Antitumoral compounds

FIELD: biotechnologies.

SUBSTANCE: invention relates to compounds of general formula I, having cytostatic or cytotoxic activity, its pharmaceutically acceptable salts, tautomers or stereoisomers, a pharmaceutical composition on their basis. Compounds may be used for treatment of cancerous diseases. In the general formula I

Y is selected from the group comprising -CHRay- and -CHRay-CRby-CRcy-; each Ray, Rby and Rcy are independently selected from hydrogen and non-substitute C1-C12-alkyl; each R1, R2, R3, R4 and R5 are independently selected from hydrogen and non-substitute C1-C12-alkyl; R6 is selected from NR8R9 and OR10; A means , W means NR7; R7 means hydrogen; R8 means hydrogen; R10 means non-substitute C2-C12-alkenyl; each dotted line means unnecessary additional link, but when there is a triple link between atoms of carbon, to which R1 and R2 are attached, then R1 and R2 are absent, and when there is a triple link between carbon atoms, to which R3 and R4 are attached, then R3 and R4 are absent; R9 is selected from substitute C2-C12-alkenyl and substitute C4-C|2-alkenylyl, where substitutes are selected from the group, consisting of: halogen, OR', OCONHR' and OH, protected with a simple silyl ether; where R' means hydrogen; provided that whenever Y means -CHRay-CRby=CRcy- and there is a single or double link between atoms of carbon, to which R3 and R4 are attached, then R9 means substitute C4-C12-alkenylyl; and each R16, R17 and R18 are independently selected from hydrogen and ORa; each Ra is selected from hydrogen or non-substitute C1-C12-alkyl.

EFFECT: higher efficiency of compound application.

 

The technical field to which the invention relates.

The present invention relates to novel antitumor compounds, pharmaceutical compositions containing them and their use as antitumor agents.

Background of invention

In 1990, Gunasekera et al. described the isolation of a new polyhydroxyalkane of lactone, (+)-discodermolide, from deep-water Caribbean sponge, Discodermia dissoluta (Gunasekera SP et. al., J. Org. Chem., 1990, 55, 4912-4915, and J. Org. Chem., 1991, 56, 1346).

It is shown that this compound is effective antimitoticheskoy agent (Hung DT et. al., Chem. Biol., 1996, 3, 287-293 and E. ter Haar et. al., Biochemistry, 1996, 35, 243-250), with a mode of action similar to that of clinically proven anti-cancer agent paclitaxel (Schiff PB et. al., Nature, 1979, 277, 665-667). Both natural product inhibit the cell cycle in M phase, contribute to the formation of microcannulas and have similar any abscopal effects against breast cancer (IC50is 2.4 nm and 2.1 nm, respectively).

On the other hand, some exceptional linear dipeptides containing N-allenamento functionality, selected from mycobacteria belonging to the genus Chondromyces (B. Kunze et. al., J. Antibiot., 1994, 47, 881-886, and R. Jansen et. al., J. Org. Chem., 1999, 1085-1089). In particular, these compounds are crocetinate a, b, C and D, and include the amount the group of inhibitors of electron transport.

Crocetin A-D moderately inhibit the growth of some gram-positive bacteria and are effective inhibitors of cell cultures, animals and some yeast and fungi. Most activity takes crocetin D, which shows the minimum inhibitory concentration (MIC), equal to 1.4 ng/ml, against the fungi Saccharomyces cerevisiae and strong toxicity (IC50is 0.06 mg/l) in relation to culture murine L929 fibroblasts.

Gudasheva and others (Russian Journal of Bioorganic Chemistry, 2007, 44(4), 413-420, and Pharmaceutical Chemistry Journal, 2006, 40(7), 367-372) described the design of dipeptide compounds based on the structure of endogenous tetrapeptide cholecystokinin-4 (CCK-4). In this regard revealed that derivatives of L-tryptophan exhibit anxiolytic properties and derivatives of D-tryptophan - entries property. These two dipeptide compounds described Gudasheva etc. as follows:

and the following compound is described as intermediate products in the synthesis of compounds R and U:

Cancer is the leading cause of death in animals and humans. Have been made and are still making great efforts in order to obtain an antitumor agent, active and without the ACLs in relation to the introduction of his patients, suffering from cancer. The problem to be solved according to the present invention is to obtain compounds which are suitable for the treatment of cancer.

Summary of the invention

In one aspect the present invention relates to compounds of General formulaIor their pharmaceutically acceptable salts, tautomers, prodrugs or stereoisomers:

where Y is chosen from the group consisting of CHRay-, -CHRay-CHRby-, -CRay=CRby-, -C≡C-, -CHRay-CHRby-CHRcy-, -CHRay-CRby=CRcy-and-CHRay-C≡C-;

each Ray, Rbyand Rcyindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

each R1, R2, R3, R4and R5independently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R6choose from NR8R9and OR10;

And choose from:

W is chosen from O and NR7 ;

R7selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil, or R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, may form a substituted or unsubstituted heterocyclic group;

R8selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl;

R10selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

each dotted line represents an optional additional bond, but if there is a triple bond between carbon atoms, which are attached to R1and R2, R1and R2no, and if there is a triple bond between carbon atoms, which are attached to R3and R4, R 3and R4no; and,

which means:

then R9selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl, provided that when Y represents-CHRay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and there is a single or double bond between carbon atoms, which are attached to R3and R4then R9means substituted or unsubstituted With4-C12-alkenyl; and,

which means:

then R9selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl;

each R16, R17and R18independently selected from the group consisting of hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORbNRaC(=NRa)NRaRbsubstituted or unsubstituted who CSOs With 1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R19selected from the group consisting of hydrogen, CORa, COORa, CONRaRb, S(O)Ra, SO2Ra, P(O)(RaORb, SiRaRbRcsubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

and each of Ra, Rband Rcindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group.

In another aspect, the present invention also relates to the compound of the formulaIor its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer for use as a medicine.

In another aspect, the present invention also relates to the compound of the formulaIor its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer for use as a pharmaceutical environments is TBA for the treatment of cancer.

In a further aspect the present invention also relates to the use of compounds of the formulaIor their pharmaceutically acceptable salts, tautomers, prodrugs or stereoisomers for the treatment of cancer or to obtain drugs for the treatment of cancer. Other aspects of this invention are the treatment methods and compounds for use in these methods. Therefore, the present invention further relates to a method of treating any mammal, especially a person stricken cancer, which includes the introduction of the affected individual a therapeutically effective amount of the compounds of formulaIor its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer.

In a further aspect the present invention also relates to the compound of the formulaIor its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer for use as anticancer agent.

In another aspect, the present invention relates to pharmaceutical compositions containing a compound of the formulaIor its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer, together with a pharmaceutically acceptable carrier or diluent.

Detailed description of the preferred embodiments

The present invention relates to compounds of General formulaIas explained above.

In these compounds, the groups may be selected in accordance with the following guide.

Alkyl groups can be branched or unbranched, and preferably can have from 1 to about 12 carbon atoms. One more preferred class of alkyl groups has from 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1, 2, 3 or 4 carbon atoms. Methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl, sec-butyl and isobutyl, are particularly preferred alkyl groups in the compounds according to the present invention. Another preferred class of alkyl groups has from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl, nonyl are the most preferred alkyl groups in this class.

Preferred alkeneamine and alkyline group in the compounds according to the present invention can be branched or unbranched, may have one or more unsaturated linkages and from 2 to about 12 carbon atoms. One more preferred class alkenyl and etkinlik groups has from 2 to about 6 carbon atoms. Even more preferred are alkenyl and alkyline group, having 2, 3 or 4 carbon atoms. Another preferred class alkenyl and etkinlik group has from 4 to about 10 carbon atoms, even more preferably from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms.

The authors of the present invention determine alkenylamine group as alkyl group containing one or more double bonds and one or more triple relations, and preferred alkenylamine groups are those having from 4 to about 12 carbon atoms. One more preferred class alkenylamine groups have from 6 to about 10 carbon atoms.

Suitable aryl groups in the compounds according to the present invention include mono - and polycyclic compounds, including polycyclic compounds that contain isolated and/or condensed aryl group. Typical aryl groups contain 1-3 isolated or condensed cycles and from 6 to about 18 carbon atoms in the cycle. Preferred aryl groups contain from 6 to about 10 carbon atoms in the cycle. Particularly preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted tenantry and substituted or unsubstituted antril.

Under adamie heterocyclic groups include heteroaromatic and heteroalicyclic group, containing 1-3 isolated or condensed cycle and from 5 to about 18 carbon atoms in the cycle. Preferably, heteroaromatic and heteroalicyclic groups contain from 5 to about 10 carbon atoms in the cycle, most preferably 5, 6 or 7 carbon atoms in the cycle. Suitable heteroaromatic groups in the compounds according to the present invention contain one, two or three heteroatoms selected from the atoms N, O or S, and include, for example, coumarinyl, including 8-coumarinyl, hinely, including 8-chinolin, ethanolic, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolin, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazoles, indolizinyl, phthalazine, pteridine, purinol, oxadiazolyl, thiadiazolyl, furutani, pyridazinyl, triazinyl, cinnoline, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properity. Suitable heteroalicyclic group in the compounds according to the present invention contain one, two or three heteroatoms selected from the atoms N, O or S, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydrothieno, tetrahydrothiopyran, piperidyl, morpholinyl, thiomorpholine, dioxane, piperazinil, and yidiny, oxetanyl, titanyl, homopiperazin, oxetanyl, tepanil, oxazepines, diazepines, thiazepines, 1,2,3,6-tetrahydropyridine, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, dithienyl, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and finalizing.

Groups specified above may be substituted in one or more available positions by one or more suitable groups such as OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, CO2H, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or illegal is esenkoy heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list.

Suitable halogen substituents in the compounds according to the present invention include F, Cl, Br and I.

Suitable protective groups for IT is well known qualified specialist in this field. Overview in protective groups in organic chemistry presents P.G.M. Wuts and Greene, T.W. in "Protecting Groups in Organic Synthesis", 4th ed., Wiley-Interscience, and Kocienski PJ in "Protecting Groups", 3rd ed., Georg Thieme Verlag. These references are to sections of the protective groups for IT. All of these references are incorporated by reference in their entirety. Examples of such protected include ethers, simple silyl ethers, esters, sulfonates, sulfonate and sulfinate, carbonates and carbamates. In the case of ester protective group for IT can be selected from the group consisting of methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilane)-methoxymethyl, benzoyloxymethyl, p-methoxybenzyloxy, [(3,4-dimethoxybenzyl)oxy]methyl, p-nitrobenzyloxy, o-nitrobenzyloxy, [(R)-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)bromide, Guadalmedina, [(p-phenylphenyl)oxy]-methyl, tert-butoxymethyl, 4-pentyloxide, cilexitil, 2-methoxyethoxymethyl, 2-cyanoethoxy, bis(2-chloroethoxy)met the La, 2,2,2-trichloromethyl, 2-(trimethylsilyl)-ethoxymethyl, methoxymethyl, o-bis(2-acetoacetate)bromide, tetrahydropyranyl, torcetrapiblipitor, 3 brotherlike-pyranyl, tetrahydropyranyl, 1 methoxycyclohexyl, 4-methoxycarbonylpropionyl, 4-methoxycarbonylaminophenyl, 4-methoxycarbonylaminophenyl-S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidine-4-yl, 1-(2-forfinal)-4-methoxypiperidine-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidine-4-yl, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrofuranyl, 2,3,3A,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-mechanosensory-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromacil, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-veratile, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1-Daniil-2,2,2-trichlorethyl, 1,1,1,3,3,3-hexamer-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl, 2-trimethylsilylmethyl, 2-(benzylthio)ethyl, 2-(phenylseleno)ethyl, tert-butyl, cyclohexyl, 1-methyl-1'-cyclopropylmethyl, allyl, prenyl, cinnamyl, 2-finallie, propargyl, p-chlorphenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-titrator-4-(trifluoromethyl)phenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, pentadentate, pentacyanonitrosylferrate, halogenmethyl is, 2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-diferenzia, p-cyanobenzyl, tormentil, 4-voralaksana, trimethylsilylmethyl, p-phenylbenzyl, 2-phenyl-2-propyl, n-acylaminoalkyl, p-azidobenzoyl, 4-azido-3-Chlorobenzyl, 2-cryptomelane, 4-cryptomelane, p-(methylsulfinyl)of benzyl, p-militarybase, 4-acetoxyphenyl, 4-(2-trimethylsilyl)ethoxymethylene, 2-naphthylmethyl, 2-picolyl, 4-picoline, N-oxido-3-methyl-2-picolyl, 2-hyalinella, 6-methoxy-2-(4-were)-4-finalemail, 1-piridiletilen, diphenylmethyl, 4-methoxydibenzoylmethane, 4-phenyldiethanolamine, p,p'-dinitrobenzonitrile, 5-dibenzosuberyl, triphenylmethyl, Tris(4-tert-butylphenyl)methyl, α-naphthylmethyl, p-methoxyphenylethylamine, di(p-methoxyphenyl)phenylmethyl, three(p-methoxyphenyl)methyl, 4-(4'-bromination)phenyldiethanolamine, 4,4',4”-Tris(4,5-dichlorophenolindophenol)methyl, 4,4',4”-Tris(levonogestrel)-methyl, 4,4',4”-Tris(benzyloxyphenyl)methyl, 4,4'-dimethoxy-3”-[N-(imidazolylalkyl)]trityl, 4,4'-dimethoxy-3”-[N-(imidazolylalkyl)carbarnoyl]trityl, bis(4-methoxyphenyl)-1'-piridiletilen, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4”-dimethoxytrityl, 9-Anttila, 9-(9-phenyl)xanterra, 9-phenylthiomethyl, 9-(9-phenyl-10-oxo)antila, 1,3-benzodithiol-2-yl and 4,5-bis(etoxycarbonyl)-[1,3]dioxolane-2-yl, S,S-deoxycorticosterone. In the case of simple silil the different ester protective group for IT can be selected from the group composed of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, diethylhexyl-silila, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pienimuotoisilla, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and Versilia. In the case of the ester protective group for IT can be selected from the group consisting of formate, benzoylformate, acetate, CHLOROACETATE, dichloroacetate, trichloroacetate, trichloroacetimidate, triptoreline, methoxyacetate, triphenylmethane, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, diphenylacetate, 3-phenylpropionate, Victoriabank chain type propanol, 4-pentenoate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, 5-[3-bis(4-methoxyphenyl)-hydroxymethylene]levulinate, pivaloate, 1 Adamantite, crotonate, 4-ethoxycrotonate, benzoate, p phenylbenzoate, 2,4,6-trimethylbenzoic, 4-bromobenzoate, 2,5-differentate, p-nitrobenzoate, picolinate, nicotinate, 2-(azidomethyl)benzoate, 4-azidopyridine, (2-azidomethyl)Fe is racette, 2-{[(Tricity)oxy]methyl}benzoate, 2-{[(4-methoxytrityl)oxy]-methyl}benzoate, 2-{[methyl(Tricity)amino]methyl}benzoate, 2-{{[(4-methoxytrityl)thio]methylamino}methyl}benzoate, 2-(allyloxy)phenylacetate, 2-(prenylacetic)benzoate, 6-(levelingacheter)-3-methoxy-2-nitrobenzoate, 6-(levelingacheter)-3-methoxy-4-nitrobenzoate, 4-benzyloxy-butyrate, 4-triallylisocyanurate, 4-acetoxy-2,2-Dimethylbutane, 2,2-dimethyl-4-pentenoate, 2-iodobenzoate, 4-nitro-4-methylpentanoate, (dibromomethyl)benzoate, 2-formylbenzenesulfonic, 4-(methylthiomethyl)butyrate, 2-(methylthiomethyl)benzoate, 2-(chloroacetyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]-benzoate, 2-[2-(4-methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetic, 2,6-dichloro-4-(1,1,3,3-TETRAMETHYLBUTYL)-phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylmethane, isobutyrate, mononucleate, (E)-2-methyl-2-butenoate, (methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkyl-N,N,N',N'-tetramethylpiperidine and 2-chlorobenzoate. In the case of the sulfonates, sulfonato and sulfinate, the protective group for IT can be selected from the group consisting of sulfate, arylsulfonate, methansulfonate, benzylmalonate, tosilata, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-triftoratsetilatsetonom, 4-monomethoxypolyethylene, alkyl-2,4-dinitrophenols hinata, of 2.2.5.5-tetramethylpyrrolidine-3-one-1-sulfinate, Borat and dimethylformamidine. In the case of carbonates, the protective group for IT can be selected from the group consisting of methylcarbonate, methoxyethylamine, 9-fluorenylmethoxycarbonyl, ethylcarbonate, bromadiolone, 2-(methylthiomethyl)ethylcarbonate, 2,2,2-trichloromethylcarbonate, 1,1-dimethyl-2,2,2-trichloromethylcarbonate, 2-(trimethylsilyl)ethylcarbonate, 2-[dimethyl(2-naphthylmethyl)silyl]-ethylcarbonate, 2-(phenylsulfonyl)ethylcarbonate, 2-(triphenylphosphonio)ethylcarbonate, CIS[4-[[(methoxytrityl)-sulfenyl]oxy]tetrahydrofuran-3-yl]oxycarbonate, isobutyl-carbonate, tert-BUTYLCARBAMATE, vinylcarbazole, allylcarbamate, cinemeccanica, propylenecarbonate, p-chlorophenylalanine, p-nitrophenylarsonic, 4-ethoxy-1-aftercurrent, 6-bromo-7-hydroxycoumarin-4-ilmestyskirjasta, benzylmalonate, o-nitrobenzaldehyde, p-nitrobenzaldehyde, p-methoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, anthraquinone-2-ilmestyskirjasta, 2-dansylation, 2-(4-nitrophenyl)ethylcarbonate, 2-(2,4-dinitrophenyl)ethylcarbonate, 2-(2-nitrophenyl)propylmalonate, alkyl-2-(3,4-methylenedioxy-6-nitrophenyl)propylmalonate, 2-cyano-1-phenylethylamine, 2-(2-pyridyl)amino-1-phenylethylamine, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethylamine, pencilsharpener, 3',5'-dimethoxybenzophenone, metidation is rbonate and S-benzylcyanide. And, in the case of carbamates, the protective group for IT can be selected from the group consisting of dimethylthiocarbamate, N-phenylcarbamate, N-methyl-N-(o-nitrophenyl)carbamate. The mention of these groups should not be interpreted as limiting the scope of protection of this invention, as those groups referred to as just illustrations of protective groups for IT, but other groups, with the above mentioned function may be known to a qualified specialist in this field and imply that they are also included in the scope of the present invention.

The term "pharmaceutically acceptable salt, prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES, hydrate or any other compound which, after administration to the patient is able to give (directly or indirectly) a compound as described in this context.

However, we must take into account that the pharmaceutically unacceptable salts are also included in the scope of this invention, as they may be suitable when receiving pharmaceutically acceptable salts. Obtaining salts and prodrugs can be made by methods known in this field.

For example, pharmaceutically acceptable salts of the compounds presented in this context, are synthesized from the parent compound, which contains an alkaline or acid OST the current when using standard chemical methods. Generally, such salts are, for example, is obtained by introducing into the interaction of the free acid or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or a mixture of both. Generally, the preferred non-aqueous environment, such diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the additive salts of acids include additive salts of inorganic acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and additive salts of organic acids, such as, for example, acetate, triptorelin, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate. Examples of the additive salts of the bases include inorganic salts such as, for example, salts of sodium, potassium, calcium and ammonium, and salts of organic bases, such as, for example, Ethylenediamine, ethanolamine, N,N-dialkylimidazolium, triethanolamine, and salts of basic amino acids.

Compounds according to this invention may be in crystalline form or in the form of the free compounds or in the form of a solvate (e.g. hydrate), and assume that both forms are within the scope of the present invention. Ways to salvatici is generally known in this field.

Any compound which is a prodrug compounds of the formulaIincluded in the scope and essence of the present invention. The term "prodrug", as used in this application, is defined in this context as meaning a chemical compound subjected to chemical derivatization, such as substitution or introduction of another chemical group to change (for pharmaceutical use) any of its physico-chemical properties such as solubility or bioavailability, for example, ester and ether derivatives of the active compounds that give an active connection, essentially, after administration to a subject. Examples of well-known ways to obtain prodrugs of this active compounds known to the skilled person skilled in the art and can be found, for example, the manual Krogsgaard-Larsen and others, "in Textbook of Drugdesign and Discovery", Taylor & Francis (April 2002).

