as well as effective in disorders associated with accelerated cell division. 3 S. and 36 C.p. f-crystals, 4 tab., 3 Il.

The present invention is a method of inhibiting cell proliferation using class indinavir songs that were never before considered for this purpose. As inhibitors of cell proliferation data composition suitable for the treatment of cancer, cardiovascular disease, for example, restenosis, transplant rejection by the host, gout and other proliferative disorders, and are potential therapeutic agents in autoimmune diseases such as rheumatoid arthritis, lupus, diabetes type I, multiple sclerosis and similar disorders, and diseases.

Mula responsible for ATP-dependent proteolysis of most cellular proteins. The 20S proteasome (700 kDa) contains at least five different proteolytic activities, which are a new type of mechanism through which the threonine residue in the active center (SOIC O., Tanaka, K. and Goldberg, A., 1966, Ann.Rev.Biochem. 65:801-847).

The 20S proteasome was obtained in crystalline form from archaebacteria Thermoplasma acidophilum (Lowe j, Stock d, Jap Century, Zwickl, P., Bauminster W. and Huber R., 1995, Science 268:533-539). Archaebacterial the 20S proteasome contains fourteen copies of two different types of subunits, which form a cylindrical structure consisting of four stacked in a column of rings. The upper and lower rings, each containing seven subunits each, and the inner ring contains seven subunits . It's time permeates the middle of this structure, which contains the proteolytic active sites, and protein destined for destruction, passes through this channel. The eukaryotic 20S proteasome is more complex than the proteasome, archaebacteria, because during the evolution of the number of different subunits increased, although these subunits can still be classified according to the nomenclature and archebacteria according to their homology. Thus, the Quaternary structure of the eukaryotic complex is similar to the structure of the original manifests chymotrypsinogen proteolytic activity (Dahlmann Century , Corr F., L. Kuehn, Niedel C., Pfeifer, G., 1989, FEBS Lett., 251:125-131; Seemuller E., Lupas, A., Zuhl F., P. Zwickl and Bauminster W., 1995, FEBS Lett., 359:173; and Lowe j, Stock d, Jap Century, Zwickl, P., Bauminster W. and Huber R., 1995, Science, 268:533-539). Eukaryotic proteasome contains at least five identifiable protease activities. They are called chymotrypsinogen, trypsin-like and peptidylglutamyl-peptidylglutamyl. Also described two other activity, one shows preference to the destruction of peptide bonds on the carboxyl side of branched chain amino acids, and the other to the destruction of links between small neutral amino acids (M. Orlowski, 1990, Biochemistry, 29:10289-10297).

Despite the fact that the 20S proteasome contains proteolytic core, it cannot destroy proteins in vivo until then, until it forms a complex with the 19S cap group at either end of its structure, which itself contains multiple ATP-asnie activity. This increased structure known as the 26S proteasome and quickly destroys the proteins that have been targeted for degradation when adding multiple molecules of 8.5 kDa polypeptide-ubiquitin.

The first stage on the way to the ubiquitination of the protein proceeds through activation of molecules of ubiquitin in the mediate connection. This step is catalyzed by a ubiquitin-activating enzyme E1. Then, the ubiquitin is transferred to the active cysteine residue of the ubiquitin-conjugating enzyme E2. Enzyme E2 attaches ubiquitin to the E-amino group lysine residues of the substrate protein destined for degradation. In some cases, this process requires the presence of ubiquitine ligase E3. Repeat the conjugation of ubiquitin to lysine residues previously associated ubiquitin components leads to the formation of multibiometric circuits and creates the skeleton of the ubiquitin around this substrate protein. Multibillionaire substrate proteins are recognized by the 26S proteasome and dissolved, and multibillionaire chains are released from this complex and ubiquitin is returned to circulation.

What causes the protein to become ubiquitinated and then to collapse - this question is investigated so far. Clearly, this must be clearly regulated series of events since the threshold sync specific protein destruction is the key for many functions of the cell cycle. It has been suggested several signals, which, for the most part, are located in the center of the inner article the-end rule", in which aminobenzoic the remainder of the protein determines its half-life. Other proteins, such as cycline contain a short sequence highly conserved amino acids, referred to as the "frame of destruction", which, apparently, is required for degradation. Moreover, REST"sequences, which consist of regions rich in Proline, aspartate, glutamate, serine and threonine, are also probably act as signal degradation. It is assumed that these internal sequences act as recognition elements between the substrate protein and its specific ubiquitination mechanism.

