Bis-indolamine macrocyclic derivatives, the retrieval method (variants) and a pharmaceutical composition

 

(57) Abstract:

Describes the new bis-indolamine macrocyclic derivatives of the formula (I), where the values of R1, R2X, Y, W, m specified in paragraph 1 of the formula. They relate to new and strong inhibitors of protein kinase C and have high isozyme-selective. They can find application in the treatment of diseases associated with diabetes, and diseases such as ischemia, skin diseases and cancer. Also describes the retrieval method (variants) and a pharmaceutical composition based on compounds of the formula (I). 5 C. and 8 C.p. f-crystals, 3 PL.

Protein kinase C (RCC) is a family of closely related enzymes with functions serine/trionychinae. Protein kinase C plays an important role in the transmission of signals from cell to cell, gene expression, and regulation of differentiation and growth of cells. Currently, there are at least 10 isozyme of protein kinase C (CSW), which differ in their tissue distribution, regulation and its enzymatic specificity. Nishizuka Y. Annu, Rev. Biochem. 58: 31-44 (1989); Nishizuka Y. Science 258: 607-614 (1992).

The isozyme of protein kinase C are single-stranded floor is installed linker peptide. The regulatory and catalytic domains can also be divided into constant and variable regions. The catalytic domains of protein kinase C and other kinases are very similar, whereas the regulatory domain is unique for each isozyme RKS. Amino acid sequence of isozyme RKS find 40 - 80% homology within their group. However, the homology of various types of one isozyme is usually more than 97%.

Protein kinase C is a membrane-associated enzyme allosteric regulated by a number of factors, including membrane phospholipids, calcium and some membrane lipids, such as diacylglyceride released in response to activation of phospholipases Bell R. M., and Burns, D. J. J. Biol. Chem, 266: 4661 - 4664 (1991); Nishizuka Y. Science 258: 607 - 614 (1992). The isozyme of protein kinase C, alpha, beta 1, beta 2 and gamma, for its full activation requires the presence of a membrane phospholipid, calcium and diacylglycerol/furbelowed esters. Delta-, Epsilon-, ETA -, and theta forms of RCC, by way of its activation is calcium-independent. Zeta and lambda forms RKS are calcium - and diacylglycerol-independent and for its activation, obviously, require only membrane fonnum disease. For example, elevated levels of glucose in the blood that can be detected by diabetes, lead to the isozyme-specific increase in the level of isozyme beta-2 in the vascular tissues. Inoguchi and others, Proc. Natl. Acad. Sci. USA 89: 11059 - 11065 (1992). Diabetes-related increase in beta isozyme in human platelets correlates with the change in its response to agonists. Bastyr 111, E. J., and L and J. Diabetes 42: (Suppl. 1) 97A (1993). It has been shown that the receptor for vitamin D person selectively fosfauriliruetsa beta isozyme of protein kinase C. This phosphorylation is associated with changes in receptor function. Hsiel and others, Proc. Natl. Acad. Sci USA 88: 9315 - 9319 (1991); Hsiel etc., J. Biol. Chem. 268: 15118 - 15126 (1993). In addition, it was recently shown that the beta isozyme-2 is responsible for the proliferation of cells erythroleucus and alpha isozyme involved in the differentiation of megakaryocytes in these same cells. Murray and others, J. Biol. Chem. 268: 15847-15853 (1993).

The widespread prevalence of isozyme of protein kinase C and their important role in physiology encourages researchers to develop highly selective inhibitors of the RCC. If there is evidence of communication of some isozyme with certain diseases, there is every reason to assume that the best therapeutic means they are protein kinase C or other protein kinases. Due to its specificity such compounds should have more efficacy and less toxicity.

Microbial indolocarbazole, staurosporin, is a strong inhibitor of protein kinase C, which interacts with its catalytic domain. Tamaoki and others, Biochem. Biophys. Rec. Commun. 135: 397 - 402 (1986); Gross and others , Biochem. Pharmacol. 40: 343 - 350 (1990). However, therapeutic effect of this molecule and closely related compounds is limited by lack of specificity to the protein kinase C compared with other protein kinases. Reugg U. T. and Burgess, G. M., Trend Pharmacol. Sci. 10: 218 - 220 (1989). This lack of selectivity in the specified class of molecules leads to unacceptable toxicity.

In the last works was considered another class of compounds, related staurosporine, namely, beendamaged. Davis and others FEBS Lett. 259: 61 - 63 (1989); Twoemy and others, Biochem. Biophys. Res. Commun 171: 1087 - 1092 (1990); Toullec, etc., J. Biol. Chem. 266: 15771 - 15781 (1991); Davis and others, J. Med. Chem. 35: 994 - 1001 (1992); Bit etc., J. Med. Chem. 36: 21 - 29 (1993). Some of these compounds were detected selectivity for protein kinase C.

Although previously detected connection with the specificity of the protein kinase C, however, little is known about their selectivity to isozyme. For example, analysis of staurosporine on its Zeta-isozyme compared to the other isozyme. McGlynn and others, J. Cell. Biochem. 49: 239 - 250 (1992); Ward N. E. and O Brian C. A. Molec. Pharmacol. 41: 387 - 392 (1992). The study RKS-selective compound 3-[1-(3-dimethylaminopropyl)-indol-3-yl] -4-(1H-indol-3-yl)-1H-pyrrole-2,5 - dione found a weak selectivity for calcium-dependent isozyme. Toullec et al., J. Biol. Chem. 266: 15771 - 15781 (1991). Subsequent studies of this compound have not found any differences in selectivity (or there is a very weak selectivity to alpha isozyme compared with selectivity for beta-1 and beta-2 isozyme. Martiny-Baron and others , J. Biol. Chem. 268: 9194 - 9197 (1993); Wilkinson and others, Biochem. J. 294: 335 - 337 (1993). Therefore, despite years dedicated to research and identify classes of compounds inhibiting mainly protein kinase C, but not other protein kinases, the need to obtain a therapeutically effective isozyme-selective inhibitors still remains relevant.

The present invention relates to a new and strong inhibitors of protein kinase C. Compounds of the present invention are selective with respect to protein kinase C, but not in relation to other kinases, and that, quite unexpectedly, these compounds have high isozyme-selective. As selective inhibitors, these compounds can be used MIA, inflammatory diseases, disorders of the Central nervous system, cardiovascular diseases, skin diseases and cancer.

The present invention relates to compounds of the formula I

< / BR>
where W is-O-, -S-, -SO-, -SO2-, -CO-, C2-C6-alkylene, substituted alkylene, C2-C6-albaniles, -aryl-, -aryl(CH2)m-O-, heterocycle-heterocycle-(CH2)m-O-,

condensed bicikl-, -condensed bicikl-(CH2)mO-, NR3-, -NOR3-, -CONH-or-NHCO-;

X and Y are independently - C1-C4-alkylene, substituted alkylene, or X, Y, and W taken together form -(CH2)n-AA-;

R1independently is hydrogen, halogen, C1-C4-alkyl, hydroxy, C2-C4-alkoxy, halogenated, nitro, NR4R5or-NHCO(C1-C4-alkyl);

R2is hydrogen, CH3CO, NH2or hydroxy;

R3is hydrogen, (CH2)maryl, C1-C4- alkyl, -COO(C1-C4-alkyl), -CONR4R5, -(C=NH)NH2, -SO(C1-C4-alkyl), -SO2(NR4R5or-SO2(C1-C4-alkyl);

R4and R5independently is hydrogen, C1-C4-alkyl, phenyl, benzyl, or R4and R5taken the
AA - amino acid residue;

m is independently 0, 1, 2 or 3; and

n is independently 2, 3, 4 or 5.

The present invention also relates to novel intermediate compounds, intended for the production of the above compounds. Such intermediate compounds are the compounds of formula II

< / BR>
where V is-O - or N-CH3;

W IS-O-, -S-, -SO-, -SO2-, -CO-, C2-C6-alkylene, substituted alkylene, C2-C6- albaniles, aryl, aryl(CH2)mO -, heterocycle - heterocycle-(CH2)mO - condensed bicikl-, -condensed bicikl-(CH2)mO-, -NR3-, -NOR3-, -CONH - or-NHCO-;

X and Y independently - C1-C4-alkylene, substituted alkylene, or X, Y, and W taken together form -(CH2)n-AA-;

R1independently is hydrogen, halogen, C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halogenated, nitro, NR4R5or-NHCO(C1-C4-alkyl);

R3is hydrogen, (CH2)m-aryl, C1-C4-alkyl, -COO (C1-C4-alkyl), -CONR4R5, -(C=NH)NH2, - SO(C1-C4-alkyl), -SO2(NR4R5or-NO2(C1-C4-alkyl);

R4and R5the independent is which they are associated, form a saturated or unsaturated 5 - or 6-membered ring;

AA - amino acid residue;

m is independently 0, 1, 2 or 3;

n is independently 2, 3, 4 or 5.

In another embodiment, the present invention relates to a method for producing compounds of formula II, namely, that the mixture of compounds having a concentration of from about 1.5 M to 0.001 M, and the formula

< / BR>
where V is O or N-CH3;

R1independently is hydrogen, halogeno, C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halogenated, nitro, NR4R5or-NHCO(C1-C4-alkyl);

m is independently 0, 1, 2 or 3;

and an alkylating agent having a concentration of from about 1.5 M to about 0.001 M, and the formula:

< / BR>
where L is a leaving group;

W IS-O-, -S-, -SO-, -SO2-, -CO-, C2-C6-alkylene, substituted alkylene, C2-C6-albaniles, -aryl-, -aryl(CH2)m-O-, -heterocycle-, -heterocycle-(CH2)mO-, condensed bicikl-, -condensed bicikl-(CH2)mO-, -NR3-, -NOR3-, -CONH - or-NHCO-;

X and Y independently - C1-C4-alkylene or substituted alkylene;

R3is hydrogen, (CH2)m-aryl, C1-C4-alkyl, -COO(C12(C1-C4-alkyl);

R4and R5independently is hydrogen, C1-C4-alkyl, phenyl, benzyl, or R4and R5taken together with the nitrogen to which they are linked, form a saturated or unsaturated 5 - or 6-membered ring;

m is independently 0, 1, 2 or 3;

combine with about 0.5 to 10 equivalents Cs2CO3at a dose of from about 0.1 ml/HR to about 2.0 ml/h in a polar aprotic solvent.

Another method of preparing compounds of the formula II is the compound in a concentration of from about 3 M to about 0.001 M, having the formula

< / BR>
where L2independently is a leaving group;

V is-O - or N-CH3;

W IS-O-, -S-, -SO-, -SO2-, -CO-, C2-C6-alkylene, substituted alkylene, C2-C6- albaniles, -aryl-, -aryl (CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, condensed bicikl, is condensed bicikl-(CH2)mO-, -NR3-, -NOR3-, -CONH - or-NHCO-;

X and Y independently - C1-C4-alkylene or substituted alkylene;

R1independently is hydrogen, halogen, C1-C4-alkyl, hydroxy, C1-C4-alkoxy, halogenated, nitro, NR4R5or-NHCO(C1-C4-alkyl);<>5, -(C=NH)NH2, -SO(C1-C4-alkyl), -SO2(NR4R5or-SO2(C1-C4-alkyl);

R4and R5independently is hydrogen, C1-C4-alkyl, phenyl, benzyl, or R4and R5taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated 5 - or 6-membered ring;

m is independently 0, 1, 2 or 3;

combine approximately 0.5 to 10 equivalents Cs2CO3at a dose of from about 0.1 ml/HR to about 2.0 ml/h in a polar aprotic solvent.

In another embodiment, the present invention relates to a method of inhibiting protein kinase C, which consists in the fact that the mammal in need of such treatment, administered pharmaceutically effective amount of the compounds of formula I. the Present invention also relates to a method of selective inhibition of beta-1 and beta-2 isozyme of protein kinase C, which consists in the fact that the mammal in need of such inhibition, enter pharmaceutically effective amount of the compounds of formula I.

In addition, the present invention relates to methods of treating conditions known to a role in the pathology plays proteinkinase disease, skin diseases and cancer; moreover, these methods are that the mammal in need of such treatment, administered pharmaceutically effective amount of the compounds of formula I.

The present invention is particularly preferably used for the treatment of complications associated with diabetes. Therefore, the present invention also relates to a method of treatment of diabetes, namely, that the mammal in need of such treatment, administered pharmaceutically effective amount of the compounds of formula I.

Finally, in yet another embodiment, the present invention relates to pharmaceutical compositions containing a compound of formula I in combination with one or more pharmaceutically acceptable excipients, carriers or diluents.

As mentioned above, the present invention relates to compounds of the formula I, which are capable of selective inhibition of protein kinase C. the Preferred compounds of the present invention are the compounds of formula I, where part-X-W-Y - contain 4 to 8 atoms which can be substituted or unsubstituted. Most preferably, if the parts-X-W-Y - containing 6 atoms.

Friends who SUB> is hydrogen; and W - substituted alkylene, -O-, -S-, -CONH-, -NHCO -, or-NR3-.

Especially preferred compounds are the compounds of formula Ia

< / BR>
where Z is -(CH2)p- or -(CH2)p-O-(CH2)p-;

R6- hydroxy, -SH, C1-C4-alkyl, (CH2)m-aryl, -NH(aryl), or-NR4R5;

R4is hydrogen or C1-C4-alkyl;

R5is hydrogen or C1-C4-alkyl or benzyl;

p = 0, 1, or 2;

m = 2 or 3, independently.

The most preferred compounds of formula Ia are compounds in which Z is CH2, R6- -NH2or N(CH3)2.

Other preferred compounds are compounds in which W is-O-; Y is substituted alkylene; and X - alkylen. These compounds can be represented by formula I

< / BR>
where Z is -(CH2)p-;

R6- NR4R5;

R4and R5independently - H or C1-C4-alkyl;

p = 0, 1, or 2;

m = 2 or 3, independently.

The most preferred compounds of formula Ib are compounds in which p = 1 and R4and R5is methyl.

The term "halogen" means fluorine, chlorine, bromine and iodine.

Termite 1 to 4 carbon atoms, for example, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.

The term "halogenated" means one of the above alkyl groups substituted by one or more halogen atoms, preferably 1 to 3 atoms. An example of halogenoalkane is trifluoromethyl.

"C1-C4-alkoxy" means C1-C4is an alkyl group, covalently linked via-O bonds.

The term "C1-C4-alkylene" means direct and containing 1 to 4 carbon atoms alkylenes part of the formula -(CH2)rwhere r = 1 - 4. Examples of C1-C4-alkylene are methylene, ethylene, trimethylene, mutilation, tetramethylene etc.

Similarly, the term "C2-C6-alkylene" means alkylenes part containing 2 to 6 carbon atoms. Preferably, if C2-C6-alkylen is alkylene having 2 to 4 carbon atoms.

The term "C2-C6-albaniles" means a straight or branched hydrocarbon having 2 to 6 carbon atoms and one or more double bonds, preferably one or two double bonds. Examples of C2-C6-Alcanena are attilan, propylen, 1,3-butadiene which may be optionally substituted by one or two groups independently selected from hydroxy, carboxy, C1-C4-alkoxy, C1-C4-alkyl, halogenoalkane, nitro, - NR4R5, -NHCO (C1-C4-alkyl), -NHCO(benzyl), -NHCO (phenyl), SH, S(C1-C4-alkyl), -SO2(NR4R5), -SO2(C1-C4-alkyl), -SO2(phenyl) or halogen.

The term "(CH2)maryl" is preferably a benzyl or phenyl.

The term "substituted alkylene" means the part of the formula:

< / BR>
where Z is -(CH2)por -(CH2)p-O-(CH2)p-;

R6- C1-C4-alkyl, C1-C4-alkoxy, (CH2)m-aryl, (CH2)m-aryloxy, hydroxy, carboxy, -COO- (C1-C4-alkyl), -COO(CH2)m-aryl, -CO(C1-C4-alkyl), -NR4R5,

-N(R4R5)(OR5), -NH(CH2)m-aryl, -NH(CH2)m-pyridyl, -CONH(CH2)m-aryl,

-CONH(C1-C4-alkyl), -NHCO- (C1-C4-alkyl), -NHCO(CH2)m-aryl, -OCONH (C1-C4-alkyl), -OCONH(CH2)m-aryl, -NHCOO(alkyl), -NHCOO(benzyl), -NHSO2(C1-C4-alkyl), -NHSO2(CH2)m-aryl, -CN, -SH, -S(C1-C4-alkyl), S(aryl), -SO2(NR4RUB> independently - C1-C4-alkyl, phenyl, benzyl, or R4and R5taken together with the nitrogen atom to which they are linked, form a saturated or unsaturated 5 - or 6-membered ring;

p independently is 0, 1 or 2;

m independently is 0, 1, 2, or 3.

Preferably, when Z is-CH2-, and R6- C1-C4is alkyl, aryl, or-NR4R5.

The term "heterocycle" means a stable substituted or unsubstituted, saturated or unsaturated 5 - or 6-membered ring having 1 to 4 heteroatoms which may be the same or different and are sulfur atoms, oxygen, and nitrogen; and in the case that the heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of formula-CH=CH-; provided that (1) if the heterocyclic ring has 5 members, the heteroatoms may contain more than two sulfur atom or two oxygen atom, but not both; and (2) if the heterocyclic ring has 6 members and is aromatic, sulfur atoms and oxygen are absent. The heterocycle may be attached at any carbon atom or nitrogen, which makes the structure stable. The heterocycle may be substituted by one, and the sludge, carboxy, halogenoalkane, nitro, -NR4R5, -NHCO (C1-C4-alkyl), -NHCO(benzyl), -NHCO(phenyl), SH, S (C1-C4-alkyl), -OCO(C1-C4-alkyl), -SO2(NR4R5), -SO2(C1-C4-alkyl),

-SO2(phenyl) or halogen. Examples of the heterocycle can be pyrazole, pyrazoline, imidazole, acetylimidazole, isoxazol, triazole, tetrazole, oxazole, 1,3-dioxolan, thiazole, oxadiazole, thiadiazole, pyridine, dipyridyl, pyrimidine, piperazine, morpholine, pyrazin, pyrrolidine, piperidine, piperazine, oxazolidinone, imidazolidinone and aminopyridine.

The term "glycosyl" means sugar with 5 or 6 carbon atoms selected from the group comprising allail, ultrasil, glucosyl, Minotel, gulail, galactosyl talosi, arabinosyl, xylosyl, lexoil, rhamnosyl, ribosyl, deoxyguanosine, deoxyribosyl and desoxyribose. Glicose may be substituted, O-acetylated and O-methylated, aminosilanes, monosubstituted, di alkylamino-substituted or arylaminothiourea.

The term "condensed Bicycle" means a stable condensed bicyclic ring system of the formula:

< / BR>
where Hetero - substituted or unsubstituted, saturated or nenas ablaut a sulfur atoms, oxygen and nitrogen; and if Hetero contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of formula-CH=CH-; provided that (1) if the Hetero-ring has 5 members, the heteroatoms can include in their number is not more than two sulfur atom, or two atoms of oxygen, but not both; and (2) if the Hetero-ring has 6 members and is aromatic, sulfur atoms and oxygen are absent. Condensed Bicycle can be attached at any carbon atom or nitrogen, ensuring the stability of the structure. Condensed Bicycle may be substituted by one or two groups independently selected from the following groups: C1-C4-alkyl, C1-C4-alkoxy, hydroxy, carboxy, halogenated, nitro, -NR4R5, -NHCO(C1-C4-alkyl), -NHCO(benzyl), -NHCO(phenyl), SH, S(C1-C4-alkyl), -OCO (C1-C4-alkyl), -SO2- (NR4R5), -SO2(C1-C4-alkyl), -SO2(phenyl) or halogen.

Examples of condensed Bicycle are indole, imidazo(1,2-a)pyridine, benzotriazole, benzimidazole, benzotriazole, benzoxazole, benzoxadiazole, quinoline, isoquinoline, phthalazine, hinzelin, heatline, cinoxacin and hell R - variable side chain of amino acids;

R7is hydrogen or hydroxy.

Variable side chain of amino acids is an atom or group associated with the atom of carbon, which is also associated with a carboxyl or amino group. Examples of variable regions of the natural amino acids are the following patterns:

< / BR>
< / BR>
CH3-S-CH2-CH2-,

(Met)

H-,

(Gly)

HO-CH2,

(Ser)

H2N-CH2-CH2-CH2-CH2-

(Lys)

< / BR>
In addition to natural amino acids, the term "amino acid residue" includes isomers provisions and options. Examples of isomers provisions and options can serve the following amino acid residues: 2-aminoadenosine acid (Aad), 3-aminoadenosine acid (bAad), -alanine (bAla), 2-aminobutyric acid (Abu), 4-aminobutyric acid (4Abu), 6-aminocaproic acid (Acp), 2-aminoheptanoic acid (Ahe), 2-aminoadamantane acid (Aib), 3-aminoadamantane acid (bAib), 2-aminofilina acid (Apm), 2,4-diaminopentane acid (Dbu), desmosine (Des), 2,2'-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), hydroxyzine (Hyl), allowedactions (aHyl), 3-, -methylisoleucine (Melle), N-methyllysine (MeLys), Norvaline (Nva), norleucine (Nle), ornithine (Orn), phenylglycine, cyanoalanine (CA)- carboxyglutamate, O-phosphoserine-nafcillin (NA), -nafcillin (bNA), S-galactosyl, cysteine, glycinamide, N-formylmethionine, tyrosine-O-sulfate, etc., These amino acid residues may be present in either D-or L-configuration. If these are not specifically mentioned amino acids have L-configuration.

The term "leaving group", as used in the present description, has its ordinary meaning and is well known to specialists. Basically, the leaving group may be any group or atom, which increases ELECTROPILOT atom with which it is associated for a replacement. Preferred leaving groups are triphala, mesilate, toilet, imidate, chloride, bromide and iodide. If the alkylating agent contains an amino acid residue (i.e., X, W, and Y taken together form -(CH2)n-AA), the leaving group associated with carboxypropyl is preferably pentafluorophenyl ester or paranitrophenol ether.

The term "carboxyamide group" used in the present description, means one of the ester derivatives carbonisation group, usually Aut other functional groups of this compound. Specifically selected carboxyamide group is not critical, because derivativesa carboxylic acid is stable to the conditions of subsequent reactions and can be removed at any suitable stage of this reaction, without exerting adverse effects on the rest of the molecule. T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, N. Y., 1991, the chief 5 (which includes a list of commonly used protective groups). Cm. also, E. Haslam, Protective Groups in Organic Chemistry, J. G. W. McOmie, Plenum Press, New York, N. Y. 1973.

The term "protected carboxypropyl" corresponds to the term "carboxyamide group".

The term "replacement group" used in the present description, refers to one of the ether or ester derivatives of the hydroxy-group, usually used to block or protect in the case when the reaction is carried out on other functional groups of this compound. Specifically selected carboxyamide group is not critical, because derivativesa the hydroxy-group is stable to the conditions of subsequent reactions and can be removed at any suitable stage of this reaction, without exerting adverse effects on the rest of chastyah protective groups). Preferred hydroxyamine groups are tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl), methoxytrityl or Elgiloy or arrowy ester.

The term "protected hydroxy-group" corresponds to the term "hidroxizina group".

The term "aminosidine group" used in the present description, refers to substituents of the amino group commonly used to block or protect the functional amino groups in the case when the reaction is carried out on other functional groups of this compound. Specifically selected aminosidine group is not critical, because derivativesa amino group is stable to the conditions of subsequent reactions and can be removed at any suitable stage of this reaction, without exerting adverse effects on the rest of the molecule. T. W. Green and P. Wuts, Protective Groups in Organic Synthesis, mainly 7 (which includes a list of commonly used protective groups). Cm. also J. W. Barton, Protective Groups in Organic Chemistry, the main 2. Preferred aminosidine groups are t-butoxycarbonyl, phthalimide, cyclic alkyl and benzyloxycarbonyl.

The term "protected amino" snaketongue in the present description, belongs to the subclass aminosidine groups, usually used to block or protect-NH-functional group, in the case when the reaction is carried out on other functional groups of this compound. Specifically selected type protective groups is not critical, because derivativesa amino group is stable to the conditions of subsequent reactions and can be removed at any suitable stage of this reaction, without exerting adverse effects on the rest of the molecule. T. W. Greene and P. Wuts, Proptective Groups in Organic Synthesis, mainly 7 (which includes a list of commonly used protective groups). Preferred-NH-protective group is a carbamate, amide, alkyl-, or arylsulfonate.

The term "protected-NH" means a group substituted by-NH-protecting group, as defined above.

The term "pharmaceutically effective amount", as used in the present description, means the amount of compound of the present invention, is able to inhibit RKS-activity in mammals. The specific dose of a compound, introduced in accordance with the present invention, can be determined in each case and depends on the input connection, the method of administration, the con is oral, rectal, percutaneous, subcutaneous, local, intravenous, intramuscular or intranasal. Basically, the usual daily dose may contain from about 0.01 mg/kg to about 20 mg/kg of active compound of the present invention. The preferred daily dose can be from about 0.05 to about 10 mg/kg, and most preferably from about 0.1 to about 5 mg/kg However, for external use, the typical dose is from about 1 to about 500 μg of the compound on cm2the affected tissue. Preferably, the number of locally applied compounds is from about 30 to about 300 g/cm2more preferably from about 50 to about 200 μg/cm2and most preferably, from about 60 to about 100 μg/cm2.