Assume that any connection referred to in this context represents a particular connection, as well as some variations or shape. In particular the compounds mentioned in this context, may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds mentioned in this context, and mixtures thereof, usmatrivayutsya in the framework of the present invention. Thus, imply that any given connection, referred to in this context, is any one of the racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropoisomeric forms, and mixtures thereof. In particular, the compounds according to the present invention represented by the above formulaImay include enantiomers depending on their asymmetry, or diastereoisomer. Stereoisomeric double bond is also possible, therefore, in some cases, the molecule can exist in the form of (E)-isomer or (Z)-isomer. If the molecule contains several double bonds, each double bond has its stereoisomer, which may be the same or different than stereoisomeric other double bonds in the molecule. Individual isomers and mixtures of isomers are within the scope of the present invention.

In addition, the compounds mentioned in this context, can exist as geometric isomers (i.e., CIS - and TRANS-isomers), in the form of tautomers, or as atropoisomeric. In particular, the term "tautomer" refers to one of the two or more structural isomers compounds that exist in equilibrium and easily converted from one isomeric form to another. Well-known tautomeric pairs are amine-Imin, amide-imide, ke the o-enol, lactam-lactim etc. also mean that any connection referred to in this context, is a hydrate, solvate and polymorph and mixtures thereof, where such forms exist in the environment. In addition, the compounds mentioned in this context, can exist in the labeled isotope forms. All geometric isomers, tautomers, atropoisomeric, hydrate, solvate, polymorph, and labeled isotopes forms of the compounds mentioned in this context, and mixtures thereof are within the scope of the present invention.

To provide a more concise description of some of the quantitative expressions presented in this context, is not qualified by the term "about". It is clear that, if they use the term "approximately" or definitely not, implies, that each amount specified in this context, refers to the actual given value, and also imply that it refers to the approximation to such given value that should be reasonably justified by the opinion of a qualified expert in this field, including equivalents and approximation, due to the experimental conditions and/or conditions of measurement in the case of this value of this property.

In the compounds of General formulaIparticularly preferably, Y represents-CHRay-, -CRay=CRby-and-CHRay-CRby=CRcy-where Ra , Rbyand Rcyhave the meanings as described above.

Particularly preferably Ray, Rbyand Rcymean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably Ray, Rbyand Rcymean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents for the above mentioned groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred substituents of the above groups are HE, SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen and methyl are preferred for groups of Ray, Rbyand Rcy. Particularly, when Y represents-CHRay-then particularly preferably Raymeans methyl when Y represents-CRay=CRby-then particularly preferably Raymeans hydrogen and particularly preferably Rbydenotes methyl and Y denotes-CHRay-CRby=CRcy-then particularly preferably Raymeans hydrogen or methyl, particularly preferably Rbymeans hydrogen and particularly preferably Rcymeans methyl.

Particularly preferably, R1, R2, R3, R4and R5mean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably, R1, R2, R3,R 4and R5mean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents for the above mentioned groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. the cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred substituents of the above groups are HE, SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen, methyl, isopropyl, tert-butyl and benzyl are preferred groups R1, R2, R3, R4and R5. Specifically, particularly preferably R1, R2, R3and R4mean hydrogen. And particularly preferably R5means methyl, isopropyl and tert-butyl.

Particularly preferred W is NR7where R7has the meaning as described above.

Particularly preferred R6is NR8R9and OR10where R8, R9and R10have the meanings as described above, and even more preferably R6mean NR8R9.

Particularly preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen is the most PR is pactically.

In another embodiment is especially preferred that R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, form a substituted or unsubstituted heterocyclic group. In this regard, the preferred heterocyclic group is heteroalicyclic group containing one, two or three heteroatoms selected from the atoms N, O or S, most preferably one nitrogen atom and having from 5 to about 10 atoms in the cycle, most preferably 5, 6 or 7 atoms in the cycle. Pyrolidine group is most preferred.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of one additional link between carbon atoms, which are attached to R1and R2and the presence of one or two additional bonds between carbon atoms, which are attached to R3and R4. In addition, the stereochemistry of each double bond can exist in the form of (E) or (Z). Individual isomers and mixtures of these isomers are within the scope of the present invention.

In compounds, where a represents:

when Y means: (a) CHRay-, -CHRay-CHRby-, -CRay=CRby-, -C≡C - or-CHRay-C≡C-; or (b) -CR ay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and a triple bond exists between the carbon atoms to which are attached R3and R4then particularly preferably R9means hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. More preferably R9means hydrogen, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. Preferably, substituted alkyl, substituted alkenyl, substituted quinil and substituted alkenyl may be present not only one but also two or more substituents. More preferred alkyl groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl, nonyl are the most preferred alkyl groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. OCTA-1,6-dienyl, OCTA-1,5-dienyl, OCTA-1,4-dienyl, OK the a-1,3-dienyl, Nona-1,7-dienyl, Nona-1,6-dienyl, Nona-1,5-dienyl, Nona-1,4-dienyl, Nona-1,3-dienyl, hepta-1,5-dienyl, hepta-1,4-dienyl, hepta-1,3-dienyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms. Oct-7-inyl, Oct-6-inyl, Oct-5-inyl, Oct-4-inyl, Oct-3-inyl, Oct-2-inyl, Oct-1-inyl, non-8-inyl, non-7-inyl, non-6-inyl, non-5-inyl, non-4-inyl, non-3-inyl, non-2-inyl, non-1-inyl, hept-6-inyl, hept-5-inil, hept-4-inyl, hept-3-inyl, hept-2-inyl and hept-1-inyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-1-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents for the above alkyl, alkenyl, etkinlik and alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')N R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted aryl. Even more preferably the mi substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, dimethylhexylamine, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, and where each of R'groups are more preferably selected from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diatrizoate-silila, dimethylhexylamine, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, define methylsilyl, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, which are the most preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups.

When Y represents-CHRay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and single or double bond exists between the carbon atoms to which are attached R3and R4then R9means substituted or unsubstituted With4-C12-alkenyl. Preferred substituted alkenyl may contain not only one but also two or more substituents. More preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-1-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents is for the above alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and and substituted and unsubstituted aryl. Even more preferred substituents for these alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, dimethylhexylamine, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and fluorinated silila, and where each of R'groups are more preferably selected from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, dimethylhexylamine, 2-norbornyl-dimethylsilane, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-xylella, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)aminobutiramida-silila, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, which are the most preferred substituents for these alkenylamine groups.

Particularly preferably R16means hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted With1-C12-alkyl. Particularly preferably, Rameans hydrogen and substituted or unsubstituted With1-C6-alkyl; and even more preferably means hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, HE and methoxy are preferred groups R16.

Particularly preferably R17and R18mean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably R17and R18mean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen.

On the other hand, in the compounds, where a represents:

particularly preferably R9Osnach the em hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl and more preferably means hydrogen, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. Preferred substituted alkali, replaced alkenyl, substituted alkinyl and substituted alkenyl may be present not only one but also two or more substituents. More preferred alkyl groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl, nonyl are the most preferred alkyl groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. OCTA-1,6-dienyl, OCTA-1,5-dienyl, OCTA-1,4-dienyl, OCTA-1,3-dienyl, Nona-1,7-dienyl, Nona-1,6-dienyl, Nona-1,5-dienyl, Nona-1,4-dienyl, Nona-1,3-dienyl, hepta-1,5-dienyl, hepta-1,4-dienyl, hepta-1,3-dienyl are the most preferred alkenylamine groups. On the other hand, valueproposition alkenylamine groups are such, having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-7-inyl, Oct-6-inyl, Oct-5-inyl, Oct-4-inyl, Oct-3-inyl, Oct-2-inyl, Oct-1-inyl, non-8-inyl, non-7-inyl, non-6-inyl, non-5-inyl, non-4-inyl, non-3-inyl, non-2-inyl, non-1-inyl, hept-6-inyl, hept-5-inil, hept-4-inyl, hept-3-inyl, hept-2-inyl and hept-1-inyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-1-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents for the above alkyl, alkenyl, etkinlik and alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and replacement of the seal or unsubstituted heterocyclic group, where each of R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted aryl. Even more preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylenediamine is Lila, dimethylhexylamine, 2-norbornyl-dimethylsilane, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)aminobutiramida-silila, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, and where each of the R'groups are more preferably selected from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, diethylhexyl-silila, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]siloxan-1-yl and forcella, which are the most preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups.

Particularly preferably R16means hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted With1-C12-alkyl. Particularly preferably Rameans hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably means hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, HE and methoxy are preferred groups R16.

Particularly preferably R17and R18mean hydrogen and substituted or unsubstituted With1-C12-alkyl and particularly preferably R19means hydrogen, substituted or unsubstituted With1-C12-alkyl and CORawhere Rameans substituted or unsubstituted With1-C12-alkyl. More preferably, R17and R18mean hydrogen and substituted or unsubstituted With1-C6-alkyl, and, more preferably, R19means hydrogen, substituted or unsubstituted With1-C6-alkyl and CORawhere Rameans substituted or unsubstituted With1-C6-alkyl. Particularly preferably, Rameans methyl, ethyl, propyl, isopropyl and butyl, which including tert-butyl. Even more preferably, R17, R18and R19mean hydrogen.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of one additional link between carbon atoms, which are attached to R1and R2and the presence of one or two additional bonds between carbon atoms, which are attached to R3and R4. In addition, the stereochemistry of each double bond can exist in the form of (E) or (Z). Individual isomers and mixtures of these isomers are within the scope of the present invention.

More specifically, the preferred compounds of General formulaIare they also having a General formulaIAor their pharmaceutically acceptable salts, tautomers, prodrugs or stereoisomers:

where Y is chosen from the group consisting of CHRay-, -CHRay-CHRby-, -CRay=CRby-, -C≡C-, -CHRay-CHRby-CHRcy-, -CHRay-CRby=CRcy-and-CHRay-C≡C-;

each Ray, Rbyand Rcyindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12 -quinil;

R5selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R6choose from NR8R9and OR10;

W is chosen from O and NR7;

R7selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil, or R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, may form a substituted or unsubstituted heterocyclic group;

each R8and R9independently selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl; provided that when Y represents-CHRay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and single or double bond exists between the C3and C4then R9means alseny or unsubstituted With 4-C12-alkenyl;

R10selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R16selected from the group consisting of hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORband NRaC(=NRa)NRaRbsubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil; and

each Raand Rbindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and

each dotted line represents an optional bond.

In the compounds of General formulaIAparticularly preferably, Y represents-CHRay-, -CRay=CRby-and-CHRay-CRby=CRcy-where Ray, Rbyand Rcyhave the meanings as described above.

Particularly preferably Ray, RbyR cymean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably, Ray, Rbyand Rcymean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents for the above mentioned groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2 12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred substituents of the above groups are HE, SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen and methyl are preferred groups Ray, Rbyand Rcy. Particularly, when Y represents-CHRay-then particularly preferably Raymeans methyl when Y represents-CRay=CRby-then particularly preferably Raymeans hydrogen and particularly preferably Rbymeans methyl, and Y means-CHRay-CRby=CRcy-then particularly preferably Raymeans hydrogen or methyl, particularly preferably Rbymeans hydrogen and particularly preferably Rcymeans methyl.

Particularly preferably R5means hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably R5means hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably means hydrogen, substituted or unsubstituted methyl, semese the hydrated or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents for the above mentioned groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred substituents of the above groups are HE, SCH3, SH, NH2, NHC(=NH)NH 2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen, methyl, isopropyl, tert-butyl and benzyl are preferred groups R5and even most preferred are methyl, isopropyl and tert-butyl.

Particularly preferably, W means NR7where R7has the meaning as described above.

Particularly preferably R6mean NR8R9where R8and R9have the meanings as described above.

Particularly preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C6-alkyl; and even more preferably represent hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen is most preferred.

In another embodiment is especially preferred that R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, form a substituted or unsubstituted heterocyclic group. In this regard, the preferred heterocyclic group is heteroalicyclic group containing one, two or three heteroatoms selected from the atoms N, O or S, Naib is more preferably one nitrogen atom and having from 5 to about 10 atoms in the cycle, most preferably, 5, 6 or 7 atoms in the cycle. Pyrolidine group is most preferred.

When Y means: (a) CHRay-, -CHRay-CHRby-, -CRay=CRby-, -C≡C - or-CHRay-C≡C-; or (b) -CHRay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and a triple bond exists between the C3and C4then, particularly preferably, R9means hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. More preferably means hydrogen, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. Preferably, substituted alkyl, substituted alkenyl, substituted quinil and substituted alkenyl may be present not only one but also two or more substituents. More preferred alkyl groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl, nonyl are the most preferred alkyl groups. On the other hand, preferred alkene is lname groups are such, having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. OCTA-1,6-dienyl, OCTA-1,5-dienyl, OCTA-1,4-dienyl, OCTA-1,3-dienyl, Nona-1,7-dienyl, Nona-1,6-dienyl, Nona-1,5-dienyl, Nona-1,4-dienyl, Nona-1,3-dienyl, hepta-1,5-dienyl, hepta-1,4-dienyl, hepta-1,3-dienyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-7-inyl, Oct-6-inyl, Oct-5-inyl, Oct-4-inyl, Oct-3-inyl, Oct-2-inyl, Oct-1-inyl, non-8-inyl, non-7-inyl, non-6-inyl, non-5-inyl, non-4-inyl, non-3-inyl, non-2-inyl, non-1-inyl, hept-6-inyl, hept-5-inil, hept-4-inyl, hept-3-inyl, hept-2-inyl and hept-1-inyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-1-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents for vishey is connected alkyl, alkenyl, etkinlik and alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12 -alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted aryl. Even more preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, dimethylhexylamine, 2-norbornyl-dimethylsilane, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)aminobutiramida-silila, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, and where each of R'groups are more preferably selected from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, dietilico propylsilane, diethylhexyl-silila, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, which are the most preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups.

When Y represents-CHRay-CHRby-CHRcy-or-CHRay-CRby=CRcy-and single or double bond exists between the C3and C4then R9means substituted or unsubstituted With4-C12-alkenyl. Preferred substituted alkenyl may contain not only one but also two or more substituents. More preferred alkenylamine groups are those having from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents for the above alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted is whether unsubstituted With 1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted aryl. Even more preferred substituents for these alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, diethylhexyl-silila, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, and where each of R'groups are more preferably selected from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, d is methylisoborneol, diatrizoate-silila, dimethylhexylamine, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, which are the most preferred substituents for these alkenylamine groups.

Particularly preferably R16means hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted With1-C12-alkyl. Particularly preferably Rameans hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably means hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, HE and methoxy are preferred groups R16.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of one additional communication between the C1and C2and/or the presence of one or two extra is niteljnykh ties between 3and C4and/or the presence of one additional communication between the C5and C6. In addition, the stereochemistry of each double bond can exist in the form of (E) or (Z). Individual isomers and mixtures of these isomers are within the scope of the present invention.

Other especially preferred compounds of General formulaIare those having the General formulaIBor their pharmaceutically acceptable salts, tautomers, prodrugs or stereoisomers:

where Y is chosen from the group consisting of CHRay-, -CHRay-CHRby-, -CRay=CRby-, -C≡C-, -CHRay-CHRby-CHRcy-, -CHRay-CRby=CRcy-and-CHRay-C≡C-;

each Ray, Rbyand Rcyindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R5selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R6choose from NR8R9and OR10;

W is chosen from O and NR7;

R7selected from the group consisting of toroda, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil, or R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, may form a substituted or unsubstituted heterocyclic group;

each R8and R9independently selected from the group consisting of hydrogen, CORa, COORasubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl;

R10selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R16selected from the group consisting of hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORband NRaC(=NRa)NRaRbsubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil;

R19selected from the group consisting of hydrogen, CORa, COORa, CONRaRb, S(O)Ra, SO2Ra, P(O)(RaORb, SiRaRbRcsubstituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl and substituted or unsubstituted With2-C12-quinil; and

each Ra, Rband Rcindependently selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and

each dotted line represents an optional bond.

In the compounds of General formulaIBparticularly preferably, Y represents-CHRay-, -CRay=CRby-and-CHRay-CRby=CRcy-where Ray, Rbyand Rcyhave the meanings as described above.

Particularly preferably Ray, Rbyand Rcymean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably, Ray, Rbyand Rcymean hydrogen and substituted or unsubstituted With1-C6-alkyl, and even more preferably, OSN is given hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents for the above mentioned groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred mandated what indicators for the above groups are HE SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen and methyl are preferred groups Ray, Rbyand Rcy. Particularly, when Y represents-CHRay-then particularly preferably Raymeans methyl when Y represents-CRay=CRby-then particularly preferably Raymeans hydrogen and, particularly preferably, Rbymeans methyl, and Y means-CHRay-CRby=CRcy-then particularly preferably Raymeans hydrogen or methyl, particularly preferably, Rbymeans hydrogen and particularly preferably Rcymeans methyl.

Particularly preferably, R5means hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably, R5means hydrogen and substituted or unsubstituted With1-C6-alkyl, and even more preferably means hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Predpochtitel the different substituents of the above groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R'groups is independently selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. Even more preferred substituents of the above groups are HE, SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, and imidazolyl, including 4 - and 5-imidazolyl. Hydrogen, methyl, isopropyl, tert-butyl and benzyl are preferred groups R5and even most preferred are methyl, isopropyl and tert-butyl.

OS is especially preferably W means NR 7where R7has the meaning as described above.

Particularly preferably R6mean NR8R9where R8and R9have the meanings as described above.

Particularly preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C12-alkyl. More preferably R7and R8mean hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably signify hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen is most preferred.

In another embodiment, a particularly preferred that R7and R5together with the corresponding nitrogen atom and carbon atom to which they are attached, form a substituted or unsubstituted heterocyclic group. In this regard, the preferred heterocyclic group is heteroalicyclic group containing one, two or three heteroatoms selected from the atoms N, O or S, most preferably one nitrogen atom and having from 5 to about 10 atoms in the cycle, most preferably 5, 6 or 7 atoms in the cycle. Pyrolidine group is most preferred.

Particularly preferably, R9means hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12 alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl and, more preferably means hydrogen, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted With4-C12-alkenyl. Preferably, substituted alkyl, substituted alkenyl, substituted quinil and substituted alkenyl may be present not only one but also two or more substituents. More preferred alkyl groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Heptyl, octyl, nonyl are the most preferred alkyl groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. OCTA-1,6-dienyl, OCTA-1,5-dienyl, OCTA-1,4-dienyl, OCTA-1,3-dienyl, Nona-1,7-dienyl, Nona-1,6-dienyl, Nona-1,5-dienyl, Nona-1,4-dienyl, Nona-1,3-dienyl, hepta-1,5-dienyl, hepta-1,4-dienyl, hepta-1,3-dienyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and d is more preferably 7, 8 or 9 carbon atoms. Oct-7-inyl, Oct-6-inyl, Oct-5-inyl, Oct-4-inyl, Oct-3-inyl, Oct-2-inyl, Oct-1-inyl, non-8-inyl, non-7-inyl, non-6-inyl, non-5-inyl, non-4-inyl, non-3-inyl, non-2-inyl, non-1-inyl, hept-6-inyl, hept-5-inil, hept-4-inyl, hept-3-inyl, hept-2-inyl and hept-1-inyl are the most preferred alkenylamine groups. On the other hand, preferred alkenylamine groups are those having from 6 to about 10 carbon atoms and even more preferably 7, 8 or 9 carbon atoms. Oct-1-EN-7-inyl, Oct-1-EN-6-inyl, Oct-1-EN-5-inyl, Oct-1-EN-4-inyl, Oct-1-EN-3-inyl, non-1-EN-8-inyl, non-1-EN-7-inyl, non-1-EN-6-inyl, non-1-EN-5-inyl, non-1-EN-4-inyl, non-1-EN-3-inyl, hept-1-EN-6-inyl, hept-1-EN-5-inyl, hept-1-EN-4-inyl and hept-1-EN-3-inyl are the most preferred alkenylamine groups. Preferred substituents for the above alkyl, alkenyl, etkinlik and alkenylamine groups are OR', =O, SR', SOR', SO2R', NO2That other', NR'r R', =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', protected, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each R'group is ezavisimo selected from the group consisting of hydrogen, HE, NO2, NH2, SH, CN, halogen, SON, CO-alkyl, COOH, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. In cases where such groups are substituted, the substituents can be selected from the above list. More preferred substituents for the above alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCOR', OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where each of the R'groups are preferably selected from the group consisting of hydrogen, substituted or unsubstituted With1-C12-alkyl, substituted or unsubstituted With2-C12-alkenyl, substituted or unsubstituted With2-C12-quinil and substituted or unsubstituted aryl. Even more preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups are halogen, OR', =O, OCONHR', OCONR'R', CONHR', CONR'R' and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, dimethylhexylamine, 2-norbornylene-Seeley is a, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pureelectric, Tris(trimethylsilyl)silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)aminobutiramida-silila, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, and where each of R'groups are more preferably chosen from the group consisting of hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl, Cl, OH, =O, OCONH2, OCONH-phenyl and protected IT, where the protective group for IT is preferably chosen from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, diethylhexyl-silila, 2-norbornanamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-xolisile, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-pienimuotoisilla, Tris(trimethylsilyl)-silila, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)-diisopropylaniline, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and forcella, which are h is the most preferred substituents for these alkyl, alkenyl, etkinlik and alkenylamine groups.