There were described two types of inhibitors, which inhibit the proteolytic activity of the proteasome. It was reported on some of peptide aldehydes, which inhibit chymotrypsinogen activity associated with the proteasome (Vinitsky, A., Michaud, S., Powers J. and M. Orlowski, 1992, Biochemistry, 31: 9421-9428; Tsubuki , S., Hiroshi K., Saito Y., Miyashita N., Inomata, M. and Kawashima, S., 1993, Biochem.Biophys.Res. Commun., 196:1195-1201; Rock, K. I., Gramm C , Rothstein L., Clark K, Stein R, Dick L., Hwang D. and Goldberg, A. L. , 1994, Cell 78:761-771). These include N-acetyl-L-leucinol-L-leucinol-L-norleucinal (ALLN) and the closely related compound, N-acetyl-L-leucinol-L-leucinol-national (LLM) with Ki's 0,14 MK-leucinol-L-leucinol-L-Norvaline MS 115, which manifests Kiequal 0,021 mm. Although these peptide aldehydes are most effective against chymotrypsinogen proteolytic activity of proteasomes, careful studies have shown that they are not specific ProcessName inhibitors. In a recent message described a number of strong dipeptide inhibitors, which have in vitro values IC50in the range of 10-100 nm (Iqbal M., Chatterjee, S., Kauer, J. C., Das, M., Messina P., Freed Century, Biazzo W. and Siman R., 1995, J. Med. Chem., 38:2276-2277) and the number of similar strong in vitro dipeptide inhibitors, derivatives-Methocarbamol and boric ester (Iqbal, M., Chatterjee, S., Kauer, J. C., J. P. Mallamo, Messina P. A., Reiboldt A. and Siman R., 1996, Bioorg. Med. Chem.Lett., 6:287-290).

In another report described a class of compounds, which show specificity in the inhibition of proteasome activity (Fenteany, G., Standaert, R. F. , Lane, W. S., Choi, S., Corey E. J. and Schreiber, S. L., 1995, Science, 268: 726-731). Lactacystin is a Streptomyces metabolite that specifically inhibits the proteolytic activity of this proteasome complex. This molecule, originally opened as possessing the ability to induce trigeminus growth in neuroblastoma cell lines (Omura et al. , 1991, J. Antibiot. 44:113), was subsequently shown the ability to inhibit proliferate tristina, in studies on the binding (Fenteany et al., 1995, Science 268:726-731) identified the binding site and mechanism of action. In these studies it was shown that lactacystin reversible associated with the threonine residue located on aminocore-subunit of the proteasome. Was investigated by a number of analogues based on the structure lactacystin (Fenteany et al., 1995, Science, 268:726-731). These studies suggest that the structure-lactone was essential for its inhibitory activity.

It is now well proved that the proteasome is a major validatenow proteolytic system, which is involved in the ways of splitting affecting numerous and diverse cellular functions such as cell division, antigen processing and degradation of short-lived regulatory proteins such as transcription factors, oncogenic products and cyclina (review Ciechanover, A., 1994, Cell 79:13-21). The first function of the proteasome is catalyzed proteolysis of proteins to small peptides. However, it was also demonstrated that the ubiquitin-proteasome path can catalyze regulated proteolytic processing of a large inactive precursor into an active protein. The most well l, 78:773-785). The active form of NF-KB is heterodimer consisting of subunits P65 and subunit P50. The latter are represented in the cytosol of cells in an inactive form predecessor, namely R, 105 kDa polypeptide precursor of P50. Proteolytic processing R with the formation of P50 occurs through the ubiquitin-proteasome pathway. In addition, versions of the P50 and P65 are supported in the cytosol as an inactive complex with the inhibitory protein I QR. Signals inflammation activate NF-KB in the initiation of signaling pathways for the complete degradation of IQ and also stimulate the transformation R in P50. Thus, for a signal, which induces the activation of NF-KB requires two proteolytic events, both defined by the ubiquitin-proteasome path. What causes termination of proteolysis R after the formation of P50 remains unknown, but it was hypothesized that the conformation P50 can give it stability for further processing and to cause its dissociation from 268 complex.

The fact that the proteasome plays a key role in the activation of NF-KB could be used for clinical purposes by the use of inhibitors that control the proteasome proteolysis. In some diseases policlinic responses after bacterial, fungal or viral infection. Thus, inhibitors of the activation of NF-KB associated with their ability to prevent the secretion of cytokines, may be potentially useful for the treatment of ARDS (acute respiratory distress syndrome) and AIDS (AIDS). Since the activation of NF-KB essential for angiogenesis, proteasome inhibitors may be useful in treating diseases associated with abnormal neovascularization.