The term "treatment" used in the present description means to help the patient in order to eliminate the disease, condition or violation by introducing compounds of the present invention to prevent the onset of the symptoms or complications, relief of symptoms or complications, or eliminating the disease, condition or disorder.

The term "isozyme-selective" refers to the preferred inhibition of beta-1 or beta-2 isozyme Proteus is the RAM, as defined in the RCC-analysis, the dose of a compound of the present invention required for inhibition of beta-1 or beta-2 isozyme RKS at least 8 times and preferably 10 times the dose required for equal inhibition of the alpha isozyme of protein kinase C. These compounds also find differences in the ranges of inhibition with IC50, i.e., 50% inhibition. So, for example, isozyme-selective compounds inhibit beta-1 and beta-2 isozyme of protein kinase C at much lower concentrations with much less toxicity than their minimal inhibition of other isozyme RKS.

Due to its acidic groups, the compounds of formula I can exist in the form of their pharmaceutically acceptable basic additive salts. These salts can be obtained using inorganic bases, such as hydroxides, carbonates, bicarbonates of ammonium, alkali metals and alkaline earth metals, etc. and using basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxylamine, etc. are Examples of bases that can be used to obtain the above-mentioned salts are ammonium hydroxide, ka is elamin etc.

Thanks to its main groups, the compounds of formula I may also exist in the form of a pharmaceutically acceptable acid additive salts. Acids commonly used to obtain such salts are hydrochloric, Hydrobromic, itestosterone, sulfuric and phosphoric acid and organic acids such as para-toluensulfonate, methanesulfonate, oxalic acid, paraprofessional, carbonic, succinic, citric, benzoic, acetic and related organic and inorganic acids. These pharmaceutically acceptable salts may be sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, monolithicflat, debivort, metaphosphate, pyrophosphate, chloride, iodide, acetate, propionate, decanoate, kaprilat, format, isobutyrate, heptanoate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-Butin-1,4-diet, 3-hexyne-2,5-diet, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts.

In addition to the pharmaceutically p the internal connections for the purification of target compounds, for other salts, or for identification and characterization of compounds or intermediates.

Pharmaceutically acceptable salts of compounds of formula I may also exist in different solvate, for example, water, methanol, ethanol, dimethylformamide, ethyl acetate, etc. can also be obtained mixture such solvate. A source of formation of such a MES can serve as the solvent of crystallization, specially used for such purposes, or any other solvent. These solvate included in the scope of the present invention.

It should be noted that the compound of formula I may exist in different stereoisomeric forms, for example, W may contain a chiral carbon atom in a substituted alkalinous part. Basically, these connections get in the form of the racemates, which can be used as such, but, if necessary, can be obtained and the individual enantiomers by their separation or synthesis using traditional techniques. These racemates, individual enantiomers and mixtures thereof are part of the present invention.

The present invention also relates to pharmaceutically receiving stennie means, which have been chemically modified and may be biologically inactive in the field of their actions, but which may be degraded or modified under the action of one or more enzymes, or under the action of the other in vivo processes with the formation of the parent bioactive form. Specified prodrug usually has a different pharmacokinetic profile than its parent form that promotes its absorption by the epithelium of the mucosa, the best salt formation or solubility, and/or increase system stability (for example, increase the time half-life in blood plasma). These chemical modifications are usually the following forms:

1) ester or amide derivatives which can be converted by esterases or lipases;

2) peptides that can be recognized by specific or nonspecific proteases; or

3) derivatives that accumulate in areas of their action through membrane selection proletarienne form or modified proletarienne form;

or any combination of the above forms (1) - (3). Standard procedures for selection and obtain the appropriate proletarienne derivatives the derivatives described by Davis and others in U.S. patent N 5057614, which is introduced into the present description by reference. In General, the compounds of the present invention can be obtained in the following way:

Circuit 1

< / BR>
R1, m, "halogen" are the same as defined above. "Halogeno are preferably chloro-, bromo - or iodo-. The compound of formula III, preferably, is a 2,3-sodium dichloro-N-methylmaleimide.

The reaction between the compound III and indole (Compound IV) is known as the Grignard reaction. This reaction is carried out in an inert organic solvent such as toluene, at a temperature in the range from room temperature to the temperature of the distillation of the reaction mixture. It is important to note that the reaction illustrated in scheme 1, depends on the chosen solvent. When using the solvent system: toluene: THF: simple ester, compound V is obtained in more than 80% and with a purity of more than 95%. The product precipitated from the reaction mixture with ammonium chloride (H4Cl). The obtained intermediate compound V may be isolated by standard methods.

After that, the connection V (bis-3,4-(3'-indolyl)-1N-methylpyrrole-2,5-dione) can be, by alkaline hydrolysis, pre is Islam and described Breenner and others, Tetrahedron 44: 2887 - 2892 (1988). Then, preferably, the connection V is subjected to reaction with 5 H. KOH in ethanol at a temperature in the range of 25oC to the temperature of distillation.

< / BR>
The compounds of formula V are generally more stable than the compounds of formula VI. Therefore, it is preferable that the reaction of the compound V proceeded in accordance with the following scheme 2. As a result of this reaction is a compound of formula I. However, any specialist it is known that the compound of formula VI can also be subjected to reaction according to scheme 2.

Scheme 2

< / BR>
where X, Y and W are as defined above. L is a good leaving group such as chloro, bromo, iodo, mesyl, tosyl, etc. L can also be a hydroxy-group or another precursor that can be converted into a good leaving group by standard methods. For example, the hydroxy-group can be easily converted into a sulfonic ester group, such as mesyl, through reaction with hydroxy-methanesulfonamido education mutilates leaving groups.

The reaction, shown in scheme 2, can be carried out by any conventional methods, which usually uses the two reagents, though other ratios, for example, where the alkylating reagent is used in excess amounts. Preferably, if the reaction proceeds in a polar aprotic solvent in the presence of a salt of an alkali metal, or other alkylating conditions, well known to specialists. If the leaving group is bromo or chloro, to accelerate the reaction may be added catalytic amount of iodide salt such as potassium iodide. The reaction conditions are: hexamethyldisilazide potassium in dimethylformamide or tetrahydrofuran, sodium hydride in dimethylformamide.

Preferably, if the reaction is carried out in conditions of slow reverse addition of cesium carbonate in acetonitrile, dimethylformamide (DMF) or tetrahydrofuran (THF). In General, the reaction proceeds at a temperature in the range of from about room temperature to the temperature of the distillation of the reaction mixture.

It should be noted that the reaction described in scheme 2, can be carried out using compounds of the formula VIIa:

L - Y'

L - X' (VIIa)

where X' and Y' are protected carboxy group, a protected hydroxy group or a protected amine. After Alki who eat W. This method is the preferred method for obtaining compounds of formula I, where W represents-S-, -O - or-NR3. The reaction of interaction of X' and Y' with the formation of various ether, thioester or aminoether derivatives is known and described, for example, Ito and others, Chem. Pharm. Bull. 41(6): 1066 - 1073 (1993); Kato and others, J. Chem. Pharm. Bull. 34: 486 (1986); Goodrow, etc., Synthesis 1981: 457; Harpp and others, J. Am. Chem. Soc. 93: 2437 (1971); and Evans and others, J. Org. Chem. 50: 1830 (1985).

It should also be noted that the compounds of formula V can be converted into compounds of formula II through a two-step synthesis as shown in scheme 3.

Scheme 3

< / BR>
R1, X, W, Y, V and L are the same as defined above. L2is protected hikkoshi group or another group that can be converted into a good leaving group by standard methods. The interaction between compound V or VI and compound VII is the alkylation reaction described above. Monoalkylamines intermediate compound IX is subjected to unlock, and L2transformed into a leaving group. For example, if the hydroxy group protected by t-butyldimethylsilyl (TBDMS), TBDMS may be selectively removed using acidified Enid, and preferably, alkylated or bromide (CBr4in triphenylphosphine) or sulfonate (methylchloride and triethylamine). Then form a macrolide (connection microlithiasis lactone ring) through alkylation by slow reverse addition of base to the solution, such as hexamethyldisilazide potassium or sodium hydride, but preferably Cs2CO3in the polar aprotic solvent such as acetonitrile, DMF, THF, at a temperature in the range from room temperature to the temperature of distillation.

Schemes 2 and 3 illustrate the method of the present invention. Most surprising is the fact that the compounds of formula II can be obtained with a significantly higher output when the condition is slow to add back to Cs2CO3in a polar aprotic solvent. Under slow reverse addition is meant the Union of a mixture of compounds and alkylating agent (scheme 2) or compound (scheme 3) with base speeds of from about 0.1 ml/HR to about 2.0 mg/h Concentration of each reagent in the mixture ranged from about 1.5 M to about 0,001 M If the reaction used monoalkylamines compound (scheme 3), its concentration ranged from about 3 M to the eye At the same time, it should be noted that can be used over a high speed adding at lower concentrations of reagents. Similarly, at a lower rate of addition can be used a higher concentration of reagents. Preferably, if the connection type with a speed of about 0.14 ml/h, when the concentration of the compound and alkylating agent 0,37 M Preferably also, if Cs2CO3add in an excessive amount, and more preferably, if the number of Cs2CO3the amount of alkylating agent is 4 : 1. Preferred polar aprotic solvents are acetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), dioxane, methyl ether of diethylene glycol (diglyme), tetrahydrofuran (THF) or other polar aprotic solvents in which the reactants are soluble. The reaction was carried out at a temperature of from 0oC to the temperature of distillation. It should be noted that the ratio of compound and alkylating agent in the mixture is not a critical parameter. However, preferably, these reagents were mixed together in a ratio of 0.5:3. Most preferably, this ratio is the anhydride (V is O) using alkaline hydrolysis. Alkaline hydrolysis is the reaction of the compound with base such as sodium hydroxide or potassium, C1-C4-alcohol (preferably ethanol), or in a mixture of DMSO/water, dioxane/water or acetonitrile/water, at a temperature in the range from about 25oC and preferably to approximately the temperature of distillation. The concentration of the reactants is not critical.

Anhydride (V is O) is converted into maleimid formula I by ammonolysis. The ammonolysis is a reaction of the anhydride with excess hexamethyldisilazane or ammonium salts (acetate, bromide or ammonium chloride) and C1-C4-alcohol (preferably methanol) in a polar aprotic solvent such as DMF, at room temperature. In this reaction, it is preferable that the ratio of the number of hexamethyldisilizane or ammonium salt to the number of anhydride was more than 5 : 1.

Another method of preparing compounds of the formula I is illustrated in scheme 4. This method can be, in particular, used, if W is NH, and X or Y is replaced by alkylene.

Scheme 4

< / BR>
Ac is acetyl, and R1, R6, Z, n and m are the same as they were Oprescu. Similarly, the alkylation reaction of compound XI with halogenation (compound XII) is carried out in the conditions discussed above. The reaction conversion of the anhydride in maleimide (compound XV) is carried out as described previously. For example, the anhydride can be converted into bis-indomalaysia through reaction of the anhydride with hexamethyldisilazane and methanol in an inert organic solvent such as DMF, at room temperature.

Protected hydroxy group, represented OAc, can be easily hydrolyzed with the formation of alcohol (e.g., K2CO3in aqueous methanol and THF). The resulting alcohol is converted into a leaving group known methods, for example by reaction of the alcohol with methylchloride in triethylamine at 0oC. Leaving group substituted azide, such as NaN3in DMF at 50oC. the Obtained azide restore using Lindlar catalyst in the presence of H2, resulting in the received Amin. The macrocycle was completed by intramolecular Schiff's base. The Schiff base was restored under standard conditions, for example, using NaCNBH3or other remedial agent, resulting in the obtained compounds of formula I.

To lower the in particular, used if X, W and Y taken together form -(CH2)n-AA-.

Scheme 5

< / BR>
R1, Ac, V, m, and n are as defined above. R1represents an amino-protective group, R is a variable side chain of amino acids. The acylation reaction of compound XVI with an activated amino acid such as para-nitrophenyloctyl ester; shown) was performed using 18-crown-6 - KF in THF, DMF or dimethoxyethane at room temperature, as described Klaunser etc., J. Chem. Soc. PERKIN I 607 - 631 (1977); and Nakagawa, etc., J. Am. Chem. Soc. 105: 3709 - 3710 (1983). The closure of the macrocycle with the formation of compound XIX was carried out by intramolecular Schiff's base as described in scheme 4.

In scheme 6, below, shows another method of preparing compounds of the formula I, which is preferably used in the case when W is-CONH - or-NHCO-.

Scheme 6

< / BR>
R1Ac , V; P1, m and n are such as defined previously. The reaction between the compound XX and connection XXI proceeds in the presence of ethyldiethanolamine in methylene chloride at 0oC. Maciel is formed as a result of intramolecular the x above. Protected maleimide unlock, as discussed earlier, resulting in the received connection XXIII.

An alternative method of obtaining the intermediate compounds XI and XX is illustrated in figure 7.

Scheme 7.

< / BR>
Ac is the same as it was defined above; P represents indolamine group, such as t-butoxycarbonyl, or some other indolamine group, known to specialists. T. W. Greene and P. Wuts. Protecting Groups in Organic Synthesis, mainly 7, page 385. The reaction illustrated in scheme 7, known as the Perkin condensation. This reaction is described by Hill and others , J. Med. Chem. 36: 21 - 29 (1993). To an anhydrous solution of compound XXIV in an inert organic solvent such as a halogenated hydrocarbon, e.g. methylene chloride, was added oxalicacid at a temperature in the range from -78oC to temperature distillation (preferably, at 0oC). Approximately 1 to 3 hours, volatiles were removed. The obtained solid material was dissolved in anhydrous halogenated aliphatic hydrocarbon solvent such as methylene chloride, was added to the compound XXV in the presence of an acid acceptor, preferably a tertiary amine such as triethylamine, at room temperature is resale in maleimid or protected maleimide, as explained above.

Protected hydroxy group (preferably OAc, as shown) of compound XI can be turned into alcohol by known techniques, for example, compound XI is subjected to reaction with NH4OH or aqueous ammonia in DMF at elevated temperatures, for example, 140oC. the resulting alcohol is converted into amine (compound XX) by known methods. For example, alcohol in dichloroethane and collidine in nitrogen atmosphere is subjected to reaction with anhydride triperoxonane acid in dichloromethane. After about two hours, the mixture is treated with an aqueous ammonia. The obtained amine (compound XX) is then subjected to reaction according to scheme 6.

Intermediate compounds of the present invention can be obtained in accordance with the following scheme 8. This scheme is preferably used for producing compounds where W is-O-, Y is substituted by alkylene, and X - alkylene.

Scheme 8.

< / BR>
R8represents the N3, NH-protective group, aminosidine group or hydroxyamino group; m is independently 0, 1, 2 or 3; and L is a good leaving group such as chloro, bromo, iodide, mesyl, tosyl, etc., Preferably L is mesilim. R8and scheme 8 illustrates the stereoselective synthesis of the linker part (-X-W-Y-) of the macrocycle. S-enantiomer shown above; however, it should be noted that similarly can be obtained complementary enantiomer or mixture of enantiomers. In addition, it should be noted that the analogous reaction with methyl-substituted epoxide or a Grignard reagent can be used for various linkers (-X-W-Y -) containing methyl-substituted alkylene.

In the above reaction of the epoxide (compound XXVI) is subjected to reaction ring opening using a Grignard reagent. This reaction is carried out in the presence of an agent forming a complex with copper; however, there may be used and other conditions of alkylation. The reaction is carried out in an inert solvent at a temperature in the range from -30oC to the temperature of the distillation of the reaction mixture. The result of this reaction receive the connection XXVII, which can be subjected to further reaction without additional purification. Compound XXVII is subjected to allilirovanii in conditions that are typically used for simple esters. The reaction illustrated in scheme 8, known as the Williamson synthesis. After the formation of the alkoxide of sodium using NaH, NaOH or KOH, followed by allilirovanii allylbromide get deenie XXVIII can be converted into ozonid by treatment with ozone at low temperature. Then ozonid restore using NaBH4, LiAlH4, BH3or by using catalytic hydrogenation with excessive amounts of H2in the result, get the alcohol (compound XXIX). Hydroxy-part compound XXIX is transformed into a leaving group L standard methods, for example by reaction of the alcohol with methylchloride in triethylamine.

In all the diagrams above, it is preferable that the reaction was carried out using appropriate protective groups. In particular, it is preferable that in the reaction of alkylation and/or acylation, R1was protected, and then unlocked. Similarly, if R6is-NR4R5the reaction is preferably conducted using aminosidine group. However, it should be noted that many of these reactions can be carried out without the use of protective groups, and permitting the reaction conditions, using blocking reagents or etc., If W contains hydroxy-part, preferably, in the process of alkylation or acylation of indole, this hydroxy-part was protected as tert-butylanisole (TBDPS) or triphenylmethyl (trityl). The compounds obtained XXIV, XXV, XXVI, and any other reagents required for the above reactions are either commercially available or they can be obtained by standard methods. For example, compound III can be obtained by the method described Edge, etc., Chem. and. Ind. 130 (1991); compound IV receive, preferably in situ through the reaction of appropriately substituted indole with halide alkylamine, such as bromide of etermine, using standard equipment.

For a more detailed description of the present invention are given below to Obtain and Examples. However, these examples should not be construed as a limitation of the scope of the present invention. For clarity, below is the structure characteristic of the compounds in accordance with the nomenclature adopted in the present description:

< / BR>
In the following Examples and the Receipts were the following notation is used:

the melting point is so square,

nuclear magnetic resonance - NMR,

mass spectroscopy - MS,

liquid chromatography high-pressure silica gel - ihvd,

N,N-dimethylformamide - DMF),

palladium charcoal - Pdc,

tetrahydrofuran - THF,

the ethyl acetate - EtOAc.

The terms "NMR" and "MS" Uchaly)-furan-1,4-dione

To a solution containing 2,3-dichloromaleic anhydride (5,56 g, 33.3 mm) and methylaminopropane (3.50 g, 55,0 mm) in 40 ml of acetic acid was added ethoxide sodium (of 3.56 g, 50 mm). Then the mixture was stirred in vitro in the presence of CaCl2as drying substances at 25oC and for 16 h, then was heated under reflux for 4 hours, the Cooled mixture was poured into water (350 ml) and was extracted with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with 100 ml portions of saturated aqueous sodium hydrogen carbonate solution, water and brine, and then dried with magnesium sulfate. After that, the solvent is evaporated under reduced pressure. The resulting residue was recrystallized from ethanol and obtained 3,82 g (64%) of 2,3-sodium dichloro-N-methylmaleimide in the form of white crystals. After concentrating the mother liquor, the residue was subjected to radial preparative thin-layer chromatography (Chromatotron, Harrison Research) and got another 0,81 g of 2,3-sodium dichloro-N-methylmaleimide (yield 77%).

A solution of indole (10.5 g, 90 mm) in 175 ml of dry toluene drop within hours and in an atmosphere of nitrogen was treated with a solution of ethylmagnesium (1.0 M in THF, 90 ml, 90 mm). When you are finished adding, light green ri a solution of 2,3-sodium dichloro-N-methylmaleimide (3.8 g, 21 mm) in 50 ml of toluene. The resulting reaction mixture was heated 3 h at 100oC, cooled to 25oC and extinguished 100 ml of 20% aqueous citric acid. Then the layers were separated. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were dried with anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue was dissolved in 30 ml of acetone and left for 40 h at 5oC. the Solids were collected and washed with ice/cold ether, resulting received a 5.25 g (73%) of 3,4-bis-(3'-indolyl)-1-methyl-pyrrole-2,5-dione as a red solid product with so pl. 276 - 278oC.

To a solution of 3,4-bis-(3'-indolyl)-1-methyl-pyrrole-2,5-dione in 150 ml of ethanol was added 5 N. KOH (50 ml). The resulting mixture was stirred for 4 h at 25oC and was diluted with 150 ml of water. A large part of the ethanol is evaporated under reduced pressure. After that, the mixture was acidified to pH 1. The precipitated product was filtered and washed with water. The resulting crude product was dissolved in a minimum amount of methylene chloride and slowly filtered through a 2-inch column of silica gel, elwira 50% ethyl acetate in hexane. The result of this procedure has been the target connection (3,10 g, 77%) as a red and, containing 2,6-pyridinedimethanol (375 mg, 5,28 mm) and triphenylphosphine (3,20 g, 12.2 mm) in 35 ml of dry methylene chloride, at 0oC and in an atmosphere of nitrogen portions over 10 min was added N-bromosuccinimide (2.16 g, 12.2 mm). Then the mixture was stirred for one hour at 0oC, and then left for 16 h at 5oC. the Greater part of the solvent was removed under reduced pressure. To the resulting residue were added 100 ml of ether. Then the ether layer decantation and concentrated to a volume of 20 ml, then diluted with hexane/ethyl acetate (3 : 1) (50 ml). The resulting hazy solution was placed overnight in a refrigerator. After evaporation of the solvents in vacuo, the crude product is recrystallized from hexane, resulting in received 766 mg (55%) bis-2,6-dibromopyridine in the form of a white crystalline solid. MS.

Getting 3

()-3-(Benzyloxy)methylene-1,6-dibromohexane

A solution of t-butoxide potassium (1.0 M in THF, 8,27 ml of 8.27 mm) at 25oC in nitrogen atmosphere for one drop was added to a solution of ()-3-cyclohexane-1-methanol (853 mg, 7,60 mm) in THF (35 ml). The resulting mixture was stirred at 25oC for 30 minutes then drop added benzylbromide (1.0 ml, of 8.37 mm). The reaction mixture was left for l and concentrated. The resulting residue was dissolved in ether (50 ml), washed with water (20 ml) and brine (20 ml) and then dried with magnesium sulfate. The solvent is evaporated under reduced pressure. The residue was subjected to radial chromatography on silica gel, elwira 5% EtOAc in hexane, resulting received ()-3-(benzyloxy)methyl-1-cyclohexen (1.42 g, 92%) as a colorless oily substance. NMR analysis.

Ozone was barbotirovany through a solution of ()-3-benzoyloxymethyl-1-cyclohexene (1.35 g, 6,70 mm) in methylene chloride (65 ml) at -78oC as long as he observed the blue color of unreacted ozone. The reaction mixture was left to warm to room temperature, and at this time through the mixture barbotirovany dry nitrogen. Then in a few minutes with a syringe was added borane-dimethylsulfide complex (10,0 M in THF, 2.7 ml, 27.8 mm) and the reaction mixture was left at room temperature for 24 hours thereafter, the reaction mixture was treated with 5% aqueous solution of hydrochloric acid (1 ml) and vigorously stirred for one hour. Then was added solid sodium bicarbonate until then, until the mixture has not been fully tested with litmus paper. This mixture was dried anhydrous self the 1,6-hexandiol (1,49 g, approx. 100%) as an oily substance. This material, which was found mainly one spot, as evidenced by TLC analysis (Rf= 0,25, 25% EtOAc in hexane) was used in the subsequent stage without further purification.

To a stirred mixture of ()-3-(benzyloxy)methyl-1,6-hexandiol (1.45 g, 6,10 mm) and triphenylphosphine (3,67 g, 14,0 mm) in dry methylene chloride (50 ml), at 0oC and under nitrogen atmosphere was added N-bromosuccinimide (2,49 g, 14,0 mm). After 12 h the reaction mixture was concentrated and to the residue was added ether (100 ml). This mixture was stirred for 15 min and the ether layer decantation of the solid residues. This procedure was repeated with 50 ml of ether. The combined ether extracts were concentrated to a volume of 50 ml, and then diluted with 100 ml of hexane. After settling in 5oC overnight, the solution decantation of the precipitated solids and concentrated, resulting in a received dibromide ()-3-(benzyloxy)methyl-1,6-dibromohexane (1,09 g, 49%) as a pale yellow oily substance. This substance was largely homogeneous, as evidenced by TLC, Rf= 0,75 (10% EtOAc in hexane). NMR analysis.

Getting 4

1-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphenylsilyl) b 42 M 2 EQ.), and then tert-butyldimethylsilyl (32 g, 0.22 M). After 90 min the reaction was completed, as it was shown by TLC (10% EtOAc in hexane). Methylenchloride the solution was transferred into a separating funnel, diluted with methylene chloride (110 ml), washed with water (200 ml) and brine (200 ml). The organic layer was collected, dried with magnesium sulfate, filtered, and the solvent is evaporated, resulting in the obtained oily substance (1-(O-TBDMS)-3-butene), which was used for subsequent reactions. MS.

The above oily substance was dissolved in a mixture of acetone (400 ml) and water (50 ml). After this was added N-methylmorpholine-N-oxide (to 85.2 g, 0,63 M, 3 equivalent). The resulting suspension was cooled to 0oC and after 10 min was added 0.3 g of a catalytic amount OsO4. This suspension was left to stir overnight, slowly warming to room temperature. TLC (25% EtOAc/hexane) indicated complete reaction. Then the reaction mixture was extinguished sodium bisulfite, diluted with ether (1 l) and then washed with water (400 ml) and brine (400 ml). The organic layer was collected and the aqueous layer was extracted with ether (2 x 500 ml). The combined organic layers were dried, filtered and contenti reaction.