Particularly preferably R16means hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted With1-C12-alkyl. Particularly preferably Rameans hydrogen and substituted or unsubstituted With1-C6-alkyl and even more preferably means hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, HE and methoxy are preferred groups R16.

Particularly preferably R19means hydrogen, substituted or unsubstituted With1-C12-alkyl and CORawhere Rameans substituted or unsubstituted With1-C12-alkyl. More preferably R19means hydrogen, substituted or unsubstituted With1-C6-alkyl and CORawhere Rameans substituted or unsubstituted With1-C6-alkyl. Particularly preferably Rameans methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Even more preferably R19means hydrogen.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of one additional communication between the C1and C2and/or the presence of one or the Vuh additional links between 3and C4and/or the presence of one additional communication between the C5and C6. In addition, the stereochemistry of each double bond can exist in the form of (E) or (Z). Individual isomers and mixtures of these isomers are within the scope of the present invention.

Compounds according to this invention can be obtained synthetically by attaching different pieces as shown in diagram A.

where R1, R2, R3, R4, R5, R6And, Y and W denote the desired group or a suitable protective group as required, and J, K, L, and M indicate the appropriate reactive or delete the group.

Compounds according to this invention can be obtained by any of the following strategies:

1) Fragments a and b can be associated, following standard techniques in organic chemistry (i.e. M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, 1993).

2) the Fragments C and D can be associated, following the standard methods of ORGANOMETALLIC chemistry (i.e. R.B. Crabtree, The Organometallic Chemistry of the Transition Metals”, 2nd ed., Wiley, Nueva York, 1994).

Fragments a, b, C and D can be independently obtained by following the standard methods in organic synthesis.

Remove protection against protective groups can be achieved in accordance with known methods in organic synthesis (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd from the., Wiley-Interscience; Burke and Danheiser, Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Agents, Wiley; Pla D. et. al., J. Org. Chem., 2005, 70, 8231).

When necessary, suitable protective groups can be used as substitutes to ensure that were not affected by the reactive group. The synthesis can be performed using the predecessors of the substituents that can be transformed, at a suitable stage in a desirable substitute. Saturation or unsaturation in the cyclic structure can be entered or removed as part of the synthesis. Source materials and reagents can be modified, as desired, to ensure the implementation of the synthesis of the desired compounds. In addition, the analogs can be synthesized from compounds prepared by the usual methods in synthetic organic chemistry that are known to a qualified specialist in this field.

The above synthesis pathway can be modified, as desired, to obtain stereospecific compounds as well as mixtures of stereoisomers. Specific stereoisomers or a particular mixture can be synthesized in various ways, including the use of stereospecific reagent or by the introduction of chiral centers in the compounds during synthesis. You can enter one or more stereocentres during synthesis and also to invert the existing CTE is ocentry. In addition, you can separate the stereoisomers, if the connection is already synthesized by standard methods of separation known to a qualified specialist in this field.

An important property of the above compounds of the formulaIis their bioactivity and, in particular, their cytotoxic activity.

According to the present invention, the authors offer new pharmaceutical compositions comprising compounds of General formulaIthat possess cytotoxic activity, and their use as antitumor agents. Thus, the present invention further relates to pharmaceutical compositions containing a compound according to this invention, its pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer, pharmaceutically acceptable carrier.

The term "carrier" refers to a solvent, adjuvant, excipient or diluent, which is administered active ingredient. Suitable pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences", E.W. Martin, 1995.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) compositions for oral, local or parenteral administration.

Introduction compounds or compositions according to the n of the present invention can be accomplished in any suitable way, such as intravenous infusion, oral dosage forms and intraperitoneal and intravenous. Preferably, the infusion was up to 24 hours, more preferably 1 to 12 hours, most preferably 1-6 hours. Especially desirable short infusion times, which allow treatment without staying overnight in the hospital. However, the infusion can last from 12 to 24 hours or even longer if necessary. The infusion can be performed at suitable intervals, comprising from 1 to 4 weeks. Pharmaceutical compositions containing compounds according to this invention, can be delivered through liposomal or nanospheres encapsulation, using finished dosage forms with prolonged release, or using other standard methods of delivery.

The exact dose of the compounds varies in accordance with a particular finished pharmaceutical form, route of administration and the particular site, host and tumor, which is subjected to the treatment. You need to take into account other factors such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, the sensitivity against reaction and the severity of the disease. Introduction it is possible to perform continuous the VNO or periodically, within the maximum permissible doses.

The compounds and compositions according to this invention can be used with other medicines to combined therapy. Other medicines may form a part of the same composition or may be provided as a separate composition for administration at the same time or at another time.

The antitumoral aktivnosti these compounds include, but are not limited to, activity in relation to cancer of the lung, cancer of the colon and breast cancer.

EXAMPLES

Example 1

Synthesis of fragment 9

Scheme 1 shows an example of the synthesis of fragment 9.

Synthesis of intermediate product 1

It cooled down to 0°C. a solution of (2S,3S) - for 3,5-bis{[(tert-butyl)dimethylsilane]oxy}-2-methylpentan-1-ol (P. Phukan, S. Sasmal and M.E. Maier, Eur. J. Org. Chem., 2003, 1733-1740) (50 g, 0.14 mol)in a mixture of dichloromethane/DMSO (331 ml/149 ml)through an addition funnel add Et3N (96,1 ml, 0.69 mol). After 10 minutes add parts SO3·Pyr (54,8 g, 0.34 mol) and the solution stirred for a further 2 hours at 0°C. Then it was diluted with dichloromethane (800 ml) and quenched with HCl (0.5 n solution, 800 ml). The organic layer is decanted, dried over MgSO4and concentrate in vacuum is. Purified by column chromatography (hexane/EtOAc = 100:0 to 10:1)to give 45 g (yield: 90%) of aldehyde1.

1H NMR (CDC13, 300 MHz) δ: 9,79 (s, 1H), 4,30 (m, 1H), 3,65 (m, 2H), of 2.51 (m, 1H), 1.69 in (m, 2H), was 1.04 (d, 3H, J=6.9 Hz), 0,85-to 0.88 (m, 18H), 0,03-0,07 (m, 12H).

13C-NMR (CDCl3, 75 MHz) δ: 205,4, 69,4, 59,6, 51,7, 37,5, 26,1, 26,0, 18,4, 18,2, 8,0, -4,3, -4,5, -5,2.

Synthesis of the intermediate product 2

To a solution of aldehyde1(45 g, 0.12 mol)in toluene (625 ml), add carbethoxymethylthio (113 g, 0.31 mol) and the mixture is heated at 60°C for 17 hours. Then the solvent is removed under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 100:0 to 10:1), obtaining the level of 53.3 g (yield: 96%) of ester, the compounds of the2.

1H NMR (CDCl3, 300 MHz) δ: of 6.71 (DD, 1H, J=1,5, 10,2 Hz), 4,19 (m, 2H), of 3.77 (m, 1H), 3,66 (m, 2H), 2,61 (m, 1H), of 1.85 (d, 3H, J=1.5 Hz), 1,68 (m, 2H), of 1.30 (t, 3H, J=7,2 Hz), and 0.98 (d, 3H, 6.9 Hz), of 0.90 (m, 18H), of 0.05 (m, 12H).

13C-NMR (CDCl3, 75 MHz) δ: 168,3, 145,4, 126,7, 72,2, 60,4, 59,7, 38,4, 38,0, 25,9, 18,2, 18,1, 14,3, 14,3, 12,6, -4,4, -4,6, -5,4.

Synthesis of the intermediate product 3

To a solution of ester2,cooled to a temperature of -78°C(46,7 g, 0,105 mol)in anhydrous THF (525 ml)in an argon atmosphere, was added 1 M solution diisobutylaluminium-hydride (DIBAL) in toluene (231 ml, 0,231 mol) over a period of time 10 mi the ut and the mixture was stirred at -78°C. After 4 hours the reaction mixture was quenched with Meon (10 ml), add a saturated solution of sodium tartrate, potassium (800 ml) and diluted with ethyl acetate (EtOAc) (1000 ml). This mixture is stirred for 2 hours and then the organic layer decanted. The aqueous residue is extracted with additional EtOAc (2 x 400 ml) and the combined organic layers dried over anhydrous Na2SO4and the solvent is evaporated. The resulting oil purified by column chromatography (hexane/EtOAc = 20:1 to 10:1), receiving of 32.5 g (yield: 77%) of alcohol3.

1H NMR (CDCl3, 300 MHz) δ: 5,31 (d, 1H, J=9.6 Hz), 3,98 (m, 2H), 3,66 (m, 3H), 2.49 USD (m, 1H), 1,67 (s, 3H), 1.70 to of 1.62 (m, 2H), of 0.91 (d, 3H, J=6.9 Hz), to 0.88 (m, 18H), 0,03 (m, 12H).

13C-NMR (CDCl3, 75 MHz) δ: 133,9, 129,8, 73,1, 69,1, 59,9, 37,8, 37,5, 25,9, 18,3, 18,1, 15,9, 13,9, -4,4, -4,4, -5,3.

Synthesis of the intermediate product 4

To a solution of alcohol3(31,2 g, 77.5 mmol) in ethyl ether (387 ml)in an argon atmosphere, add MnO2(101 g of 1.16 mol) and the mixture is stirred at room temperature for 2 hours. This mixture is filtered through a column of silica gel, elwira with EtOAc (3 l)and the resulting solution was dried under reduced pressure, obtaining of 29.1 g (yield: 94%) of aldehyde4.

1H NMR (CDCl3, 300 MHz) δ: 9,37 (s, 1H), 6,44 (d, 1H, J=9.6 Hz), 3,82 (DD, 1H, J=6.3, in the 10.8 Hz), the 3.65 (m, 2H), 2,82 (m, 1H), 1,74 (s, 3H), 1,67 (m, 2H), of 1.02 (d, 3H, J=6.9 Hz), 0,86 (s, 18H), 0,04-0,01 (m, 2H).

13C-NMR (CDCl3, 75 MHz) δ: 195,4, 157,8, 138,3, 72,0, 59,5, 38,7, 37,5, 25,8, 18,2, 18,0, 14,3, 9,4, -4,4, -4,5, -5,4.

Synthesis of intermediate product 5

To a suspension of iodocyclization (Gilbert Stork KZ., Tetrahedron letters, 1989, 30(17), 2173) (96,3 g 181,7 mmol) in anhydrous THF (727 ml), at 0°C, slowly through an addition funnel was added 1 M solution matrikelstyrelsen (NaHMDS) (181,7 ml 181,7 mmol) for 10 minutes. After stirring for an additional 5 minutes the solution is cooled to a temperature of -78°C and then through the cannula add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (43,9 ml, 363,4 mmol), and then add the aldehyde4(29,1 g, 72,7 mmol)dissolved in anhydrous THF (727 ml). Maintain a temperature of -78°C. while stirring the reaction mixture for 2 hours. Add hexane (1 l) and the resulting suspension is filtered through celite and washed with additional hexane (3 l). The filtrate is evaporated under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 100:0 to 20:1)to give 32 g (yield: 84%) of iodide5.

1H NMR (CDCl3, 300 MHz) δ: was 6.73 (d, 1H, J=8,4 Hz)6,09 (DD, 1H, J=8,4, 1.2 Hz), to 5.57 (DD, 1H, J=a 9.6, 1.2 Hz), 3,63-3,71 (m, 3H), 2,58 (m, 1H), 1,90 (s, 3H), of 1.70 (m, 2H), 0,96 (DD, 3H, J=6,6, 1.2 Hz), to 0.88 (s, 18H), 0,04 (m, 12H).

13C-NMR (CDCl3, 75 MHz) δ: 142,3, 138,1, 131,8, 74,6, 72,9, 59,8, 38,, 37,9, 26,0, 18,3, 18,2, 15,7, 15,7, -4,4, -5,2, -5,2.

Synthesis of the intermediate product 6

To a solution of iodide5(12 g, to 22.9 mmol) in EtOH (114 ml) add pyridine-p-toluensulfonate (PPTS) (2,01 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 25 hours. Then the solvent is removed under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 10:1)to give 8.7 g (yield: 93%) of alcohol6.

1H NMR (CDCl3, 300 MHz) δ: 6,69 (d, 1H, J=8,4 Hz), 6,12 (d, 1H, J=8,4 Hz), vs. 5.47 (d, 1H, J=9.9 Hz), 3,67-a 3.87 (m, 4H), 2,71 (m, 1H), 1,89 (s, 3H), 1,73 is 1.86 (m, 2H), 1,01 (d, 3H, J=6.9 Hz), of 0.91 (s, 9H), 0,087-0,115 (m, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 142,4, 136,4, 132,6, 75,8, 75,2, 60,0, 38,1, 36,4, 26,1, 18,2, 17,1, 16,0, -4,1, -4,2.

Synthesis of the intermediate product 7

It cooled down to 0°C solution of alcohol6(8.7 g, of 21.2 mmol)in a mixture of dichloromethane/DMSO (50,9 ml/22,9 ml)through an addition funnel add Et3N (of 14.8 ml, 106 mmol). After 10 minutes add parts SO3·Pyr (8,43 g, to 53.0 mol) and the solution stirred for a further 2 hours at 0°C. Then it was diluted with dichloromethane (800 ml) and quenched with HCl (0.5 n solution, 50 ml). The organic layer is decanted, dried over MgSO4and concentrated in vacuo. Purified by column chromatography (hexane/EtOAc = 10:1)to give 6.9 g (yield: 80%) Aldagi the and 7.

1H NMR (CDCl3, 300 MHz) δ: 9,89 (t, 1H, J=1.5 Hz), to 6.67 (d, 1H, J=8,4 Hz), 6,13 (d, 1H, J=8,4 Hz), 5,43 (d, 1H, J=10,2 Hz), 3,98 (m, 1H), 2,59-2,69 (m, 3H), of 1.85 (s, 3H), of 1.01 (d, 3H, J=6.6 Hz), 0,86 (s, 9H), 0.06 to (C, 3H), of 0.03 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 201,8, 141,9, 135,2, 133,3, 76,3, 71,9, 49,3, 39,3, 25,8, 18,0, 16,7, 15,9, -4,4, -4,5.

Synthesis of the intermediate product 8

To a solution of diethyl - (methoxy[methoxycarbonyl]methyl)phosphonate (5,51 g, accounted for 14.45 mmol) and 18-crown-6 (11.5g, 43,34 mmol)in anhydrous THF (390 ml), stirred in an argon atmosphere at a temperature of -78°C., added dropwise a 0.5 M solution of bis(trimethylsilyl)amide potassium (KHMDS) (43,34 ml, 21,67 mmol). After 15 minutes, added dropwise to the aldehyde7(5.9 g, accounted for 14.45 mmol) in anhydrous THF over 30 minutes and stirred at -78°C for 90 minutes. Then the reaction mixture was quenched with a saturated solution of NH4Cl (200 ml), warmed to room temperature and diluted with dichloromethane (1000 ml). The organic phase is dried over anhydrous Na2SO4and evaporated under reduced pressure. Purified by column chromatography (hexane/Et2O = 20:1), receiving of 4.2 g (yield: 59%) of pure(E)-8.

1H NMR (CDCl3, 300 MHz) δ: 6,70 (d, 1H, J=8,4 Hz), between 6.08 (d, 1H, J=8,4 Hz), vs. 5.47 (d, 1H, J=9.9 Hz), lower than the 5.37 (t, 1H, J=7,2 Hz), of 3.78 (s, 3H), of 3.60 (s, 3H), of 3.60 (m, 1H), and 2.79 (m, 1H), 2,52-to 2.67 (m, 2H)and 1.83 (s, 3H), 0,99 (d, 3H, J=6.6 Hz), to 0.89 (s, 9H), of 0.05 (s, 3H), of 0.04 (s, 3H).

13C-NMR (CDCl3

Synthesis of intermediate 9

To a solution of ester8(4.15 g, 8,39 mmol) in Meon (125 ml)at room temperature, add 37%HCl solution (1,04 ml) and the reaction mixture is stirred for 6 hours. The mixture is then neutralized with a saturated aqueous solution of NaHCO3(pH=7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension is extracted with dichloromethane (3 x 200 ml), dried and evaporated. Filter using column chromatography (hexane/EtOAc = 10:1 to 2:1)to give 2.76 g (yield: 94%) of lactone9.

1H NMR (500 MHz, CDCl3) δ: of 6.68 (d, 1H, J=9.0 Hz), of 6.20 (d, 1H, J=8.5 Hz), 5,63 (DD, 1H, J=2.5 and 6.5 Hz), 5,43 (d, 1H, J=10.0 Hz), 4,19 (m, 1H), the 3.65 (s, 3H), 2,84 (m, 1H), to 2.55 (m, 1H), 2,43 (DS, 1H, J=3.0 a, 12,0, of 15.0 and 18.0 Hz), 1,87 (s, 3H), of 1.16 (d, 3H, J=6.5 Hz).

13C-NMR (125 MHz, CDCl3) δ: 161,6, 145,2, 141,8, 134,4, 132,7, 108,3, 81,7, 77,4, 55,4, 37,1, 26,6, 16,5, 16,1.

Example 2

Synthesis of fragments 21 and 22

Figure 2 presents an example of the synthesis of fragments 21 and 22.

Synthesis of the intermediate product 11

To a solution of the intermediate product10(72,3 g to 0.39 mol) in anhydrous dichloromethane (DCM) (918 ml) at room temperature in parts add 3-chlormadinone acid (m-CPBA) (100 g, of 0.58 mol and the mixture is stirred at room temperature for 18 hours. The precipitated white quenched with saturated aqueous NaHCO3, extracted with dichloromethane (DCM) (3 times 250 ml) and again washed with a saturated aqueous solution of NaHCO3(3 times 250 ml). The organic layers are combined, dried over anhydrous Na2SO4and concentrated in vacuo. The resulting oil purified on silica gel (hexane-EtOAc = 15:1)to give the epoxide as a colorless oil (64,5 g, yield 82%). To a solution of racemic epoxide (30 g, 0.15 mol) in anhydrous THF (7.5 ml) is added (R,R)-(-)-N,N'-bis(3,5-di-tert-butylchloride)-1,2-cyclohexanediamine-cobalt-(II) [(R,R)Co(II)-complex] (448 mg, of 0.74 mmol), then Asón (0,14 ml). The solution is cooled to a temperature of 0°C and added dropwise water (1.2 ml). The reaction mixture was left to warm to room temperature and stirred for 18 hours. After this time, the volatiles evaporated in vacuo and the crude product is immediately loaded into a column of silica gel. Perform flash chromatography using hexane/EtOAc (15:1 to 12:1) as eluent, obtaining chiral epoxide(+)-11(to 13.6 g, yield: 46%) as a colourless oil.

[α]D=+14,1 (C=1, CHCl3).

1H NMR (CDCl3, 300 MHz) δ: 3,74 (t, 2H, J=6.3 Hz), 3,01 (m, 1H), 2,74 (t, 1H, J=4,6 Hz), 2,48 (DD, 1H, J=5,1, 3.1 Hz), to 1.70 (m, 2H), 0,87 (s, 9H), of 0.04 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 60,2, 50,2, 47,3, 36,1, 26,1, 18,4, -5,2.

SinTe the intermediate product 12

Propyne (10 ml, 0,176 mol) condense at a temperature of -78°C and dissolved in anhydrous THF (165 ml). Added dropwise n-utility (75,1 ml, 0,188 mol), under nitrogen atmosphere, for 30 minutes and the resulting white suspension is stirred for a further 30 minutes at -78°C. Then, dropwise, add a solution of (+)-(R)-2-[2-(tert-butyldimethylsilyloxy)-ethyl]oxirane11(23.7 g, 0,117 mol) in anhydrous THF (125 ml), and then adding BF3.OEt2(22,1 ml, 0,176 mol). The mixture is stirred for 1 hour at -78°C and for another hour at 0°C. the Reaction mixture was quenched with saturated aqueous solution of NH4Cl (150 ml) and extracted with Et2O (3 x 150 ml). The combined organic layers dried over Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 10:1 to 1:1)to give alcohol12(22,7 g, yield: 80%) as a colourless oil.