p53 was first described as oncoprotein, but it was subsequently shown that he is involved in many cellular processes (review To L. J. and Proves S., 1996, Genes Dev., 10, 1054-1072). It was shown that p53 induces apoptosis in some hematopoietic cell lines (Oren M., 1994, Semin. Cancer Biol. , 5, 221-227) through exposure to many different stimuli, including DNA damage, viral infection, and removal of growth factors. However, it is important to note that apoptosis can be induced by the way, is not dependent on p53, for example, by the action of glucocorticoids. Induction of p53 leads to cessation of cell growth in the G1-phase of the cell cycle, and cell death due to apoptosis. Both of these features allow p53 to monitor DNA damage, reducing, thus, the distribution of DNA mutations is RA P21, which, in turn, causes an accumulation hypophosphorylated form of the retinoblastoma gene product. It is assumed that p53 acts as a checkpoint in the cell after DNA damage, causing first stop cell division and apoptosis. As is known, the degradation of p53 via the ubiquitin-proteasome path, and induced p53 degradation is a likely method of induction of apoptosis. Another potential benefit of the proteasome inhibitors may lie in the treatment of diseases that occur when abnormalities of cell proliferation.

Just found that the ubiquitin-proteasome path is crucial for the regulation of degradation of tsiklonov that regulate exit from mitosis and allow cells to move into the next phase of the cell cycle. Therefore, the inhibition of the degradation of tsiklonov using proteasome inhibitors causes stunting. For this reason, another potential benefit of proteasome inhibitors is their use for the treatment of diseases that occur from rapid cell division. These include cancer, cardiovascular diseases such as myocarditis, restenosis after angioplasty, see diseases, such as psoriasis, abnormal wound healing, keloid, immunological diseases such as autoimmune, asthma and allergies, acute and allergic reaction of the delayed type, graft versus host disease, graft rejection and neuro-diseases such as multiple sclerosis and acute disseminated encephalomyelitis.

The purpose of the present invention to create a method of inhibiting cell proliferation in mammals, which uses a therapeutically effective amount of a previously unknown compositions with properties of inhibition they cell proliferation.

The purpose of the present invention is to provide a method for effective treatment of diseases that lead to accelerated cell division.

Another objective of the present invention is to provide a method for treatment of proliferative diseases, which acts by inhibiting the degradation of proteasome inhibitors.

Another objective of the present invention is to use therapeutically effective amount of the composition for the inhibition of disorders of cell proliferation in humans.

In the first embodiment, the present invention p is the mammal a therapeutically effective amount of the compounds having the formula:

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In this connection, R1-R4each separately selected from the group comprising hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano.

R5-R9each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, oxo, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano;

X is selected from the group of compounds including hydrogen, -D1, -D2, -E, -D1,-E, -D2-E, -D1-D2or the compounds having the formula:

< / BR>
where D1and D2each separately selected from the group of compounds including the compound oblada, alkylalcohol, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes or alkylcyclopentanes;

where E is selected from the group of compounds including:

< / BR>
or hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes or alkylcyclobutanones.

If D1D2and/or E is selected from compounds containing substituents R10-R14J1and J2, R10-R14each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, oxo, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcyclohexane, including N-R15, CR16R17, O, S(O)0-2, P(O)0-3where R15-R17individual may be selected from the group of compounds including hydrogen, halogen, hydroxyl, oxo, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocyclic compound, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes or cyano.

These compositions are suitable if you are prescribed in therapeutic amounts, for the treatment of mammals, and preferably for the treatment of people suffering from disorders of cell proliferation, infectious diseases, and immunological diseases.

Fig. 1 is a Western blot analysis of immunoreactivity with antibodies to anti-IQ cellular extract RAW that were treated with compounds 173 and 187, which are described in the table. 1 and 2;

Fig. 2 is a Western blot analysis of immunoreactivity to anti-P50-antibody cell extracts RAW, which were treated with compound 187, which is described in the table. 1 and 2, the gel of nuclear extract, obtained from RAW cells that were pretreated with compound 187, which is described in the table. 1 and 2, before keeping with LPS.

The present invention is a method of inhibiting disorders of cell proliferation, infectious diseases, and immunological diseases in mammals, and especially humans, using compositions having the following General formula:

< / BR>
In this composition R1-R4each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano.

In this composition R5-R9each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, thio, oxo, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, closetoreal, nitro or cyano.

X is selected from the group of compounds including hydrogen, -D1, -D2, -E, D1-D2, -D1-E1, -D2-E or compound with the formula:

< / BR>
in which D1and D2each separately selected from the group of compounds including

< / BR>
hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocyclic compound, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes or alkylcyclopentanes and

in which E is selected from the group of compounds including:

< / BR>
hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes or alkylcyclobutanones.

In the above compounds, R5-R9each separately selected from the group of compounds including hydrogen, halogen, hydrox is kiltie, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano.