The above oily substance was dissolved in anhydrous methylene chloride (250 ml). To the solution was added imidazole (30 g, 0,44 M, 2.5 equiv.) stirring the while. The resulting solution was cooled to 0oC. After 15 minutes of cooling, drop by drop within 45 min was added methylenechloride (50 ml) solution of tert-butyldiphenylsilyl (50 g, 0.18 M, 1 EQ.). After complete addition, stirring was continued for 2.5 h at 0oC. Then the solution was transferred into a separating funnel, diluted with methylene chloride (250 ml), washed with water, brine and dried with magnesium sulfate, and then filtered. The solvent was removed under reduced pressure, resulting in the obtained crude product as an oily substance. The crude product was purified by elution (10% EtOAc/hexane) through a narrow column with silica gel. Eluting solvent was removed in vacuum and the received target intermediate compound in the form of a viscous oily substance (78,1 g, total yield 93%). MS.

Getting 5

1-(tert-Butyldimethylsilyloxy)-3-(3-iodopropionic)-4- (tert-butyldiphenylsilyl)-butane

To methylenechloride (20 ml)/cyclohexane (100 ml) solution of the alcohol 4, in nitrogen atmosphere (balanoidea material, 0,92 ml). After 20 h, the solution was filtered and the filtrate was washed with a saturated aqueous solution of sodium bicarbonate, water and then brine. The organic layer was collected and dried with magnesium sulfate. The solvent was removed to obtain an oily substance, which was purified using flash chromatography on silica gel (eluent: hexane) and increased the polarity of the mobile phase, using more than a few liters of a 5% ethyl acetate in hexane. The result of this procedure received 19,27 g allyl ether, 1-(tert-butyldimethylsilyloxy)-3-(propionoxy)- 4-(tert-butyldiphenylsilyl)-butane in the form of a light brown oily substance (yield 97%). MS.

To a THF-solution (60 ml) of the above allyl ether (14,16 g, 28,38 mm, 1 equiv.) drop in nitrogen atmosphere was added 9-BBN (9-borabicyclo 3.3.1 Noonan, 0.5 M solution in THF, 60 ml, 30 mm, 1.1 equiv.). After 3 h, TLC (10% EtOAc in hexane), the reaction mixture indicated the complete depletion of the source material. To the solution was added a 3 M aqueous NaOH (10,41 ml, 31,22 mm, 1.1 equiv.) and then slowly (over 1.5 hours) one drop was added 30% hydrogen peroxide (10.3 ml, 90,82 mm, 3.2 EQ.). The reaction temperature during the addition was maintained below the 50oC (using an ice bath).

the ski layer was removed, the aqueous layer was extracted with ether, the combined organic layers were dried and filtered, and the filtrate was concentrated to obtain an oily substance. The crude oily substance was purified by pleskrestore on silica gel, elwira 10% EtOAc/hexane and increasing polarity using about 1.5 liters of 20% EtOAc/hexane, received at 9.53 g of light yellow oily substance (yield 65%). MS.

To anhydrous (0oC) ether (150 ml) solution of the above alcohol was added triethylamine (2,93 g, 28,91 mm, 1.5 equiv.) and then one drop was added methylchloride (of 3.31 g, 28,91 mm, 1.5 equiv.) vigorously stirring the while. After keeping the mixture at 0oC for 3 h, TLC (10% EtOAc/hexane) indicated the possibility of running out of source material. The reaction mixture was diluted with ether, washed with water, brine, dried with magnesium sulfate and the solvent was removed. The obtained oily substance was passed through a layer of silicon dioxide, elwira 25% EtOAc-hexane, after which the eluent was concentrated. To acetone (200 ml) solution of the obtained oily substance was added sodium bicarbonate (0.17 g, 1,93 mm, 0.1 EQ.) and NaI (28,88 g, 192,7 mm, 10 EQ.). After 30 minutes stirring at room temperature texana) indicated complete expenditure, or nelfinavir. The reaction mixture was diluted with ether (500 ml) and then washed with cold saturated aqueous Na2SO3, water, brine and dried with magnesium sulfate. The solvent was removed. The obtained oily substance was passed through a layer of silica (eluent: 5% EtOAc in hexane) and got cleared the target compound as a colorless oily substance (yield 85%, 10.3 g).

Getting 6

3-Bromopropylate

3-Bromopropane-1-ol (0.54 M, 75 g) in methylene chloride (500 ml) at 0oC in nitrogen atmosphere was treated with acetylchloride (0.5 M, 40,2 ml). Then to this solution slowly with a syringe, portions (5 ml) was added triethylamine (0.54 M, 75 ml). The reaction mixture was left for 12 h for the gradual warming to room temperature. The precipitate was filtered and the filter was rinsed with methylene chloride. The filtrate was washed twice with water, and then twice washed with saline and dried with sodium sulfate, and then filtered. The filtrate was concentrated and obtained target compound (acetate) in the form of oily substance (91 g, yield 93%). MS.

Getting 7

N-(3-Acetoxyphenyl)-indole

To mixed (0oC) dimethylformamide (400 ml) suspension of NaH (60% in oncol, added dimethylformamide (150 ml) solution of indole (55 g, 0,47 M). After 30 - 60 min dimethylformamide (50 ml) solution of alkylhalides was added to a solution of indole, and then added 3-bromopropionate (170 g, 0,94 M). The reaction mixture was heated for 6 h at 50oC, and then left to stir at room temperature for 5 to 15 hours

The solvent was removed in vacuum. The resulting residue was distributed between methylene chloride and water. The organic layer was washed 3 times with 1 N. hydrochloric acid, water and brine, and then dried with sodium sulfate and filtered. The filtrate was concentrated and the received target alcheringa (102 g) as an oily substance, which was slowly led. MS.

Getting 8

N-(tert-Butoxycarbonyl)-indol-3-yl-acetic acid

To stirred acetone (800 ml) solution of indole-3-acetic acid (26,25 g, 0.15 M) was added cesium carbonate (48,9 g, 0.15 M), and then allylbromide (15 ml, 0.17 M, 1.16 EQ.). After 12 h the solvent was removed. The residue was distributed between water and CHCl3. The organic layer was washed with saline, dried with sodium sulfate and filtered. The filtrate was concentrated and received 27.9 g allyl complex ester as an oily substance (indicaron (29,1 g, of 0.133 M, 1.2 equiv.) and 4-dimethylaminopyridine (1,36 g to 0.011 M, 0.1 EQ.). After 15 min the reaction mixture was diluted with ethyl acetate (1.2 l), and then washed with 0.1 N. hydrochloric acid, water (2 times) and brine (2 times). The organic layer was dried with sodium sulfate, filtered and concentrated to obtain the BOC-protected ether complex (32,9 g, 94%) as an oily substance, which was slowly led.

To methylenchloride/an ethyl acetate (10 : 3) (325 ml) solution of the BOC-protected ether complex was added 2-ethylhexanoate, sodium (17.3 g, 0.104 g M), triphenylphosphine (4,93 g, 18,8 mm to 0.18 EQ.) and Pd (PPh3)4(4,56 g, 3,95 M, and 0.04 EQ.). After one hour the solvent was removed. The residue was distributed between ethyl acetate and water. Basically the aqueous layer was subjected to reverse extraction with ethyl acetate and then with ether, then carefully acidified 0,10 N. hydrochloric acid. The acidified aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, dried with sodium sulfate and filtered. The filtrate was concentrated and the obtained BOC-protected acid (21.8 g, yield 77%) as an oily substance, which was slowly led. The output of this target connection of the three phases accounted for over 53%. MS is Teal)-pyrrole-2,5-dione

Dimethylformamide (50 ml) solution of bis-(3,3'-indolyl)]-1-(methyl)-pyrrole-2,5-dione (3,41 g, 10.0 mm) containing 3-tert-butyldiphenylchlorosilane-1,6-dibromohexane (5,64 g, 11 mm, obtained by the method similar to that described in Getting 2 for benzilovogo derived), via syringe over 15 min and at 60oC was added to dimethylformamide (350 ml) suspension Cs2CO3(11.2 g, 34,3 mm). After 4 h after complete addition, the reaction mixture was cooled to room temperature, poured into water (1.5 l) and extracted with methylene chloride (3 x 300 ml). The organic phase is washed with water, dried, filtered and concentrated. The concentrate was purified by means of flash chromatography elwira 10 to 25% ethyl acetate/hexane, and received 2,95 g macrocyclic 3,4-[(N,N'-1,1'-(3"-3-tert - butyldiphenylchlorosilane)hexane)-bis-(3,3'-indolyl)] -1-(methyl)-pyrrole - 2,5-dione (yield 43%) as a red oily substance. MS.

Receive 10

(S)-Methyl 4-tert-butyldiphenylsilyl-3-(allyloxy)-butyrate

To cyclohexane (400 ml) solution of (S)-methyl 4-tert-butyldiphenylsilyl-3-(hydroxy)butyrate (20,0 g, 53,7 mm) was added allyltrichlorosilane (21,74 g, 107,4 mm), and then trifluromethanesulfonate acid (1 m nitrogen. After 70 hours, the solids were filtered off, the filter cake was washed with cyclohexane, and the volatiles removed in vacuum. The obtained oily substance was filtered through a layer of silica, washed with hexane and the product was suirable 10% ethyl acetate/hexane. NMR analysis indicated the presence of residual imidate (approx. 10%); however, the material was used without additional purification. The result of this procedure received 24,76 g of the material (yield 100%). MS.

Receipt 11

(S)-4-tert-Butyldiphenylsilyl-3-(2-iodoethane)-1-iodobutane

To a solution of (S)-methyl 4-tert-butyldiphenylsilyl-3-(allyloxy)-butyrate (23,8 g, 57 mm) dissolved in anhydrous THF (1.0 l), drop by drop, at -75oC, in an atmosphere of nitrogen for 40 min was added DIBAL-H (231 ml, 1.0 M in toluene, 231 mm). After stirred for 1.5 hours, the mixture was left to warm to -10oC and extinguished 5% water in methanol and a large number of celite. The reaction mixture was filtered through a layer of celite, and the filtrate was concentrated and distributed between ether and 20% citric acid. The ether layer was dried and concentrated in vacuum. The residual oily substance was passed through a layer of silicon dioxide, elwira chloroform is annaloveme (500 ml) solution of (S)-4-tert-butyldiphenylsilyl-3-allyloxymethyl-1-it (20.6 g, 53,6 mm) at -78oC and approximately 12 minutes of added ozone. After the appearance of the faint blue color of the reaction mixture, to the contents of the reaction vessel was added NaBH4(12.2 g, 321 mm, 6 EQ. ). The resulting reaction mixture was left to warm to room temperature. Volatiles were removed in vacuum. The resulting residue was passed through a layer of silica gel, elwira with ethyl acetate, which was obtained 16.4 g (79%) (S) 4-tert-butyldiphenylsilyl-3-(2-hydroxy)ethoxy)-butane-1-ol as a colorless oily substance.

To the ether (600 ml) solution (S) 4-tert-butyldiphenylsilyl-3-(2-hydroxy-ethoxy)-butane-1-ol (15.7 g, 40,4 mm) at 0oC and under nitrogen atmosphere was added triethylamine (16,8 ml, 121 mm), and then methylchloride (9,38 ml, 121 mm). After 3 hours the solution was filtered, the filtrate washed with water (2 times), brine (2 times), dried with sodium sulfate and concentrated in vacuum. The result of this procedure was given to 21.9 g (> 99%) of bismesylate in the form of a yellow oily substance, which was used immediately in subsequent reactions. This bismesylate was dissolved in acetone (1.4 l), which person to distil from potassium carbonate. To the resulting solution was added NaI (90,4 g, 603 mm) and 0.05 EQ. NaH what was tribali in vacuum. The resulting residue was distributed between ether and 10% Na2CO3ethereal layer was washed with saline, dried with sodium sulfate and concentrated to obtain 17.9 g (73.2 per cent) (S)-4-tert-butyldiphenylsilyl-3-(2-iodoethane)-1-iodobutane in the form of a colorless oily substance. The total yield was 54%, MS: MW = 608,39; Found: 559 (M-tert-butyl; FD, CHCl3).

< / BR>
Getting 12

(S)-3,4-[(N, N'-1,1')-((2"-Ethoxy)-3"'-(O)-4"- (methanesulfonate)-butane)-(bis)-(3-indolyl)]-1H-pyrrole-2,5-dione

3,4-(bis)-(3-Indolyl)-1H-pyrrole-2,5-dione (10,04 g, 29,4 mm) and (S)-4-(tert-butyldiphenylsilyl)-3-(2-iodoethane)-1-(iodo)butane (17.9 g, 29,4 mm) were combined and dissolved in anhydrous DMF (80 ml). Then the solution with a syringe, for 72 hours at 50oC and under nitrogen atmosphere was added to a suspension of cesium carbonate (38,3 g, 118 mm) in anhydrous dimethylformamide (1.7 l). Then DMF was removed in vacuum. The residue was distributed between CHCl31 N. hydrochloric acid. The acid layer was subjected to back extraction with chloroform, and ethyl acetate. The combined organic layers washed with 1 N. hydrochloric acid, 2 times washed with water, 2 times with saline, and then dried with sodium sulfate and concentrated to obtain a solid Magenta. This neocs suspended in ethanol (700 ml) and was treated with 5 N. a solution of KOH (800 ml). The reaction temperature was raised to 80oC. After 72 h, the ethanol was removed in vacuo; the aqueous suspension was cooled to 0oC and acidified 5 N. hydrochloric acid. The purple precipitate was collected and passed through a layer of silicon dioxide, elwira with ethyl acetate. Eluent was concentrated and obtained 8.7 g of partially similarbank of maleimide in the form of a purple solid dye that was used in the subsequent stage without further purification.

To dimethylformamide (1 l) solution of the above anhydride (8.7 g, 19,7 mm) at room temperature and under nitrogen atmosphere was added 1,1,1,3,3,3-hexamethyldisilazane (41,6 ml, 197 mm) and methanol (4 ml, 98,5 mm). After 40 hours the reaction mixture was concentrated in vacuo, and then was added a solution of MeCN/1 N. hydrochloric acid (2 : 1, V/V) (100 ml). The resulting residue was stirred for one hour. The organic solvent was removed, and the aqueous suspension was extracted with ethyl acetate. After removal of solvents was obtained 8,9 g maleimide, which was used without further purification.

To methylenchloride (800 ml) suspension of the above maleimide (8,9 g, 20 mm), in nitrogen atmosphere and at room temperature was added pyridine (4,85 ml, 60 mm) and excess cloti, salt solution and the organic layer was concentrated. The residue was passed through a layer of silicon dioxide, elwira gradient 0 to 10% MeCN in CH2Cl2. Allentow fraction containing the desired mesilate, concentrated and obtained 2.8 g of target compound in the form of a solid Magenta dye. Full output in relation to the diiodide was 18%. MS: MW = 520; found: 520 (FD, CHCl3).

13

3-(tert-Butyldiphenylchlorosilane)-1-cyclohexen

To a mixture of 3-cyclohexen-1-methanol (Aldrich, 13,0 ml of 0.11 M), N,N-diisopropylethylamine (43 ml, 0,244 M) and 4-dimethylaminopyridine (2.70 g, of 0.022 M) in 375 ml of anhydrous methylene chloride, under nitrogen atmosphere and at 25oC was added tert-butyldiphenylchlorosilane (32 ml, 0,123 M). After that, the mixture was stirred at 25oC for 48 hours the reaction mixture is washed with 150 ml portions of 1 N. hydrochloric acid and then with water and brine, then was dried with anhydrous magnesium sulfate. The solvent is evaporated. The residue was loaded onto a column (4" by 4") with silicon dioxide and slowly took suirable hexane. Thus was obtained a 33.6 g (86%) of 3-(tert-butyldiphenylchlorosilane)-1-cyclohexene in the form of a colorless oily substance, which was homogeneous on what the witness
Calculated: C 77,6; H 8,67.

Found: C 77,38; H 8,72.

Getting 14

3-(tert-Butyldiphenylchlorosilane)-1,6-hexanediol

Ozone was barbotirovany through the thoroughly mixed solution of 3-(tert-butyldiphenylchlorosilane)-1-cyclohexene (18.0 g, 51,3 mm) in methylene chloride (550 ml) at -78oC as long as he observed the blue tint unreacted ozone. The resulting reaction mixture was left to warm to 25oC. and Then for 30 minutes the solution was barbotirovany dry nitrogen. Then to the solution drop by drop within 10 minutes was added borane-dimethylsulfide complex (10,0 M, 23 ml of 0.23 M). The mixture is slowly stirred in nitrogen atmosphere at 25oC for 24 h After addition of 5% hydrochloric acid (15 ml), the reaction mixture was stirred for one hour. To the mixture was added solid sodium bicarbonate until then, until this mixture did not become the mainstream, as evidenced by the indicator paper to determine the pH (wet surface). After filtration, the filtrate was washed with 200 ml portions of 5% aqueous sodium bicarbonate, then water, then dried with anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the crude product was purified Pamali 17.8 g (90%) of 3-tert-(butyldiphenylsilyl)methylene)-1.6-hexanediol in the form of colorless viscous oily substance, which was homogeneous, as it was shown by TLC analysis (Rf= 0,5, ether).

Analytical analysis for C23H34O3Si (0,2 H2O):

Calculated: C 70,80; H 8,88.

Found: C 70,72; H 8,86.

Receive 15

3-tert-butyldiphenylchlorosilane-1,6-dibromohexane

At 0oC and under nitrogen atmosphere to a stirred solution containing 3-(tert-butyldiphenylchlorosilane)-1,6-hexanediol (17.5 g, 45.2 mm) and triphenylphosphine (28.6 g, 109 mm) in anhydrous methylene chloride (550 ml) in portions for 5 min was added N-bromosuccinimide (19.3 g, 109 mm). The resulting reaction mixture was stirred 5 h at 0oC and then placed in a refrigerator (at 5oC) for 16 hours After removal of the greater part of the solvent, to the residue was slowly added to dry ether (300 ml). The ether layer decantation of the precipitated solids. The solids were washed in 200 ml of freshly prepared ether. The combined ether layers were concentrated (100 ml), triturated with 300 ml of hexane, and then decantation of the precipitated solids. After that, the solids washed with 25% ether in hexane, and the combined organic layers were dried with magnesium sulfate (anhydrous) and concentrated. The crude product was placed initiliazation-1.6-dibromohexane (20,1 g, 86%) as a colorless oily substance was homogeneous, as evidenced by TLC (Rf= 0,75, 10% EtOAc in hexane).

1H-NMR (300 MHz, CDCl3): of 1.06 (s, 9H); 1,35 is 2.10 (m, 7H); 3,55 (m, 4H); 3,56 (prbl. d, 2H, J = 4 Hz), 7,40 and to 7.64 (m, 10H).

13C-NMR (75 MHz, CDCl3): 19,2, 26,9, 29,3, 30,0, 31,9, 33,8, 34,7, 38,5, 65,0, 127,7, 129,7, 133,4, 135,5.

Getting 16

(S)-(-)-3-Cyclohexen-1-methanol

To a chilled solution of ester (Ireland and others, J. Org. Chem. 1992, 57(19), 5071 - 5073 and their references), namely (S)-(-)-3-cyclohexen-1-methoxy-(S)-N-methyl-2-hydroxysuccinimide (8,20 g, 34,5 mm) in THF (90 ml), one drop for 15 min was added a solution of LiAlH4(1.0 M in THF, to 75.8 ml, to 75.8 mm). The resulting reaction mixture was left to warm to room temperature and then was stirred for 2 h at 25oC, cooled and extinguished with water and 1 N. NaOH solution. After that, the mixture was filtered through celite. The solids were washed with tetrahydrofuran (100 ml). After evaporation of the filtrate under reduced pressure, the residue was dissolved in 150 ml of ether, and then washed with water (2 x 50 ml), brine (50 ml) and was dried with anhydrous magnesium sulfate. After evaporation of solvent received 3,24 g (83%) of (S)-(-)-3-cyclohexen-1-methanol in the form of a transparent makooooo identity with racemic material (Aldrich).

1H-NMR (300 MHz, CDCl3): 1,21 - of 1.42 (m, 2H); 1,68 - of 1.88 (m, 3H); 2,04 - of 2.21 (m, 3H); 3,54 (Shir.s, 2H); 5,69 (s, 2H).

Getting 17

(S)-(-)-3-Tetramethylpiperidinyloxy-1-cyclohexen

(S)-(-)-3-Cyclohexen-1-methanol (3,17 g, 28.3 mm) was treated with tert-butyldiphenylchlorosilane (8,15 ml, 31,1 mm), N,N-diisopropylethylamine (10.9 ml, 62,3 mm) and dimethylaminopyridine (1,03 g, 8.5 mm) in methylene chloride (100 ml), resulting after processing and chromatography got 8,73 g (88%) salelologa of ester, (S)-(-)-3-tributyltinchloride-1-cyclohexene as a transparent oily substance. TLC properties and1H-NMR spectrum of this material showed complete identity with racemic sillavan ether, 3-tert-butyldiphenylchlorosilane)-1-cyclohexanol.

1H-NMR (300 MHz, CDCl3): of 1.05 (s, 9H); of 1.29 (m, 1H); 1,71 - to 2.18 (m, 4H), of 3.54 (d, 2H, J = 6 Hz), 5,66 (Shir.s, 2H), 7,38 and 7,66 (m, 10H).

Getting 18

(S)-(-)-3-tert-Butyldiphenylchlorosilane)-1,6-hexandiol

In accordance with the same procedure described for obtaining the racemic diol, namely 3-(tert-butyldiphenylchlorosilane)-1,6-hexandiol, silloway ether, namely (S)-(-)-3-tert-butyldiphenylchlorosilane)-1-cyclohexen (8,35 g 23,9 mm) was subjected to ozone�)-(-)-3-(tert-butyldiphenylchlorosilane)-1,6-hexanediol (approx. 5,01 g, 55%) as a colorless viscous oily substance, which was homogeneous, as evidenced by TLC (Rf= 0,4, EtOAc).

1H-NMR (300 MHz, CDCl3): of 1.05 (s, 9H), 1,21 - of 1.81 (m, 7H), 2,32 (Shir.s, 2H), 3,50 - 3,75 (m, 6H), 7,32 and of 7.70 (m, 10H).

Getting 19

(S)-3-(tert-Butyldiphenylchlorosilane)-1,6-dibromohexane

In accordance with the procedure described to obtain racemic dibromide, namely 3-(tert-butyldiphenylsilyl)-1.6-dibromohexane, (S)-(-)-3-(tert-butyldiphenylsilyl)-1,6-hexanediol (4,85 g, 12,53 mm) was subjected to reaction with N-bromosuccinimide (5.35 g, 30.1 mm) and triphenylphosphine (7.87 in g, 30.1 mm) in methylene chloride (150 ml) at 0oC. Thus was obtained the compound (S)-(-)-3-(tert-butyldiphenylchlorosilane)-1,6-dibromohexane (to 4.81 g, 75%) as a colorless transparent oily substance, which was homogeneous, as evidenced by TLC (Rf= 0,8, 10% EtOAc in hexane). TLC properties and1H-NMR-spectrum of this compound showed identical to the racemic isomer. MS.

1H-NMR (300 MHz, CDCl3): of 1.06 (s, 9H), 1,35 is 2.10 (m, 7H), 3,55 (m, 4H), 3,56 (ACC.d, 2H, J = 4 Hz), 7,40 and to 7.64 (m, 10H).

Receive 20

(R)-3-(tert-Butyldiphenylchlorosilane)-1,6-di the ilen)-1.6-dibromohexane, (S)-(-)-3-(tert-butyldiphenylchlorosilane)-1,6-hexanediol (of 5.05 g, 13,04 mm) was subjected to reaction with N-bromosuccinimide (5.75 g, 31,32 mm) and triphenylphosphine (8,21 g, 31,32 mm) in methylene chloride (160 ml) at 0oC. Thus received chiral dibromide, (R)-3-(tert-butyldiphenylchlorosilane)-1,6-dibromohexane (5,85 g, 87%) as a colorless transparent oily substance, which was homogeneous, as it was shown by TLC (Rf= 0,8, 10% EtOAc in hexane). MS.

1H-NMR (300 MHz, CDCl3): of 1.06 (s, 9H), 1,35 is 2.10 (m, 7H), 3,55 (m, 4H), 3,56 (ACC.d, 2H, J = 4 Hz), 7,40 and to 7.64 (m, 10H).