[α]D= +5,6 (s = 0,1, CHCl3).

1H NMR (500 MHz, CDCl3) δ: 3.75 to 3,90 (m, 3H), 3,47 (d, 1H, J=2.7 Hz, OH), was 2.34 (m, 2H), 1,79, (t, 3H, J=2,4 Hz)of 1.75 (m, 2H), 0,89 (s, 9H), of 0.07 (s, 6H).

13C-NMR (125 MHz, CDCl3) δ: 77,8, 75,8, 70,7, 62,4, 37,6, 27,6, 26,1, 18,3, 3,7, -5,3, -5,4.

MS (ES)m/z: 243,2 [M+H]+, 265,2 [M+Na]+.

Synthesis of intermediate 13

To a solution of the product12(41.8 g, 0,173 mol) and 18-the development round-6-ether (50,27 g, 0,190 mol) in anhydrous THF (1190 ml) at -78°C in an atmosphere of nitrogen, through an addition funnel add 0.5 n solution of KHMDS in toluene (380 ml, 0,190 mol)over 30 minutes. The mixture was stirred at the same temperature for 45 minutes, then add a solution of 4-methoxybenzylamine (PMBCl) (23,89 g, 0,176 mol) in anhydrous THF (100 ml). After incubation for 2 hours at -78°C, the mixture was quenched with saturated aqueous solution of NH4Cl (600 ml). The organic layer is separated and the aqueous phase is exhaustively extracted with EtOAc (3 x 500 ml). The combined organic layers washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated, obtaining the product13in the form of a yellow oil, which is used in the following stage without further purification (61,3 g, yield: 99%).

1H NMR (CDCl3, 300 MHz) δ: of 7.25 (d, 2H, J=8.7 Hz), 6.90 to (d, 2H, J=8.7 Hz), of 4.45 (m, 2H), 3,80 (s, 3H), of 3.65 (m, 3H), 2.40 a (m, 2H), equal to 1.82 (m, 2H), 1,79 (t, 3H, J=2,4 Hz)to 0.92 (s, 9H), of 0.05 (s, 6H).

Synthesis of intermediate product 14

To a solution of the product13(61,3 g, 0,169 mol) in anhydrous toluene (2.1 liters), under nitrogen atmosphere and at 0°C, add the reagent Schwartz, (bis(cyclopentadienyl)zirconium(IV)-chloridized, Cp2ZrHCl) (130,3 g, 0,507 mol) and the reaction mixture is stirred for 5 minutes at room tempera is ur. The reaction temperature was raised to 50°C. for 20 minutes and stirred at 50°C for 2.5 hours. During this time the reaction solution becomes orange. The reaction solution is cooled to a temperature of 0°C. and add N-chlorosuccinimide (58,45 g, 0,440 mol) in one portion. Continue to mix for 30 minutes at room temperature and the reaction mixture was diluted with hexane/EtOAc (95:5; 500 ml). Remove the solid by filtration and evaporated volatile substances, getting the product14in the form of a yellow oil, which was used without further purification (15,1 g, yield: 86%).

[α]D=+20,5 (C=1, CHCl3).

1H NMR (CDCl3, 300 MHz) δ: of 7.25 (d, 2H, J=8.7 Hz), 6.87 in (d, 2H, J=8.7 Hz), 5,64 (TD, 1H, J=7,8, and 0.9 Hz), of 4.45 (q, 2H, J=11,1 Hz), 3,80 (s, 3H), 3,70 (m, 2H), 3,62 (m, 1H), and 2.27 (t, 2H, J=6.9 Hz), 2,03 (s, 3H), of 1.70 (m, 2H), 0,89 (s, 9H), of 0.05 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 159,4, 130,9, 130,7, 129,6, 124,2, 114,0, 75,2, 71,4, 59,8, 55,5, 37,7, 33,8, 26,1, 21,2, 18,5, -5,1.

Synthesis of intermediate 15

To a solution of the product14(23 g, 0,058 mol) in anhydrous THF (288 ml), under nitrogen atmosphere and at a temperature of 0°C is added dropwise a solution of tetrabutylammonium (TBAF) (115,3 ml, 0,115 mol) over 20 minutes (the solution becomes red). The reaction mixture was stirred at room temperature for 2 hours and then quenched with OSU saturated aqueous solution of NH 4Cl (200 ml). The layers are separated and the aqueous phase is exhaustively extracted with EtOAc (3 x 150 ml). The combined organic layers dried over Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 4:1 to 1:1)to give the product15in the form of a colorless oil (11.9 g, yield: 73%).

1H NMR (CDCl3, 300 MHz) δ: of 7.25 (d, 2H, J=8.7 Hz), 6,86 (d, 2H, J=8.7 Hz), 5,62 (t, 1H, J=7.8 Hz), of 4.45 (m, 2H), 3,80 (s, 3H), 3,70 (m, 3H), 2,35 (m, 2H), 2,03 (s, 3H), of 1.75 (m, 2H).

Synthesis of the intermediate product 16

(Diacetoxy)benzene (BAIB) (11.5g, to 35.7 mmol) are added to a solution of alcohol15(9.2 grams, 32,4 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (TAMRA) (515 mg, 3.3 mmol) in anhydrous dichloromethane (92 ml). The reaction mixture was stirred at room temperature for 20 hours up until the alcohol no longer be detected (TLC), and then this mixture is quenched with saturated aqueous solution of NH4Cl and extracted with DCM (3 times 100 ml). The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:1)to give the product16in the form of a colorless oil (6.3 g, yield: 69%).

1H NMR (CDCl3, 300 MHz) δ: 9,78 (s, 1H), 7,25 (d, 2H, J=8.7 Hz), 6,85 (d, 2H, J=8.7 Hz), 5,64 (t, 1H, J=7.8 Hz), of 4.45 (q, 2H, J=11,1 Hz), was 4.02 (m, 1H), 3,80 (s, 3H), 2,60 (m, 2H), 2,35 (m, 2H), 2,03 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 201, 159,6, 132,1, 130,1, 129,7, 122,8, 114,1, 73,3, 71,5, 55,5, 48,3, 33,5, 21,3.

Synthesis of intermediate 17

To a suspension of iodocyclization (16.6 g, 31 mmol) in anhydrous THF (126 ml), at room temperature, slowly add 1 M solution of NaHMDS in anhydrous THF (31,27 ml, 31,27 mol). After stirring for 2 minutes, the mixture is yellow cooled to a temperature of -78°C and then add a solution of the product16(6.3 g, 22 mmol) in anhydrous THF (82 ml). The reaction mixture was stirred at -78°C for 2 hours and at room temperature for 5 minutes, diluted with hexane and filtered through a layer of celite (Celite®). Layer celite washed with hexane, and the combined filtrates evaporated under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 12:1 to 8:1)to give the product17in the form of a yellow oil (5.6 g, yield: 62%).

1H NMR (CDC13, 300 MHz) δ: of 7.25 (d, 2H, J=8.7 Hz), 6,85 (d, 2H, J=8.7 Hz), and 6.25 (m, 2H) 5,64 (t, 1H, J=7.8 Hz), 4,42 (m, 2H), 3,80 (s, 3H), 3,55(m, 1H), 2.40 a (m, 2H, in), 2.25 (m, 2H), 2,03 (s, 3H).

Synthesis of intermediate 18

2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ) (3.6 g, 16 mmol) are added to a solution of the product17(5 g, 12 mmol) in a mixture of DCM-H2O (20:1, 98 ml), under nitrogen atmosphere, at room temperature. the item 1.5 hours (hexane/EtOAc = 4:1, TLC shows the absence of starting material), the reaction mixture was quenched by pouring in Et2O (200 ml) and washing with 1 M NaOH solution (3 times 50 ml) and saturated saline (50 ml). The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. Chromatographic separation of n-methoxybenzaldehyde facilitated recovery to p-methoxybenzylthio alcohol. After this, the solution of the obtained residue in the Meon (98 ml) with NaBH4(0,60 g, 16 mmol), under nitrogen atmosphere, maintained at room temperature for 1 hour. The reaction mixture was then quenched by pouring in Et2O (100 ml) and washing with 1 M HCl solution (40 ml) and saturated brine (40 ml). The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. The resulting oil purified on silica gel (hexane/EtOAc = 10:1 to 4:1)to give the secondary alcohol as a colourless oil (2.8 g, yield: 80%).

To a solution of secondary alcohol (2.8 g, 10 mmol) in anhydrous DCM (38 ml), under nitrogen atmosphere and at a temperature of 0°C., added dropwise 2,6-lutidine (2,28 ml, 20 mmol)and then tert-butyldimethylchlorosilane (TBSOTf) (2,33 ml, 12 mmol). The reaction mixture is stirred for 2 hours. At this point, the crude mixture was quenched with 0.5 M HCl solution (25 ml) and extracted with DCM (2 x 25 ml). United on the organic layers washed with saturated aqueous NaHCO 3and saturated salt solution. The organic phase is dried over Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 100:1 to 20:1)to give the product18in the form of a colorless oil (3,14 g, yield: 80%).

1H NMR (CDCl3, 300 MHz) δ: 6,25 (m, 2H) 5,64 (t, 1H, J=7.8 Hz), 3,82 (m, 1H), of 2.38 (t, 2H, J=6.0 Hz), measuring 2.20 (t, 2H, J=6.3 Hz), 2,03 (s, 3H), 0,86 (s, 9H), of 0.05 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 137,7, 130,9, 124,3, 84,6, 70,6, 42,5, 36,6, 25,9, 21,3, 18,2, -4,4.

Synthesis of intermediate 19a

In a tightly closed tube Slinka injected iodide copper(I) (148 mg, 0.78 mmol), potassium carbonate (1,076 g, 7,78 mmol) and BOC-tert-LeuCONH2(obtained by the procedure described Pozdnev V.F., Tetrahedron Letters, 1995, 36, 7115-7118) (0.96 g, 4,15 mmol), create a vacuum and filled with nitrogen. Add N,N'-dimethylethylenediamine (DMEDA) (0,166 ml, 1.55 mmol), vinylite18(1.04 g, at 2.59 mmol) and anhydrous DMF (15 ml), under nitrogen atmosphere. Tube Slinka, sealed, heated at 90°C for 18 hours and cooled to room temperature. The resulting mixture was diluted with EtOAc and quenched with water. The organic layer is washed with water and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue purified using flash chromatography on silica gel (hexane/EtOAc = 20:1 to 15:1). The intermediate product19a(670 mg, yield: 3%) are obtained in the form of oil.

1H NMR (CDC13, 300 MHz) δ: 7,72 (d, 1H, J=9.9 Hz), 6,70 (t, 1H, J=9.6 Hz), 5,54 (t, 1H, J=7.8 Hz), to 5.35 (d, 1H, J=9.0 Hz), was 4.76 (q, 1H, J=7.8 Hz), with 3.89 (d, 1H, J=9.0 Hz), to 3.73-3,68 (m, 1H), 2,12 (m, 4H), to 1.98 (s, 3H), of 1.40 (s, 9H), of 0.97 (s, 9H), from 0.84 (s, 9H), of 0.02 (s, 3H), of 0.01 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 168,9, 156,0, 131,1, 123,9, 122,6, 108,2, 79,9, 71,6, 62,5, 36,5, 34,8, 33,8, 28,1, 26,7, 25,9, 21,2, 18,3, -4,3, -4,4.

Synthesis of intermediate product 19b

In a tightly closed tube Slinka injected iodide copper(I) (40,4 mg, 0,213 mmol), potassium carbonate (294 mg, 2,13 mmol) and BOC-Val-CONH2(obtained by the procedure described Pozdnev V.F., Tetrahedron Letters, 1995, 36, 7115-7118) (230 mg, 1.06 mmol), create a vacuum and filled with nitrogen. Add N,N'-dimethylethylenediamine (45 μl, 0,426 mmol), vinylite18(283 mg, 0.71 mmol) and anhydrous DMF (35 ml), under nitrogen atmosphere. Tube Slinka, sealed, heated at 90°C for 18 hours and cooled to room temperature. The resulting mixture was diluted with EtOAc and quenched with water. The organic layer is washed with water and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue purified using flash chromatography on silica gel (hexane/EtOAc = 7:1 to 3:1). The intermediate product19b(270 g, yield: 77%) are obtained in the form of oil.

1H NMR (CDC13, 300 MHz) δ: 7,80 (d, 1H, J=9.3 Hz), 6,79-of 6.73 (m, 1H), 5,58 (t, 1H, J=7.5 Hz), 5,02 (USS, 1H), 4,85 was 4.76 (m, 1H), 3,93 (DD, 1H, J=8,4, 6,0 Hz), 3,80-to 3.73 (who, 1H), 2,12-2,22 (m, 5H), 2,02 (s, 3H), 1,45 (s, 9H), and 0.98 (d, 3H, J=6.9 Hz), of 0.93 (d, 3H, J=6.9 Hz), to 0.89 (s, 9H), of 0.07 (s, 3H), 0,06 (s, 3H).

Synthesis of intermediate 20A

A solution of protected amino19a(670 mg, of 1.33 mmol) in ethylene glycol (30 ml) is heated at 200°C for 15 minutes. The reaction mixture is then cooled to room temperature, diluted with DCM, quenched with saturated salt solution and poured into water. Add a few drops of 3 M NaOH solution up until the pH of the solution reaches 14, and is then thoroughly extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo, obtaining primary amine20A(510 mg, yield: 95%) as a yellow oil, which was used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 8,77 (d, 1H, J=9.9 Hz), of 6.71 (t, 1H, J=9.6 Hz), to 5.56 (t, 1H, J=7.8 Hz), 4,71 (m, 1H), and 3.72 (m, 1H), 3,14 (s, 1H), and 2.14 (m, 4H), of 1.97 (s, 3H), of 0.97 (s, 9H), from 0.84 (s, 9H), of 0.02 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 171,2, 131,0, 124,1, 122,5, 107,1, 71,5, 64,3, 36,2, 34,5, 33,8, 26,5, 26,0, 21,2, 18,2, -4,4, -4,5.

Synthesis of intermediate product 20b

A solution of protected amino19b(255 mg, 0.52 mmol) in ethylene glycol (15 ml) is heated at 200°C for 15 minutes. The reaction mixture is then cooled to room temperature, diluted with DCM, g is placed with saturated salt solution and poured into water. Add a few drops of 3 M NaOH solution up until the pH of the solution reaches 14, and is then thoroughly extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo, obtaining primary amine20b(170 mg, yield: 85%) as a yellow oil, which was used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 9,27 (d, 1H, J=10,2 Hz), 6,76 (DD, 1H, J=11,1, 9.6 Hz), 5,61 (t, 1H, J=7.8 Hz), 4.80 to 4.72 in (m, 1H), 3,81-to 3.73 (m, 1H), and 3.31 (d, 1H, J=3.6 Hz) 2,44 is 2.33 (m, 1H), 2,20-of 2.16 (m, 4H), 2,03 (s, 3H), 1,59 (OSS, 2H), and 1.00 (d, 3H, J=6.9 Hz), to 0.89 (s, 9H), of 0.82 (d, 3H, J=6.9 Hz), of 0.05 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 172,1, 131,1, 124,1, 122,5, 107,4, 71,5, 60,2, 36,2, 33,7, 30,8, 26,0, 21,3, 20,0, 18,3, 16,1, -4,3, -4,4.

Synthesis of intermediate product 21A

To a solution of amine20A(918 mg, of 2.27 mmol) in anhydrous mixture of DCM/DMF (10:1, 39,6 ml) add a solution of (Z)-3-tributylstannyl acid (1028 mg, 2,84 mmol) in anhydrous DCM under nitrogen atmosphere, and then cooled to a temperature of 0°C. To the solution add diisopropylethylamine (DIPEA) (0.6 ml, 3.4 mmol), 1-hydroxy-7-asobancaria (HOAt) (310 mg, of 2.27 mmol) and N,N,N, N'-tetramethyl-O-(7-asobancaria-1-yl)orangestriped (HATU) (860 mg, of 2.27 mmol) and after 30 minutes the cooling bath is put aside. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous process is and NH 4Cl, poured into water and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 15:1)to give amide21A(1,11 g, yield: 66%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 7,63 (d, 1H, J=10.5 Hz), 6,97 (d, 1H, J=12.3 Hz), 6.75 in (d, 1H, J=12.3 Hz), 6,72 (t, 1H, J=9.5 Hz), 6,50 (d, 1H, J=9.0 Hz), to 5.56 (t, 1H, J=6.6 Hz), a 4.83 (q, 1H, J=9.0 Hz), to 4.41 (d, 1H, J=9.6 Hz) 3,76 (m, 1H), 2,17 (m, 4H), for 2.01 (s, 3H), of 1.45 (m, 6H), 1,25 (m, 8H), 1,0 (s, 9H), to 0.88 (s, 9H), 0,84 (m, 13H), is 0.06 (s, 6H).

Synthesis of intermediate 21b

To a solution of amine20b(170 mg, 0,437 mmol) in anhydrous mixture of DCM/DMF (10:1, and 7.7 ml) add a solution of (Z)-3-tributylstannyl acid (197,2 mg, 0,546 mmol) in anhydrous DCM under nitrogen atmosphere, and then cooled to a temperature of 0°C. To the solution was added DIPEA (of 0.11 ml, 0,655 mmol), HOAt (59,4 mg, 0,437 mmol) and HATU (166 mg, 0,437 mmol) and after 30 minutes the cooling bath is put aside. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous solution of NH4Cl, poured into water and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 15:1)to give amide21b(250 mg, yield: 78%) as a white foam C is ETA.

1H NMR (CDC13, 300 MHz) δ: 7,94 (d, 1H, J=10,8 Hz), 7,00 (d, 1H, J=5 to 12.3 Hz), 6.75 in (d, 1H, J=12.3 Hz), 6,72 (t, 1H, J=9.5 Hz), 6,50 (d, 1H, J=9.0 Hz), to 5.56 (t, J=6,6 Hz, 1H), a 4.83 (q, 1H, J=9.0 Hz), to 4.41 (t, 1H, J=9,0 Hz), 3,76 (m, 1H), 2,17 (m, 4H), for 2.01 (s, 3H), of 1.45 (m, 7H), 1,25 (m, 8H), to 0.88 (s, 9H), 0,84 (m, 19H), is 0.06 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 169,2, 166,8, 153,8, 136,2, 131,1, 123,9, 122,6, 108,7, 71,6, 59,2, 36,5, 33,7, 31,4, 29,5, 27,6, 26,1, 21,3, 19,5, 18,5, 14,0, 11,8, -4,3, -4,4.

Synthesis of intermediate product 22A

To a solution of the product20A(120 mg, 0.30 mmol) and propionovoi acid (23 μl, of 0.37 mmol) in anhydrous mixture of DCM/DMF (10:1, 4,2 ml), at 0°C, added HATU (113 mg, 0.30 mmol), HOAt (40 mg, 0.30 mmol) and DIPEA (0,78 μl, 0.44 mmol). The reaction mixture was stirred at 0°C for 30 minutes and for 2 hours at room temperature. Then the crude mixture is treated with saturated aqueous solution of NH4Cl and extracted with CH2Cl2. The combined filtrates washed with water. After drying and evaporation of the solvent under reduced pressure, the crude product is purified by column chromatography (mixture of ethyl acetate/hexane), receiving net connection22A(50 mg, yield: 40%).

1H NMR (CDCl3, 300 MHz) δ: to 8.20 (d, 1H, J=10,2 Hz), 6,83 (d, 1H, J=Hz), 6,72 (t, 1H, J=9.3 Hz), of 5.55 (t, 1H, J=6.9 Hz), 4,88 (kV, 1H, J=Hz), 4,58 (d, 1H, J=9.6 Hz in), 3.75 (m, 1H), 2,90 (s, 1H), 2,17 (m, 4H), 2.00 (evens with, 3H), of 1.02 (s, 9H), of 0.87 (s, 9H), of 0.05 (s, 3H), of 0.04 (s, 3H).