If D1D2and/or E is selected from compounds containing substituents R10-R14I , J1and J2then: R10-R14each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, oxo, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano; a J1and J2each separately selected from the group comprising N-R15, CR16R17OH , S-(O)0-2, P(O)0-3in which R15-R17each individually replaced component selected from the group comprising hydrogen, halogen, hydroxyl, oxo, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, ar is l, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes or cyano.

For descriptions of the various substituents chemical composition suitable for the method of the present invention, the following terms are used. These terms are defined as follows:

The term "halogen" refers to fluorine atoms, bromine, chlorine and iodine.

The term "hydroxyl" refers to the group-HE.

The term "oxo" refers to the group =O.

The term "thiol" or "mercapto" refers to the group-SH, and-S(O)0-2.

The term "lower alkyl" refers to a cyclic, branched or non-branched chain alkyl group of from one to ten carbon atoms. This term is additionally illustrated by such groups as methyl, ethyl, n-through, 1-through n-bucilina, tert-bucilina, 1-bucilina (or 2-methylpropionate), cyclopropylmethyl, 1-amilina, n-amilina, exilda and the like.

The term "substituted lower alkyl" refers to lower alkyl that you just described that includes one or more groups such as hydroxyl, thiol, alkylsilane, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl the other, substituted aryl, aryloxy, geurilla, substituted geurilla, kalkilya, heteroalkyl, alkylalkoxysilane, alkylalkoxysilane, alkylcyclohexane, alkylcyclohexane, cyano. These groups can be attached to any carbon atom component lower alkyl.

The term "alkenyl" refers to the group- (CR'=CR"R"', where R', R", R"' are each selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or the like.

The term "quinil" refers to the group-CC-R, where R' is selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or the like.

The term "alkylaryl" refers to the group-R-CR'=CR"'R"", where R represents a lower alkyl or substituted lower alkyl, R', R'", R"" are each separately selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

The term "alkylamine" refers to the group-RCCR, where R is a lower alkyl or substituted lower alkyl, R' is vodkatini below.

The term "alkoxy" refers to the group-OR where R represents lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroallyl, cycloalkyl, substituted cycloalkyl, cyclogeranyl or substituted cyclogeranyl, as indicated below.

The term "alkylthio" refers to the group-SR, -S(O)n=1-2-R, where R represents lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, as indicated below.

The term "acyl" refers to the groups-C(O)R, where R represents hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and the like, as indicated below.

The term "aryloxy" refers to the groups-OAS, where AG represents aryl, substituted aryl, heteroaryl or substituted heteroaryl group as described below.

The term "amino" refers to the group NRR', where R and R' can independently represent hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, cycloalkyl or substituted hetaryl as defined below, or acyl.

The term "amido" refers to the group-C(O)NRR', where R and R' can independently represent hydrogen, lower alkyl, min "carboxyl" refers to the group-C(O)OR, where R may independently be a hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl, and the like.

The term "aryl" or "AG" refers to an aromatic carbocyclic group having at least one aromatic ring (such as phenyl or diphenylene) or multiple condensed rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydronaphthalene, raftiline, antennae or phenanthroline ring).

The term "substituted aryl" refers to aryl, optionally substituted by one or more functional groups, for example, the group of halogen, lower alkyl, lower alkoxy, lower alkylthio, trifloromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "heterocycle" refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridinium or FullName ring or multiple condensed rings (e.g., naphthylvinyl, Minoxidil one heteroatom, such as N, O or S, which may be optionally unsubstituted or substituted, e.g. by halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyla, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The terms "heteroaryl" or "Garni" refers to a heterocycle in which at least one heterocyclic ring is aromatic.

The term "substituted heteroaryl" refers to a heterocycle, optionally mono - or polishmaster one or more functional groups, for example, the group of halogen, lower alkyl, lower alkoxy, lower alkylthio, trifloromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "aralkyl" refers to the group-R-Ar, where AG represents an aryl group, a R is a lower alkyl or substituted lower alkyl group. Aryl groups can be optionally unsubstituted or substituted, e.g. by halogen, lower alkyl, alkoxy, alkylthio, trifluoromethyl, who, is iano, alkylthio, thiol, sulfamido and the like.

The term "heteroalkyl" refers to the group-R-Het, where Het represents a heterocyclic group, and R represents a lower alkyl group. Heteroalkyl group may be optionally unsubstituted or substituted, e.g. by halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyla, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "heteroaromatic" refers to the group-R-HetAr where HetAr is a heteroaryl group and R is lower alkyl or substituted lower alkyl. Heteroallyl group may be optionally unsubstituted or substituted, e.g. by halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "cycloalkyl" refers to a divalent cyclic or polycyclic alkyl group containing 3 to 15 carbon. As for polycyclic groups, they may represent mnogostradalnoe, tetrahydronaphthalene and so on, and so on).