Getting 21

2-Allyl-4-pontenova acid

To a stirred suspension of sodium methoxide (59,4 g, 1.1 M) in dry methanol (1 l) at 0oC, drop by drop and under nitrogen atmosphere was added diethylmalonate (57 ml, 0.5 M). After 30 minutes, one portion was added allylbromide (95 ml, 1.1 mm). After settling in for 14 h at room temperature, the reaction mixture was concentrated in vacuum. The residue was dissolved in methanol (0.5 l) and was treated with 500 ml of 5 N. NaOH. After 20 hours stirring, the methanol was removed in vacuo, and the basic aqueous layer was twice washed with ethyl acetate. Then the aqueous layer was acidified by adding 0.5 l 5 N. hydrochloric acid, and then extragere sodium sulfate and concentrated in vacuum to obtain a white solid. The obtained solid is triturated with pentane and dried under atmospheric pressure. Thus received is 51.4 g (yield 57%) dibasic acid. This acid (50 g, 274 mm) was heated at 150oC up until not stopped the production of CO2(about 2 hours). The residual brown oily substance was suirable with ethyl acetate through a small layer of silicon dioxide, resulting in a received 32,8 g (85%) of target compound in the form of Golden oily substance. The total yield of the three stages was 48%.

1H-NMR (CD3CN) : 2,4 (m, 4H), 2,5 (m, 1H), of 5.05 (DD, 2H), further 5.15 (DD, 2H), 5,9 (m, 2H), 12,8 (Shir.s, 1H). MS.

Getting 22

3-(tert-Butyldiphenylchlorosilane)-pentane-1,5-diol

To a stirred at 0oC suspension of NaH (4,33 g, 114 mm) in anhydrous ether (125 ml), one drop in an atmosphere of nitrogen was added 2-allyl-4-pontenova acid (16.0 g, 114 mm). The resulting reaction mixture was left to warm to room temperature. Then the reaction was suppressed by adding ethanol (25 ml) and 40 ml of 4 N. hydrochloric acid, then was extracted twice with ether, dried and concentrated in vacuum to obtain alcohol, 2-allyl-4-penten-1-ol as a colorless oily substance (11,7 g, 82%) which was used in bosentan-1-ol (11.7 g, 93 mm) was added imidazole (12,6 g, 185 mm), and then chloro-tert-butyldiphenylsilyl (25,48 g, 93 mm) and the mixture was stirred 16 h, the Reaction mixture was filtered, the filtrate washed with water and brine, and then dried and concentrated in vacuum to obtain salelologa ether, 3-(tert-butyldiphenylchlorosilane)-Penta-1,4-ene (32,5 g, 96%) as an oily substance, which was used without further purification.

At -78oC, via methanol (500 ml) solution of 3-(tert-butyldiphenylchlorosilane)-1,5-pentadione (17 g, 477 mm) was barbotirovany ozone until, while there was a blue tinge (30 min). Then the reaction mixture was purged with nitrogen (20 min) was added NaBH4(17.6 g, 47 mm). The cold bath was removed and the reaction mixture was brought to room temperature. Then the reaction mixture was concentrated in vacuo, and the residue was distributed between ether and brine. The ether layer was concentrated and the resulting residue was suirable through a layer of silica using as eluent a mixture of 0 to 50% ethyl acetate/hexane. The minor component was collected and concentrated to obtain diol, 3-(tert-butyldiphenylchlorosilane)-pentane-1,5-diol (3.8 g, 22%) as colorless oily substances is 6H), 7,41 (t, 4H), 7,45 (t, 2H), 7,66 (d, 4H).

23

1.5-Diiodo-3-(tert-butyldiphenylchlorosilane)-pentane

To the ethereal (0oC) (300 ml) solution of 3-(tert-butyldiphenylchlorosilane)-pentane-1,5-diol (6,9 g, 19 mm) was added methanesulfonamide (4.3 ml, 56 mm), and then Et3N (7.7 ml, 56 mm). After 3 to 16 h, the reaction mixture was slowly heated to room temperature, and then washed with water and brine, then were dried with magnesium sulfate and concentrated, resulting in a received 8.5 g (90%) of 1,5-bis(methanesulfonate)-3-(tert-butyldiphenylchlorosilane)- pentane in the form of a colorless oily substance, which was used without further purification.

To freshly distilled acetone (500 ml) solution of bis-nelfinavir, namely 1,5-bis(methanesulfonate)-3-(tert-butyldiphenylchlorosilane)- pentane (8.5 g, 16 mm) was added excess amount of NaI (36,1 g, 241 mm) and NaHCO3(67 mg, 0.8 mm). The reaction mixture was heated under reflux, with 57oC for 72 h, cooled to room temperature and filtered. The filtrate was concentrated in vacuum. The residue was diluted with ether, washed with 10% Na2SO3was dried and concentrated, resulting in received of 7.4 g (is.

1H-NMR: (DMSO-d6) : of 1.06 (s, 9H), of 1.78 (m, 1H), 1,8 - to 2.06 (m, 4H), of 3.13 (m, 4H), 3,57 (d, 2H), 7,38 - 7,46 (m, 3H), of 7.64 (d, 2H).

Getting 24

2-(2'-Bromoethoxy)-benzylbromide

Ozone was barbotirovany through dry methanol solution of 2-(allyloxy)benzyl alcohol (LaChapelle and others, Tetrahedron 44(16), 5033 - 5044 (1988)) (7,0 g 43 mm) at -78oC for 13 min, controlling the TLC profile of the reaction every 2 min to complete disappearance of the original olefin (Rf= 0,8, 75% EtOAc/hexane). The resulting reaction mixture was purged with nitrogen, was added NaBH4(9.7 g, 0.25 M) and the reaction temperature raised to the 0oC. After 30 min the reaction mixture was heated to room temperature, concentrated, diluted with ether, washed with water and brine, and then dried and concentrated to obtain a residue. This residue was suirable through a layer of silica (gradient of 25% EtOAc /75% hexane). After evaporation of the eluting solvent was obtained diol, 2-(2'-hydroxyethoxy)-benzyl alcohol (4.8 g, 67%) as an oily substance. MS: MW = 168; found: 168, FD, CHCl3.

At 0oC to dry methylenechloride (250 ml) solution of diol, 2-(2'-hydroxyethoxy)-benzyl alcohol (of 4.38 g, 26 mm) was added triphenylphosphine (15,8 g, 60 mm) and N-bromosuccinimide (10, the analysis (20% EtOAc/CH2Cl2), and the resulting reaction mixture was concentrated in vacuum. The concentrate was suirable gradient of hexane/15% EtOAc in hexane, through a layer of silica gel. After concentration of eluting fractions were obtained dibromide, 2-(2'-bromoethoxy)-benzylbromide (6,91 g, yield 90%) as a colourless solid. MS.

13C-NMR (CHCl3, 75,4 MHz): 28,7, 29,1; 68,2; 112,3, 121,6, 126,8, 130,2, 131,1, 156,0.

1H-NMR (CHCl3, 200 MHz): and 3.72 (2H, t, J = 5 Hz), 4,34 (2H, t, J = 5 Hz), 4,59 (2H, s) 6,84 (H, d, J = 7 Hz), 6,95 (H, t, J = 7 Hz), 7,25 - 7,38 (2H).

Receive 25

1-(tert-Butyldimethylsilyloxy)-3-(2-iodoethane)-4-(tert - butylbiphenyl)-butane

Allyl ether, namely, 1-(tert-butyldimethylsilyloxy)-3-(allyloxy)-4-(tert-butylbiphenyl)- butane (21,6 g, 43,4 mm) was dissolved in methanol (500 ml) and cooled to -78oC in nitrogen atmosphere. After the reaction mixture was barbotirovany ozone, and after 11 min of the completion of the reaction was controlled by TLC (9% hexane/1% acetic acid ethyl ester). After this was added borohydride sodium (9,9 g, 6 EQ.) and after 5 min the reaction mixture was left to warm to room temperature. The methanol was removed in vacuum. The resulting residue is suspended in ether (800 ml). The ether was washed with water, and the aqueous layer was subjected to reverse were extracted and concentrated in vacuum to obtain an oily substance. This substance was passed through a layer of silica (eluent: 5% ethyl acetate/hexane and then with 25% ethyl acetate/hexane), resulting in a received 11,0 g (50%) of the alcohol, 1-(tert-butyldimethylsilyloxy)-3-(2-(hydroxy)ethoxy)-4-(tert - butylbiphenyl)-butane in the form of a light yellow oily substance. MS. NMR.

To anhydrous ether (200 ml) solution of the alcohol, 1-(tert-butyldimethylsilyloxy)-3-(2-(hydroxy)ethoxy)-4-(tert - butylbiphenyl)-butane (11,0 g, 21.9mm), in nitrogen atmosphere and at the 5oC was added triethylamine (4.6 ml, 1.5 EQ. and methansulfonate (2.5 ml, 1.5 EQ.). After 1.5 h the reaction was completed, as evidenced by TLC (5% ethyl acetate/dichloromethane). The reaction mixture was diluted with ether (250 ml), washed with water (twice), and then brine (twice). After drying with sodium sulfate, filtration and concentration in vacuum was obtained oily substance. This substance was passed through a layer of silica (eluent: 5% ethyl acetate/hexane, and then 25% ethyl acetate/hexane), which was obtained 11.6 g (yield 91%) nelfinavir, 1-(tert-butyldimethylsilyloxy)-3-(2-(methanesulfonate) ethoxy)-4-(tert-butylbiphenyl)-butane in the form of an oily substance. MS. NMR.

To acetone (300 ml) solution nelfinavir, 1-(tert-butylimide the sodium iodide (44 g, 15 EQ.) and sodium bicarbonate (170 mg, 0.1 EQ.). The resulting mixture was heated under reflux for 18 h followed by removal of the acetone under vacuum. The resulting residue is suspended in ether, washed twice with water and the aqueous layer was washed with ether. The combined ether fractions were washed in 10% solution of sodium sulfite, and then twice washed with saline, dried with magnesium sulfate, filtered and concentrated in vacuo, resulting in a received 10.7 g (yield 87%) of the target iodide in the form of an oily substance, which was used without further purification. MS. NMR.

Getting 26

1-(2-(Methylsulfonylamino)-ethoxy)-2-((methylsulfonyl)ethyl)- 3-(tert-butyldiphenylsilyl)-propane

To a stirred solution of dimethylethanolamine (34 g, 0.2 M) in t-butyl alcohol (0.5 l) was added solid borohydride sodium (19 g, 0.5 M). The resulting reaction mixture was heated at 70oC, and then drop by drop in the course of an hour was added methanol (162 ml). Then the mixture was stirred over night at room temperature. To decompose excess sodium borohydride was added 20 ml of water. The resulting mixture was filtered through celite. The filtrate was concentrated (100 ml) and was extracted with etnie, as a result, we obtained relatively pure diol, 2-allprop-1,3-diol (19 g, yield 83%) which was used in the subsequent stage without further purification.

To a stirred solution of diol, 2-(2-propen-1-yl)-propane-1,3-diol (23,2 g 0,19 M) in toluene (1 l) was added anisaldehyde (27,3 g, 0.20 M) and PPTS-acid (4 g, 10 M). The reaction mixture was loaded into a flask equipped with a trap Dean-stark, and then the reaction mixture was heated under reflux. After 5 h the reaction mixture was cooled to room temperature, diluted with ether (1 l), washed with saturated sodium bicarbonate (50 ml x 3) and then water (50 ml x 3) and brine (50 ml). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to obtain a residue. This residue was suirable through the narrow column of silica gel (eluent: 10% ethyl acetate in hexane). After evaporation of the eluting solvent was received anisylidene, 1,3-O-anisylidene-2-(2-propen-1-yl)propane (40 g, 89%) with Rf= 0,62 (25% ethyl acetate in hexane).

To a stirred solution of anisylidene, 1,3-O-anisylidene-2-(2-propen-1-yl)propane (20,0 g, 85,3 mm) in CH2Cl2(500 ml) and buffer (pH 7.0; 25 ml), at 0oC was added DDQ (38,7 g, 170,4 mm). The resulting reaction mixture satelefono (1 l), washed with aqueous saturated sodium bicarbonate (200 ml x 2) and 10% aqueous Na2SO3(200 ml x 3) and then dried and concentrated under reduced pressure to obtain a residue. This residue was suirable through a column of silica gel (10 to 25% ethyl acetate in hexane). After evaporation of the eluting solvent was received anisot containing alcohol, 3-O-(4-methoxybenzoyl)-2-(2-propen-1-yl)propan-1-ol (12.7 g, 61%). Rf= 0,14 (25% ethyl acetate in hexane). NMR.

To a stirred solution of alcohol, 3-O-(4-methoxybenzoyl)-2-(2-propen-1-yl)-propan-1-ol (16,58 g, 66,32 mm) in methylene chloride (250 ml) was added trichloroacetimidate (24,80 g, 132,64 mm) in cyclohexane (500 ml). To this mixture under nitrogen atmosphere was added 1 ml triperoxonane acid. After 12 h formed a white precipitate. The reaction mixture was filtered. The filtrate was diluted with ether (500 ml), washed with water (100 ml x 3) and brine (100 ml) and then dried and concentrated under reduced pressure to obtain a residue. This residue was suirable through a column of silica gel, elwira with ethyl acetate/hexane (gradient 0 to 25% ethyl acetate). The resulting diene, 1-(2-propen-1-oxy)-2- (2-propen-1-yl)-3-O-(4-methoxybenzoyl)-propane (24 g), containing a number of ndimethylacetamide, ispolnenii ether, 1-(2-propen-1-oxy)-2-(2-propen-1-yl)-3-O-(4-methoxybenzoyl)-propane (24 g) was dissolved in THF (60 ml) was added methanol (100 ml) and 1 N. aqueous NaOH (40 ml). The resulting mixture was stirred overnight and the methanol and THF were removed under reduced pressure. A concentrated reaction mixture was diluted with ether (250 ml), was extracted with ether (100 ml x 3), dried and concentrated under reduced pressure to obtain a residue. This residue was suirable through a column of silica gel (10% ethyl acetate/hexane) as an eluting solvent evaporated, resulting in a received alcohol, 1-(2-propen-1-oxy)-2-(2-propen-1-yl)-propen-3-ol (4,10 g, 30% from 2 stages). NMR: Rf= 0,23 (25% ethyl acetate in hexane).

To mixed methylenchloride (150 ml) solution of the alcohol, 1-(2-propen-1-oxy)-2-(2-propen-1-yl)-propen-3-ol (4,10 g, 26,2 mm) under nitrogen atmosphere was added imidazole (2.70 g, 39,7 mm). After dissolution of imidazole for 10 min was added tert-butylchloroformate (8,24 g, 29,97 M) in methylene chloride (50 ml). After a 12-hour stirring, the reaction mixture was diluted with ether (100 ml), and then extinguished with water (100 ml) and was extracted with ether (100 ml x 3). The combined organic phase was washed brine (100 ml), dried and concentrated under reduced pressure to receive the of the eluting solvent was received silloway ether, 1-(2-propen-1-oxy)-2-(2-propen-1-yl)-3-(tert - butyldiphenylsilyl)-propane (to 7.61 g, yield 72%). Rf= 0,76 (25% ethyl acetate in hexane).

Ozone was barbotirovany through methanol (-78oC, 500 ml) solution of diene, 1-(2-propen-1-oxy)-2-(2-propen-1-yl)-3-(tert - butyldiphenylsilyl)-propane (7,41 g, 18,80 mm). After the disappearance of starting material (TLC: 25% ethyl acetate/hexane), the reaction mixture was purged with nitrogen and added borohydride sodium (2,13 g, 56,30 mm). The reaction mixture was heated to room temperature. After 12 h the reaction mixture was concentrated. The white residue was suppressed by addition of water, and then extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with salt solution, dried and concentrated under reduced pressure with the formation of residue. The residue was suirable through the narrow column of silica gel (gradient 10 to 50% ethyl acetate/hexane). After evaporation of the eluting solvent was received 1,7-diol, 1-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-3-(tert-butyldiphenylsilyl)- propane (5,48 g, yield 72%). Rf= 0,21 (50% ethyl acetate in hexane). NMR.

To mixed methylenchloride (400 ml) solution of diol, 1-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-3-(tert-butyldiphenylsilyl)- propane (5,48 g, 13,6 mm), OTL, 39,00 mm) in methylene chloride (100 ml). After 12 h the reaction mixture was diluted with ether (500 ml), then washed with water (100 x 3) and brine (100 ml) and then dried and concentrated under reduced pressure to obtain a residue. The residue was suirable through the narrow column of silica gel (gradient 10 to 50% ethyl acetate/hexane). Eluting solvent evaporated and get bismesylate, 1-(2-methylsulfonylamino)-ethoxy)-2-((methylsulfonyl)ethyl)-3- (tert-butyldiphenylsilyl)-propane (7,40 g, 97%). Rf= 0,55 (50% ethyl acetate in hexane). NMR.

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Example 1

3,4-[(N,N'-Ethoxyethyl)-bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione

In nitrogen atmosphere, to a solution of 3,4-bis(3'-indolyl)-furan-2,5-dione (337 mg, 1,02 mm) in 5 ml of dry DMF, portions over 15 min was added sodium hydride (60% dispersion in mineral oil, 113 mg, 2,82 mm). The resulting mixture was stirred for 1.5 h, and then diluted to 5 ml of DMF. To the resulting green solution drop by drop) was added bis 2,2'-dibromo-ethyl ester (0,14 ml of 1.13 mm). The resulting reaction mixture was stirred for 30 min at 25oC, and then heated overnight at 50oC. the Cooled mixture was poured into dilute aqueous citric acid (75 ml) and was extracted with ethyl acetate (2 x 40 ml). what LifeCam magnesium. The solvent is evaporated under reduced pressure. The residue was passed through a narrow column with silica gel (50% EtOAc/hexane), and then subjected to radial preparative thin-layer chromatography (Chromatotron), elwira 50% ethyl acetate/hexane. The result of this procedure was obtained 82 mg (20%) of 2,3-[(N, N'-1,1'-ethoxyethyl)-bis-(3,3'-indolyl)] -1H-furan-2,5-dione in the form of a solid color Bordeaux, so pl. > 320oC.

A solution of 2,3-[(N, N'-1,1'-ethoxyethyl) bis(3,3'- indolyl)]-1H-furan-2,5-dione (58 mg, 0.15 mm) in DMF (1.5 ml), under nitrogen atmosphere was treated with a mixture of 1,1,1,3,3,3-hexamethyldisilazane (0.33 ml, 1,45 mm) and CH3OH (23 mg, 0,73 mm) (pre-mixed for 10 min). After stirring for 16 h at room temperature the mixture was poured into water (20 ml) and was extracted with ethyl acetate (3 x 5 ml). The combined organic extracts washed several times with water, dried with magnesium sulfate and concentrated. The resulting residue was purified using radial chromatography (eluent: 3% CH3OH in CHCl3) and received 3,4-[(N,N'-1,1'-ethoxyethyl)-bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione (of 41.5 mg, 72%) as a purple solid, so pl. > 320oC. MS: Analysis for C24H19N3O3: calculated: 3971426; found: 3971438.

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To methanol (100 ml) solution of the above alkylated product (3,14 g, 3,74 mm) was added toluensulfonate acid (60 mg, 2%). After 2 h TLC (50% ethyl acetate/hexane) indicated the possibility of running out of source material. The resulting reaction mixture was concentrated to half volume, diluted with ethyl acetate (300 ml), washed with 1 BC hydro is the formation through a layer of silica (50% ethyl acetate/hexane), as a result, we obtained the desired alcohol, 3-[(N-1-(3-propoxy-O-4-tert-butyldiphenylchlorosilane-1-ol] -4-(3'- indolyl)-1-(methyl)-pyrrole-2,5-dione (1,76 g, yield 65%) as a red foam substance. MS.

To the ethereal (0oC) (200 ml) solution of the above alcohol 3-[(N'-1-(3-propoxy-O-4-tert-butyldiphenylsilyl-butane-1-ol] -4- (3'-indolyl)-1-(methyl)-pyrrole-2,5-dione (1,76 g, 2.4 mm) was added triethylamine (0.5 ml, 1.5 EQ. ), and then methylchloride (of 0.28 ml, 1.5 EQ.). The reaction mixture was brought to room temperature and was completed after 1 h then the reaction mixture was diluted with ether (200 ml) and then washed with water and brine. After drying and concentration, the concentrate was passed through a layer of silica (eluent: 50% ethyl acetate/hexane), resulting in a received mutility product which was used directly in the subsequent stage.

To acetone (250 ml) solution of the above nelfinavir was added sodium iodide (3.6 g, 10 EQ.) and NaHCO3(20 mg). After 4 hours stirring TLC revealed the presence of starting material (50% ethyl acetate/hexane) and the reaction mixture was added an additional amount of sodium iodide (10 EQ.), and then the mixture was heated at 60oC. After 4 h, TLC (50% etilize with ethyl acetate (250 ml), washed with water and 10% sodium sulfite, and then dried and concentrated. The concentrate was purified by elution through a layer of silica gel (50% ethyl acetate/hexane), resulting in a received desired iodide in the form of an oily substance, namely, 3-[(N-1-(3-propoxy-3(O)-4-tert-butyldiphenylsilyl-1-iodobutane] - 4-(3'-indolyl)-1-(methyl)-pyrrole-2,5-dione (1,71 g, yield 85%). MS.

Dimethylformamide (10 ml) solution of the above iodide, 3-[(N-1-(3-propoxy-3(O)-4-tert-butyldiphenylsilyl-1-iodobutane] -4- (3'-indolyl)-1-(methyl)-pyrrole-2,5-dione (2.0 g, 2.4 mm), slowly via syringe over 80 h was added to dimethylformamide (400 ml) solution of cesium carbonate (3.12 g, 9.6 mm). After 3 h after adding TLC (50% ethyl acetate/hexane) indicated the possibility of running out of source material. The reaction mixture was diluted with ethyl acetate (1 l) and then washed with water and brine. The water portion of the solution was extracted with 500 ml of ethyl acetate. The combined organic layers were concentrated and the obtained concentrate was purified on columns with silica (eluent: 50% ethyl acetate/hexane). After concentration of eluent received the desired macrocyclic 3,4-[(N,N'-1,1')-(3"-propoxy)-3"'(O)-4"'(hydroxy)butane)-bis-(3,3-indolyl)] -1-(methyl)pyrrole-2,5-dio is epoxy)-3"'(O)-4"'-(hydroxy)butane)-bis) 3,3-indolyl)] -1-(methyl)-pyrrole-2,5-dione (1.7 g, 2.4 mm) was added 50 ml of 5 N. KOH. After 12 h the reaction mixture was heated for 2 h at 50oC. then the reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated, resulting in a received desired anhydride, 2,3-[(N,N'-1,1'-(3"-propoxy-3"'-(O)-4"'-hydroxybutyl)-bis-(3,3'- indolyl)] -furan-1,4-dione (1,37 g, yield 83%) as a red oily solid. MS.

To dimethylformamide (100 ml) solution of the above anhydride, 2,3-[(N, N'-1,1'-((3"-propoxy)-3"'-(O)-4"'-(hydroxy)-butane)-bis- (3,3'-indolyl)] -furan-1,4-dione (1,37 g, 3 mm) was added 1,1,1,3,3,3-hexamethyldisilazane (of 12.6 ml, 20 EQ.) and methanol (1,21 ml, 10 EQ.). After 24 h, TLC (50% ethyl acetate/hexane) indicated complete depletion of the source material. The reaction mixture was diluted with ethyl acetate, washed with 1 N. hydrochloric acid and water, and then dried and concentrated. The concentrate was stirred in 1 N. hydrochloric acid or with cesium fluoride to remove residual TMS group. After that, the reaction mixture was diluted with ethyl acetate, washed with water, and then dried and concentrated, resulting in received of 1.02 g (yield 75%) of the desired maleimide, 3,4-[(N, N'-1,1')-((3"-propoxy)-3"'(O)-4"'- (hydroxy)-C in DMSO-d6): 2,1 (m, 4H), 2,4 (m, 2H), 3,28 (Shir.s,m), 3,4 (m, 4H), 4,5 (so J= 6 Hz, 1H), 7,0-7,9 (m, 10H), and 11.0 (s, 1H).

13C-NMR (75 MHz in DMSO-d6): 20,9, 28,9, 30,3, 30,9, 34,3, 40,4, 41,6, 42,4, 62,4, 65,9, 78,1, 104,0, 104,1, 110,0, 110,1, 119,6, 119,7, 121,4, 121,8, 24,8, 126,5, 126,6, 127,9, 131,5, 131,6, 131,7, 135,8, 135,9, 139,1, 151,4, 172,2.

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Example 3

3,4-[(N, N'-1,1'-(2"-ethoxy)-3"'(O)-4"'-(hydroxy)-butane)-bis- (3,3'-indolyl)]-1(H)-pyrrole-2-,5-dione

To dimethylformamide (250 ml) solution of bis-(3,3'-indolyl)-1-(methyl)-pyrrole-2,5-dione (17.9 g, 52,5 mm, 3 equiv.) in an atmosphere of nitrogen was added cesium carbonate (68,4 g, 4 EQ.). To the resulting suspension were added iodide, 1-(tert-butyldimethylsilyloxy)- 3-(2-iodoethane)-4-(tert-butyldiphenylsilyl)-butane (10.7 g, 17.5 mm). The reaction mixture was stirred at room temperature for 18 hours TLC (5% ethyl acetate/hexane) indicated the disappearance of iodide. After that, the reaction mixture was poured into ethyl acetate (1200 ml) and washed with 400 ml of 1 N. hydrochloric acid, and then subjected to reverse washing with ethyl acetate (twice). United an ethyl acetate portion was washed with saturated sodium bicarbonate solution, washed twice with saline, dried with magnesium sulfate, filtered and concentrated in vacuum. The dimethylformamide was removed by azeotropic distillation with the use of xylene. Pospisil. After concentration, was added dichloromethane, and the suspension was cooled and filtered to obtain a red solid. Some of the desired product was extracted from the obtained solid substance by repeated trituration in dichloromethane and then ethyl acetate. The filtrate was concentrated in vacuo and the resulting residue was absorbed on silica and then placed in a large flash column. Dialkylamino by-products were removed by elution with 5% hexane/1% acetic acid ethyl ester, and then by elution with 3% hexane/1% acetic acid ethyl ester, which was obtained 8.2 g (57%) monoalkylamines product, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'-(tert - butyldimethylsilyloxy)-butane))-indol-3-yl] -4-[indol-3-yl]1N(methyl)-pyrrole-2,5 - dione, MS, NMR.