13C-NMR (CDCl3

Synthesis of intermediate product 22b

To a solution of the product20b(200 mg, 0.51 mmol) and propionovoi acid (39 μl, 0.64 mmol) in anhydrous mixture of DCM/DMF (10:1, 8 ml), at 0°C, added HATU (194 mg, 0.51 mmol), HOAt (69 mg, 0.51 mmol) and DIPEA (133 μl, from 0.76 mmol). The reaction mixture was stirred at 0°C for 30 minutes and for 2 hours at room temperature. Then the crude mixture is treated with saturated aqueous solution of NH4Cl and extracted with CH2Cl2. The combined filtrates washed with water. After drying and evaporation of the solvent under reduced pressure the crude product is purified by column chromatography (mixture of ethyl acetate/hexane), receiving net connection22b(150 mg, yield: 67%).

1H NMR (CDCl3, 300 MHz) δ: 7,02 (d, 1H, J=11A Hz), 6.75 in (DD, 1H, J=20 to 10.8, 9.0 Hz), 6,53 (d, 1H, J=10,2 Hz), to 5.58 (DD, 1H, J=9,0, 7,8 Hz), to 4.87 (q, 1H, J=7.8 Hz), 4,33 (DD, 1H, J=8,7, 6.3 Hz), 3,84 is 3.76 (m, 1H), and 2.83 (s, 1H), 2,23-2,11 (m, 5H), 2.05 is-2,03 (m, 3H), 0,99 (d, 6H, J=6.9 Hz), to 0.89 (s, 9H), and 0.08 (s, 3H), 0,06 (s, 3H).

Example 3

Synthesis of fragment 27

Figure 3 presents an example of the synthesis of fragment 27.

Synthesis of intermediate product 23

To a suspension of iodocyclization (Gilbert Stork KZ., Tetrahedron letters 1989, 30(17), 2173) (6.6 g, 12,47 mmol) in anhydrous THF (50 ml), at 0°C, slowly through an addition funnel was added 1 M solution matrikelstyrelsen (NaHMDS) (12.5 ml, 12,47 mmol) for 10 minutes. After stirring for an additional 5 minutes the solution is cooled to a temperature of -78°C and then through the cannula add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (3,02 ml, 24,95 mmol), then the aldehyde1(1.80 g, 4,99 mmol)dissolved in anhydrous THF (50 ml). Support -78°C until the reaction mixture is stirred for 2 hours. Add hexane (200 ml)and the resulting suspension is filtered through celite (Celite®) and washed with additional hexane (200 ml). The filtrate is evaporated under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 100:0 to 20:1)to give 1.64 g (yield: 68%) of iodide23.

1H NMR (CDCl3, 300 MHz) δ: 6,18-6,09 (m, 2H), 3,79 (m, 1H), to 3.67 (m, 2H), 2.57 m (m, 1H), 1,75-to 1.63 (m, 2H), of 0.96 (d, 3H, J=6.9 Hz), to 0.89 (m, 18H), 0,04 (m, 12H).

Synthesis of intermediate product 24

To a solution of iodide23(520 mg, 1.07 mmol) in ethanol (5,3 ml) add pyridine-p-toluensulfonate (PPTS) (94,4 mg, 0.38 mmol) and the reaction mixture was stirred at room temperature for 25 hours. Then the solvent is removed under reduced pressure and the oil obtained is cidaut using column chromatography (hexane/EtOAc = 4:1), getting 380 mg (yield: 87%) of alcohol24.

1H NMR (CDCl3, 300 MHz) δ: 6,20 (d, 1H, J=7.5 Hz), between 6.08 (m, 1H), a 3.87-and 3.72 (m, 3H), 2,69 (m, 1H), of 1.85 and 1.80 (m, 1H), 1,71-of 1.65 (m, 1H), 0,99 (d, 3H, J=6.6 Hz), of 0.90 (m, 9H), and 0.09 (m, 6H).

Synthesis of intermediate product 25

It cooled down to 0°C solution of alcohol24(380 mg, of 1.03 mmol) in anhydrous DCM (10.3 ml) add periodinane dess-Martin (870 mg, 2.05 mmol). After 1 hour, add saturated aqueous solution of NaHCO3(50 ml) and the organic layer is filtered, dried over anhydrous MgSO4and concentrated in vacuo. Purified by column chromatography (hexane/EtOAc = 1:1)to give 350 mg (yield: 93%) of aldehyde25.

1H NMR (CDCl3, 300 MHz) δ: 9,82 (t, 1H, J=2.1 Hz), of 6.26 (DD, 1H, J or=0.6, 7.5 Hz), equal to 6.05 (DD, 1H, J=1.5 and 9.0 Hz), 4,14 (m, 1H), 2,68 (m, 1H), 2,58 (m, 2H), 1,01 (d, 3H, J=6.6 Hz), 0.87 (m, 9H), of 0.07 (s, 3H), of 0.03 (s, 3H).

Synthesis of intermediate product 26

To a solution of diethyl - (methoxy[methoxycarbonyl]methyl)phosphonate (362 mg, of 1.42 mmol) and 18-crown-6 (754 mg, to 2.85 mmol) in anhydrous THF (27 ml), stirred in an argon atmosphere at a temperature of -78°C., added dropwise a 0.5 M solution of bis(trimethylsilyl)amide potassium (KHMDS) (2,85 ml of 1.42 mmol). After 15 minutes, added dropwise to the aldehyde25(350 mg, 0.95 mmol) in anhydrous THF (14 ml) over 30 minutes and stirred at -78°C for 90 minutes. Then reactio the ing the mixture is quenched with a saturated solution of NH 4Cl (20 ml), warmed to room temperature and diluted with dichloromethane (50 ml). The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/Et2O = 20:1)to give 370 mg (yield: 86%) of pure(E)-26.

1H NMR (CDCl3, 300 MHz) δ: 6,12 (d, 1H, J=7,2 Hz), 6,03 (m, 1H), 5,32 (t, 1H, J=7.5 Hz), of 3.78 (s, 3H), of 3.77-3,70 (m, 1H), 3,63 (s, 3H), 2,69 (m, 2H), 2,58 (m, 1H), 0,97 (d, 3H, J=6.6 Hz), to 0.88 (s, 9H), of 0.04 (s, 6H).

Synthesis of intermediate product 27

To a solution of ester26(95 mg, 0.21 mmol) in Meon (3.15 ml), at room temperature, added 37% aqueous HCl (26 ml) and the reaction mixture is stirred for 6 hours. The mixture is then neutralized with a saturated aqueous solution of NaHCO3(pH=7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension is extracted with dichloromethane (4 x 20 ml), dried and evaporated. Perform filtering using column chromatography (hexane/EtOAc = 10:1 to 2:1)to give 210 mg (yield: 84%) of lactone27.

1H NMR (CDCl3, 300 MHz) δ: 6,32 (DD, 1H, J or=0.6, 7.5 Hz), between 6.08 (DD, 1H, J=1,5, and 9.3 Hz), 5,62 (DD, 1H, J=3,0, 6.3 Hz), 4,28 (m, 1H), 3,63 (s, 3H), 2,84 (m, 1H), 2,54 (m, 1H), 2,34 (m, 1H), 1,13 (d, 3H, J=6.6 Hz).

Example 4

Synthesis of fragment 30

Figure 4 presents an example of the synthesis of fragment 30.

the Synthesis of intermediate product 28

To a mixture of L-Boc-tert-leucine (300 mg, 1.3 mmol) in anhydrous DCM (13 ml) and dicyclohexylcarbodiimide (DCC) (295 mg, 1,43 mmol), at 0°C, in nitrogen atmosphere, add 3-butanol (0.3 ml, 3.9 mmol) and dimethylaminopyridine (DMAP) (15,9 mg, 0.13 mmol). The reaction mixture is stirred for 5 minutes at a temperature of 0°C and for 4 hours at room temperature. The organic solvent is evaporated under reduced pressure and the resulting solid purified by column chromatography (hexane/EtOAc = 10:1)to give ester28(300 mg, yield: 81%).

1H NMR (CDCl3, 300 MHz) δ: of 5.82-5,71 (m, 1H), 5,14-of 5.06 (m, 2H), 4,24-4,12 (m, 2H), 4,08 (d, 1H, J=9.8 Hz), is 2.41 (q, 2H, J=6,7 Hz), USD 1.43 (s, 9H), is 0.96 (s, 9H).

Synthesis of intermediate 29

A solution of ester28(180 mg, 0,63 mmol) in 1 M HCl solution·in methanol (3.6 ml) was stirred at room temperature for 24 hours. The organic solvent is evaporated under reduced pressure and the resulting solid is dissolved in DCM and washed with water, the organic phase is dried over anhydrous Na2SO4, filtered and the solvent is evaporated, getting 116 mg (yield: 100%) of the product29.

1H NMR (CDC13, 300 MHz) δ: 5,85-5,72 (m, 1H), 5,15-of 5.06 (m, 2H), 4.16 the (t, 2H, J=6,7 Hz), 3.15 in (s, 1H), of 4.44-4,37 (m, 2H), of 0.96 (s, 9H).

Synthesis of intermediate por the product 30

DIPEA (of 0.24 ml, 1.4 mmol), HOAt (123,3 mg, 0.9 mmol) and HATU (345 mg, 0.9 mmol) are added to a solution of the product29(168 mg, 0.9 mmol) and (Z)-3-tributylstannyl acid (393 mg, 1.2 mmol) in anhydrous mixture of DCM/DMF (10:1, 14 ml)at 0°C. in an argon atmosphere. After 2 hours, the cooling bath is put aside and the reaction mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous solution of NH4Cl, poured into water and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 15:1 to 10:1)to give the product30(340 mg, yield: 72%).

1H NMR (CDCl3, 300 MHz) δ: 7,01 (d, 1H, J=12.3 Hz), 6.75 in (d, 1H, J=12.3 Hz), 6,03 (d, 1H, J=9,73 Hz), of 5.84-5,69 (m, 1H), 5,14-of 5.05 (m, 2H), 4,60 (d, 1H, J=9,76 Hz), 4,19-to 4.14 (m, 2H), 2.40 a (q, 2H, J=6,70 Hz), 1,48-of 1.40 (m, 6H), 1,31-1,19 (m, 6H), is 0.96 (s, 9H), 0,93-0,83 (m, 15H).

Example 5

Synthesis of fragment 37

Figure 5 presents the synthesis of fragment 37.

Synthesis of intermediate 31

A solution of alcohol12(2,88 g, to 11.9 mmol), tert-butyldiphenylsilyl (4,39 ml, 16,89 mmol) and 4-(dimethylamino)pyridine (43,6 mg) in DMF (14 ml) is stirred overnight at room temperature. The mixture is diluted with water and extracted with Et2O, and the content of inorganic fillers phase is washed with saturated salt solution, dried over anhydrous Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 95:1)to give silyl ether31(5,3 g, yield: 93%) as a colourless liquid.

1H NMR (300 MHz, CDCl3) δ: 7,70-7,66 (m, 4H), 7,40-7,34 (m, 6H), 3,99-3,95 (m, 1H),3,70-3,62 (m, 2H), 2.23 to-2,22 (m, 2H), 1,84-of 1.81 (m, 2H), 1.69 in (t, 3H, J=2.7 Hz), of 1.05 (s, 9H), from 0.84 (s, 9H), of 0.01 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 136,1, 134,6, 129,7, 127,8, 77,8, 76,2, 69,9, 60,1, 39,6, 27,5, 27,2, 26,2, 19,6, 18,5, 3,7, -5,1.

Synthesis of intermediate product 32

PPTS (837,7 mg of 3.33 mmol) added in one portion to a solution of the product31(4 g, with 8.33 mmol) in ethanol (80 ml). The reaction mixture was stirred at room temperature for 7 hours and then concentrated. The residue was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer is extracted, dried over anhydrous Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 95:1)to give silyl ether32(2,12 g, yield: 69%), as colourless oil.

1H NMR (500 MHz, CDCl3) δ: 7,71-7,63 (m, 4H), 7,45-7,26 (m, 6H), 4,14-4,01 (m, 2H), 3,80-3,71 (m, 1H), 2,31-of 2.28 (m, 2H), 1,94 and 1.80 (m, 2H), 1,79 (t, 3H, J=2,4 Hz)of 1.07 (s, 9H).

Synthesis of intermediate 33

(Diacetoxy)benzene (BAIB) (1,93 g, 6,00 mmol) are added to a solution of alcohol32(2.0 g, 5.46 mmol) and 2,26,6-tetramethylpiperidine-1-oxyl (TAMRA) (85 mg, 0.55 mmol) in anhydrous dichloromethane (27 ml). The reaction mixture was stirred at room temperature for 18 hours up until the alcohol no longer be detected (TLC), and then quenched with saturated aqueous solution of NH4Cl and extracted with DCM (3 x 500 ml). The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 10:1)to give the product33in the form of a colorless oil (1.64 g, yield: 82%).

1H NMR (CDCl3, 300 MHz) δ: 9,72 (s, 1H), 7,71-7,63 (m, 4H), 7,45-7,26 (m, 6H), the 4.29 (m, 1H), 2,65 (m, 2H), 2,33 (m, 2H), 1.70 to (s, 3H), was 1.04 (s, 9H).

Synthesis of intermediate product 34

To a suspension of iodocyclization (3,14 g, 6,04 mmol) in anhydrous THF (60 ml), at room temperature, slowly add 1 M solution of NaHMDS in THF (6.0 ml). After stirring for 2 minutes, the mixture is yellow cooled to a temperature of -78°C and then add a solution of the product33(1,57 g, or 4.31 mmol) in anhydrous THF (35 ml). The reaction mixture was stirred at -78°C for 2 hours and at room temperature for 5 minutes, diluted with hexane and filtered through a layer of celite (Celite®). Layer celite washed with hexane and the combined filtrates evaporated under reduced pressure and obtained the oil is purified by column chromatography (hexane/EtOAc = 50:1), getting the product34in the form of a yellow oil (1.31 g, yield: 62%).

1H NMR (500 MHz, CDCl3) δ: 7,70-7,66 (m, 4H), 7,44-7,34 (m, 6H), 6,27-6,24 (m, 2H), 3,99-3,95 (m, 1H), 2,47-to 2.41 (m, 2H), 2,27-of 2.23 (m, 2H), 1,71 (t, 3H, J=2.7 Hz), with 1.07 (s, 9H).

Synthesis of intermediate 35

In a tightly closed tube Slinka injected iodide copper(I), (85,1 mg, 0,447 mmol), potassium carbonate (0,618 g, 4,47 mmol) and BOC-tert-LeuCONH2(obtained by the procedure described Pozdnev V.F., Tetrahedron Letters, 1995, 36, 7115-7118) (0,514 g of 2.23 mmol), create a vacuum and filled with argon. Add N,N'-dimethylethylenediamine (DMEDA) (0,095 ml, 0.89 mmol), vinylite34(0,727 g, 1,49 mmol) and anhydrous DMF (11 ml)in an argon atmosphere. Tube Slinka, sealed, heated at 90°C for 18 hours and cooled to room temperature. The resulting mixture was diluted with EtOAc and quenched with water. The organic layer is washed with water and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue purified using flash chromatography on silica gel (hexane/EtOAc = 20:1 to 15:1). The intermediate product35(388 mg, yield: 44%) are obtained in the form of oil.

1H NMR (300 MHz, CDCl3) δ: 7,70-7,66 (m, 4H), 7,53 (d, 1H, J=10.5 Hz), 7,43-7,26 (m, 6H), 6.73 x (t, 1H, J=9.6 Hz), from 5.29 (m, 1H), 4,79 (m, 1H), 3,85-3,81 (m, 2H), 2,39-of 2.30 (m, 1H), 2,27-of 2.21 (m, 3H), of 1.88 (s, 3H), USD 1.43 (s, 9H), of 1.06 (s, 9H), of 0.97 (s, 9H).

Synthesis of the intermediate product 36

A solution of protected amino35(288 mg, 0,487 mmol) in ethylene glycol (17 ml) is heated at 200°C for 15 minutes. The reaction mixture is then cooled to room temperature, diluted with DCM, quenched with saturated salt solution and poured into water. Add a few drops of 3 M NaOH solution up until the pH of the solution reaches 14, and is then thoroughly extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo, obtaining primary amine36(165 mg, yield: 69%) as a yellow oil, which was used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 8,46 (d, 1H, J=11,1 Hz), 7,71-7,63 (m, 4H), 7,45-7,26 (m, 6H), 6,76 (t, 1H, J=10,2 Hz), 4,77 (kV, 1H, J=10,2 Hz)to 3.89 (m, 1H), 3,06 (s, 1H), 2,30 (m, 2H), 2,24 (m, 2H), 1.70 to (s, 3H), of 1.05 (s, 9H), and 0.98 (s, 9H).

Synthesis of intermediate 37

To a solution of amine36(221 mg, 0,450 mmol) in anhydrous mixture of DCM/DMF (4:1, 5 ml) add a solution of (Z)-3-tributylstannyl acid (195 mg, 0.54 mmol) in anhydrous DCM, in argon atmosphere, and then cooled to a temperature of 0°C. To the solution was added DIPEA (0,094 ml, 0.54 mmol), HOAt (of 73.5 mg, 0.54 mmol) and HATU (205 mg, 0.54 mmol) and after 30 minutes the cooling bath is put aside. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated is about aqueous solution of NH 4Cl, poured into water and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 15:1)to give amide37(288 mg, yield: 77%) as oil.

1H NMR (300 MHz, CDCl3) δ: 7,70-7,66 (m, 4H), to 7.61 (d, 1H, J=10,2 Hz), 7,42-7,38 (m, 6H), 7,02 (d, 1H, J=12.0 Hz), 6,77-6-70 (m, 2H), 6,28 (d, 1H, J=9.6 Hz), 4,82 (kV, 1H, J=8,4 Hz), 4,36 (d, 1H, J=9.6 Hz), 3,89-3-86 (m, 1H), 2,39 amounts to 2.24 (m, 4H), of 1.94 (s, 3H), 1,50-of 1.41 (m, 6H), 1.30 and 1-23 (m, 6H), of 1.07 (s, 9H), to 0.92 (s, 9H), 0,92-0,84 (m, 15H).

Example 6

Synthesis of fragment 40

Figure 6 presents the synthesis of fragment 40.

Synthesis of intermediate product 38

2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ) (8,70 g, 38 mmol) are added to a solution of the product17(12 g, 30 mmol) in a mixture of dichloromethane-H2O (20:1, 236 ml)in an argon atmosphere at room temperature. After 1.5 hours (hexane/EtOac = 4:1, TLC shows the absence of starting material), the reaction mixture was quenched by pouring in Et2O (400 ml) and washing with 1 M aqueous NaOH (3 times 200 ml) and saturated saline (200 ml). The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. Chromatographic separation of n-methoxybenzaldehyde facilitated recovery to p-methoxybenzylthio alcohol. Windows is assured that a solution of the obtained residue in the Meon (236 ml) with NaBH 4(1.5 g, 38 mmol)in an argon atmosphere, maintained at room temperature for 1 hour. The reaction mixture was then quenched by pouring in Et2O (400 ml) and washing with 1 M aqueous HCl (200 ml) and saturated saline (200 ml). The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. The resulting oil purified on silica gel (hexane/EtOAc = 10:1 to 4:1)to give the secondary alcohol as a colourless oil (6 g, yield: 73%).

To a solution of secondary alcohol (6 g, 21 mmol) in anhydrous DMF (25 ml)in an argon atmosphere and at room temperature, the parts add imidazole (3.3 grams, to 48.6 mmol)and then tert-butyldiphenylsilyl (TBDPSCl) (7,6 ml of 29.3 mmol) and DMAP (77 mg, to 0.63 mmol). The mixture is stirred over night and at this point in time, the crude product is quenched with water (30 ml) and extracted with Et2O (3 times 30 ml). The combined organic layers thoroughly washed with water and saturated salt solution. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 100:1 to 30:1)to give the product38(9.6 g, yield: 92%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: to 7.67 (m, 4H), 7,45-7,37 (m, 6H), and 6.25 (m, 2H), 5,51 (t, 1H, J=7.8 Hz), with 3.89 (m, 1H), 2,30 (t, 2H, J=5.5 Hz), and 2.14 (t, 2H, J=6.4 Hz), of 1.85 (s, 3H), of 1.07 (s, 9H).