The term "substituted cycloalkyl" refers to cycloalkyl group that includes one or more substituents, for example halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "cyclogeranyl" refers to cycloalkyl group in which one or more carbon atoms replaced with a heteroatom (e.g. N, O, S, or P).

The term "substituted cyclogeranyl" refers, as is indicated here, to cyclogeraniol group, which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "alkyl cycloalkyl" refers to the group-R-cycloalkyl where cycloalkyl is cycloalkyl group, a R is a lower alkyl or substituted lower alkyl. Cycloalkyl group may be optionally unsubstituted or substituted, for example, halogen, NISS is iloxi, a heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term "amino acid" refers to D - or L-isomer of the naturally occurring or synthetic alpha-amino acids, the preferred amino acids are naturally occurring amino acids alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, serine, threonine, tryptophan, tyrosine or valine.

Usually D1D2and E, in the presence of this composition can be an amino acid. Usually are preferred lipophilic amino acids. In General, amino acid abbreviations follow from the Rules of the IUPAC-IUB joint Commission on Biochemical Nomenclature given in Eur. J. Biochem., 158, 9(1984).

Preferably, when R3represents methoxy, -D1represents leucine and D2represents leucine, and E is a R NR'r". More preferably, when D1is a 1-leucine, a-D2is a d-leucine, and when E is selected from the group of compounds consisting of benzu> and glycinamide.

In one preferred composition R3represents methoxy, D1represents leucine, D2represents leucine, and E represents benzylamine. In another preferred composition R3represents methoxy, D1represents leucine, D2represents leucine, and E is a 1-indanamine. In another preferred composition R3represents methoxy, D1represents leucine, D2represents leucine, and E represents N,N-dibenzylamine. In another preferred composition R3represents methoxy, D1represents leucine, D2represents leucine, and E represents a 2,6-differentiatin.

In these preferred compositions preferably, in addition, when D1represents L-leucine, and D2is a D-leucine. Known compounds that may be suitable for this therapeutic method of the present invention set forth in the table. 1.

Professionals in this field know that the stereoisomers compositions described herein, as well as isomers and stereoisomers componentheight for therapeutic method of the present invention.

If this connection is suitable for the method of the present invention contains a basic group, it is possible to obtain an acid additive salt. Acid additive salts of these compounds was obtained in the usual manner with a suitable solvent from the parent compound and an excess of acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methansulfonate. If the target compound contains an acidic group, it is possible to obtain a cationic salt. Usually the original compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations, such as Na+TO-, CA+2and NH4+are examples of cations present in pharmaceutically acceptable salts. Some compounds form an internal salt or zwitterion, which is also acceptable.

The connection described above is suitable for treatment of disorders of cell proliferation, infectious diseases, and immunological diseases in mammals, particularly human patient in need of such treatment. Disorders of cell proliferation, which can be treated using vysheukazannye, renal diseases such as lupus and polycystic kidney disease, rejection of graft versus host disease, gout and other proliferative disorders. Autoimmune diseases that can be treated using the above compositions include rheumatoid arthritis, lupus, diabetes type I, multiple sclerosis and similar disorders, and diseases. Infectious diseases that can be treated using the above-described compositions include IBD (inflammatory bowel disease), Crohn's disease, AIDS (AIDS), ARDS (acute respiratory distress syndrome and similar disorders. The above compositions can also be used to treat fungal infections, dermatological diseases such as psoriasis, abnormal wound healing, keloids, immunological diseases such as autoimmune, asthma, allergies, acute and delayed-type Allergy, graft versus host disease, graft rejection and neuro disease such as multiple sclerosis and acute disseminated encephalomyelitis.

The treatment of these diseases and disorders include introduction, parenterally or orally, an effective amount of a selected connection or it is usual were chosen in the range from 0.01 to 100 mg/kg, and to the person skilled in the art it will be easy to determine, depending on the route of administration, the age and condition of the patient. These dose units can be entered 1-10 times daily during acute or chronic disease. When the compounds of the present invention is administered in accordance with the present invention, undesired Toxicological effects were observed.