To methanol (450 ml) solution of tert-butyldimethylsilyl ether, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'- (tert-butyldimethylsilyloxy)-butane))-indol-3-yl]-4-[indol-3-yl]-1N- (methyl)-pyrrole-2,5-dione (8,2 g, 9.9 mm), in the atmosphere of nitrogen and 5oC was added monohydrate toluensulfonate acid (0.16 g, 0,085 EQ.). After 2 h TLC (50% ethyl acetate/hexane) indicated complete reaction. After the reaction CME is astoral in ethyl acetate, washed with 0.1 N. sodium hydroxide, and then washed twice with saline. After drying with magnesium sulfate, filtration and concentration in vacuum, received a red foamy substance. This substance was absorbed on silica and was placed on the layer of silicon dioxide. Residual starting material was suirable 2% hexane/1% acetic acid ethyl ester, and then 1% hexane/1% acetic acid ethyl ester. After that, the residual of the original material was removed and obtained 6.4 g (91%) alcohol, 3-[(N-1-(2-ethoxy-(3"'(O)-4"'-(tert-butyldiphenylsilyl)-1-(hydroxy)- butane))-indol-3-yl] -4-[indol-3-yl] -1N (methyl)-pyrrole-2,5-dione, MS, NMR.

To anhydrous ether (500 ml) solution of the alcohol, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'-(hydroxy)- butane))-indol-3-yl]-4-[indol-3-yl]-1N (methyl)-pyrrole-2,5-dione (6,36 g, 8.9 mm), in nitrogen atmosphere and at the 5oC was added triethylamine (1.9 ml, 1.5 EQ.) and methanesulfonamide (1.0 ml, 1.5 EQ.). After 3 hours was added 1.25 ml of triethylamine (1.0 EQ) and 0.7 ml (1.0 EQ.) methanesulfonanilide. After one hour the reaction was completed, as it was shown by TLC (50% ethyl acetate/hexane). The reaction mixture was diluted with ether (250 ml), washed with water, 0.1 G. of hydrochloric acid and twice with saline. The ether layer asslike-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'- (methanesulfonate)-butane))-indol-3-yl] -4-[indol-3-yl]-1N (methyl)-pyrrole-2,5-dione, MS.

To acetone (200 ml) solution nelfinavir, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'- (methanesulfonate)-butane))-indol-3-yl] -4-[indol-3-yl] -1N-(methyl)-pyrrole-2,5 - dione (7.0 g, 8.9 mm), in an atmosphere of nitrogen was added sodium iodide (13.3 g, 10 EQ.) and sodium bicarbonate (75 mg, 0.1 EQ.). After that, the mixture was stirred at 50oC for 13 h, the Reaction mixture was concentrated in vacuo, and the residue was dissolved in ether and washed with a 10% solution of sodium sulfite. Then the layers were separated, and the ether portion was washed for 10% sodium sulphate solution, water and then washed twice with saline. After drying and concentration in vacuo, the residue was passed through a layer of silicon dioxide, elwira 1% hexane/1% acetic acid ethyl ester and 1% hexane/2% ethyl acetate. As a result of these procedures was obtained 7.6 g of iodide, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'-(iodo)- butane))-indol-3-yl] -4-[indol-3-yl] -1N (methyl)-pyrrole-2,5-dione as a red solid (quantitative yield two steps), MS, NMR.

To dimethylformamide (1 l) suspension of cesium carbonate (12.0 g, 4 equiv.) in nitrogen atmosphere, with a syringe and for 65 h was added iodide, 3-[(N-1-(2-ethoxy-(3"'-(O)-4"'-(tert-butyldiphenylsilyl)-1"'- (iodo)-butale finished adding, the reaction mixture was concentrated in vacuum. The residue was dissolved in ethyl acetate (700 ml), washed with water (I ml) and the aqueous layer was subjected to reverse washing with ethyl acetate (CH ml). United an ethyl acetate portion was washed with saline (CH ml), dried with magnesium sulfate, filtered and concentrated in vacuo to obtain a residue purple. This residue was absorbed on silica and loaded into the flash column. After elution with 3% hexane/1% acetic acid ethyl ester and then with 1% ethyl acetate/1% hexane received 5,2 g (82%) macrocyclic 3,4-[(N,N'-1,1'-((2"'-ethoxy)-3"'-(O)-4"'-(tert-butyldiphenylsilyl)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, MS, NMR.

A suspension of N-methylmaleimide, 3,4-[(N,N'-1,1'-[(2-ethoxy)-3"'(O)-4"'-(tert-butyldiphenylsilyl)-butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione in 5 B.C. KOH (150 ml) and ethanol (300 ml) was stirred at room temperature for 65 h, and then 1 h at 60oC. the Reaction mixture was concentrated in vacuo to a volume of 150 ml and the resulting residue suspended in water, cooled to 5oC, then acidified to pH 3 by addition of concentrated hydrochloric acid. Received the red aqueous suspension was extracted with ethyl acetate (CH ml), drained and end the'(O)-4"'-(hydroxy)-butane)-bis-(3,3 - indolyl)-furan-1,4-dione as a purple solid, MC.

To dimethylformamide (250 ml) solution of the anhydride, 2,3-[(N,N'-1,1'-(2"'-ethoxy)-3"'-(O)-4"'-(hydroxy)butane)-bis-(3,3 - indolyl)] -furan-1,4-dione (3.3 grams, 7.5 mm), in an atmosphere of nitrogen was added 1,1,1,3,3,3-hexamethyldisilazane (32 ml, 2 EQ.) and methanol (3 ml, 10 EQ.). The resulting reaction mixture was stirred at room temperature for 16 h and then was heated at 60oC for 2 hours, the Dimethylformamide was removed in vacuo and the resulting residue was dissolved in acetonitrile (250 ml), then added 1 N. hydrochloric acid (50 ml). The reaction mixture was stirred for 15 min, then concentrated and distributed between ethyl acetate and water (250 ml). The solid product was besieged and received alcohol maleimide, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'(O)-4"'-(hydroxy)-butane-bis-(3,3'- indolyl)] -1(H)-pyrrole-2,5-dione (0,92 ml, 28%). A small amount (50 ml) of this product was absorbed on silica and loaded in the flash column. After elution of dichloromethane, 5% acetonitrile-dichloromethane, and then 10% acetonitrile/dichloromethane received 38 mg of analytically pure material. The ethyl acetate was concentrated and chromatographically, resulting in an additional 8% of the crude product. MS.

1H-AMN (DMSO-d is), 7,44 (1H, s), 7,46 (1H, d, J = 9 Hz), 7,51 (1H, s), 7,53 (1H, d, J = 9 Hz), 7,79 (1H, d, J = 8 Hz), 7,83 (1H, d, J = 8 Hz), 10,91 (1H, s).

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Example 4

3,4-[(N, N'-1,1'-((2"-Ethoxy)-3"'(O)-4"'-(amino)-butane)-bis- (3,3'-indolyl)]-1(H)-pyrrole-2,5-dione trifurcata salt

To anhydrous tertrahydrofuran ring (15 ml) solution of alcohol, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'(O)-4"'(hydroxy)-butane)-bis- (3,3'-indolyl)] -1(H)-pyrrole-2,5-dione (155 mg, 0.35 mm), in an atmosphere of nitrogen was added 2,4,6-kallidin (280 μl, 3 EQ.). The resulting solution was cooled to -78oC and treated anhydride triftormetilfullerenov acid (118 μl, 2 EQ.). After kept for 1.5 h at -78oC, was added excess amount of concentrated ammonium hydroxide (2 ml). After 10 min the reaction mixture was heated up to -42oC in a bath of dry ice/acetonitrile, after which it was stirred for 18 h, was heated up to room temperature. The reaction mixture was concentrated in vacuum. The obtained residue was dissolved in ethyl acetate (400 ml) and then washed with water and brine, then dried and concentrated in vacuum, resulting in the obtained crude primary amine. This amine was absorbed on silica and loaded in the flash column, and then was suirable 1% of the methanol/2% Isopropylamine, resulting received Amin, namely, 3,4-[(N,N'-1,1'-(2"-ethoxy)-3"'(O)-4"'-(amino)-butane)-bis-(3,3' -indolyl)] -1(H)-pyrrole-2,5-dione (38 mg). Also stood out the source alcohol (104 mg, 67%). This product was purified using reverse-phase chromatography high resolution (eluent: 85% acetonitrile/0.01% of TFA-water). Combined fractions were subjected to azeotropic distillation using ethyl acetate, resulting in a received 23 mg (12%) TFA salt in powder form, MS.

1H-NMR (d6-DMSO): 1,99 (1H, m), of 2.08 (1H, m), 2,82 (1H, m), 3,18 (1H, m), of 3.57 (2H, m in), 3.75 (1H, m), 4,13 (2H, m), the 4.29 (1H, m), of 4.44 (1H, m), to 7.09 (2H, t, J = 7 Hz), 7,18 (2H, t, J = 7 Hz), 7,47 (4H, m), of 7.70 (3H, Shir. C), 7,78 (2H, m).

In a similar way have been obtained S-enantiomer (4s) as cleaners containing hydrochloride salt and R-enantiomer (4r) as cleaners containing hydrochloride salt.

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Example 5

3,4-[(N, N-1,1'-((2"-Ethoxy)-3"'(O)-4"'-(N, N-dimethylamino) butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione cleaners containing hydrochloride salt

To anhydrous dichloromethane (140 ml) suspension of alcohol, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(hydroxy)-butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione (472 mg, 1,07 mm) under nitrogen atmosphere was added pyridine (260 μl, 3 EQ.) and methanesulfonyl anhydride (242 mg, 1.3 EQ.). After 4 h the reaction mixture was diluted with dichloromethane, washed twice 1 left solution (twice), was dried and concentrated to obtain the crude nelfinavir in the form of a purple solid. This substance was absorbed on silica and loaded in the flash column, after which he suirable dichloromethane, 5% acetonitrile/dichloromethane and 10% acetonitrile/dichloromethane, resulting in received 288 mg (yield 52%) nelfinavir, 3,4-[(N, N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(methane-sulfonyloxy)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, MS, NMR.

To tertrahydrofuran ring (20 ml) solution nelfinavir, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'(O)-4"'-(methanesulfonate)-butane)- bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione (304 mg, 0,59 mm) was added 8.9 M solution of dimethylamine in tetrahydrofuran (7 ml, 100 equiv.). After heating at 65oC for 24 h in a tightly closed vessel, the reaction mixture was diluted with ethyl acetate (200 ml), washed twice with saline, dried and concentrated to obtain the crude dimethylamino derived in the form of solids. This substance was absorbed on silica and loaded in the flash column, after which he suirable 3% ethyl acetate/1% hexane, ethyl acetate and 2% Isopropylamine/ethyl acetate, resulting in a received 193 mg (yield 70%) dimethylamino derived, which had 90% of pureness is Jalil)] -1(H)-pyrrole-2,5-dione was purified to more than 95%. This substance was obtained as trichloroacetate salt, which was subjected to reversed-phase exclusion GHUR, elwira 85% acetonitrile/15% of a mixture of TFA/water.

Trifloromethyl salt of 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N, N'-dimethylamino)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione was converted into cleaners containing hydrochloride salt by suspension of the salt in ethyl acetate and careful washing of 0.1 N. sodium hydroxide (CH ml). An ethyl acetate portion was twice washed with saline, dried and concentrated to obtain the free base, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N,N'-dimethylamino)-butane)- bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione. To anhydrous methanol suspension (50 ml) of the free base, 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N, N'-dimethylamino)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, was added 1 N. hydrochloric acid in anhydrous ether (13 ml, 50 EQ.). After evaporation of the ether, the residue was dried in vacuum and received 143 mg (yield 52%) cleaners containing hydrochloride salt of 3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N, N-dimethylamino)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione as a red solid, MS.

1H-NMR (d6-DMSO): 2,03 (1H, m), and 2.26 (1H, m), 2,68 (6H, t, J = 5 Hz), 3,24 (1H, m), or 3.28 (1H, m, after shaking with D2O) to 3.64 (1H, m), of 3.77 (2H, m), 4,07 - to 4.38 (4H, -[(N, N'-1,1'-((2"-Ethoxy)-3"'-(O)-4"'-(N, N-dimethylamino)- butane)-bis-(3,3'-indole)]-1(H)-pyrrole-2,5-dione cleaners containing hydrochloride salt

To tertrahydrofuran ring (300 ml) solution nelfinavir, (S)-3,4-[(N,N'-1,1')-((2"-ethoxy)-3"-(O)-4"'-(methanesulfonate)- butane-(bis)-(3-indolyl)] -1H-pyrrole-2,5-dione (2.8 g, 5,30 mm), in a tightly closed container was added dimethylamine (100 ml, 40% in water). After heating at 50oC for 24 h the reaction mixture was concentrated. The resulting residue was passed through a layer of silicon dioxide, elwira with ethyl acetate and then 10% triethylamine/ethyl acetate, resulting in a received desired (S)-dimethylamino derived. Eluent was concentrated to obtain 1.7 g (yield 67%) of free base, namely, (S)-3,4-[(N,N-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N, N-dimethylamino)-butane)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione as a purple solid substances. This free base was converted into cleaners containing hydrochloride salt by suspension of the free base, namely, 3,4-[(N, N'-1,1')-(4"-N, N-dimethylamino-3-(S)-"ethoxy-butane)] -(bis)- (3-indolyl)-1H-pyrrole-2,5-dione (1.7 g, 3.6 mm) in methanol (300 ml) and added to 1.0 N. anhydrous hydrochloric acid in ether (10 ml, 10 mm). After settling in for 0.5 h at room temperature, a bright orange precipitate was collected, washed with ether, and the Ino-3-(S)-"-ethoxy-butane)]-(bis)- (3-indolyl)-1H-pyrrole-2,5-dione, MS.

1H-NMR (d6-DMSO): 2,1 (m, 1H), 2,35 (m, 1H), 2,68 (s, 6H), 3,2 (m, 1H), 3.33 and (m, 1H), 3,66 (Shir.T., 1H), 3,8 (Shir. t, 1H), 3,85 (m, 1H), 4,17 (m, 1H), 4,2 - 4,4 (m, 3H), and 7.1 (d, 1H), 7,13 (d, 1H), 7,2 (m, 2H), 7,44 (s, 1H), of 7.48 (s, 1H), 7.5 (d, 1H), 7,56 (d, 1H), 7,82 (Shir.t, 2H), 10,59 (Shir. t, 1H), 10,96 (s, 1H),.

Example 5r

(R)-3,4-[(N,N'-1,1-'-((2"-Ethoxy)-3"'-(O)-4"'-(N,N-dimethylamino)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione cleaners containing hydrochloride salt

(R)-Enantiomer was obtained in a manner analogous to the method of obtaining (S)-enantiomer, except that the starting material used (R)-4-tert-butyldiphenylsilyl-3-(2-iodoethane)- 1-iodobutane, MS, NMR.

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Example 6

3,4-[(N, N'-1,1'-(2"-Ethoxy-(3"'(O)-methylene)-4"'-(hydroxy)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione

Dry dimethylformamide (100 ml) solution of (bis)nelfinavir, 1-(2-methylsulfonylamino)-ethoxy)-2-((methylsulfonyl)ethyl)-3- (tert-butyldiphenylsilyl)-propane (7,4 g, 13,30 mm) and bis-(3,3'-indolyl)]-1(methyl)-pyrrole-2,5-dione (4,43 g, 13,30 mm) for 16 h at 50oC was added to a stirred suspension Cs2CO3(25.4 g, 78 mm) in DMF (400 ml). After 8 hours the reaction mixture was concentrated under reduced pressure (80oC) and received the remainder. This residue was diluted with ethyl acetate (200 ml) and then washed with water (50 E. part was dried and concentrated to obtain a residue. The residue was suirable on a column of silica gel (25% ethyl acetate in hexane, then 5% methanol in methylene chloride), which received three predominant product: similairly macrocyclic product, 2,3-[(N, N'-1,1'-(4"'-ethoxy-1'-yl-(3"'-(tert - butyldiphenylsilyl)methylene)butane-1-yl)- bis-(3,3'-indolyl)] -1-(methyl)-pyrrole-1,4-dione (2.35 g); MS: Analysis for C44H45N3O4Si: Mol. weight: 707,31 found: 708; Rf= 0,84 (50% ethyl acetate in hexane) and desilusiony alcohol (macrocyclic product; 600 mg), MS.

To a stirred EtOH (500 ml) solution of N-methylacrylates product, 2,3-[(N, N'-1,1'-(-4"'-ethoxy-1'-yl-(3"'-(tert - butyldiphenylsilyl)methylene)butane-1-yl)- bis-(3,3'-indolyl)] -1(methyl)-pyrrole-1,4-dione (1.65 g, 2,33 mm) was added to 100 ml of 5 n KOH. After incubation for 12 h at 50oC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The obtained residue was acidified by adding concentrated hydrochloric acid to pH 1 and then extracted with ethyl acetate (200 ml x 5). The combined organic phases were dried, concentrated under reduced pressure, and then suirable through a narrow column with silica (5% methanol in dichloromethane) is XI-(1'-yl-(3"'-(tert - butyldiphenylsilyl)methylene)-butane-1-yl)-bis-(3,3'-indolyl)] - furan-1,4-dione, which was used in the subsequent stage.

To anhydrous dimethylformamide (250 ml) solution of the anhydride, 2,3-[(N, N'-(4"'-ethoxy-1'-yl-(3"'-(tert - butyldiphenylsilyl)methylene)-butane-1-yl)-bis-(3,3'- indolyl)] -furan-1,4-dione (600 mg, 1.3 mm) was added HMDS (2.1 g, 13 mm), and then methanol (209 mg, 6.5 mm). After 48 h the reaction mixture was concentrated and the obtained residue was dissolved in ethyl acetate (100 ml) and then washed with 25 ml of 1 N. hydrochloric acid, water (25 ml) and brine (25 ml). The organic phase was dried and concentrated in vacuum to obtain a residue. The obtained residue was suirable on a column of silica gel (0 to 5% methanol/CH2Cl2). After evaporation of the eluting solvent was 300 mg (yield 50%) of imide, 3,4-[(N, N'-1,1'-(2"-ethoxy-(3"'(O)-methylene)-4"'-(hydroxy)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione in the form of solids, MS.

1H-NMR (CDCl3) : 9,65 (s, 1H), 7,79 (t, J = 7,65 Hz), to 7.61 (s, 1H), 7,54 (s, 1H), 7,46 - 7,40 (m, 2H), 7.24 to was 7.08 (m, 2H), 7,07 - 7,02 (m, 2H), 4,43 - to 4.33 (m, 2H), 4,30 - is 4.21 (m, 1H), 4,14 - 4,06 (m, 1H), 3,64 (t, J = with 4.64 Hz), to 3.58 - to 3.38 (m, 5H), 3,71 (t, J = 8,64 Hz, 1H), 1,89 - of 1.85 (m, 1H).

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Example 7

3,4-[(N, N'-1,1'-(2"-Ethoxy-(3"'((O)-methylene)-4"'-(N-pyrrolidino)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione cleaners containing hydrochloride salt

To be the an)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione (140 mg, 0.30 mm) containing pyridine (120 mg, 1.5 mm) under nitrogen atmosphere was added methanesulfonyl anhydride (106 mg, and 0.61 mm). After 12 h the reaction extinguished with water (25 ml), diluted with methylene chloride (50 ml) and then washed with 0.2 G. hydrochloric acid (20 ml x 2), aqueous sodium bicarbonate solution (20 ml), again with water (20 ml) and brine (20 ml), then dried and concentrated to obtain a residue. This residue was suirable through a narrow column with silica gel (5% methanol in dichloromethane) and after evaporation of the eluting solvent was received mesilate, 3,4-[(N,N'-1,1'-(2"-ethoxy-(3"'(O)-methylene)-4"'-(methanesulfonate)- butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, which was used in the subsequent stage.

In a tightly closed container, tertrahydrofuran ring (20 ml) solution nelfinavir, 3,4-[(N,N'-1,1'-(2-ethoxy-(3"'(O)-methylene)-4"'-(methanesulfonate)-butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione (157 mg, 0,29 mm) was added pyrrolidine (203 mg, 2,90 mm). After heating at 50oC for 12 h, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, dissolved in methylene chloride (50 ml), washed with water (20 ml x 2) and brine (20 ml), then dried and concentrated under reduced pressure to get the OST is actuarial evaporated and got pyrrolidin, 3,4-[(N,N'-1,1'-(2'-ethoxy-(3"'(O)-methylene)-4"'-(N-pyrrolidino)- butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione. Mass spectroscopy for C31H32N4O3: Molar mass: 508,62; found: 508, Rf= 0,14 (5% methanol in dichloromethane, trace amounts of triethylamine). Pyrrolidin, moreover, was purified using reverse-phase gel chromatography, resulting in a received pyrology macrocyclic product as triperoxonane salt (50 mg, yield 37%). Salt triperoxonane acid pyrrole turned cleaners containing hydrochloride in the target connection by extraction of 1 n sodium hydroxide (5 ml) suspension of salt triperoxonane acid (55 mg) and a mixture of ethyl acetate (25 ml) and methanol (2 ml). The obtained extract was dried and concentrated, resulting in the formation of residue. The residue is suspended in ether/methanol (10 : 1) and then added cleaners containing hydrochloride a solution of ether. After 30 min the suspension was concentrated and dried under vacuum, resulting in the obtained target compound (48 mg, yield 88%), MS.

1H-NMR: 10,98 (s, 1H), of 7.90 (s, 1H), 7,82 (s, 1H), 7,70 to 7.62 (m, 3H), 7,56 is 7.50 (m, 1H), 7.24 to 7,02 (m, 4H), 4,50 - 4,20 (m, 4H), 2,82 is 2.44 (m, 4H), 2.26 and amounts to 2.24 (m, 1H), 1,82 is 1.60 (m, 6H), 1.26 in - 1,02 (m, 2H).

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Example 8

3,4-[(N, N'-1,1'-(2"-Ethoxy-(3"'(O)-methylamin was obtained by replacement of nelfinavir on dimethylamine (58 mg, yield 75%). MS.

1H-NMR (CDCl3): of 10.93 (s, 1H), to 7.84 (s, 1H), to 7.77 (s, 1H), 7,69 - to 7.64 (m, 3H), 7,47 (d, J = 7,97 Hz, 1H), 7,13 - 7,02 (m, 4H), 4,40 - 4,11 (m, 4H), to 3.73 - 3,20 (m, 4H), of 2.50 (s, 3H), 2,33 (s, 1H), 2.13 and is 1.96 (m, 2H), 1,86 is 1.70 (m, 1H), 1,21 - 1,10 (m, 2H).

The following compounds were obtained in a manner analogous to the method described in the Examples of this application, and, in addition, illustrates the connection of the present invention. In the following examples, the structures of these compounds were confirmed by NMR analysis, MS and/or elemental analysis. In the process of synthesis R represents a protected hydroxy group, preferably silylating group, and more preferably, tert-butyldiphenylsilyl group (TBDPS). Silloway ether can be converted into a leaving group and substituted to obtain the following compounds (see examples 9 - 25r at the end of the description).

Example 26

3,4-[(N, N'-1,1'-(2-Methylene-6-methyleneimine)-bis-(3,3'- indolyl)-1H-pyrrole-2,5-dione

In accordance with the same procedure described in example 1, 2,3-bis-indomalaysia anhydride (287 mg, 0,88 mm) in 5 ml of dimethylformamide was treated with sodium hydride (60% in mineral oil, 88 mg, 2,19 mm) within one and a half hours, then diluted with dimethylformamide to volume of 11 l and was treated with bis-2,6-atively with ethyl acetate and filtered through a narrow tube of silica (50% EtOAc in hexane). Thus was obtained N,N-(2,6-pyridine-bridge link)-bis-indomalaysia anhydride (142 mg, 37%) as a dark red solid, which showed mainly one spot (TLC analysis) and was used directly in the next stage without additional purification.

3,4-[(N,N'-1,1'-(2-Methylene-6-methyleneimine)-bis-(3,3'- indolyl)-1H-furan-2,5-dione (140 mg, 0.32 mm) in 2 ml of DMF was treated with a mixture of 1,1,1,3,3,3-hexamethyldisilazane (to 0.72 ml, 3.2 mm) and CH3OH (0,063 ml, 1.6 mm), resulting after processing and purification using radial chromatography on silica gel was obtained 42 mg of the target compound, N,N'-(2,6-pyridine-bridge link)-bis - indomalaysia in Burgundy solid. This substance was homogeneous, as it was shown by TLC (Rf= 0,35, 3% CH3OH in CHCl3).