Synthesis of intermediate products is that 39

In a tightly closed tube Slinka injected iodide copper(I) (1,05 g, 5,54 mmol), potassium carbonate (7,65 g, a 55.4 mmol) and BOC-tert-LeuCONH2(obtained by the procedure described Pozdnev V.F., Tetrahedron Letters, 1995, 36, 7115-7118) (6.8 g, 29.6 mmol), create a vacuum and filled with argon. Add N,N'-dimethylethylenediamine (DMEDA) (1,18 ml, 11.1 mmol), vinylite38(9.7 g, 18.5 mmol) and anhydrous DMF (92 ml)in an argon atmosphere. Tube Slinka, sealed, heated at 90°C for 18 hours and cooled to room temperature. The resulting mixture was diluted with EtOAc and quenched with water. The organic layer is washed with water and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue purified using flash chromatography on silica gel (hexane/EtOAc = 20:1 to 15:1)to give compound39(5.8 g, yield: 51%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: to 7.67 (m, 4H), 7,47-7,37 (m, 6H), 7,02 (d, 1H, J=10,2 Hz), to 6.67 (t, 1H, J=9.4 Hz), the 5.51 (t, 1H, J=7,3 Hz), 5,23 (d, 1H, J=8,4 Hz), 4.72 in (q, 1H, J=8.1 Hz), 3,81 (m, 2H), 2,18-2,04 (m, 4H), 1,86 (s, 3H), of 1.42 (s, 9H), of 1.05 (s, 9H), of 0.97 (s, 9H).

Synthesis of compound 40

A solution of protected amino39and 4.75 g, 7.6 mmol) in ethylene glycol (140 ml) is heated at 200°C for 15 minutes. The reaction mixture is then cooled to room temperature, rasb the keys dichloromethane, quenched with saturated salt solution and poured into water. Add a few drops of 3 M NaOH solution up until the pH of the solution reaches 14, and is then thoroughly extracted with dichloromethane. The combined organic phases are washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, obtaining a primary amine40(3.8 g, yield: 95%) as a yellow oil, which was used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 8,66 (d, 1H, J=10.5 Hz), 7,66 (m, 4H), 7,47-7,33 (m, 6H), of 6.71 (t, 1H, J=9.3 Hz), of 5.53 (t, 1H, J=8,3 Hz), 4.72 in (q, 1H, J=8,4 Hz), 3,83 (m, 1H), 3,19 (s, 1H), 2,22-2,05 (m, 4H)and 1.83 (s, 3H), of 1.05 (s, 9H), 0,99 (s, 9H).

Example 7

Synthesis of fragment 45

Figure 7 presents an example of the synthesis of fragment 45.

Synthesis of intermediate 41

To a solution of anhydrous CrCl2(2,03 g, 16,55 mmol) in anhydrous THF (30 ml), at 0°C, add a solution of aldehyde1(0,995 g, was 2.76 mmol) and iodoform (2.17 g, 5,52 mmol) in anhydrous THF (10 ml). After 4 hours stirring at a temperature of 23°C, the mixture was diluted with Et2O and filtered through celite (Celite®). The filtrate is concentrated and receiving the remnant that purify using flash chromatography on silica gel (hexane/dichloromethane = 50:1 to 5:1)to give vinylite41(0,79 g, yield: 57%) in the ideal oil slightly yellow color.

1H NMR (CDCl3, 300 MHz) δ: return of 6.58 (DD, 1H, J=14,5, 6,7 Hz), 5,98 (DD, 1H, J=14.5 m, 1.3 Hz ), 3,76-3,70 (m, 1H), 3,67-3,59 (m, 2H), 2,37 of-2.32 (m, 1H), 1,62-of 1.53 (m, 2H), of 0.96 (d, 3H, J=7.2 Hz), to 0.89 (m, 18H), 0,04 (m, 12H).

Synthesis of intermediate product 42

To a solution of iodide41(786 mg, was 1.58 mmol) in EtOH (15 ml) add pyridine-p-toluensulfonate (PPTS) (139 mg, 0.55 mmol) and the reaction mixture was stirred at room temperature for 25 hours. Then the solvent is removed under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 4:1), receiving 379,7 mg (yield: 63%) of alcohol42in the form of a colorless oil.

1H NMR (CDCl3, 300 M Hz) δ: 6,56 (DD, 1H, J=14,5, 6,7 Hz), 6,01 (DD, 1H, J=14.5 m, 1.3 Hz ), 3,78-3,3,69 (m, 3H), 2,45-2,39 (m, 1H), 1,87 of-1.83 (m, 1H), 1,71-to 1.59 (m, 2H), and 1.00 (d, 3H, J=6.6 Hz), of 0.90 (s, 9H), and 0.09 (s, 3H), 0,07 (, 3H).

Synthesis of intermediate 43

At a temperature of 0°C. to a solution of alcohol42(389 mg, 1.01 mmol) in anhydrous DCM (10 ml) add periodinane dess-Martin (644 mg, of 1.52 mmol). After 1 hour stirring at 0°C and 30 minutes at a temperature of 23°C. the reaction mixture was quenched with saturated aqueous NaHCO3. The organic layer is filtered, dried over anhydrous Na2SO4and concentrate under reduced pressure. Purified by column chromatography (hexane/EtOAc = 20:1 to 2:1), is the learn 349,3 mg (yield: 90%) of aldehyde 43in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 9,77 (t, 1H, J=2.1 Hz), of 6.52 (DD, 1H, J=14,7, 7.5 Hz), equal to 6.05 (DD, 1H, J=14,7, 1.2 Hz), 4,12-4,07 (m, 1H), 2,52-2,47 (m, 2H), 2,43-of 2.36 (m, 1H), and 0.98 (d, 3H, J=7.2 Hz), of 0.87 (s, 9H), of 0.07 (s, 3H), 0.03 to (s, 3H).

Synthesis of intermediate product 44

To a solution of diethyl - (methoxy[methoxycarbonyl]methyl)phosphonate (348,4 mg, 1.37 mmol) and 18-crown-6 (722,3 mg, 2,73 mmol) in anhydrous THF (13 ml), stirred in an argon atmosphere at a temperature of -78°C., added dropwise a 0.5 M solution of bis(trimethylsilyl)amide potassium (KHMDS) in toluene (2,74 ml, 1.37 mmol). After 15 minutes, added dropwise to the aldehyde43(349,4 mg of 0.91 mmol) in anhydrous THF (9 ml) for 30 minutes and stirred at -78°C for 90 minutes. Then the reaction mixture was quenched with saturated aqueous solution of NH4Cl (20 ml), warmed to room temperature and diluted with dichloromethane (50 ml). The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/EtOAc = 30:1 to 5:1)to give 410 mg (yield: 99%) of product44in the form of a mixture of E/Z-isomers (regioselectivity > 5:1 defined using the1H-NMR).

1H NMR (CDCl3, 300 MHz) (2E,7E)-44 δ: 6,51 (DD, 1H, J=14,4, and 7.8 Hz), 5,97 (DD, 1H, J=14,4, 1.2 Hz), from 5.29 (t, 1H, J=7,7 Hz), 3,82 (s, 3H), of 3.77-3,70 (m, 1H), 3,60 (s, 3H), 2,65-2,61 (m, 2H), 2,39-of 2.21 (m, 1H), 1,0 (d, 3H, J=6.9 Hz), to 0.89 (s, 9H), of 0.04 (s, 6H).

Synthesis of intermediate 45

To a solution of ester44(410,9 mg, 0.90 mmol) in Meon (13,5 ml), at room temperature, added 37%aqueous HCl solution (160 μl) and the reaction mixture is stirred for 6 hours. The mixture is then neutralized with a saturated aqueous solution of NaHCO3(pH=7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension extracted with dichloromethane (4 x 20 ml), dried and evaporated. The crude product is purified by column chromatography (hexane/EtOAc = 10:1 to 2:1)to give 192 mg (yield: 69%) of lactone45in a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 6,32 (DD, 1H, J=14,7, and 8.4 Hz), 6,21 (DD, 1H, J=14,7, 1.2 Hz), 5,62 (DD, 1H, J=6,6, 2.7 Hz), 4,27-4,19 (m, 1H), to 3.64 (s, 3H), 2,61-of 2.54 (m, 1H), 2,43-of 2.34 (m, 2H), 1.14 in (d, 3H, J=6.9 Hz).

MS (ES) [m/z] = 331,1 [M+Na]+.

Example 8

Synthesis of fragment 51

Figure 8 presents an example of the synthesis of fragment 51.

Synthesis of intermediate 46

To a solution of tetrabromide carbon (total of 8.74 g, 26,35 mmol) in anhydrous dichloromethane (26 ml) is added dropwise a solution of triphenylphosphine (1,38 g, 52,69 mmol) in anhydrous DCM (50 ml)at 0°C. the Solution is dark yellow cooled to a temperature of -78°C and quickly add the keys aldehyde 1and 4.75 g of 13.2 mmol) in anhydrous DCM (13 ml). The resulting mixture was stirred at -78°C (30 minutes) and at a temperature of 0°C (10 minutes). The reaction mixture was diluted with Et2O and then washed with saturated salt solution. The aqueous layer was extracted with Et2O and the organic layers combined, dried, filtered and evaporated under reduced pressure. Purify using flash chromatography (hexane/dichloromethane = 10:1), receiving 4,37 g (yield: 66%) of vanillylamide in the form of a colorless oil. To a solution of dibromomethane in anhydrous THF (80 ml) is added dropwise a 2.5 M solution of n-utility in hexane (7,03 ml)at -78°C. the Reaction mixture is heated to a temperature of -25°C and stirred for 1 hour. The reaction mixture is again cooled to a temperature of -78°C and added dropwise to methyliodide (0,55 ml, 8,79 mmol) in anhydrous THF (9 ml). The resulting mixture was left to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous solution of NH4Cl, then diluted with Et2O. the Organic layer is dried, filtered and evaporated under reduced pressure. Purify using flash chromatography (hexane/dichloromethane = 50:1 to 5:1), receiving 2,77 mg (yield: 89%) of alkyne46in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 3,74-3,66 (m, 3H), 2.49 USD is 2.46 (m, 1H), 1,83-1,72 (m, 2H), 1,7 (s, 3H), a 1.08 (d, 3H, J=7.2 Hz), to 0.89 (m, 18H), of 0.07 (s, 3H), 0,06 (s, 3H), of 0.05 (s, 6H).

Synthesis of intermediate 47

To a solution of the product46(200 mg, 0,56 mmol) in anhydrous toluene (7 ml)in an argon atmosphere and at a temperature of 23°C, add bis(cyclopentadienyl)zirconium(IV)-chloridized (432,3 mg, 1,68 mmol) and the reaction mixture was stirred at 50°C for 1 hour. After this time the reaction solution becomes orange. The reaction mixture is cooled to a temperature of 23°C and in the form of one portion add iodine (at 284.3 mg, 1.12 mmol). Continue to mix for 30 minutes at room temperature and the reaction mixture is diluted with hexane and filtered through celite (Celite®). The filtrate is concentrated and receiving the remnant that purify using flash chromatography, elwira a mixture of hexane/dichloromethane (10:1 to 1:2)to give vinylite47(140,4 mg, yield: 49%) in the form of oil pale yellow color.

1H NMR (CDCl3, 300 MHz) δ: 6,07 (DD, 1H, J=9,9, 1.5 Hz), 3.72 points-to 3.67 (m, 1H), 3,65-3,61 (t, 2H, J=6.6 Hz), 2,53-2,47 (m, 1H), is 2.37 (s, 3H), 1,68-to 1.61 (m, 2H), to 0.92 (d, 3H, J=6.6 Hz), to 0.89 (m, 18H), of 0.05 (m, 12H).

Synthesis of intermediate 48

To a solution of iodide47(140,4 mg, 0.27 mmol) in EtOH (2 ml) added pyridine-p-toluensulfonate (PPTS) (24 mg, 0.09 mmol) and the reaction mixture was stirred at room temperature is 25 hours. Then the solvent is removed under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 4:1)getting to 90.3 mg (yield: 83%) of alcohol48in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 6,01 (DD, 1H, J=9,9, 1.5 Hz), 3,78-to 3.67 (m, 3H), 2,62 is 2.55 (m, 1H), 2,39 (s, 3H), 2.00 in to 1.98 (m, 1H), 1,80-of 1.62 (m, 2H), of 0.96 (d, 3H, J=6.6 Hz), to 0.89 (s, 9H), and 0.09 (s, 3H), and 0.08 (s, 3H).

Synthesis of intermediate 49

It cooled down to 0°C solution of alcohol48(87 mg, 0.22 mmol) in anhydrous DCM (2 ml) is added periodinane dess-Martin (140 mg, 0.33 mmol). After stirring for 1 hour at 0°C and for 30 minutes at a temperature of 23°C, the reaction mixture was quenched with saturated aqueous NaHCO3. The organic layer is filtered, dried over anhydrous Na2SO4and concentrate under reduced pressure. Purified by column chromatography (hexane/EtOAc = 20:1 to 2:1)getting to 76.6 mg (yield: 86%) of aldehyde49in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 9,79 (t, 1H, J=2.4 Hz), 5,98 (DD, 1H, J=9,9, 1.5 Hz), was 4.02-of 3.97 (m, 1H), 2.57 m) is 2.51 (m, 3H), of 2.38 (s, 3H), of 0.97 (d, 3H, J=6.6 Hz), of 0.87 (s, 9H), and 0.08 (s, 3H), of 0.04 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 201,5, 143,5, 95,1, 71,3, 49,3, 41,9, 28,3, 26,0, 18,2, 15,8, -4,2, -4,4.

Synthesis of the intermediate product 50

To a solution of diethyl - (methoxy[metuximab the yl]methyl)phosphonate (73,7 mg, 0.29 mmol) and 18-crown-6 (153,4 mg of 0.58 mmol) in anhydrous THF (3 ml), stirred in an argon atmosphere at a temperature of -78°C., added dropwise a 0.5 M solution of bis(trimethylsilyl)amide potassium (KHMDS) in toluene (of 0.58 ml, 0.29 mmol). After 15 minutes, added dropwise to the aldehyde49(76,6 mg, 0,19 mmol) in anhydrous THF (2 ml)over 10 minutes and stirred at -78°C for 90 minutes. Then the reaction mixture was quenched with saturated aqueous solution of NH4Cl, warmed to room temperature and diluted with dichloromethane. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/EtOAc = 30:1 to 5:1), receiving 89,0 mg (yield: 100%) of the product50in the form of a mixture of E/Z-isomers (regioselectivity >2,5:1 defined using the1H-NMR), in the form of a colorless oily mixture.

1H NMR (CDCl3, 300 MHz) (2E,7E)-50δ: 6,28 (d, 1H, J=9.0 Hz), 5,33 (t, 1H, J=9.0 Hz), of 3.84 (s, 3H), 3,61 is 3.57 (m, 1H), 3,61 (s, 3H), 2.77-to 2,70 (m, 1H), 2,64 is 2.55 (m, 1H), 2,49-is 2.37 (m, 1H), 2,30 (s, 3H), of 0.96 (d, 3H, J=6.6 Hz), to 0.89 (s, 9H), is 0.06 (s, 3H), of 0.05 (s, 3H).

Synthesis of intermediate product 51

To a solution of ester50(90,8 mg, 0,19 mmol) in Meon (3 ml)at room temperature, added 37%aqueous HCl solution (34 ml) and the reaction mixture is stirred for 6 hours. Then the mixture is neutral the form with saturated aqueous NaHCO 3(pH=7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension is extracted with dichloromethane, dried and evaporated. The crude product is purified by column chromatography (hexane/EtOAc = 10:1 to 2:1)to give 34 mg (yield: 50%) of lactone51in a solid white color.

1H NMR (CDCl3, 300 MHz) δ: of 5.99 (DD, 1H, J=9,9, 1.2 Hz), 5,62 (DD, 1H, J=5,1, 4,2 Hz), 4,19-4,11 (m, 1H), to 3.64 (s, 3H), 2,78-2,70 (m, 1H), 2,41 (s, 3H), 2,42-is 2.37 (m, 2H), 1,11 (d, 3H, J=6.6 Hz).

Example 9

Synthesis of fragment 56

Figure 9 presents an example of the synthesis of fragment 56.

Synthesis of intermediate 52

1.8 M Solution of sitedisability in a mixture of heptane/THF/ethylbenzene (8,96 ml, 16,13 mmol) diluted with 88 ml of anhydrous THF. After cooling to a temperature of -78°C. add trimethylsilyldiazomethane (of 8.06 ml, 2 M solution in THF, 16,13 mmol) and the resulting mixture is stirred for 30 minutes. Add a solution of the product4(4,377 g of 10.75 mmol) in anhydrous THF (35 ml) and allowed to mix for 1 hour at -78°C and for 2 hours at 23°C. the Reaction mixture was added to a mixture of ice water and extracted with Et2O. the combined organic layers are dried (anhydrous Na2SO4) and the solvent is removed. The residue is purified using flash chromatography, is the learn of 2.38 g (yield: 55%) of product 52in the form of a yellow oil.

1H NMR (CDCl3, 300 MHz) δ: 5,86 (d, 1H, J=9.9 Hz), to 3.73-3,63 (m, 3H), 2,74 (s, 1H), 2,58-of 2.50 (m, 1H), 1,80 (s, 3H), 1.70 to to 1.63 (m, 2H), of 0.93 (d, 3H, J=6.6 Hz), 0.88 to (m, 18H), 0,04 (m, 12H).

13C-NMR (CDCl3, 75 MHz) δ: 143,3, 116,3, 87,1, 73,7, 72,8, 60,0, 38,6, 38,0, 26,1, 26,1, 18,5, 18,3, 17,4, 15,3, -4,2, -5,1.

Synthesis of intermediate product 53

To a solution of the product52(2,05 g, 5.17 mmol) in EtOH (50 ml) added pyridine-p-toluensulfonate (PPTS) (511,7 mg, 2.04 mmol) and the reaction mixture was stirred at room temperature for 25 hours. Then the solvent is removed under reduced pressure and the resulting oil purified by column chromatography (hexane/EtOAc = 4:1), receiving of 1.055 g (yield: 72%) of alcohol53in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: USD 5.76 (d, 1H, J=9.9 Hz), to 3.73-3,63 (m, 3H), and 2.79 (s, 1H), 2,64 at 2.59 (m, 1H), 2,24 (USS, 1H), 1,80 (s, 3H), 1.70 to to 1.60 (m, 2H), of 0.95 (d, 3H, J=6.9 Hz), to 0.88 (s, 9H), and 0.08 (s, 3H), 0,06 (s, 3H).

Synthesis of intermediate product 54

It cooled down to 0°C solution of alcohol53(140 mg, 0.48 mmol) in anhydrous DCM (5 ml) is added periodinane dess-Martin (308,5 mg, 0.73 mmol). After stirring for 30 minutes at a temperature of 0°C and for 60 minutes at a temperature of 23°C. the reaction mixture was quenched with saturated aqueous NaHCO3. The organic layer is filtered, dried over betwo the major Na 2SO4and concentrate under reduced pressure. Purified by column chromatography (hexane/dichloromethane = 5:1 to 1:1)to give 100 mg (yield: 73%) of aldehyde54in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 9,79 (t, 1H, J=2.4 Hz), 5,72 (d, 1H, J=10,2 Hz), was 4.02-of 3.96 (m, 1H), 2,77 (s, 1H), 2,64 of $ 2.53 (m, 3H), of 1.80 (s, 3H), and 0.98 (d, 3H, J=6.9 Hz), of 0.87 (s, 9H), and 0.08 (s, 3H), of 0.04 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 201,7, 141,2, 117,9, 86,6, 74,5, 71,8, 49,4, 39,7, 26,0, 18,2, 17,6, 16,2, -4,3, -4,4.

Synthesis of intermediate 55

To a solution of diethyl - (methoxy[methoxycarbonyl]methyl)phosphonate (768,6 mg, to 3.02 mmol) and 18-crown-6 (1.60 g, the 6.06 mmol) in anhydrous THF (30 ml), stirred in an argon atmosphere at a temperature of -78°C., added dropwise a 0.5 M solution of bis(trimethylsilyl)amide potassium (KHMDS) in toluene (6,1 ml of 3.05 mmol). After 15 minutes, added dropwise to the aldehyde54(578 mg, 2.02 mmol) in anhydrous THF (20 ml) for 10 minutes and stirred at -78°C for 90 minutes. Then the reaction mixture was quenched with saturated aqueous solution of NH4Cl, warmed to room temperature and diluted with dichloromethane. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/EtOAc = 30:1 to 5:1), receiving 839,4 mg (yield: >100%) of the product55in the form of a colorless oily is a mixture of E/Z-isomers (regioselectivity > 4:1 defined using the1H-NMR).