Pharmaceutical compositions from the compounds of the present invention or derivatives thereof may be prepared as solutions or lyophilized powders for parenteral administration. Before use, the powder can be reconstituted by adding a suitable diluent or other pharmaceutically acceptable carrier. This liquid preparation is usually a buffered isotonic aqueous solution. Examples of suitable diluents are isotonic saline solution, a standard 5% dextrose in water or solution, buffered with sodium acetate or ammonium acetate. This drug is particularly suitable for parenteral administration, but can also be used for oral administration. Desirable may be the addition of fillers, tikitricia. Or these compounds can be enclosed in a capsule, tableted or prepared in an emulsion or syrup for oral administration. To enhance or stabilize the composition, or to facilitate the preparation of this composition can be added pharmaceutically acceptable solid or liquid carriers. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, digidrirovanny calcicola, magnesia, ministerof or stearic acid, talc, pectin, acacia, agar or gelatin. The media may also include a strengthening substance, such as glycerylmonostearate or glycerylmonostearate, alone or with a wax. The quantity of solid carrier will vary, but preferably, it has been concluded between about 20 mg and about 1 g per dose unit. Data pharmaceutical preparations prepared, adhering to the traditional methods of pharmacy, covering milling, mixing, granulating and, if necessary, pressing for tablet forms; or milling, mixing and filling of hard gelatin capsule forms. When using liquid but the th liquid drug can be administered orally or enclosed in a soft gelatin capsule.

Example 1.

Compounds suitable for therapeutic method of the present invention, was prepared using conventional methods of organic chemistry. The combination of reagents well known in the art, such as DCC and other carbodiimide, EDC, the THIEF and the PPA, and they may not necessarily be used with other reagents, such as NOT, N and DMAP that may contribute to this reaction. The compounds of formula (1) in which D1D2and E represent amino acids that are well known in the art, obtained using either traditional liquid-phase or solid-phase methods, as described by Bodanszky, "The Practice of Peptide Synthesis", Springer-Verlag, First Edition, 1984. Suitable protective groups for a specific amino group are such protective groups are described in Greene et al., "Protective Group in Organic Synthesis," Second Edition, John Wiley and Sons, New York, 1991. Benzyloxycarbonyl, tert-butoxycarbonyl and fluorenylmethoxycarbonyl groups are particularly suitable aminosidine groups.

Solid-phase peptide synthesis was carried out as follows. Rolled amide resin was placed in a syringe equipped with armored filter. Remove protection from resin using 20%-ATEM five times in DMF. A solution of amino acid (S), carbodiimide and NOT in DMF was pulled into the syringe and this reaction mixture was stirred for 4-20 hours. The resulting reaction solution was pushed out and this mixture was washed five times with DMF five times with methanol and then five times with DMF. This cycle was repeated to attach the desired sequence. End-joining was used 5-methoxy-1-indanone-3-acetic acid, carbodiimide and NOWT. After the final grayloc this resin obtained peptide fragment was tsalala from the resin using 95% triperoxonane acid (TFU)/5% water. Concentration derived mixture gives a white solid.

Example 2.

Compounds of the present invention obtained in accordance with the method of Example 1 was tested as follows. Catalytic subunit of the 20S proteasome (also known as multicatalytic proteinase complex) were isolated by purification to homogeneity from the brain of cattle, in accordance with published methods (S. Wilk and Orlowski M, 40, 842, J. Neurochem. (1983)). Chymotrypsinogen activity of this complex was measured by the increase in fluorescence upon cleavage of the substrate peptide succinyl-leucine-leucine-valine-th inhibitor in 200 μl of 50 mm HEPES, containing 0.1% sodium dodecyl sulfate, pH 7.5. The proteolytic reaction was initiated by adding 50 μm fluorogenic peptide substrate and allowed to develop for 15 minutes at 37oC. the reaction was stopped by addition of 100 mm acetate buffer, pH 4.0. The rate of proteolysis is directly proportional to the number of released aminoethylamino, which was measured by fluorescent spectroscopy (EX 370 nm, EM 430 nm). The structure of the tested compounds, and the results of this experiment is shown in table. 2.

Example 3.

The compounds obtained in accordance with the method of Example 1, were analyzed in several different cell lines. Cell monolayers were cultured in the presence of test compounds for 18 hours, to determine its ability to inhibit cell proliferation. The level of cell proliferation was determined colorimetrically using non-radioactive analysis of cell proliferation Celltiter 96 Aqueous (Promega), where cell proliferation was directly proportional to the absorption at 490 nm. The results are shown in the form of the IC50in μg/ml inhibition of cell proliferation in different cell types (table. 3).

Example 4.
Example 5.

This Example tests the ability of the compounds 173 and especially compounds 187, described in table. 1 and 2, to inhibit proteasome activity, as indicated partially in the presence of IQ and/or R in inhibiting the cells. In order to transliterate NF-KB in the nucleus in response to a stimulus such as lipopolysaccharide (LPS), and to activate transcription, it is necessary that happened two proteolytic events, namely the degradation of the inhibitory protein IQ and turning R in P50. These proteolytic events are used to signal detection of NF-KB, localized in the nucleus.