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Example 27

Hydrochloride, 3,4-[(N,N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'- indolyl)]-1(H)-pyrrole-2,5-dione

Dry dimethylformamide (45 ml) solution of dibromide, 2-(2"-bromoethoxy)-benzylbromide (2.0 g, 6.8 mm) and bis-(3,3'-indolyl)]-1(methyl)-pyrrole-2,5-dione (2.3 g, 6.8 mm), with a syringe and for 20 h was added to the suspension Cs2CO3(8,9 g, 27 mm) in dry DMF (550 ml), carefully stirring in nitrogen atmosphere. After 2 h the reaction is the first solution, after that was dried and concentrated in vacuo, resulting in a received purple oily substance. This oily substance was passed through a narrow tube of silicon dioxide, elwira hexane/ethyl acetate (1:1). Eluent was concentrated and received macrocyclic 3,4-[(N, N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'-indolyl)]-1-(methyl)- pyrrole-2,5-dione (2.76 g, 71% yield) as a purple solid dye. After recrystallization from isopropanol/methylene chloride was obtained analytically pure material.

MS: MW = 473; found: 473 (FD, CHCl3). EA: Calculated: C 76,09 (75,86); H 4,90 (4,93); N 8,87 (8,79).

To an ethanol (100 ml) solution of macrocyclic 3,4-[(N,N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'-indolyl)] -1-(methyl)- pyrrole-2,5-dione (710 mg, 15 mm) containing THF (20 ml), was added 5 N. KOH (80 ml). The reaction mixture was heated at 55oC for 70 h, stirred at this, and then cooled to room temperature and ethanol was removed in vacuum. The concentrate was acidified by adding 5 G. hydrochloric acid to pH 1 (325 ml), extracted with ethyl acetate, washed twice with saline, dried and concentrated in vacuo, resulting in a received anhydride, 3,4-[(N,N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'-indolyl)] -furan - 2,5-dione (700 mg, quantity, ,4-[(N,N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'-indolyl)] -furan - 2,5-dione (760 mg, 17 mm) was added methanol (0,34 ml, 8.3 mm) and 1,1,1,3,3,3-hexamethyldisilazane (3.5 ml, 17 mm). After a 22-hour heating at 55oC the reaction mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 0.1 G. of hydrochloric acid. The combined organic layer was dried and concentrated to obtain a purple residue. This residue was passed through a narrow tube with silica gel and was suirable CH2Cl2/hexane (gradient 0 to 100% CH2Cl2). After evaporation of the eluting solvent was received H-maleimide, 3,4-[(N,N'-1,1'-(2"-ethoxy)-benzyl)-bis-(3,3'-indolyl)] -1(H)- pyrrole-2,5-dione (483 mg, yield 70%) as a purple solid. The obtained target compound was led out of CH2Cl2/hexane. MS.

1H-NMR: (DMSO-d6): the 4.29 (2H, Shir.C), 4,59 (2H, Shir.C) 5,23 (2H, Shir. s), 6.90 to - 6,99 (2H), 7,01 - to 7.18 (3H), 7,20 - 7,27 (2H), to 7.59 - 7.68 per (2H), 7,71 - 7,80 (5H), 10,92 (H, C).

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Example 28

3,4-[(N,N'-1,1'-Hexane)-bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione

To a solution of 3,4-bis-(3-indolyl)]-1-methyl-pyrrole-2,5-dione (499 mg, 1,46 mm) in 10 ml of DMF, under nitrogen atmosphere, portions over 30 min was added sodium hydride (60% in oil, 146 mg, 3,65 mm). Received green solution was stirred tip the Reaction mixture was stirred 30 min at room temperature, and then was heated for 16 h at 45oC. the Cooled mixture was poured into dilute aqueous NH4Cl (125 ml) and was extracted with ethyl acetate (3 x 40 ml). The combined organic extracts were washed with water and dried with magnesium sulfate. After removal of solvent in vacuo, the residue was purified using flash chromatography on silica gel (eluent: gradient of CH2Cl2/hexane, 1 : 1 - 3 : 1), the result has been the target connection, namely, 3,4-[(N,N'-1,1'-hexane)-bis-(3,3'-indolyl)]-1-methyl-pyrrole-2,5-dione (137 mg, 22%) as a purple solid, so pl. > 320oC.

A mixture containing 3,4-[(N,N'-1,1'-hexane)-bis-(3,3'-indolyl)]-1-methyl-pyrrole-2,5-dione (137 mg, 322 mm), ethanol (15 ml), 5 N. KOH (5 ml) and THF (2 ml) was stirred for 4 h at room temperature. At this time TLC analysis indicated the possibility of running out of source material. The resulting mixture was diluted with water (15 ml) and concentrated on a rotary evaporator. The mixture was cooled, acidified 3 N. hydrochloric acid to pH 1 and extracted with methylene chloride (3 x 10 ml). The combined organic extracts were thoroughly washed with water, dried with anhydrous magnesium sulfate and concentrated. Received a purple solid (116 mg), identified by NMR analysis, predstavleniya stage without additional purification.

In accordance with the procedure described in example 1, a solution of 3,4-[(N, N'-1,1'-hexane)-bis-(3,3'-indolyl)-furan-2,5-dione (108 mg, to 0.263 mm) in DMF (1.5 ml), during the night and in the atmosphere of nitrogen was treated with a mixture of 1,1,1,3,3,3-hexamethyldisilazane (0,59 ml, 2,62 mm) and CH3OH (0.05 ml, 1,31 mm). After treatment with ethyl acetate, the crude product was subjected to flash chromatography on silica gel (elwira gradient of CH2Cl2/EtOAc, 10 : 1 - 5 : 1), as a result, we received two colored faction. First painted Polyana fraction contained 3,4-[(N,N'-1,1'-hexane)-bis-(3,3'-indolyl)-1-methyl-pyrrole-2,5-dione in the form of impurities, leaving the previous fractions. The colored fraction contained the desired product, 3,4-[(N,N'-1,1'-hexane)-bis-(3,3'-indolyl)-1H-pyrrole-2,5-dione (56 mg). So pl. > 320oC. MS.

Analysis for C26H32N3O2(0,3 H2O):

Calculated: C 76,26, H 5,66, N 10,26.

Found: C 75,21, H 5,65, N Of 10.05.

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Example 29

3,4-[(N,N'-1,1'-(3"-Benzylcarbamoyl)methylene)hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione

At 0oC to a dichloromethane solution of 3,4-[(N,N'-1,1'-(3"-(hydroxy)methylene)hexane)-bis-(3,3'-indolyl)] -1H - pyrrole-2,5-dione (24 mg, 0,054 mm) was added diisopropylethylamine (10,6 mg of 0.081 mm), and then benzylchloride (13,8 mg of 0.081 m who was agarawala dichloromethane. The combined organic layers were combined, washed with brine, dried with magnesium sulfate, filtered and concentrated to obtain an oily substance. This substance was purified using reverse-phase GHUR (5% acetonitrile in water/0.1% of TFA in 100% acetonitrile) on C18-columns, resulting in a received 6 mg of target compound. MS.

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Example 30

(a) 3,4-[(N, N'-1,1'-(3"-Benzyloxyethyl)hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione

In accordance with the same procedure described in the previous examples, 3,4-bis-(3'-indolyl)]-1-methyl-pyrrole-2,5-dione (400 mg, 1,17 mm) in 8 ml DMF was treated with sodium hydride (60% in oil, 117 mg of 2.93 mm), and then ()-3-benzoyloxymethyl-1,6-dibromohexane in 7 ml of DMF. After heating at 50oC during the night the crude product was treated and purified using flash chromatography on silica gel, elwira CH2Cl2/hexane(1 : 1 - 2 : 1), and got clean ()-3,4-[(N,N'-(3"-(benzoyloxymethyl)hexane)-bis- (3,3'- indolyl)] -1-methyl-pyrrole-2,5-dione (149 mg, 23%) as a purple solid.

A mixture containing (a) 3,4-[(N,N'-1,1'-(3"-benzyloxyethyl)hexane)-bis- (3,3'-indolyl)]-1-methyl-pyrrole-2,5-dione (141 mg, 0,259 mm), ethanol (15 ml) and 5 N. KOH (5 ml) was stirred at room temperary with methylene chloride, the crude product (101 mg) showed two spots (TLC analysis) (methylene chloride), corresponding to the source material and the desired anhydride ()-3,4-[(N,N'-1,1'-(3"-benzyloxyethyl)hexane)-bis-(3,3'-indolyl)] -furan-2,5-dione. By a rough estimate, NMR analysis indicated the presence of a mixture (4 : 1) of the anhydride and the source material. This material was used directly in the next stage without additional purification.

(a) 3,4-[(N, N'-1,1'-(3"-Benzyloxyethyl)hexane)-bis- (3,3'-indolyl)] -furan-2,5-dione (98 mg, 0,180 mm) in 1 ml DMF was treated with a mixture of 1,1,1,3,3,3-hexamethyldisilazane (0,41 ml, 1,80 mm) and CH3OH (0.036 ml, 0,90 mm) overnight at 25oC. thereafter, the mixture was treated with ethyl acetate and subjected to flash chromatography on silica gel (elwira gradient of CH2Cl2and then CH2Cl2- EtOAc, 10 : 1), resulting in received 30 mg of purified (a) 3,4-[(N, N'-1,1'-(3"-(benzyloxy)methylene)hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione, So pl. 171 - 173oC. MS.

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Example 31

3,4-[(N, N'-1,1'-(3"-(hydroxy)methylene)hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione

A mixture containing bis-(3,3'-indolyl)]-1-(methyl)-pyrrole-2,5-dione (3,41 g, 10.0 mm) and 3-tert-butyldiphenylchlorosilane-1,6-dibromohexane (5,64 g, 11,0 mm) in 50 ml of DMF, under nitrogen atmosphere with Pomos,3 mm) in DMF (350 ml). After complete addition, the reaction mixture was heated at 55oC for another 16 h Then cooled mixture was poured into 1.2 l of water containing 20 ml of 3 N. hydrochloric acid, then was extracted with 300-ml portions of methylene chloride. The combined organic extracts were washed with water and brine, and then dried with magnesium sulfate and concentrated. The residue was passed through a column (3 of 3) silica gel, elwira chloroform. Thus obtained crude product was purified using flash chromatography on silica gel (eluent: CHCl3), resulting in a received 2,87 g (41%) of 3,4-[(N,N'-(3"-tert-butyldiphenylchlorosilane)-hexane)-bis- (3,3'-indolyl)] -1-(methyl)-pyrrole-2,5-dione as a purple solid, so pl. 220 - 224oC.

VRMS for C44H45N3SiO [M + 1]:

Calculated: 6923307.

Found: 6923299.

A mixture containing 3,4-[(N,N'-1,1'-(3"-tert-butyldiphenylchlorosilane)-hexane)-bis- (3,3'-indolyl)] -1(H)-methyl-pyrrole-2,5-dione (1.55 g, 2,22 mm), 4 H. KOH (100 ml), THF (10 ml) and 95% EtOH (200 ml) was heated for 16 h at 90oC. After removal of the greater part of EtOH on a rotary evaporator, the mixture was acidified to pH 1 by adding 6 N. hydrochloric acid, and then extracted with methylenchlorid the aqueous sodium sulfate. After removal of solvent in vacuo, the resulting residue was dissolved in a minimum amount of 5% methanol in CHCl3and was placed on 3" 3"-a column of silica gel. After elution with chloroform, and then 100% methanol in chloroform received two factions. After evaporation the second fraction was obtained anhydrous alcohol in the form of a purple solid, which was homogeneous, as it was shown by TLC (Rf= 0,5; 10% methanol in CHCl3). This substance is used directly in the next stage without additional purification.

To a solution of the above anhydride (510 mg, 1.15 mm) in DMF (11 ml) was added a pre-mixed solution containing 1,1,1,3,3,3-hexamethyldisilazane (5,14 ml, 23 mm) and CH3OH (0.45 ml, 11.5 mm). The resulting mixture was heated for 24 h at 50oC) in nitrogen atmosphere. The cooled reaction mixture was poured into 100 ml of water. The precipitated product was washed with water and drained during the night, resulting in a received 409 mg of 3,4-[(N,N'-1,1'-(3"-hydroxymethylene)-hexane)-bis-(3,3'-indolyl)] -1H - pyrrole-2,5-dione in the form of a reddish purple solid. In accordance with reversed-phase GHUR-analysis, this substance had 93% purity with impurity unidentified compounds with analgine: 4391911.

Example 31r

(R)-3,4-[(N, N'-1,1'-(3"-(Hydroxymethylene)-hexane)-bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione

In accordance with the procedure described above in example 31, (R)-3,4-[(N, N'-1,1'-(3"-(hydroxymethylene)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione was obtained with a full 25% of the output of the dibromide, (R)-3-(tert-butyldiphenylchlorosilane)-1.6 - dibromohexane by dialkylamide bis-(3,3'-indolyl)] -1-(methyl)-pyrrole-2,5-dione, followed by hydrolysis and the formation of 1-H-pyrrole-2,5-dione, so pl. > 300oC.

1H-NMR (300 MHz, DMSO-d6): of 1.05 to 2.25 (m, 7H), Android 4.04 is 4.45 (m, 6H), (m, 8H), 7,08 - 7,88 (m, 10H).

Example 31s

(S)-3,4-[(N, N'-1,1'-(3"-(Hydroxymethylene)-hexane)-bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione

In accordance with the same procedure described above in example 31, (S)-3,4-[(N, N'-1,1'-(3"-(hydroxymethylene)-hexane)-bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione was obtained (4.5 g) with a full 39% yield from dibromide, (S)-3-(tert-butyldiphenylchlorosilane)-1.6 - dibromohexane by dialkylamide bis-(3,3'-indolyl)] -1-(methyl)-pyrrole-2,5-dione, followed by hydrolysis and the formation of 1-H-pyrrole-2,5-dione. MS.

1H-NMR (d6-DMSO): 1,05 was 2.25 (2H), 1,23 - 1,24 (1H), 1,50 - of 1.52 (1H), 1,71 (1H), 1,94 (1H), 2,07 - 2,12 (1H), 4,05 - 4,4 (m, 6H), 7,09 - 7,21 (m, 4H), 7,35 (d, J = 15 Hz, 2H), 7,49 (d, J = 9 Hz, 2H), 7,8 (d, J = 9 Hz, 2H)dione of example 32 as a TFA-salt and example 33 as a HCl-salt

To a stirred solution of anhydrous alcohol, 2,3-[(N,N'-1,1'-(3"-(hydroxymethylene)-hexane)-bis-(3,3'- indolyl)]-furan-1,4-dione (0.18 g, 0,41 mm) in anhydrous dichloromethane (10 ml) under nitrogen atmosphere was added triethylamine (0.10 g, 1,06 mm) and methanesulfonamide (0.11 g, 0,98 mm). The resulting solution was stirred 30 min at room temperature. The solvent was removed in vacuum. The resulting residue was dissolved in 10 ml of anhydrous dimethylformamide, and then was added sodium azide (0.26 g, 4.1 mm). The reaction mixture was heated in nitrogen atmosphere at 50oC for 1.5 hours then cooled reaction mixture was distributed between 0.2 N. hydrochloric acid and ethyl acetate. The combined organic extract was dried with magnesium sulfate, filtered and evaporated, resulting in a received 185 mg azide, which is used directly in the next reaction. This crude azide was dissolved in dimethylformamide (3 ml) and under nitrogen atmosphere was added 1,1,1,3,3,3-hexamethyldisilazane (1,25 g of 7.75 mm) and methanol (0.12 g, a 3.87 mm). The resulting reaction mixture was heated at 50oC. After 12 h the reaction mixture was cooled, diluted with ethyl acetate, washed with water, and then 2 N. hydrochloric acid. Water washing was subjected to reverse extraction etilize is those which received azide-imide, 3,4-[(N,N'-1,1'-(3"-azidomethyl)-hexane)-bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione (175 mg) as a purple solid. This substance was chromatographically C18-column (Rainin Dynamex R-60 (21,4 x 250 cm) using a linear gradient from 80% A (0.1% of TFA and 5% acetonitrile in water) to 100% B (pure acetonitrile) over 60 minutes at 15 ml/min was Thus given a purified 3,4-[(N, N'-1,1'-(3"-azidomethyl)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione with a full 57% yield. MS. NMR.

To a solution of azide, 3,4-[(N,N'-1,1'-(3"-azidomethyl)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione (0.1 g, 0.21 mm) in ethyl acetate (15 ml) and ethanol (5 ml) was added 0.1 g of Lindlar catalyst. Then the reaction mixture was stirred under the hydrogen pressure of 1 atmosphere at room temperature. After 12 h the catalyst was removed by filtration and concentrated in vacuum. After purification using preparative reversed-phase GHUR C18-columns (Rainin Dynamex R-60) (21,4 x 250 mm) using a linear gradient from 80% A (0.1% of TFA and 5% acetonitrile in water) to 100% B (pure acetonitrile) over 60 min at a flow rate of 15 ml/min, received primary amine as TFA-salt, namely, triperoxonane salt of 3,4-[(N, N'-1,1'-(3"-aminomethyl)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione at 1.34 (m, 1H), USD 1.43 (m, 1H), 1,52 - of 1.65 (m, 4H), 1,60 by 1.68 (m, 1H), 1,90 - of 1.94 (m, 1H), 3,17 - is 3.21 (m, 1H), 3,35, to 3.38 (m, 1H), 3,64 - to 3.67 (m, 1H), 3.75 to 3,82 (m, 2H), 6,61 - 6,72 (m, 4H), 6,824 (d, J = 16 Hz, 2H), 6,936 (t, J = 8,31 Hz, 2H), 7,397 (t, J = 7,83 Hz, 2H), and 9.3 (s, 1H).

13C-NMR (d6-acetone): 26,0, 28,0, 32,1, 35,4, 40,8, 41,0, 41,1, 45,1, 45,8, 50,9, 105,1, 105,2, 110,8, 111,0, 121,24, 121,29, 122,7, 122,9, 123,0, 128,4, 128,6, 131,5, 132,0, 134,0, 134,1, 136,8, 137,1, 172,6, 172,7, 192,5.

< / BR>
Example 34

Trichoroethane salt of 3,4-[(N, N'-1,1'-(3"-N-benzylamino) methylene)-hexane)-bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione

In a nitrogen atmosphere to a stirred solution of the primary amine, 3,4-[(N, N'-1,1'-(3"-aminomethyl)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione (40 mg, 0.05 mm) in anhydrous THF was added benzaldehyde (9,39 mg, 0.08 mm). After 30 min, to the mixture was added triacetoxyborohydride sodium (18,75 mg, 0.08 mm). After an hour of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated in vacuum. After purification using reversed-phase GHUR C18-columns (Rainin Dynamex R-60) (21,4 x 250 mm) using a linear gradient from 80% A (0.1% of TFA and 5% acetonitrile in water) to 100% B (pure acetonitrile) over 60 min and 15 ml/min, received two different fractions of monobenzylether the I) dibenzylamino connection, namely, 3,4-[(N, N'-1,1'-(3"-(N,N-dibenzylamino)methylene)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione (7 mg, yield 20%). MS.

1H-NMR (d6-acetone): 1,1 - 1,3 (m, 1H), a 1.5 - 1.6 (m, 1H), 1,71 - to 1.77 (m, 1H), 1.93 and is 2.10 (m, 3H), 2,5 (m, 1H), 3,1 - 3,2 (m, 1H), 3,37 - to 3.41 (m, 1H), 3,37 - to 3.41 (m, 1H), 4,13 (t, J = 5,1 Hz, 2H), 4,28 (t, J = 5,1 Hz, 2H), 4,36 (d, J = 3,6 Hz, 2H), 7,13 - 7,24 (m, 4H), 7,33 (d, J = 25 Hz, 2H), 7,39 - 7,51 (m, 7H), 7,89 - of 7.96 (m, 2H), 9,76 (s, 1H).

13C-NMR (d6-acetone): 25,6, 27,3, 32,1, 32,9, 44,7, 45,4, 50,1, 52,2, 105,0, 105,2, 110,8, 111,1, 121,8, 121,3, 122,8, 122,9, 123,1, 128,5, 129,8, 130,3, 131,2, 131,3, 132,0, 132,4, 133,7, 134,0, 136,8, 137,0, 172,5, 172,6.

< / BR>
Example 35

3,4-[(N, N'-1,1'-(3"-(N, N-Dibenzylamino)methylene)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione trichoroethane salt

In accordance with the method described in example 34, there was obtained 3,4-[(N, N'-1,1'-(3"-(N,N-dibenzylamino)methylene)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione. MS.

1H-NMR (d6-acetone): 0,2 - 0,3 (m, 1H), 0.6 to 0.9 (m, 4H), 1,2 - 1,3 (m, 1H), 1,50 (d, J = 5.4 Hz, 2H), and 2.27 (m, 1H), 3,3 - 3,8 (m, 8H), 6,6 - 6,9 (m, 18H), 7,35 (DD, J = 7.5 Hz, J = 24,9 Hz, 2H), and 9.1 (s, 1H).

< / BR>
Example 36r

(R)-3,4-[(N, N'-1,1'-(3"-(N-Pyrrolidino)methylene)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione cleaners containing hydrochloride salt

The stirred mixture nelfinavir, (R)-3,4-[(N,N'-1,1'-(3"-(methanesulfonate)methylene)-hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione (202 mg) and Pyrrhus what about the material (16 h). After this was added EtOAc (30 ml). The organic phase is washed with 10-ml portions of 5% aqueous sodium bicarbonate, water and brine. In the concentration was obtained a dark red residue, which was subjected to preparative GHUR (reversed-phase column Waters of 0.1% TFA and 5% CH3CN in water/100% CH3CN), which was obtained pure (R)-3,4-[(N, N'-1,1'-(3"-(N-pyrrolidinyl)-hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione as its TFA-salt. Similarly, the transformation of the TFA-salt in the HCl-salt was obtained (R)-3,4-[(N,N'-1,1'-(3"-(N-pyrrolidinyl)-hexane)-bis- (3,6'-indolyl)] -1H-pyrrole-2,5-dione cleaners containing hydrochloride salt (42 mg) as a pale red solid product, so pl. 220oC (Razlog.).

VRMS for C31H33N4O2[M + 1]:

Calculated: 4932604.

Found: 4932605.

< / BR>
Example 37

3,4-[(N, N'-1,1'-(3"-Methoxymethyl)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione

A solution of 3,4-[(N, N'-1,1'-(3"-tert-butyldiphenylchlorosilane)-hexane)-bis- (3,3'-indolyl)]-1(methyl)-pyrrole-2,5-dione (1.25 g, 1,81 mm) in THF (20 ml) was treated with a solution of fluoride, Tetra-n-butylamine in THF (1 M, 2.0 ml, 2.0 mm). The resulting mixture was stirred for one hour at 25oC. then the reaction mixture was extinguished cue layer was dried with magnesium sulfate and concentrated. The resulting residue was purified using flash chromatography on silica gel, elwira 3 - 5% methanol in a mixture of THF/hexane (1 : 1), resulting in a received alcohol, 3,4-[(N,N'-1,1'-(3"-hydroxymethylene)-hexane)-bis- (3,3'-indolyl)] -1(methyl)-pyrrole-2,5-dione (509 mg, 62%) as a purple solid. This substance is used directly in the next stage. To the mixed solution containing the above alcohol (285 mg, 0,63 mm) and 47% aqueous triptorelin acid (170 mg of 0.95 mm) in methylene chloride (6 ml), at 0oC, drop by drop within 5 min was added to the solution trimethylsilyldiazomethane (Aldrich, 2.0 M hexane, to 0.47 ml of 0.95 mm). The resulting mixture was stirred at 0oC for 2 h and then at 25oC for 4 hours TLC analysis of the reaction mixture indicated the presence of a large amount of unreacted starting material. After that, the mixture was cooled and added additional number (1 EQ.) trimethylsilyldiazomethane acid. Then this mixture was stirred for 2 h at 0oC, and then stirred 6 h at 25oC. the resulting mixture was diluted with methylene chloride (20 ml), then washed with water (10 ml) and 2 N. hydrochloric acid (10 ml). The organic layer was dried with magnesium sulfate and kontsentrirovannoy ether, 3,4-[(N, N'-1,1'-(3"-methoxymethyl)-hexane)-bis- (3,3'-indolyl)] -1(methyl)-pyrrole-2,5-dione (114 mg, 39%) as a reddish-purple solid, so pl. 234 - 236oC NMR.

VRMS for C29H29N3O3:

Calculated: 4672208.

Found: 4672210.