1H NMR (CDCl3, 300 MHz) (2E,7E)-55δ: 5,73 (d, 1H, J=9.9 Hz), 5,33 (DD, 1H, J=7,8 and 6.9 Hz), 3,80 (s, 3H), 3,61 is 3.57 (m, 1H)and 3.59 (s, 3H), 2.77-to of 2.68 (m, 1H), 2,73 (USS, 1H), 2,58 is 2.44 (m, 2H), 1,72 (USS, 3H), of 0.95 (d, 3H, J=6.6 Hz)to 0.85 (s, 9H), of 0.05 (s, 3H), of 0.04 (s, 3H).

Synthesis of intermediate 56

To a solution of ester55(839,4 mg, to 2.29 mmol) in Meon (30 ml), at room temperature, added 37%aqueous HCl solution (766 μl, 9,16 mmol) and the reaction mixture is stirred for 4 hours. The mixture is then neutralized with a saturated aqueous solution of NaHCO3(pH=7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension is extracted with dichloromethane, dried and evaporated. The crude product is purified by column chromatography (hexane/EtOAc = 10:1 to 1:3), receiving 312,7 mg (yield: 62%) of lactone56in a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 5,72 (DD, 1H, J=10,2, 1.8 Hz), the ceiling of 5.60 (DD, 1H, J=5,1, 4,2 Hz), 4,20-4,10 (m, 1H), to 3.64 (s, 3H), 2,85-2,2,77 (m, 1H), 2,81 (s, 1H), 2,41-of 2.36 (m, 2H), of 1.84 (s, 3H), of 1.13 (d, 3H, J=6.9 Hz).

13C-NMR (CDCl3, 125 MHz) δ: 161,3, 145,1, 138,6, 118,9, 108,0, 85,9, 81,3, 74,8, 55,4, 37,2, 26,2, 17,5, 16,2.

MS (ES) [m/z] = 243,2 [M+Na]+.

Example 10

Synthesis of fragment 62

Figure 10 presents an example of the synthesis of fragment 62.

Synthesis temporarily the CSO product 57

In a flask containing a mixture of31(4,73 g, 9,85 mmol), quinoline (0,582 ml, to 4.92 mmol) and Lindlar catalyst (2,18 g), in ethyl acetate, create a vacuum and filled with hydrogen. The reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 2 hours and then filtered through a layer of celite. Layer celite washed with ethyl acetate and the combined filtrates washed with 0.1%HCl solution. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated, obtaining the intermediate product57(4,27 g, yield: 90%) as a colourless oil which is used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 7,70-to 7.67 (m, 4H), 7,44 and 7.36 (m, 6H), of 5.48 (m, 1H), are 5.36 at 5.27 (m, 1H), 3.95 to a 3.87 (m, 1H), 3,71-3,55 (m, 2H), 2,16 (DD, 2H, J=6,9, and 6.3 Hz), 1,73-of 1.66 (m, 2H), 1,41 (DD, 3H, J=6,6, 1.2 Hz), of 1.05 (s, 9H), is 0.84 (s, 9H), to-0.02 (s, 6H).

13C-NMR (CDCl3, 75 MHz) δ: 136,2, 134,8, 129,8, 127,8, 126,4, 125,8, 70,9, 60,4, 39,6, 34,8, 27,3, 26,2, 19,7, 18,5, 13,1, -5,1.

Synthesis of intermediate 58

PPTS (837,7 mg of 3.33 mmol) added in one portion to a solution of the product57(4 g, with 8.33 mmol) in ethanol (80 ml). The reaction mixture was stirred at room temperature for 7 hours and then concentrated. The residue was diluted with DCM and washed with a saturated solution of NaHCO3. The organic layer is extracted, the tub over anhydrous Na 2SO4, filtered and concentrated. Perform flash chromatography (hexane/EtOAc = 95:1)to give silyl ether58(2,12 g, yield: 69%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 7,73-of 7.69 (m, 4H), 7,44 and 7.36 (m, 6H), 5,44 is 5.38 (m, 1H), to 5.21-5,17 (m, 1H), 4,01-of 3.94 (m, 1H), 3,84 is 3.76 (m, 1H), 3,69-to 3.64 (m, 1H), 2,32 with 2.14 (m, 2H), 1,89-of 1.78 (m, 1H), 1.70 to to 1.60 (m, 1H), 1,37 (d, 3H, J=6.9 Hz), with 1.07 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 136,2, 134,1, 130,0, 127,8, 126,3, 125,9, 72,3, 60,1, 37,7, 34,3, 27,2, 19,5, 13,0.

Synthesis of intermediate 59

BAIB (1.97 g, 6,11 mmol) are added to a solution of alcohol58(2,05 g, to 5.56 mmol) and TAMRA (86,87 mg, 0,56 mmol) in 25 ml DCM. The reaction mixture was stirred at room temperature for 16-18 hours until the alcohol no longer be detected (TLC), and then quenched with saturated aqueous solution of NH4Cl and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/DCM = from 5:1 to 1:2)to give the product59(1,733 mg, yield: 79%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 9,72 (t, 1H, J=2.7 Hz), 7,74-to 7.67 (m, 4H), of 7.48-7,37 (m, 6H), 5,56-of 5.45 (m, 1H), 5,32-5,23 (m, 1H), 4,29-4,20 (m, 1H), of 2.51-2,48 (m, 2H), 2,31-of 2.27 (m, 2H), USD 1.43 (DD, 3H, J=6,9, 1.5 Hz), of 1.06 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 202,3, 136,1, 134,0, 130,1, 127,9, 127,4, 125,1, 69,4, 50,1, 35,1, 27,2, 19,5, 13,1.

Synthesis of intermediate por the product 60

To a suspension of iodocyclization (of 3.32 g, 6.38 mmol) in anhydrous THF (60 ml), at room temperature, slowly add 6,83 ml of 1 M solution of NaHMDS (6.38 mmol) in THF. After stirring for 2 minutes, a mixture of yellow cooled to a temperature of -78°C and then add a solution of the product59(1,67 g, 4,56 mmol) in anhydrous THF (40 ml). The reaction mixture was stirred at -78°C for 90 minutes, then at room temperature for 5 minutes, diluted with hexane and filtered through a layer of celite/SiO2. A layer of celite/SiO2washed with a mixture of hexane/EtOAc (10:1 to 5:1)to give compound60(2 g, yield: 89%) as a colourless oil which is used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 7,70-7,66 (m, 4H), 7,45-7,34 (m, 6H), 6,21 of 6.31 (m, 2H), 5,49-5,43 (m, 1H), 5,35 at 5.27 (m, 1H), 3,94 of 3.75 (m, 1H), 2,30-of 2.27 (m, 2H), 2,24-2,04 (m, 2H), USD 1.43 (d, 3H, J=6.6 Hz), 1.06 a (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 138,2, 136,2, 134,3, 129,9, 127,8, 126,4, 126,0, 84,1, 71,9, 41,6, 34,5, 27,2, 19,6, 13,2.

Synthesis of intermediate 61

In a tightly closed tube Slinka injected iodide copper(I) (232,4 mg, 1,22 mmol), potassium carbonate (1,688 g, 12,23 mmol) and BOC-tert-LeuCONH2(2,474 g, 6.12 mmol), create a vacuum and filled with argon. Add N,N'-dimethylethylenediamine (of 0.26 ml, 2.45 mmol), vinylite60(2 g, 4,08 mmol) and Betwa the hydrated DMF (35 ml), in an argon atmosphere. Tube Slinka, sealed, heated at 90°C for 18 hours and cooled to room temperature. The resulting mixture was diluted with EtOAc and quenched with water. The organic layer is washed with water and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residue purified using flash chromatography on silica gel (hexane/EtOAc = 20:1 to 15:1). The intermediate product61(1.06 g, yield: 44%) are obtained in the form of oil.

1H NMR (CDCl3, 300 MHz) δ: 7,70-to 7.67 (m, 4H), 7,43-7,35 (m, 6H), 7,13 (d, 1H, J=10.5 Hz), to 6.67 (DD, 1H, J=10,2, 9.6 Hz), 5,56-of 5.45 (m, 1H), are 5.36 is 5.28 (m, 2H), 4,86-4,78 (m, 2H), 3,88-of 3.77 (m, 1H), 2.26 and-2,04 (m, 4H), of 1.44 (d, 3H, J=6.9 Hz), USD 1.43 (s, 9H), of 1.06 (s, 9H), is 0.96 (s, 9H).

Synthesis of intermediate 62

A solution of protected amino61(847 mg, 1,43 mmol) in ethylene glycol (50 ml) is heated at 200°C for 10-20 minutes. The reaction mixture is then cooled to room temperature, diluted with DCM, quenched with saturated salt solution and poured into water. Add a few drops of 3 M NaOH solution up until the pH of the solution reaches 14, and is then thoroughly extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo, obtaining primary amine62(435 mg, yield: 62%) as a white foam, PEFC is purification using flash chromatography (hexane/EtOAc = 10:1 to 1:2).

1H NMR (CDCl3, 300 MHz) δ: 8,50 (d, 1H, J=10,8 Hz), 7,70-7,66 (m, 4H), 7,45-7,33 (m, 6H), to 6.67 (DD, 1H, J=11,1, and 9.3 Hz), 5,48-of 5.40 (m, 1H), are 5.36 is 5.28 (m, 1H), 4,79 (DD, 1H, J=16,2, 7.5 Hz), a 3.87-with 3.79 (m, 1H), is 3.08 (s, 1H), 2,22-and 2.14 (m, 4H), USD 1.43 (d, 3H, J=6.9 Hz), of 1.05 (s, 9H), of 0.97 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 171,0, 136,1, 134,5, 129,8, 127,8, 126,3, 126,2, 122,1, 107,6, 72,6, 64,4, 34,0, 34,4, 32,8, 27,2, 26,9, 19,6, 13,2.

Example 11

Synthesis of fragment 63

Figure 11 presents an example of the synthesis of fragment 63.

Synthesis of intermediate 63

To a solution of amine62(575 mg, 1,17 mmol) in anhydrous mixture of DCM/DMF (4:1, 12.5 ml) add a solution of (Z)-3-tributylstannyl acid (505,6 mg, 1.4 mmol) in anhydrous DCM, in argon atmosphere, and then cooled to a temperature of 0°C. To the solution was added DIPEA (0,243 ml of 1.76 mol), 7-hydroxybenzotriazole (HOBt) (189,2 mg, 1.4 mmol) and HATU (532,28 mg, 1.4 mmol)and, after 30 minutes, the cooling bath is put aside. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous solution of NH4Cl, poured into water and extracted with DCM. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 15:1)to give amide63(780,4 mg, yield: 77%) as a white foam.

1H NMR (CDCl3, 300 MHz) δ: 7,70-to 7.68 (m, 4H), 7,43 and 7.36 (m, 6H), 7,02 (d, 1H, J=12.3 Hz), 7,00 (d, 1H, J=10,8 Hz), 6.75 in (d, 1H, J=12.3 Hz), of 6.66 (t, 1H, J=9.3 Hz), of 6.26 (d, 1H, J=9.6 Hz), 5,57-of 5.34 (m, 1H), 5,38 is 5.28 (m, 1H), a 4.83 (DD, 1H, J=16.5, and 7,8 Hz), or 4.31 (d, 1H, J=9.6 Hz), 3,89-3,82 (m, 1H), 2.26 and-2,02 (m, 4H), 1,50-of 1.42 (m, 6H), USD 1.43 (d, 3H, J=6.9 Hz), 1,33-of 1.20 (m, 6H), of 1.06 (s, 9H), is 0.96 (s, 9H), 0.95 to-0,83 (m, 15H).

13C-NMR (CDCl3, 75 MHz) δ: 168,0, 166,2, 153,8, 136,3, 136,1, 134,3, 130,0, 127,8, 126,7, 126,0, 121,6, 109,0, 72,6, 60,7, 35,7, 34,0, 32,7, 29,5, 27,7, 27,2, 26,7, 19,5, 14,0, 13,2, 11,8.

Example 12

Figure 12 presents the synthesis of some compounds according to this invention.

Synthesis of intermediate product 64A

To a solution of iodotope connection9(11 mg, 0,033 mmol) in a mixture of DMF/Et3N (0.25 ml and 0.05 ml)in nitrogen atmosphere at a temperature of -20°C, add Pd(Ph3P)2Cl2(2.3 mg, 0,0033 mmol) and CuI (1.9 mg, 0.01 mmol). Then add connection22A(15 mg, 0.03 mmol in 0.1 ml DMF) and the reaction mixture is stirred at a temperature of from -20°C. to room temperature for 3 hours. The crude product is quenched with water and extracted with ethyl acetate. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (mixture of ethyl acetate/hexane), receiving net connection64A(10 mg, yield: 46%).

1H NMR (CDCl3, 300 MHz) δ: of 7.75 (d, 1H, J=10.5 Hz), 6,70 (t, 1H, J=10,2 Hz), 6,50 (d, 1H, J=9.3 Hz), 6,38 (d, 1H, J=12.3 Hz), the ceiling of 5.60 (m, 3), the 5.45 (d, 1H, J=12.0 Hz), to 4.87 (q, 1H, J=8.1 Hz), 4,37 (d, 1H, J=9.3 Hz), is 4.21 (m, 1H), of 3.77 (m, 1H), to 3.64 (s, 3H), 2,87 (m, 1H), 2.40 a (m, 2H), measuring 2.20 (m, 4H), of 2.09 (s, 3H), a 2.01 (s, 3H)and 1.15 (d, 3H, J=and 6.6 Hz), of 1.02 (s, 9H), to 0.89 (s, 9H), of 0.07 (s, 3H), of 0.05 (s, 3H).

Synthesis of intermediate product 64b

To a solution of compound9(40 mg, 0,113 mmol) in a mixture of DMF/Et3N (1 ml to 0.19 ml), at -20°C, add Pd(Ph3P)2Cl2(7.9 mg, 0,113 mmol) and CuI (6.5 mg, 0,034 mmol). Then add connection22b(50 mg, 0,113 mmol in 0.4 ml DMF) and the reaction mixture is stirred at a temperature of from -20°C. to room temperature for 3 hours. The crude mixture was quenched with water and extracted with ethyl acetate. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (mixture of ethyl acetate/hexane)to give pure product64b(40 mg, yield: 54%).

1H NMR (CDCl3, 300 MHz) δ: to 7.77 (d, 1H, J=11,4 Hz), 6.75 in (t, 1H, J=10,2 Hz), 6,41-6,36 (m, 2H), 5,64-5.56mm (m, 3H), 5,46 (d, 1H, J=11.7 Hz), a 4.86 (q, 1H, J=8.1 Hz), or 4.31 (DD, 1H, J=8,4; and 6.6 Hz), 4,25-4,16 (m, 1H), 3,84 is 3.76 (m, 1H), the 3.65 (s, 3H), 2,92-of 2.81 (m, 1H), 2,44-2,39 (m, 2H), 2,22-2,12 (m, 5H), 2,10 (s, 3H), 2,03 (s, 3H), of 1.16 (d, 3H, J=6.6 Hz), 0,99 (DD, 6H, J=9,3; 6,9 Hz)to 0.89 (s, 9H), 0,0080 (s, 3H), 0,0064 (s, 3H).

Synthesis of compound 65A

To a solution of the product64A(15 mg, of 0.022 mmol) in anhydrous THF (0.5 ml), under nitrogen atmosphere and at room temperature, was added 1 M RA the TBAF solution in THF (0,044 ml, 0,044 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 3:1 to 1:2)to give alcohol65A(5 mg, yield: 42%).

1H NMR (CDCl3, 300 MHz) δ: 8,78 (d, 1H, J=9.6 Hz), 6,77 (t, 1H, J=9.0 Hz), to 6.57 (d, 1H, J=9.0 Hz), 6,38 (d, 1H, J=12.3 Hz), the ceiling of 5.60 (m, 3H), of 5.45 (d, 1H, J=12.0 Hz), the 4.90 (q, 1H, J=8.7 Hz), the 4.29 (d, 1H, J=9.6 Hz), to 4.23 (m, 1H), 3,80 (m, 1H), the 3.65 (s, 3H), of 2.86 (m, 1H), 2,66 (USS, 1H), 2.40 a (m, 2H), of 2.21 (m, 4H), 2,07 (s, 3H), 2,04 (s, 3H)and 1.15 (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

Synthesis of compound 65b

To a solution of the product64b(40 mg, 0.06 mmol) in anhydrous THF (0.9 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (0,12 ml 0,067 mmol). The reaction mixture was stirred at room temperature for 16 hours, then quenched with NH4Cl and extracted with CH2Cl2. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (mixture of ethyl acetate/hexane), receiving net connection65b(15 mg, yield: 45%).

1H NMR (CDCl3, 300 MHz) δ: 8,95 (d, 1H, J=10,2 Hz), 6,77 (t, 1H, J=9.3 Hz), 6,60 (d, 1H, J=9.0 Hz), 6,38 (d, 1H, J=12,6 Hz), 5,64-the ceiling of 5.60(m, 3H), the 5.45 (d, 1H, J=12.0 Hz), 4,88 (kV, 1H, J=8,4 Hz), 4,34 (DD, 1H, J=8,7; 7,2 Hz), 4,27-4,20 (m, 1H), 3,82-3,74 (m, 1H), the 3.65 (s, 3H), 2,92-2,82 (m, 1H), 2,45-of 2.38 (m, 2H), 2,11-2,04 (m, 5H), 1,57-of 1.45 (m, 6H), 1,28-of 1.23 (m, 3H)and 1.15 (d, 6H, J=6.6 Hz).

Synthesis of compound 66A

To a solution of compound65A(3.5 mg, 0,0062 mmol) in anhydrous DCM (0.45 ml)at room temperature, add trichlorotriazine (TCAI) (1 μl, 0,0075 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add neutral aluminum oxide (100 mg). The mixture is stirred for 30 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of DCM/Meon = 50:1. The filtrate is evaporated in vacuum to give crude product, which was purified by column chromatography (hexane/EtOAc = 2:1 to 1:2)to give compound66A(2.5 mg, yield: 70%).

1H NMR (CDCl3, 500 MHz) δ: 8,72 (d, 1H, J=10.5 Hz), at 6.84 (t, 1H, J=9.0 Hz), of 6.66 (d, 1H, J=10.0 Hz), 6,38 (d, 1H, J=12.0 Hz), the ceiling of 5.60 (m, 3H), 5,46 (d, 1H, J=12.0 Hz), 4,82 (kV, 1H, J=8.0 Hz), 4,42 (m, 2H), 4,22 (m, 1H), 3,65 (s, 3H), 2,88 (m, 1H), 2,44 of-2.32 (m, 6H), 2,10 (s, 3H), of 2.06 (s, 3H)and 1.15 (d, 3H, J=7.0 Hz), of 1.05 (s, 9H).

MS (ES) (m/z): 604,2 [M+1]+, 626,2 (M+Na+).

Synthesis of compound 66b

To a solution of compound65b(32 mg, 0.06 mmol) in CH2Cl2(4,2 ml), at room temperature, add trichlorotriazine (TCAI) (8,5 μl, 0,072 mmol). The reaction mixture was premesis the Ute at room temperature for 30 minutes and then add neutral aluminium oxide (450 mg) with stirring for an additional 30 minutes. The reaction mixture is filtered through alumina using a mixture of CH2Cl2/Meon (1:1) and after evaporation of the filtrate under reduced pressure the product was then purified using column chromatography (hexane/EtOAc)to give pure compound66b(12 mg, yield: 35%).

1H NMR (CDCl3, 300 MHz) δ: 8,90 (d, 1H, J=10,8 Hz), at 6.84 (t, 1H, J=9.0 Hz), 6,74 (d, 1H, J=8.7 Hz), 6,38 (d, 1H, J=12.0 Hz), 5,64-to 5.58 (m, 3H), of 5.45 (d, 1H, J=12.0 Hz), 5,38 (USS, 2H), 4,86-4,78 (m, 1H), of 4.44-4,39 (m, 2H), 4,27-4,19 (m, 1H), the 3.65 (s, 3H), 2,96-2,84 (m, 1H), of 2.51-2,39 (m, 2H), 2,37-of 2.30 (m, 5H), 2,18-2,04 (m, 6H)and 1.15 (d, 3H, J=6.6 Hz), 1.00 and-of 0.96 (m, 6H).

Example 13

Figure 13 presents the synthesis of some compounds according to this invention.

Synthesis of compound 67

To a solution of alkenylbenzene21A(50 mg, 0.07 mmol) and iodide27(24,8 mg, 0.08 mmol) in 1-methyl-2-pyrrolidinone (NMP) (1 ml), at 0°C, add thiophencarboxylic copper (CuTC) (19.2 mg, 0.1 mmol). The reaction mixture was stirred at 0°C for 45 minutes and for 20 minutes at room temperature. Then the crude mixture is filtered through a bed of neutral alumina, washed with a mixture of EtOAc/diethyl ether (50:50) and the combined filtrates washed with 0,5N HCl solution (3 times 5 ml). The organic solution is dried and evaporated, to give crude product which is purified by the th column chromatography (hexane/EtOAc = 10:1 to 6:1), getting triene67(19 mg, yield: 44%) as oil.