Inhibition of degradation of IQ induced by LPS

The RAW cells pre-treated with different concentrations of test compounds for 1 hour prior to administration of lipopolysaccharide (100 ng/ml). After 1 hour, collected lysates of whole cells by electrophoresis in polyacrylamide gel with sodium dodecyl sulfate (SDS-PAGE) were divided by 10 µg EN-blots (see Fig.1) visualized using a detector set firm Boehringer Mannheim Chemiluminescent. The resulting blot showed that IQ is present in cells treated with compounds 173 and 187 in the amount of 5 µg/ml.

Inhibition of transformation of P150 in P50 induced by LPS

Compound 187, which is described in the table. 1 and 2, used for pre-treatment of RAW cells, as described above, and lysates of whole cells, obtained as described above were analyzed for immunoreactivity against P50 antibodies. The results obtained are shown in Fig. 2, indicate that P50 and P150 are present in the cells treated with compound 187, to 5 μg/ml in untreated cells the most part R was turned into P50.

Inhibition of LPS-induced translocation of NF-KB in the nuclear fraction of these cells

The RAW cells pre-treated for 1 hour with compound 187 (20 μg/ml), and then incubated with lipopolysaccharide (100 ng/ml) for a further one hour. Nuclear fractions were obtained according to standard methods. Binding assays during the analysis of the delay in the gel containing 5 μg of protein extracted from the kernel, 50000 cpm (counts per minute)32P-labeled NF-KB universal participation is ucleotide. Analysis of the delay in the gel shown in Fig. 3 shows that the connection 187 is effective in suppressing the accumulation of NF-KB in the nucleus of cells.

1. A method of treating mammals with impaired cell proliferation, immune system disorders and infectious diseases, including the introduction of a given mammal a therapeutically effective amount of a compound having the formula:

< / BR>
where each of R1-R4individually selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano; each of R5-R9individually selected from the group of compounds including hydrogen, halogen, hydroxyl, thiol, oxo, lower alkyl, substituted lower alkyl, alkenyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteros is but;

X is selected from the group of compounds including hydrogen, -D1, -D2E,- D1-D2, -D1-E, -D2-E, or is a compound having the formula:

< / BR>
in which each of the D1and D2selected from the group of compounds that includes

< / BR>
hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocyclic compound, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes or does not include them; in which E represents a connection selected from the group that includes

< / BR>
hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes or alkylcyclopentanes;

where R10-R14each separately selected from the group of compounds including hydrogen, halogen, Hydra is, is kiltia, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes, nitro or cyano;

J1and J2represents N-R15, CR16R17, O, S(O)0-2, P(O)0-3;

R15-R17each separately selected from the group of compounds including hydrogen, halogen, hydroxyl, oxo, thiol, lower alkyl, substituted lower alkyl, quinil, alkylaryl, alkylamine, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocyclic compound, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylsilanes, alkylcyclopentanes or cyano.

2. The method according to p. 1, where R1-R4each separately selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, aryloxy, substituted aryl, amino, amido, alkoxy, thio, alkylthio, hydroxyl, cyano, nitro, acyl, carboxyl and quinil, and R5-R9each separately selected from the group consisting of hydrogen, lower alkyl, aryl, substituted netspy, consisting of D1-E or-D2-E.

4. The method according to p. 3, where each of the D1and D2represents a

< / BR>
5. The method according to p. 4, where J1represents N-R15and R5-R11and R15each separately selected from the group of compounds consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl or substituted aryl, and E is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, substituted aryl, alkoxy, and amino.

6. The method according to p. 5, where R5-R11and R15each separately selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl, and E is selected from the group consisting of lower alkyl, substituted lower alkyl, aryl, substituted aryl, alkoxy, and amino.

7. The method according to p. 6, where E is selected from the group consisting of alkoxy and amino, and R1-R4selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, alkoxy, amino, nitro, hydroxyl, cyano, quinil, thio, alkylthio.

8. The method according to p. 7, where E is an R NR'r" where R' and R" are each individually selected from the group consisting of hydrogen, lower alkyl, substituted group, consisting of hydrogen, halogen, nitro, lower alkyl, substituted lower alkyl, amino, alkylthio, thio, hydroxy and alkoxy.

9. The method according to p. 8, where R1-R4each separately selected from the group consisting of hydrogen, alkoxy and lower alkyl, R5-R11and R15each separately selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl, and R' and R" are each individually selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl and cycloalkyl.

10. The method according to p. 2, where X is a

< / BR>
11. The method according to p. 10, where each of the D1of D2represents a

< / BR>
12. The method according to p. 11, where E is a compound selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, amino, cycloalkyl, substituted cycloalkyl, alkoxy or alkylcyclohexane.