A mixture of 3,4-[(N,N'-1,1'-(3"-methoxymethyl)-hexane)-bis- (3,3'-indolyl)] -1(methyl)-pyrrole-2,5-dione (110 mg, 0,243 mm) and 5 N. KOH (8 ml) in 15 ml EtOH containing 1 ml of THF was heated at 90oC for 24 h After removal of the greater part of the ethanol under reduced pressure, the mixture was acidified using 6 N. hydrochloric acid to pH 1 and then extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were washed with diluted aqueous sodium hydrogen carbonate solution and water, then dried with anhydrous magnesium sulfate. After removal of solvents in vacuo, the crude product was loaded onto 2" 2"-a column of silica gel (elwira with methylene chloride), resulting in a received anhydride, which is used directly in the subsequent stage.

To the solution obtained anhydride (76 mg, 0.17 mm) in DMF (1.5 ml) was added a pre-mixed for 5 min a solution of 1,1,1,3,3,3-hexamethyldisilazane (0.75 ml, 3,34 mm) and CH3OH (0,07 ml, 1,67 mm). The resulting reaction is Noah completion of the reaction. The cooled reaction mixture was treated with ethyl acetate. The crude product was purified using flash chromatography on silica gel (elwira gradient of methylene chloride to 4% ethyl acetate in methylene chloride), which was obtained 42 mg (55%) of 3,4-[(N, N'-1,1'-(3"-methoxymethyl)-hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione as a dark red solid. After recrystallization from acetone/water was obtained 28 mg of analytically pure 3,4-[(N,N'-1,1'-(3"-methoxymethyl)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione in the form of reddish-purple solid, so pl. 272 - 274oC.

Analytical elemental analysis for C28H27N3O3(0,1 H2O):

Calculated: C 73,86; H Of 6.02; N 9,23.

Found: C 73,51; H Of 5.92; N 8,99.

< / BR>
Example 38

3,4-[(N, N'-1,1'-(3"-(Acetoxy)methylene)-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione

To a stirred mixture of the anhydride, 2,3-[(N,N'-1,1'-(3"-(hydroxymethylene-hexane)-bis-(3,3'-indolyl)] - furan-1,4-dione (1,49 mg, 0,34 mm), 4-dimethylaminopyridine (27 mg, 0.22 mm), pyridine (0.75 ml) and THF (1.5 ml) was added acetic anhydride (0,064 ml, 0.68 mm). The resulting reaction mixture was stirred for 16 h under nitrogen atmosphere and at 25oC. Then the mixture was diluted with 20 ml EtOAc was washed 2 N. hydrochloric Ki is she under reduced pressure, the crude product was purified by chromatography on a narrow column of silica gel, elwira with methylene chloride, which was received On acetate anhydride 2,3-[(N,N'-1,1'-(3"-(acetoxymethyl)-hexane)- bis-(3,3'-indolyl)]-furan-1,4-dione (111 mg, 68%) as a purple solid, so pl. 252 - 254oC.

To a stirred solution Of acetate anhydride, 2,3-[(N,N'-1,1'-(3"-(acetoxymethyl)-hexane)-bis-(3,3'-indolyl)]- furan-1,4-dione (103 mg, 0.22 mm) in DMF (2 ml) was added a pre-mixed for 5 min a solution containing 1,1,1,3,3,3-hexamethyldisilazane (of 0.48 ml, 2.2 mm) and CH3OH (0,043 ml, 1.1 mm). The resulting reaction mixture was treated with ethyl acetate and the crude product was purified using flash chromatography on silica gel, elwira gradient of CH2Cl2- 5% EtAOc in CH2Cl2, resulting in a received On-acetylmuramic, 3,4-[(N,N'-1,1'-(3"-(Acetoxy)methylene-hexane)-bis-(3,3'-indolyl)] - 1H-pyrrole-2,5-dione (74 mg, 72%) as a dark red solid, which was homogeneous, as evidenced by TLC (methylene chloride). After recrystallization from acetone/water was obtained target compound as a red solid, so pl. 250 - 252oC.

Elemental analysis for C29H27N3

Example 40r

(R)-3,4-[(N, N'-1,1'-(3"-(N,N-Dimethylamino)methylene-hexane)- bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione cleaners containing hydrochloride salt

At 0oC to a stirred solution of chiral alcohol (R)-3,4-[(N,N'-1,1'-(3"-(hydroxy)methylene-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione (200 mg, 0.45 mm) and pyridine (0,11 ml of 1.35 mm) in methylene chloride (5 ml) for 10 min was added methanesulfonyl anhydride (84 mg, 0,54 mm). The resulting reaction mixture was stirred at 25oC for 4 h and Then was added methylene chloride (20 ml) and the mixture is washed with 10-ml portions of 3% hydrochloric acid, water and brine. After drying with anhydrous magnesium sulfate and removal of solvent in vacuo left the crude mesilate (205 mg), which was homogeneous, as evidenced by TLC (1% methanol in CHCl3). This material was used directly in the subsequent stage.

To the solution obtained nelfinavir (205 mg) in 10 ml THF was added a 40% aqueous solution of di is the t, to the residue was added 20 ml of methylene chloride. After that, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution, water and brine, and then dried with anhydrous magnesium sulfate. After concentration was obtained the crude (R)-3,4-[(N, N'-1,1'-(3"-(N, N-dimethylamine)methylene-hexane)-bis-(3,3'- indolyl)]-1H-pyrrole-2,5-dione (158 mg) as a red solid, which was purified using preparative GHUR (reversed-phase column, Waters), elwira gradient of 0.1% TFA and 5% CH3CN in water - 100% CH3CN, and received amine - TFA salt. This material was dissolved in methylene chloride and was transformed into the free base using dilute aqueous KOH. After drying the organic phase with magnesium sulfate (15 min), the solvent evaporated, and the free amine (60 mg) was dissolved in a mixture of methanol/THF (5 ml) (1:1), cooled to 0oC in nitrogen atmosphere and slowly acidified by adding 1 N. hydrochloric acid in ether to pH 4 - 5, using indicator paper to determine the pH (wetted surface). The precipitated salt was filtered and washed with dry ether in a stream of nitrogen, and then was dried in vacuum overnight to decompose CaSO4. Thus received dimethylaminohydrolase salt, (R)-3,4-[(N,N'-1,1'-(3"-(N,N-DIMET the Dogo substances, so pl. 230oC (decomposition). MS.

1H-NMR (300 MHz, acetone-d6): of 0.9 to 3.5 (m, 7H), 3,20 - of 3.42 (m, 8H), 4,05 - 4,18 (m, 4H), 7,02 - 7,80 (m, 10H), 10,94 (s, 1H).

Example 40s

(S)-3,4-[(N, N'-1,1'-(3"-(N,N-Dimethylamine)methylene)-hexane)-bis- (3,3'-indolyl)]-1H-pyrrole-2,5-dione cleaners containing hydrochloride salt

In accordance with the same procedure described in Example 40r, (S)-3,4-[(N, N'-1,1'-(3"-(N, N-dimethylamine)methylene-hexane)-bis- (3,3'-indolyl)] -1H-pyrrole-2,5-dione cleaners containing hydrochloride salt (90 mg) was obtained with a full 27% yield from the alcohol (S)-3,4-[(N,N'-1,1'-(3"-hydroxymethylene)-hexane)bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione by education nelfinavir, then replace it on the dimethylamine. MS.

1H-NMR (d6-DMSO) 0,92 (broad singlet, 1H) 1,35 (Shir. S., 1H), 1,60 (Shir. S. , 2H), 1,85 (Shir.S., 1H) 2,37 - to 2.42 (m, 2H), 2.91 in was 3.05 (m, 2H), 4,13 (Shir. S., 2H), 4,23 (Shir.S., 2H), 7,11 - of 7.23 (m, 4H), 7,34 (d, J = 20 Hz, 2H), 7,50 (DD, J = 8,1 Hz, J = 12,6 Hz, 2H), 7,79 (d, J = 8 Hz, 2H), 9,92 (Shir.S., 1H), 10,98 (1H, s).

< / BR>
Example 41

3,4-[(N, N'-1,1'-(3"-(N-imidazole)methylene)-hexane)-bis-(3,3'- indolyl)] -1H-pyrrole-2,5-dione

To a mixed solution containing 3,4-[(N,N'-1,1'-(3"- (hydroxy)methylene)-hexane)-bis-(3,3'-indolyl)] -1H-pyrrole-2,5-dione (100 mg, 0.23 mmol) and triethylamine (0.05 ml, 0.36 mm) in anhydrous CHCl3in nitrogen atmosphere, at 25oC drop we use>
, washed with water and brine, and then dried, filtered and concentrated. The resulting residue was purified by chromatography on a narrow column of silica gel, elwira chloroform, and then 10% ethyl acetate in chloroform. Thus obtained 3,4-[(N,N'-1,1'-(3"-methanesulfonylaminoethyl)-hexane)- bis-(3,3'-indolyl)] -1H-pyrrole-2,5-dione (53 mg) as a red solid, which was homogeneous, as it was shown by TLC (5% EtOAc in CH2Cl2).

To a stirred solution of 3,4-[(N,N'-1,1'-(3"-(methanesulfonate)methylene)-hexane)- bis-(3,3'-indolyl)] -1H-pyrrole-2,5-dione (49 mg, 0,095 mm) in DMF (0.75 ml) in nitrogen atmosphere at a drop of solution was added sodium salt of imidazole in dimethylformamide (obtained by adding 60% NaH (8,7 mg, 0.22 mm) to a solution of imidazole (16 mg, 0.24 mm) in DMF (0.5 ml)). The resulting reaction mixture was stirred 15 min at 25oC, and then heated at 50oC for 30 minutes then the reaction mixture was diluted with 25 ml of methylene chloride containing 3% methanol. The mixture is then washed with 10-ml portions of water and brine, then was dried with anhydrous sodium sulfate. After evaporation of the solvents under reduced pressure, the crude product was loaded onto 3 is ylamine. The result of this procedure was obtained 3,4-[(N, N'-1,1'-(3"-(N-imidazole)methylene)- hexane)-bis-(3,3'-indolyl)] -1H-pyrrole-2,5-dione (21,5 mg, 46%) as a red solid. This substance was subjected to reversed-phase GHUR (gradient 5% CH2CN in water containing 0.1% TFA/CH3CN), which was obtained analytically pure 3,4-[(N,N'-1,1'-(3"-(N-imidazole)methylene)-hexane)- bis-(3,3'-indolyl)]-1H-pyrrole-2,5-dione (12,4 mg) as a red solid, so pl. 261 - 266oC. NMR.

VRMS for C30H27N5O2[M + 1]:

Calculated: 4902244.

Found: 4902242.

The following compounds were obtained in a manner analogous to the method described in the Examples of this application, and, in addition, illustrates the connection of the present invention. In the following examples, the structure of these compounds is confirmed by NMR analysis, MS and/or elemental analysis (examples 42 - 49 see the end of the description).

Example 50

3,4-[(N, N'-1,1'-(Propertyproxy))-bis-(3,3'-indolyl)]-1H-pyrrole - 2,5-dione

To a stirred anhydrous methylenechloride (1.0 l) to a solution of N-(3-acetoxyphenyl)-indole (102 g, 0,47 M), at 0oC one drop was added oxalicacid (43,04 ml, 0,494 M of 1.05 EQ.). After 15 min the ice bath was removed. The resulting reaction mixture is Yali in vacuum, as a result, we got a solid purple dye, which was again dissolved in dry methylene chloride (1.0 l) under nitrogen atmosphere. With vigorous stirring, to the solution was added N-tert-butoxycarbonyl-indole-3-acetic acid (129,25 g, 0,47 M), then quickly added triethylamine (to 130.6 ml of 0.94 M, 2 EQ.). After 16 h the reaction mixture was concentrated and purified using flash chromatography on silica gel (eluent: hexane/ethyl acetate, 3:1). Major colored fraction was concentrated and received anhydride, 2-[1-(3-acetoxyphenyl)-3-indolyl] -3-[1-tert-butoxycarbonyl-3 - indolyl] -furan-1,4-dione (101 g, 40% yield) as crystalline red solid. MS.

To the BOC-protected anhydride (7.4 g, 14 mm) with stirring was added triperoxonane acid (27 ml, 350 mm) containing ethanthiol (1 ml, 14 mm). After one hour the reaction mixture was distributed between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with saline, dried with sodium sulfate and filtered. The filtrate was concentrated and received untreated unlocked anhydride in a red half-solid. This substance was passed through a narrow layer of silicon dioxide by washing with hexane, and then methylaniline which has received cleared unlocked anhydride, 2-[1-(acetoxymethyl)-3-indolyl] - 3-(3-indolyl)-furan-1,4-dione (5.7 g, 95% yield) as a red solid. MS.

To a stirred anhydrous dimethylformamide (125 ml) solution unlocked anhydride (3.0 g, 7 mm) at room temperature was added NaH (420 mg, 10.5 mm, 60% in mineral oil). There was observed a change of a bright orange colour to purple. After 30 min was quickly added 3 EQ. 3-bromopropylamine. The resulting reaction mixture was heated to 75oC, which led to the gradual emergence of an orange hue. After 6 hours, the dimethylformamide was removed in vacuum. The residue was loaded on a flash column with silica, elwira hexane/ethyl acetate (3:2). Major red layer was collected and the solvent evaporated, resulting in a received alkilirovanny anhydride, 2,3-bis[1-(3-acetoxyphenyl)-3-indolyl] -furan - 1,4-dione (1,36 g, 36%) as a red solid. MS.

2,3-Bis[1-(3-acetoxyphenyl)-3-indolyl]-furan-1,4-dione (1,32 g, 2,52 mm) suspended in absolute ethanol (125 ml), while stirring, and then was treated with 125 ml of 5 N. KOH. After 16 hours stirring, the reaction mixture was concentrated to a volume of 126 ml of the Resulting residue was slowly acidified 5 N. hydrochloric acid to P>oC, resulting in the received liquid anhydride (1.1 g, 99%) as a red powder.

In nitrogen atmosphere alcoholic anhydride (1.1 g, 2,47 mm) was dissolved in anhydrous DMF (30 ml), stirring the while. After this was added a pre-mixed solution of 1,1,1,3,3,3-hexamethyldisilazane (5,22 ml of 24.7 mm, 10 EQ.) and methanol (0,50 ml of 12.4 mm, 5 EQ.). The resulting reaction mixture was left for stirring at room temperature for 16 hours, the Dimethylformamide was removed in vacuum. To the resulting residue were added 100 ml of acetone and about 500 mg of excess CsF. After 4 hours stirring, the reaction mixture was concentrated. The resulting residue was distributed between ethyl acetate and water. The organic layer was washed 5 times with 1 N. hydrochloric acid and 2 times with saline, then was dried with sodium sulfate and filtered. The filtrate was concentrated to obtain bisengaliyevich, 3,4-bis[1-(3-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione (1.0 g, yield 91%) as a red powder. The total yield of the 2 stages was 90%. MS.

In nitrogen atmosphere, 3,4-bis[1-(3-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione (1.0 g, 2.25 mm) was dissolved in anhydrous methylene chloride (250 ml) PR is spin (2.83 g, 10.8 mm, 4.8 EQ.). The resulting mixture was left for 16 h under stirring. The crude reaction mixture was concentrated and purified using flash chromatography on a column of silica gel (eluent: hexane/ethyl acetate, 7:3). Thus received Polyany major red layer. After removal of the solvents from the layer received dibromo connection 3,4-bis[1-(3-bromopropyl)-3-indolyl]-1H-pyrrole-2,5-dione (876 mg, yield 68%) as a red powder.

Dibromo connection (to 47.8 mg, 0,084 mm) was dissolved in acetone at room temperature, while stirring. Then to the mixture was added excess nonahydrate of sodium sulfide (229 mg of 0.95 mm, 11,3 EQ.). The resulting mixture was stirred overnight, after which the acetone was removed in vacuum. The residue was distributed between water and methylene chloride. The organic layer was washed with saline, dried with sodium sulfate and concentrated, resulting in received of 35.5 mg (yield 94%) of the desired product as a red-orange solid. MS.

< / BR>
Example 51

3,4-[(N, N'-1,1'-(3"-(Hydroxy)methylene)pentane)-bis-(3,3'-indolyl)] - 1(H)-pyrrole-2,5-dione

When 55oC and under nitrogen atmosphere anhydrous dimethylformamide (35 ml) RAS g, 12 mm) with a syringe within 48 h was added to the suspension Cs2CO3(16,06 g, 49.3 mm) in anhydrous dimethylformamide (1 l), vigorously stirring the while. After 2 h the reaction mixture was concentrated in vacuo to obtain a residue. This residue was dissolved in methylene chloride, then washed with 1 N. hydrochloric acid, brine, and then dried and concentrated in vacuum to obtain purple oily substance. The obtained oily substance was passed through a plug of silica (eluent: hexane/ethyl acetate, 4: 1). After concentration of eluent received macrocyclic product, 3,4-[(N, N'-1,1'-(3"-(tert-butyldiphenylchlorosilane) pentanyl)-bis-(3,3'-indolyl)] -1(methyl)-pyrrole-2,5-dione (4.5 g, 55% yield) as a solid Magenta dye.

To an ethanol (300 ml) suspension of 3,4-[(N,N'-1,1'-(3"-(tert-butyldiphenylchlorosilane)pentanyl)- bis-(3,3'-indolyl)]-1(methyl)-pyrrole-2,5-dione (4,2 g, 6.2 mm) was added to 300 ml of 5 N. KOH. The resulting reaction mixture was heated under reflux (86oC) within 48 hours After mixing, cooling to room temperature and removal of the ethanol in vacuo received concentrate. This concentrate was acidified to pH 1 by adding 325 ml 5 N. hydrochloric cipalities residual anhydride, 3,4-[(N, N'-1,1'-(3"-(hydroxymethylene)pentane)- bis-(3,3'-indolyl)]-furan-2,5-dione (2.6 g, 100% yield).

To anhydrous dimethylformamide (500 ml) solution of the anhydride of 3,4-[(N, N'-1,1'-(3"-(hydroxymethylene)pentanyl)- bis-(3,3'-indolyl)]-furan-2,5-dione (2.6 g, 6.2 mm) solution was added to methanol (1,21 ml, 31 mm) and 1,1,1,3,3,3-hexamethyldisilazane (13.1 ml, 62 mm). After the 36-hour heating at 55oC the reaction mixture was concentrated in vacuum, diluted with ethyl acetate and washed with 1 N. hydrochloric acid. Acid washing, contain some amount of solids was subjected to reverse extraction with chloroform. The combined organic layers were dried and concentrated to obtain a purple residue. This residue was loaded on a thin layer of silica (eluent 2 to 10% MeCN/CH2Cl2). After elution, the fractions containing the major product were concentrated in vacuo, resulting in a received target alcohol, 3,4-[(N,N'-1,1'-(3"-(hydroxymethylene)pentanyl)- bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione 650 mg, 25%) as a solid Magenta dye. MS.

1H-NMR (DMSO-d6): 0,7 (m, 1H), 1,48 (m, 2H), equal to 1.82 (m, 2H), 3,19 (DD, 2H), 4.16 the (m, 4H), 4,4 (t, 1H), 7,05 (t, 2H), 7,16 (t, 2H), 7,46 (d, 2H), 7,17 (s, 2H), 7,65 (d, 2H), 10,96 (s, 1H).

< / BR>
Example 52

3,4-[(N, N'-1,1'-(3"-(� (80 ml) solution of 3,4-[(N,N'-1,1'-(3"-(hydroxymethylene)pentane-1", 5"-yl)-bis- (3,3'-indolyl)]-1(H)-pyrrole-2,5-dione (334120) (650 mg, 1.5 mm) was added methanesulfonyl anhydride (400 mg, to 2.29 mm), and then excess amount of pyridine (370 ml, 4,58 mm). After 16-hour sedimentation at room temperature, the reaction mixture was placed in a narrow tube with silicon dioxide and suirable with a mixture of 0 - 7% MeCN/CH2Cl2. Colored fraction was concentrated in vacuo and received mesilate, 3,4-[(N,N'-1,1'-(3"-(methanesulfonate)methylene)pentane-1",5"-yl)-bis- (3,3'-indolyl)]-1(H)-pyrrole-2,5-dione (501 mg, yield 67%) as a purple solid. MS.

1H-NMR (DMSO-d6): 0,89 (m, 1H), 1,61 m, 2H), equal to 1.82 (m, 2H), 2,99 (s, 3H), was 4.02 (d, 2H), 4,22 (m, 4H), 7,06 (t, 2H), 7,17 (t, 2H), 7,17 (s, 2H), 7,54 (d, 2H), 7,63 (d, 2H), 10,98 (s, 1H).

< / BR>
Example 53

3,4-[(N, N'-1,1'-(3"-(Aminomethyl)pentane-1", 5"-yl)- bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione cleaners containing hydrochloride salt

In a sealed reaction vessel containing tertrahydrofuran ring (20 ml) solution of nelfinavir, 3,4-[(N,N'-(methanesulfonate)methylene)pentane-1", 5"-yl)-bis- (3,3'-indolyl)]-1(H)-pyrrole-2,5-dione (250 mg, 0.5 mm), was added aqueous 33% solution of NH4OH (10 ml), the reaction vessel was tightly closed and then heated at 60oC. After 48 h the reaction mixture was cooled and was suirable through the tube of whether reddish solid residue. Part of this residue was purified using reverse-phase gel permeation GHUR (85% MeCN/water, 0.01% of TFA). Pure fractions were collected and concentrated to obtain a red solid. Then this solid substance was distributed between ethyl acetate and 0.1 G. of NaOH. The organic layer was concentrated to obtain the free base as a residue. The resulting residue was dissolved in methanol (2 ml), and within hours was treated with hydrochloric acid (2 ml, 1.0 M in ether). The reaction mixture was concentrated in vacuo and got 28.5 mg (yield 13%) of target compound in the form of a solid purple dye, which was less than 95% purity (IHVR analysis). MS.

1H-NMR (DMSO-d6): 1,17 (m, 1H), 1,5 - and 1.63 (m, 2H), 1,8 - of 1.95 (m, 2H), by 2.73 (m, 2H), 4,18 (m, 4H), 7,12 (t, 2H), 7,15 (s, 2H), 7.23 percent (t, 2H), 7,56 (d, 2H), of 7.75 (d, 2H), 7,8 (width, 3H), br11.01 (s, 1H).

< / BR>
Example 54

3,4-[(N, N'-1,1'-(3"-(N, N-(Dimethylamino)methylene)-pentenyl)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione hydrochloride

The target compound was obtained in the form of cleaners containing hydrochloride salt, using dimethylamine (40% aqueous solution; 5 ml) instead of nelfinavir, 3,4-[(N,N'-1,1'-(3"-(methanesulfonate)methylene)pentanyl)-bis- (3,3'-indolyl)] -1(H)-pyrrole-2,5-dione (110 mg, 0.2 mm), with subsequent transformation into cleaners containing hydrochloride salt as Clevo is, ,18 (m, 4H), 7,12 (t, 2H), 7,15 (s, 2H), 7.23 percent (t, 2H), 7,56 (d, 2H), of 7.75 (d, 2H), 7,8 (W, s, 3H), br11.01 (s, 1H).

In a similar manner there were obtained the following compounds, and, in addition, illustrates the following compounds of the present invention (examples 55-113 see the end of the description).

As mentioned above, the compounds of the present invention are powerful inhibitors of protein kinase C. These compounds are selective in relation to protein kinase C.

The ability of the compounds of the present invention to the selective inhibition of protein kinase C were determined using analysis of calcium-calmoduline the protein kinase, analysis on the casein protein kinase II, analysis of the catalytic subunit of camp-dependent protein kinase and analysis of protein-tyrosine kinase.

Analysis of calcium-calmoduline the protein kinase (CaM) (see tab.I).

Analysis of calcium-calmoduline the protein kinase is described in the Journal of Neuorcience, 3: 818-831 (1983). Components analysis (total volume of 250 μl) are: 55 mm HEPES (4-(2-hydroxyethyl)-1-piperazine-econsultancy acid), pH 7.5; 2,75 mm dithiotreitol; 2.2 mm EGTA (ethylenebis(oxyethylenenitrilo) tetraoxane acid used in the buffer is"empty"); 1.1 mm calcium chloride HL (Worthington); 10 μl of DMSO or DMSO/inhibitor and 30 μm (gamma-32P) ATP (DuPont). The reaction was initiated by adding calcium-calmodulinzawisimoy protein kinase (isolated from a homogenate of rats brain), then incubated for 10 min at room temperature and stopped the reaction by adding 0.5 ml ice trichloroacetic acid (Amresco) followed by addition of 100 ál of 1 mg/ml bovine serum albumin (Sigma, St. Louis, Missouri). The precipitate was collected by vacuum filtration on glass fiber filters, and then evaluated using a beta scintillation counter.

Components analysis: 165 µl buffer; 25 µl of calmoduline (250 μg/ml); 10 μl of DMSO or DMSO/inhibitor; 25 μl of kinase and 25 ál ATR.

The analysis of the casein protein kinase II (CK-II)

The analysis of the casein protein kinase II described in Neuochem Res. 13: 829 - 836 (1988). Components analysis (total volume of 250 μl) are: 20 mm Tris-HCl, pH 7.5, 5 mm sodium fluoride, 50 mg/ml casein (Sigma, St.Louis, Missouri), 10 μl of DMSO or DMSO/inhibitor and 30 μm (gamma R) ATP (DuPont). The reaction was initiated by adding casein protein kinase II (isolated from a homogenate of rats brain), incubated 10 min at room temperature and the reaction was stopped by adding 0.5 ml of ohla the Ki (Sigma, St.Louis, Missouri). The precipitate was collected by vacuum filtration on glass fiber filter, and then evaluated using a beta scintillation counter.