13. The method according to p. 11, where E is a

< / BR>
14. The method according to p. 13, where each of J1and J2represents NR15in which R10-R13and R15each separately selected from the group consisting of hydrogen, lower alkyl, substituted mississaga of alkyl, aryl, substituted aryl, amino and alkoxy.

15. The method according to p. 14, where R5-R13each separately selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl, R14selected from the group of compounds consisting of alkoxy and amino, and R15selected from the group of compounds consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl.

16. The method according to p. 15, where R1-R4each separately selected from the group of compounds consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, aryloxy, substituted aryl, amino, alkylthio, nitro, hydroxy, thio, alkoxy.

17. The method according to p. 16, where R5-R13and R15each separately selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl.

18. The method according to p. 17, where R14represents R NR'r" where R' and R" are each individually selected from the group of compounds consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl and cycloalkyl.

19. The method according to p. 18, where R1-R4each separately selected from the group consisting of vaeni, consisting of hydrogen, lower alkyl and substituted lower alkyl, and R' and R" are each individually selected from the group of compounds consisting of hydrogen, lower aklilu, cycloalkyl and substituted lower alkyl.

20. The method according to p. 12, where J1represents-NR15where R15selected from the group of compounds consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl.

21. The method according to p. 20, where R5-R11each separately selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl and substituted aryl, E is selected from alkoxy and amino, R1-R4each separately selected from the group of compounds consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, alkylthio, thio, alkoxy, amino, nitro and hydroxyl, and R15is a compound selected from the group of compounds consisting of hydrogen, lower alkyl and aryl.

22. The method according to p. 21, where E is an R NR'r" where R' and R" are each individually selected from the group of compounds consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl and cycloalkyl.

23. The method according to p. La, R5-R11each separately selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl, R' and R" are each individually selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl and cycloalkyl, and R15selected from the group of compounds selected from the group consisting of hydrogen and lower alkyl.

24. The method according to p. 10, where R3represents methoxy, -D1represents leucine and D2represents leucine, and E represents NR'r R".

25. The method according to p. 24, where-D1represents l-leucine, and D2is a d-leucine.

26. The method according to p. 25, where E is selected from the group of compounds consisting of benzylamine, 1-indanamine, N, N'-dibenzylamino, 2,6-differentiatin, 4-methoxybenzylamine, piperidylamine and NH2.

27. The method according to p. 24, where E represents glycinamide.

28. The method according to p. 1, where the specified mammal is a human.

29. The method according to p. 1, where the specified therapeutically effective amount ranges about 0.001 to 100 mg/kg weight of the specified mammal.

30. The method according to p. 1, where the specified composition is administered mlekovita is the lupus, diabetes type I, multiple sclerosis, cancer, restenosis, graft versus host and gout.

31. The method according to p. 30, where the breach of cell proliferation is a restenosis.

32. The method according to p. 30, where cell proliferation is cancer.

33. The method according to p. 30, where the specified therapeutic agent induces apoptosis.

34. The method according to p. 30, where the breach of cell proliferation is a polycystic kidney disease.

35. The method according to p. 1, where the specified composition is administered to a mammal suffering from an infectious disease.

36. The method according to p. 33, where the specified infectious disease selected from the group consisting of IBD, Crohn's disease, AIDS, ARDS and fungal diseases.

37. The method according to p. 1, where the specified composition is administered to a mammal suffering from immunological diseases, such as rheumatoid arthritis, autoimmune disease, graft rejection, and psoriasis.

38. The composition is in the form of a solution containing the above compounds of formula under item 1 in a therapeutically effective amount.

39. The composition in the form of tablets containing these modifications is

 

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< / BR>
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where R1- R7mean mostly hydrogen or alkyl or neighboring residues, R1- R4form a loop, get the one-stage reaction in which the compound of formula (I)

reacts with the compound of the formula (II)

or a compound of the formula (III)

in anhydrous hydrogen fluoride in the presence of boron TRIFLUORIDE.

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< / BR>
where R1- R7the same or different and denote hydrogen, C1- C20-alkyl, C1- C4the aryl by one-step interaction of the compounds of formula I:

< / BR>
with the compound of the formula II

< / BR>
where R1- R7above, R9- linear, WITH1- C20the alkyl in the excess of liquid hydrogen fluoride

The invention relates to a method for producing substituted indanones formula (IV) and their isomers of the formula (IVa)

< / BR>
where R1-R7mostly represent hydrogen or Alcide or neighbouring residues R1-R4form a ring, get the one-stage method by reacting the compound (I)

< / BR>
with a carboxylic acid anhydride of the formula (II)

< / BR>
or foramerica formula (III)

- in liquid hydrogen fluoride

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