Components analysis to add: 175 µl buffer; 10 μl of DMSO or DMSO/inhibitor; 25 ál ATR 300 μm magnesium chloride; 40 μl of enzyme (undiluted).

The buffer was prepared as follows:

(Final volume = 3.5 ml; 20 assays)

500 µl of each: 200 mm Tris-HCl pH 7.5

50 mm sodium fluoride

50 mg/ml casein

+ 2 ml deionized water

Full volume: 3.5 ml

Analysis of the catalytic subunit of camp-dependent protein kinase (PKA)

Components analysis (total volume of 250 μl) are: 20 mm HERES (Sigma, St. Louis, Missouri) buffer pH 7.5, 200 μg/ml histone type HL (Worthington), 10 mm magnesium chloride (Sigma, St.Louis, Missouri), 10 μl of DMSO or DMSO/inhibitor and 30 μm (gamma R) ATP (DuPont). The reaction was initiated by addition of the catalytic subunit of camp-dependent kinase, isolated from bovine heart (Sigma, St.Louis, Missouri), incubated 10 min at 30oC and the reaction was stopped by adding 0.5 ml ice trichloroacetic acid (Amresco) followed by addition of 100 ál of 1 mg/ml bovine serum albumin (Sigma). Sediment was collected from pogostkina. This analysis is identical to the analysis of the protein kinase C (CSWs), except that this analysis is not used phospholipids or diacylglycerol, and histone substrate was specific for the catalytic subunit of camp-dependent enzyme.

Analysis of protein-tyrosine kinase (src)

This analysis had the following components: 10 ál of Rafida (Paytide); 10 μl kinase; 4 μl of DMSO or DMSO/inhibitor; 6 μl of 200 mm HEPES, pH 7.5; 10 μl ATR.

This analysis is described in Onogene Science, Inc.Cat. # RK and RK (1990).

It has been unexpectedly found that the compounds of the present invention are also isozyme-selective inhibitors, that is, these compounds selectively inhibit the beta-1 and beta-2 isozyme of protein kinase C. In the analysis of the RCC-enzyme was determined selectivity in relation to these isozyme.

Analysis RKS-enzyme

RKS-enzymes = alpha, beta I, beta II, gamma, Delta, Epsilon, ETA and Zeta.

In this analysis we used the following components (in a total volume of 250 ál):

Vesicles consisting of 120 μg/ml phosphatidylserine (Avanti Polar Lipids) and a sufficient amount of diacylglycerol (Avanti Polar Dupnot) for activation of the enzyme to the maximum activity in 20 mm HEPES buffer (Sigma, St. Louis, Missouri), pH 7.5, 940 m is Ermentau, 10 mm of magnesium chloride (Sigma, St. Louis, Missouri) and 30 μm (gamma R) ATP (DuPont). For all enzymes, as the substrate used or the histone type HL (Worthington) or basic protein myelin. The reaction was initiated by adding protein kinase C, incubated 10 min at 30oC, and then the reaction was stopped by adding 0.5 ml of cold triperoxonane acid (Amresco) followed by addition of 100 ál of 1 mg/ml bovine serum albumin (Sigma, St.Louis, Missouri). The precipitate was collected by vacuum filtration on glass fiber filters using a filtration system TOMTECTMand was estimated by counting in a beta scintillation counter.

Table 1 illustrates the RCC-selectivity characteristic of the compounds used in the above analysis.

Compounds of the present invention inhibit proteinkinase C if IC50-value less than 100 microns. In addition, the compounds of the present invention selectively inhibit beta-1 and beta-2 isozyme of protein kinase C and mean IC50in relation to these isozyme, which constitute less than 10 microns.

As inhibitors of protein kinase C, the compounds of the present invention can be used for the treatment of diseases, pathological and its complications, ischemia, inflammatory diseases, disorders of the Central nervous system, cardiovascular diseases, Alzheimer's disease, skin disorders and cancer.

It has been shown that inhibitors of protein kinase C inhibit inflammatory responses such as neutrophil oxygen "explosion", C 3-suppressive activity of T-lymphocytes and forbindelsenavn swelling of the extremities. Twoemy B. and others , Biochem. Biophys, Res. Commun. 171: 1087-1092 (1990); Mulgueen, M. J. and other Agents Actions 37: 85-98 (1992). Accordingly, the compounds of the present invention as inhibitors of the RCC can be used to treat inflammatory diseases.

The activity of protein kinase C plays an essential role in the functioning of the Central nervous system. Huang K. P. Trends Neurosci 12: 425-432 (1989). In addition, it was shown that inhibitors of protein kinase C prevent violations associated with local or Central cerebral ischemia, and cerebral edema. Hara H., and others, J. Cereb Blood Flow Metab. 10: 646-653 (1990); S. Shibata and others, Brain Res 594: 290-294 (1992). Recently it was found that the protein kinase C causes complications in Alzheimer's disease. Shimohama S., and others , Neurology 43: 1407-1413 (1993). Therefore, the compounds of the present invention can be used for the treatment of Alzheimer's disease and ischemia motgage growth and cancer. Rotenberg S. A and Weinstein U. B. Biochem. Mol. Aspects Sel. Cancer 1: 25 - 73 (1991). Ahmad and others, Molecular Pharmacology, 43: 858-862 (1993). It is known that inhibitors of protein kinase C are very effective tools for preventing the growth of tumors in animals. Meyer T., etc., Int J. Cancer 43: 851-856 (1989); Akinagaka S. and others, Cancer Res. 51: 488-4892 (1991). Compounds of the present invention can also act as multiple agents reaktivatory that increase the effectiveness of chemotherapeutic agents when administered in conjunction with these compounds.

The activity of protein kinase C also plays an important role in cardiovascular diseases. It has been shown that increased activity of protein kinase C in vascular network leads to narrowing of blood vessels and hypertension. A well-known inhibitor of protein kinase C contributes to the prevention of the increase of this activity. Bilder G. E., and others, J. Pharmacol. Exp. Ther. 252: 526-530 (1990). As inhibitors of protein kinase C contributes to suppression of neutrophil oxygen "Bang", the inhibitors of protein kinase C can also be used for the treatment of ischemia of the heart and blood vessels and subsequent improvement of cardiac activity. Muid R. E., and others FEBS Lett. 293: 169-172 (1990); Sonoki H., and others , Kokyu To Junkan 37: 669-674 (1989). It was also investigated the role of proteinkinase C in platelet function, exists on the introduction agonists. Bastyr III, E, J. and Lu, J. Diabetes 42: (Suppl.I) 97A (1993). It was shown that the RCC is involved in the biochemical pathway modulation of microvascular permeability by platelet activating factor. Kooayashi and others, Amer. Phys. Soc. H1214-H1220 (1994). It was illustrated that strong inhibitors of protein kinase C effect on agonist-induced platelet aggregation. Toullec d, etc., J. Biol, Chem. 266: 15771 - 15781 (1991). Inhibitors of protein kinase C also block the agonist-induced proliferation of smooth muscle cells. Matsumoto H. and Saaki Y. Biochem. Biophys. Res. Commun. 158: 105-109 (1989). Therefore, the compounds of the present invention can be used to treat cardiovascular diseases, atherosclerosis and restenosis.

In addition, skin diseases such as psoriasis, are also associated with abnormal activity of protein kinase C. F. Horn, etc., J. Invest. Dermatol, 88: 220-222 (1987); Paynaud F. and Evain-Brion, D. Br. J. Dermatol. 124: 542-546 (1991). Psoriasis is characterized by abnormal proliferation of keratinocytes. It has been shown that known inhibitors of protein kinase C inhibit the proliferation of keratinocytes with an efficiency that depends on the potency data RKS-inhibitors. Hegemann L., and others, Arch. Dermatol. Res. 283: 456-460 (1991); Bollag W. B.. and others J. Invest. Dermatol. 100: 240-246 (1993). Accordingly, the compounds of the present invention as the beta associated with the activity of protein kinase C. Excessive activity of the enzyme is associated with impaired insulin "signal", and therefore, leads to insulin-independent diabetes Type Ii. Kasasaki A. and others, J. Biol. Chem. 265: 10226-10231 (1990); K. S. Chen and others, Trans.Assoc. Am. Physician 104: 206-212 (1991); J. E. Chin, etc. , J. Biol. Chem 268: 6338-6347 (1993). In addition, studies have shown a marked increase in RCS activity in tissues known that they are susceptible to the complications of diabetes (due to the testing of these tissues in hyperglycemic conditions). Lee T.-S., and others, J. Clin, Invest. 83: 90-94 (1989); Lee, T.-S., and others, Proc. Natl. Acad. Sci. USA 86: 5141-5145 (1989); P. A. Craven and DeRubertis F. R. J. Clin. Inve. 83: 1667-1675 (1989); Wolf, B. A., and others, J. Clin. Invest 87: 31-38 (1991); Tesfamariam B. and others, J. Clin. Invest. 87: 1643-1648 (1991).

Compounds of the present invention are also isozyme-selective. These compounds inhibit predominantly beta-1 and beta-2 isozyme of protein kinase C, in relation to the other isozyme of protein kinase C, i.e., alpha-, gamma-, Delta-, Epsilon-, Zeta -, and this is the isozyme. Basically, for the inhibition of beta-1 and beta-2 isozyme RKS, the compounds of the present invention require at least a 10 times lower dose than it would for an equal inhibition of the alpha isozyme of the RCC, as shown in the RCC-analysis. Accordingly, the compounds of nastojaschajaja for inhibition of other isozyme RKS. This isozyme-selectivity was illustrated in table. 2 for the most typical compounds of the present invention.

Due to its selectivity, the compounds of the present invention can be particularly effectively used for the treatment of diseases associated with the activity of beta-1 or beta-2 isozyme of protein kinase C. for Example, increased levels of glucose in the blood, observed in diabetes, leads to the isozyme-specific increase in the level of beta-2 isozyme in the tissues of the blood vessels. Inoguchi and others , Proc. Natl. Acad. Sci. USA, 89: 11059 - 11065 (1992). It has been shown that diabetes-associated increase in the level of beta isozyme in human platelets correlates with the change in their response to the introduction of agonists. Bastyr III, E. J. and Lu. J. Diabetes 42: (Suppl.I) 97A (1993). In addition, it was shown that the receptor for vitamin D person selectively fosfauriliruetsa beta isozyme of protein kinase. This phosphorylation is associated with changes in receptor function. Hsieh and others, Proc. Natl. Acad. Sci. USA 88: 9315 - 9319 (1991); Hsieh and others, J. Biol. Chem. 268: 15118 - 15126 (1993). In addition, it was recently shown that the beta isozyme-2 is responsible for the proliferation of cells erythroleucus and alpha isozyme involved in the differentiation of megakaryocytes in these same cells. Murrey, etc., J. Biol. Chem. 168: e compositions. Therefore, in another embodiment, the present invention relates to pharmaceutical compositions containing a compound of formula I and one or more pharmaceutically acceptable carriers, diluents or excipients.

The pharmaceutical compositions of the present invention are made using traditional techniques and ingredients. In the manufacture of the compositions of the present invention, the active ingredient is usually mixed with a carrier, or diluted by a carrier, or include in the media, which may be in the form of a capsule, case, paper or other container. When the carrier serves as a diluent, such a carrier can be a solid, semi-solid, or liquid material which acts as a carrier or medium for the active ingredient. For example, compositions of the present invention can be manufactured in the form of tablets, pills, powders, pills, sale, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid and in liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile powder packaging.

Some examples of suitable Noa gum, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In these compositions can also be entered sizing agents, wetting agents, emulsifying and suspendresume agents, preservatives, sweetening agents or flavoring agents. Compositions of the present invention can be manufactured in such a manner that a fast or slow release of the active ingredient after administration of the composition to the patient. Preferably, if the composition will be manufactured in the form of a single dosage form, each of which contains from about 1 to about 500 mg, and preferably from about 5 to about 300 mg of the active ingredient. However, it should be noted that the dose to the introduction of this therapeutic drug can be determined by the attending physician based on specific conditions, including disease, which is directed treatment, type of connection, the route of administration, etc. In accordance with this, the above dose ranges are illustrative and do not limit the volume n is the Apple with a uniform dose, intended for administration to humans and other mammals and containing a predetermined quantity of active material calculated to the desired therapeutic effect, in combination with a suitable pharmaceutical carrier.

In addition, the compounds of the present invention can be used for outdoor applications. Compositions intended for these purposes, is made in the form of ointments, creams and gels.

Ointments are usually made using either (1) an oil basis, i.e., consisting of fatty oils or hydrocarbons, such as petroleum or mineral oil; or (2) an absorbent base, i.e., consisting of the anhydrous substance or substances able to absorb water, for example, anhydrous lanolin. The amount of active ingredient (compound) is added to the composition in accordance with oil or absorbent base used in this composition.

Creams are emulsions of oil-in-water". These emulsions consist of an oil phase (dispersed phase), usually containing fatty oils, hydrocarbons, etc., such as waxes, petroleum, mineral oil, etc.; and aqueous phase (continuous phase) containing water and any in the of emulsifying agent, for example, surfactants such as sodium lauryl sulfate, hydrophilic colloids, for example, Arabian gum, colloidal clay, beeswax, etc. In the preparation of the emulsion, the active ingredient is usually added in an amount necessary to obtain a desired concentration.

The gels are made usually on oil, water or emulsion-suspension base. Based on this type of gelling agent, which forms the matrix, increasing the viscosity of the composition. Examples of gelling agents are hydroxypropylcellulose; polymers of acrylic acid, etc. Usually, the active compound added to the composition to the desired concentration before adding the gelling agent.

The number of compounds that enter into the composition for external use, is not critical; it should be only sufficient to free the specified application of the composition to the affected tissue and to provide the desired therapeutic effect.

The amount of the composition for external use depends on the size of the affected tissue and the concentration of the active compounds in the composition. Basically, the composition for external p is Ino from about 30 to about 300 μg per cm2the affected tissue, more preferably from 50 to 200 µg/cm2and most preferably from about 60 to about 100 μg/cm2.

Below are examples that illustrate the implementation of the present invention, and should not be construed as a limitation on its scope.

Composition 1

Hard gelatin capsules were obtained using the following ingredients (mg/capsule)

The active agent - 250

Starch, dried - 200

Magnesium stearate - 10

Only 460

The above ingredients were mixed and filled them hard gelatin capsules in the amount of 460 mg.

Composition 2

The tablet was obtained using the following ingredients (mg/capsule)

The active agent - 250

Microcrystalline cellulose - 400

Colloidal silicon dioxide - 10

Stearic acid - 5

Just - 65

These components were mixed and compressed into tablets weighing 665 mg each.

Composition 3

Spray the solution was obtained using the following ingredients (mg/capsule)

The active agent - 0,25

Ethanol - 29,75

The propellant 22 (Chlorodifluoromethane) - 70,0

Just 100,00

The active compound was mixed with the about to fill. Then the required number of compounds were placed in a stainless steel container and diluted with the remainder of the spray substance. After that, the container was connected valve device.

Composition 4

Tablets containing 60 mg of active ingredient, was prepared as follows, (mg/capsule)

The active agent - 60

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone (10% solution in water) - 4

Sodium carboximetilkrahmal - 4,5

Magnesium stearate and 0.5

Talc - 1

150

The active ingredient, starch and cellulose was passed through sieve No. 18 mesh, U.S., and vigorously stirred. The solution of polyvinylpyrrolidone were mixed with the obtained poroshkoobraznymi substances, which then was passed through sieve No. 14, mesh, USA. Thus obtained granules were dried at 50oC and passed through a sieve No. 18, mesh, USA. Sodium carboximetilkrahmal, magnesium stearate and talc, previously passed through sieve # 60 mesh, U.S., was added to the granules which, after mixing was compressed in a tablet press machine and received the tablets with a weight of 150 mg each.

Composition 5

Capsules containing 80 mg medicine Microcrystalline cellulose - 59

Magnesium stearate - 2

Only 200

The active ingredient, cellulose, starch and magnesium stearate were mixed, passed through sieve No. 45 mesh, U.S., and then filling hard gelatin capsules in 200 mg

Composition 6

Suppositories containing 225 mg of active ingredient each, was prepared as follows, (mg/capsule)

The active agent - 225

Glycerides of saturated fatty acids - 2000

Total - 2225

The active ingredient was passed through sieve # 60 mesh, U.S., and suspended in pre-molten glycerides of saturated fatty acids, using the minimum required temperature. After that, the mixture was poured in mass for suppositories with a nominal capacity of 2 g and left to cool.

Composition 7

Suspension containing 50 mg medicines each 5 ml dose, are made as follows: (mg/capsule)

The active agent, mg - 50

Sodium carboxymethylcellulose, mg - 50

Syrup, ml - 1,25

A solution of benzoic acid, ml - 0,10

Odorant - Hon. Qty

Dye - Hon. Qty

Purified water, ml - 5

The drug was passed through sieve No. 45 mesh, U.S., and then smesi is mesheanii solution was added benzoic acid, the perfume and dye, diluted with some water. To obtain the desired volume was added a sufficient amount of water.

Composition 8

Intravenous composition can be obtained as follows (mg/capsule:

The active agent - 250

Isotonic saline solution - 1000

The solution of the above ingredients is administered intravenously at a dose of 1 ml/1 min to a patient in need of such treatment.

1. bis-Indolamine macrocyclic derivatives of General formula I

< / BR>
where W is-O-, -S-, -SO-, -SO2-, -CO-, -NR3-, -heterocycle is selected from the group comprising 5-6-membered heterocycles containing one or two nitrogen atom; -condensed bicikl-representing a 5-6-membered nitrogen-containing heterocycle condensed with a phenyl ring, or nattinger, C2- C6-alkylene, substituted alkylene formula

< / BR>
where Z is -(CH2)p- or -(CH2)p-O-(CH2)p- when R6represents-NH2; R6- C1- C4-alkyl, C1- C4-alkoxy, (CH2)m-aryl, (CH2)m-aryloxy, hydroxy, carboxy, -COO(C1- C3-alkyl), -COO(CH2)m-aryl, -NR4R5, -NH(CH2
)m-aryl, -NHCOO(benzyl), -NHSO2(C1- C4-alkyl), -NHSO2(CH2)m-aryl, -CN, -SO2(C1- C4-alkyl, heterocycle selected from the group comprising 5-6-membered nitrogen-containing heterocycle or morpholine; aryl is phenyl;

X and Y independently represents a C1- C4-alkylen, possibly substituted by a group Z-R6;

R1independently is hydrogen, halogen, C1- C4-alkyl, hydroxy, C1- C4-alkoxy, halogenated, nitro, -NR4R5;

R2is hydrogen;

R3is hydrogen, C1- C4-alkyl;

R4and R5independently is hydrogen, C1- C4-alkyl, phenyl, benzyl;

p = 0, 1, or 2, independently;

m = 0, 1, 2 or 3, independently

or their pharmaceutically acceptable salt or MES.

2. Connection on p. 1, where W is-O-, -S-, -SO2-, -CO-, -NR3-, -heterocycle is selected from the group comprising 5-6-membered heterocycles containing one or two nitrogen atom; -condensed bicikl-representing a 5-6-membered nitrogen-containing heterocycle condensed with a phenyl ring, or nattinger, X and Y are independently - C1- C4-alkylen, possibly substituted by a group Z-R6; R1independently - Novogorod; R3is hydrogen, C1- C4-alkyl; R4and R5independently is hydrogen, C1- C4-alkyl, benzyl; m = 0, 1, 2 or 3, independently.

3. Connection on p. 2 having the formula

< / BR>
where Z - (CH2)p-;

R6is hydroxy, C1- C4-alkyl, (CH2)m-aryl, -NH(aryl), -NHSO2(C1- C4-alkyl), -NHSO2(CH2)m-aryl, or-NR4R5; aryl is phenyl;

R4is hydrogen or C1- C4-alkyl;

R5is hydrogen, C1- C4-alkyl, benzyl;

p = 0, 1, or 2;

m = 0, 1, 2, or 3.

4. Connection on p. 1, selected from the group comprising (R) -3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'(O)-4"'-(N, N-dimethylamino)-butane)-bis-(3,3'-indolyl)] -1-(H)-pyrrole-2,5-dione and (S) -3,4-[(N,N-1,1'-((2"-ethoxy)-3"'(O)-4"'-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1-(H)-pyrrole-2,5-dione, a mixture thereof or pharmaceutically acceptable salt or MES.

5. Connection on p. 1, selected from the group comprising (S) -3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N-pyrrolidine)-butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione and (R) -3,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N-pyrrolidine)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione, a mixture thereof or pharmaceutically acceptable salt or MES.

6. Connection on p. 1, selected from the group,4-[(N,N'-1,1'-((2"-ethoxy)-3"'-(O)-4"'-(N-phenylsulfonyl)-butane)-bis-(3,3'-indolyl)] -1(H)-pyrrole-2,5-dione and mixtures thereof, or their pharmaceutically acceptable salt or solvent.

7. The compound having the formula

< / BR>
where V is-O - or N-CH3;

W IS-O-, -S-, -SO-, -SO2-, -CO-, -NR3- C2- C6-alkylene, -heterocycle is selected from the group comprising 5-6-membered heterocycles containing one or two nitrogen atom; -condensed bicikl-representing a 5-6-membered nitrogen-containing heterocycle condensed with a phenyl ring, or nattinger, substituted alkylene formula

< / BR>
where Z is -(CH2)p- or -(CH2)p-O-(CH2)p- when R6represents-NH2;

R6- C1- C4-alkyl, C1- C4-alkoxy, (CH2)m-aryl, (CH2)m-aryloxy, hydroxy, carboxy, -COO(C1- C4-alkyl), -COO(CH2)m-aryl, -NR4R5, -NH(CH2)m-aryl, -NH(CH2)m-pyridyl, -CONH(CH2)m-aryl, -NHCO(C1- C4-alkyl), -OCONH(CH2)m-aryl, -NHCOO(benzyl), -NHSO2(C1- C4-alkyl), -NHSO2(CH2)m-aryl, -CN, SO2(C1- C4-alkyl, heterocycle selected from the group comprising 5-6-membered nitrogen-containing heterocycle or morpholine; aryl is phenyl;

X and Y independently - C1- C4-alkylen;

R1independently is hydrogen, halogen, >- C4-alkyl;

R4and R5independently is hydrogen, C1- C4-alkyl, phenyl, benzyl;

m = 0, 1, 2 or 3, independently

p = 0, 1, or 2, independently.

8. The compound according to any one of paragraphs.1 - 6, active inhibitor of protein kinase C in the treatment of complications of diabetes.

9. The compound according to any one of paragraphs.1 - 6, active inhibitor of protein kinase C in cancer treatment.

10. Pharmaceutical composition for inhibiting protein kinase C, characterized in that it as the active ingredient contains an effective amount of a compound according to any one of paragraphs.1 - 6 in combination with one or more pharmaceutically acceptable excipients, carriers or diluents.

11. The method of obtaining the compounds of formula

< / BR>
where the values of R1, X, W, V and m are specified in paragraph 7,

namely, that the mixture of compounds having a concentration of from about 1.5 M to about 0.001 M, the formula

< / BR>
where the values of R1, m, V are given in paragraph 7,

and an alkylating agent having a concentration of from about 1.5 M to about 0.001 M, the formula

< / BR>
where the values of X, W, V defined in paragraph 7,

L is removed by the group,

in a polar aprotic solvent priba the velocity of from about 0.1 ml/HR to about 2.0 ml/h

12. The method of obtaining the compounds of formula

< / BR>
where the values of R1, X, W, V, and m are defined in paragraph 7,

namely, that a mixture of the compound having a concentration of from about 3 M to about 0.001 M, the formula

< / BR>
where L2independently is removed by the group;

R1, X, W, V, and m are defined in paragraph 7,

combine approximately 0.5 to 10.0 equivalents Cs2CO3with a speed of from about 0.1 ml/HR to about 2.0 ml/h in a polar aprotic solvent.

13. A method of obtaining a compound according to any one of paragraphs.3 to 6, namely that: a) this will release the connection formulas

< / BR>
where Z - (CH2)p-;

R6' is a protected hydroxy-group or a protected amine;

p = 0, 1, or 2;

and b) you don't replace the hydroxy-group or the amino group to obtain a compound according to any one of paragraphs.3 - 6, where R6represents a hydroxy-group, C1- C4-alkyl, (CH2)m-aryl, -NH(aryl), -NHSO2(C1- C4-alkyl), -NHSO2(CH2)m-aryl, or-NR4R5, R4is hydrogen or C1- C4-alkyl; R5is hydrogen, C1- C4-alkyl, benzyl, aryl is phenyl.

Priority signs:

07.12.93 - all values of RA

 

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< / BR>
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< / BR>
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< / BR>
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-,or- cyclodextrin or its alkyl - or hydroxyalkylated and (6r)- or (6s)-5,10-methylenetetrahydrofolic acid or a salt thereof, a method of stabilizing aqueous solutions and the method of obtaining stable solutions" target="_blank">

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