1H NMR (CDC13, 300 MHz) δ: 7,73 (d, 1H, J=10.5 Hz), 7,41 (DD, 1H, J=11,7 and 11.1 Hz), 6,77 of 6.68 (m, 2H), 6,37 (d, 1H, J=9.3 Hz), 5,74 (d, 1H, J=11,4 Hz), 5,61-5,52 (m, 3H), 4,87-rate 4.79 (m, 1H), 4,37 (d, 1H, J=9.3 Hz), 4,21-4,14 (m, 1H), 3,79-and 3.72(m, 1H), to 3.64 (s, 3H), 3,09-2,99 (m, 1H), 2,39 to 2.35 (m, 2H), 2,20-2,10 (m, 4H), for 2.01 (s, 3H), of 1.16 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H), to 0.88 (s, 9H), of 0.07 (s, 3H), of 0.05 (s, 3H).

Synthesis of compound 68

To a solution of compound67(18 mg, 0.03 mmol) in anhydrous THF (0,42 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (0.05 ml, 0.05 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 3:1 to 1:2)to give alcohol68(16 mg, yield: 80%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 8,90 (d, 1H, J=10.5 Hz), 7,42 (DD, 1H, J=11,7 and 11.1 Hz), 6,78-6,69 (m, 2H), 6,59 (d, 1H, J=9.3 Hz), of 5.75 (d, 1H, J=11,4 Hz), 5,64-of 5.53 (m, 3H), 4,88-4,80 (m, 1H), 4,37 (d, 1H, J=9.3 Hz), 4,22-4,15 (m, 1H), of 3.77 at 3.69 (m, 1H), to 3.64 (s, 3H), 3,11-a 3.01 (m, 1H), 2,39 to 2.35 (m, 2H), 2,24 with 2.14 (m, 4H), 2,03 (s, 3H), of 1.16 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

Synthesis of compound 69

To a solution of compound68(15 mg, 0.02 mmol) in anhydrous DCM (0.3 ml)at room temperature is round, add trichlorotriazine (TCAI) (4,1 μl, 0.64 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add neutral aluminium oxide (450 mg). This mixture is stirred for 30 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of DCM/Meon (50:1). The filtrate is evaporated in vacuum to give crude product, which was purified by column chromatography (hexane/EtOAc = 3:1 to 2:1)to give compound69(14 mg, yield: 86%).

1H NMR (CDCl3, 300 MHz) δ: 8,89 (d, 1H, J=10.5 Hz), 7,45 (m, 1H), 6.87 in-6-71 (m, 2H), 6,53 (d, 1H, J=9.6 Hz), of 5.75 (m, 2H), ceiling of 5.60-to 5.57 (m, 2H), to 4.81 (m, 1H), 4,40-4,37 (m, 2H), 4,19 (DD, 1H, J=9,3, 9.5 Hz), 3,66 (s, 3H), 3,06 (m, 1H), 2.40 a-2,30 (m, 5H), 2,15-of 2.08 (m, 1H), 2,07 (s, 3H), of 1.17 (d, 3H, J=4,2 Hz), was 1.04 (s, 9H).

13C-NMR (CDCl3, 75.5 MHz) δ: 168,1, 165,9, 161,4, 157,7, 145,2, 138,3, 135,2, 132,0, 125,9, 124,5, 122,3, 121,8, 108,1, 105,2, 81,4, 75,1, 60,7, 55,4, 36,1, 35,0, 32,9, 30,8, 26,7, 26,3, 21,0, 17,0.

Example 14

Figure 14 presents the synthesis of some compounds according to this invention.

Synthesis of compound 70

To a solution of alkenylbenzene37(94 mg, 0,112 mmol) and the product9(47 mg, is 0.135 mmol) in 1-methyl-2-pyrrolidinone (NMP) (1.1 ml), at 0°C, add thiophencarboxylic copper (CuTC) (32,2 mg, has 0.168 mmol). The reaction mixture is stirred at a temperature of 0 is C for 45 minutes and within 20 minutes at room temperature. Then the crude mixture is filtered through a bed of neutral alumina, washed with a mixture of EtOAc/diethyl ether (50:50) and the combined filtrates washed with 0.5 n HCl solution (3 x 15 ml). The organic solution is dried and evaporated, to give crude product, which was purified by column chromatography (hexane/EtOAc = 2:1 to 1:1)to give triene70(81,4 mg, yield: 79%) as oil.

1H NMR (CDC13, 300 MHz) δ: 7,74 (d, 1H, J=10.5 Hz), 7,66-to 7.64 (m, 4H), 7,44-7,38 (m, 6H), 7,22 (DD, 1H, J=12,3, and 11.4 Hz), 6,86 (DD, 1H, J=11,7, and 11.4 Hz), 6,70 (DD, 1H, J=9,9, and 9.3 Hz), 6,40 (d, 1H, J=9.3 Hz), 6,17 (d, 1H, J=11,4 Hz), to 5.66 (d, 1H, J=11.4 in Hz), the ceiling of 5.60 (DD, 1H, J=5,4, 3,9 Hz), 5,26 (d, 1H, J=10,2 Hz), 4,84 was 4.76 (m, 1H), 4,3 (d, 1H, J=9.3 Hz), 4,20-4,16 (m, 1H), 3,88-of 3.80 (m, 1H), to 3.64 (s, 3H), 2,89-2,77 (m, 1H), 2,41 is 2.33 (m, 3H), 2,28-of 2.20 (m, 3H), 1.91 a (s, 3H), equal to 1.82 (s, 3H), of 1.13 (d, 3H, J=6.9 Hz), of 1.02 (s, 9H), 0,86 (s, 9H).

Synthesis of compound 71

To a solution of compound70(77,2 mg, 0,106 mmol) in anhydrous THF (7.5 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (0.2 ml, 0.2 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/tOAc = 1:2), getting alcohol71(25 mg, yield: 44%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 8,79 (d, 1H, J=9.6 Hz), 7,28-7,22 (m, 1H), 6,85 (t, 1H, J=11.7 Hz), 6.73 x (t, 1H, J=9.6 Hz), to 6.58 (d, 1H, J=8.7 Hz), 6,12 (d, 1H, J=11,4 Hz), 5,68-5,61 (m, 2H), 5,26 (d, 1H, J=9.9 Hz), 4,86 (kV, 1H, J=8.1 Hz), to 4.38 (d, 1H, J=9.3 Hz), 4,20-4,18 (m, 1H), 3,78 is 3.76 (m, 1H), to 3.64 (s, 3H), 3,10 (USS, 1H), 2,86-and 2.79 (m, 1H), 2,41 with 2.14 (m, 6H), is 1.82 (s, 6H), 1.14 in (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

Synthesis of compound 72

To a solution of compound71(to 21.6 mg, 0,0443 mmol) in anhydrous DCM (3.1 ml), at 0°C, add trichlorotriazine (TCAI) (6,4 μl, 0,053 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then add neutral alumina. This mixture is stirred for 5 to 30 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of DCM/Meon (50:1). The filtrate is evaporated in vacuum to give crude product, which was purified by column chromatography (hexane/EtOAc = 1:2). Connection72(19.1 mg, yield: 76%) are obtained in the form of a solid white color.

1H NMR (CDCl3, 500 MHz) δ: 8,61 (d, 1H, J=11,1 Hz), 7,27 (t, 1H, J=11,4 Hz), 6,92-of 6.78 (m, 2H), of 6.52 (d, 1H, J=9.3 Hz), x 6.15 (d, 1H, J=11,4 Hz), 5,69 (d, 1H, J=11,4 Hz), 5,62-5,61 (m, 1H), 5,45 (USS, 2H), 5,28 (d, 1H, J=9,6 Hz), 4,87-4,78 (m, 1H), 4.53-in is 4.45 (m, 1H), 4,42 (d, 1H, J=9.6 Hz), 4,25-4,20 (m, 1H), to 3.64 (s, 3H), 2,87 is 2.80 (m, 1H), 2,44-2,17 (m, 6H), is 1.81 (s, 6H), of 1.16 (d, 3H, J=6.5 Hz), was 1.04 (s, 9H).

Example 15

In figure 15 shows the synthesis of the compounds is of 73.

Synthesis of compound 73

To a solution of the product30(40 mg, 0,076 mmol) and the product9(31 mg, 0.09 mmol) in NMP (0.8 ml), at 0°C, add thiophencarboxylic copper (CuTC) (22 mg, 0.11 mmol). The reaction mixture was stirred at 0°C for 45 minutes and within one hour at room temperature. Then the crude mixture is filtered through a bed of neutral alumina, washed with a mixture of EtOAc/diethyl ether (50:50, 20 ml) and the combined filtrates washed with 0.5 n HCl solution (3 x 10 ml). After drying and evaporation of the solvent under reduced pressure, the crude product is purified by column chromatography (ethyl acetate/hexane = from 5:1 to 2:1)to give a pure compound73(6 mg, yield: 17%).

1H NMR (CDCl3, 300 MHz) δ: 7,27 (t, 1H, J=11,46 Hz), 6.90 to (t, 1H, J=to 11.52 Hz), 6,16 (d, 1H, J=11,7), 6,03 (d, 1H, J=of 9.55 Hz), of 5.84-5,70 (m, 1H), 5,67-the ceiling of 5.60 (m, 2H), 5,28 (d, 1H, J=10,66 Hz), 5,14-of 5.06 (m, 2H), 4.53-in (d, 1H, J=9,41 Hz), 4,22-4,10 (m, 3H), of 3.65 (s, 3H), 2.91 in-of 2.81 (m, 1H), 2,47-of 2.34 (m, 4H), of 1.84 (s, 3H), of 1.16 (d, 3H, J=6,65 Hz), 0,99 (s, 9H).

Example 16

Scheme 16 shows the synthesis of some compounds according to this invention.

Synthesis of compound 74

To a solution of the product40(2.7 g, 5,12 mmol) and propionovoi acid (0,41 ml of 6.66 mmol) in anhydrous DCM (51 ml), when the fact is the temperature value 0°C, add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (1.23 g, 6.4 mmol). The reaction mixture was stirred at 0°C for 30 minutes and for 2 hours at room temperature. Then the crude mixture was quenched with water and extracted with dichloromethane. The combined filtrates washed with water. After drying and evaporation of the solvent under reduced pressure the crude product is purified by column chromatography (mixture of EtOAc/hexane), receiving net connection74(2.25 g, yield: 85%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 7,66 (m, 4H), 7,47 and 7.36 (m, 6H), of 6.96 (d, 1H, J=10.5 Hz), of 6.66 (d, 1H, J=9,2 Hz), 6,62 (t, 1H, J=8,9 Hz), 5,52 (t, 1H, J=7.4 Hz), 4,79 (kV, 1H, J=8.6 Hz), 4,27 (d, 1H, J=9.4 Hz), 3,83 (m, 1H), 2,82 (s, 1H), 2,19-2,04 (m, 4H), to 1.87 (s, 3H), of 1.05 (s, 9H), 0,99 (s, 9H).

Synthesis of intermediate product 75

The solution propionovoi acid (45 μl, 0,726 mmol), amine62(275 mg, 0,56 mmol)in anhydrous DCM (5.6 ml), cooled to 0°C. in an argon atmosphere, and add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (134 mg, 0.7 mmol). The reaction mixture was stirred at 0°C for 10 minutes and then at a temperature of 23°C for 3 hours, quenched with water and extracted with dichloromethane. The combined organic layers are dried (anhydrous Na2SO4), filtered and concentrated. The residue is purified on OSU flash chromatography (EtOAc/hexane = 1:10 to 3:1), getting the product75(260 mg, yield: 85%) as a colorless solid foam.

1H NMR (CDCl3, 300 MHz) δ: 7,69-to 7.67 (m, 4H), 7,44 and 7.36 (m, 6H), was 7.08 (d, 1H, J=10,2 Hz), 6,67-of 6.61 (m, 2H), of 5.53-of 5.45 (m, 1H), 5,35-of 5.26 (m, 1H), 4.92 in-4,84 (m, 1H), 4.26 deaths (d, 1H, J=9.6 Hz), 3,89-3,82 (m, 1H), 2,80 (s, 1H), and 2.26-2,05 (m, 4H), of 1.44 (d, 3H, J=7,8 Hz)of 1.05 (s, 9H), of 0.97 (s, 9H).

Synthesis of intermediate 76

To a solution of the product75(244,3 mg, 0.45 mmol) in anhydrous THF (5 ml), under nitrogen atmosphere and at 0°C, was added 1 M solution of TBAF in THF (0.54 ml, 0.54 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:2)to give alcohol76(94,1 mg, yield: 69%) as oil pale yellow color.

1H NMR (CDCl3, 300 MHz) δ: 9,02 (d, 1H, J=9.9 Hz), to 7.09 (d, 1H, J=9.3 Hz), 6,74 (t, 1H, J=9.9 Hz), 5,65-to 5.57 (m, 1H), 5,43 to 5.35 (m, 1H), 4,93-is 4.85 (m, 1H), of 4.44 (d, 1H, J=9.3 Hz), 3,78-3,70 (m, 1H), 2,87 (s, 1H), 2,32-2,12 (m, 4H), to 1.61 (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 167,7, 152,4, 127,7, 126,0, 123,5, 109,4, 77,3, 74,9, 72,1, 61,3, 35,4, 34,7, 33,2, 26,8, 13,3.

Synthesis of intermediate 77

To a solution of the product76(48.6 mg, strength of 0.159 mmol) in anhydrous DCM (1.6 ml)at the room for the Noah temperature, add trichlorotriazine (TCAI) (23,0 μl, 0,19 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add neutral aluminium oxide (250 mg). This mixture is stirred for 60 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of dichloromethane/Meon (50:1). The filtrate is evaporated under reduced pressure to give crude product, which was purified by column chromatography (hexane/EtOAc = 3:1 to 1:100), receiving the connection77(43 mg, yield: 77%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 9,02 (d, 1H, J=10.5 Hz), 7,12 (USS, 1H),? 7.04 baby mortality (d, 1H, J=9.6 Hz), 6,98 (USS, 1H), 6,80 (t, 1H, J=9.7 Hz), 5,63-of 5.53 (m, 1H), 5,42-5,33 (m, 1H), a 4.86 (q, 1H, J=8,3 Hz), 4,48-4,30 (m, 1H), 4,39 (d, 1H, J=9.6 Hz), 2,87 (s, 1H), 2,46 is 2.43 (m, 1H), 2,35-of 2.30 (m, 2H), 2,18-2,11 (m, 1H), 1,61 (d, 3H, J=6.0 Hz), and 1.00 (s, 9H).

Synthesis of compound 78

To a solution of iodotope connection9(300 mg, 0.86 mmol) in Diisopropylamine (4.3 ml), under nitrogen atmosphere and at room temperature, add Pd(Ph3P)4(20 mg, is 0.017 mmol) and CuI (6.4 mg, 0,034 mmol). Then, piece by piece, add connection74(500 mg, 0.86 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The crude product is quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under pony is hinnon pressure. Purified by column chromatography (hexane/EtOAc = 3:1 to 1:1)to give a pure compound78(580 mg, yield: 85%) as a solid yellow color.

1H NMR (CDCl3, 300 MHz) δ: to 7.67 (m, 4H), of 7.48-7,37 (m, 6H), of 7.75 (d, 1H, J=10.5 Hz), of 6.65 (t, 1H, J=10.1 Hz), 6,46 (d, 1H, J=9,2 Hz), 6,38 (d, 1H, J=12.0 Hz), 5,64-of 5.48 (m, 3H), 5,43 (d, 1H, J=12.1 Hz), 4,78 (kV, 1H, J=7,7 Hz), 4,28 (d, 1H, J=9.3 Hz), 4,20 (m, 1H), 3,82 (m, 1H), the 3.65 (s, 3H), of 2.86 (m, 1H), 2.40 a (m, 2H), and 2.14 (m, 4H), of 2.09 (s, 3H), of 1.86 (s, 3H)and 1.15 (d, 3H, J=6.6 Hz), of 1.05 (s, 9H), 0,99 (s, 9H).

Synthesis of compound 79

To a solution of the product9(113 mg, 0,325 mmol) in IPA (1.6 ml)at a temperature of 23°C, add Pd(Ph3P)4(7 mg, 0,006 mmol) and CuI (2.5 mg, of 0.013 mmol). Then add connection75(195 mg, 0,358 mmol) and the reaction mixture was stirred at 23°C for 3 hours. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (EtOAc/hexane = 1:3 to 1:1)to give a pure compound79(180 mg, yield: 70%) as a colorless solid foam.

1H NMR (CDCl3, 300 MHz) δ: to 7.67-to 7.64 (m, 4H), 7,60 (d, 1H, J=10,8 Hz), 7,46-7,35 (m, 6H), of 6.66 (t, 1H, J=9.6 Hz), 6,59 (DD, 1H, J=9.9 Hz), of 6.31 (d, 1H, J=12,6 Hz), 5,62 is 5.54 (m, 2H), 5,42 lower than the 5.37 (m, 1H), 5,32 (d, 1H, J=12.0 Hz), and 5.30-5,23 (m, 1H), 4.92 in-4,84 (m, 1H), 4,42 (d, 1H, J=9.6 Hz), 4,23-to 4.15 (m, 1H), 3,86-of 3.78 (m, 1H), 3,63 (s, 3H), 2,88 is 2.80 (m, 1H), 2,41-of 2.36 (m, 2H), 2,22-2,11 (m, 4H), to 2.06 (s, 3H), of 1.39 (d, 3H, J=6,9 Hz), 1,1 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H), is 0.96 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 167,5, 161,7, 153,3, 148,2, 145,4, 138,2, 136,1, 135,7, 134,4, 129,9, 127,8, 127,8, 126,5, 126,1, 121,6, 109,5, 108,5, 103,1, 88,2, 85,1, 81,7, 72,6, 60,8, 55,6, 37,2, 35,6, 34,1, 32,6, 27,2, 26,7, 26,6, 19,5, 16,4, 15,5, 13,1. (one signal Csp2not found).

Synthesis of compound 80

To a solution of the product9(52 mg, 0.15 mmol) in IPA (0.6 ml)at 23°C, add Pd(Ph3P)4(3.5 mg, of 0.003 mmol) and CuI (1,14 mg, 0,006 mmol). Then add connection76(to 45.5 mg, 0.15 mmol) in 0.4 ml of DIPA and the reaction mixture was stirred at 23°C for 120 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (dichloromethane/Meon = from 100:1 to 20:1)to give a pure compound80(59,5 mg, yield: 75%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: to 8.94 (d, 1H, J=9.9 Hz), 6.75 in (t, 1H, J=9.3 Hz), 6,69 (d, 1H, J=9.0 Hz), 6,37 (d, 1H, J=12.0 Hz), 5,68-to 5.57 (m, 3H), 5,44 (d, 1H, J=12.0 Hz), 5,43 to 5.35 (m, 1H), 4.95 points-to 4.87 (m, 1H), 4,34 (d, 1H, J=9,3 Hz), 4,24-4,17 (m, 1H), 3,76 (m, 1H), to 3.64 (s, 3H), 2.91 in-2,78 (m, 1H), 2.63 in (USS, 1H), 2,43-of 2.38 (m, 2H), 2,32-2,11 (m, 4H), 2,07 (s, 3H), of 1.62 (d, 3H, J=6.6 Hz), 1.14 in (d, 3H, J=6.6 Hz), a 1.01 (s, 9H).

13C-NMR (CDCl3, 125 MHz) δ: 167,5, 161,5, 153,2, 147,9, 145,1, 137,8, 135,4, 127,8, 125,5, 123,6, 109,0, 108,3, 103,0, 88,0, 84,7, 81,4, 72,0, 61,1, 55,4, 37,0, 35,2, 34,5, 32,8, 26,6, 26,4, 16,2, 15,3, 13,0.

MS (ES) [m/z]: 549,2 [M+Na]+.

Synthesis of compound 81

To a solution of the product9(43 mg, 0,123 mmol) in IPA (0.6 ml)at 23°C, add Pd(Ph3P)4(2.8 mg, 0,0025 mmol) and CuI (1.0 mg, of 0.005 mmol). Then add connection77(43 mg, 0,123 mmol) in 0.4 ml of DIPA and the reaction mixture was stirred at 23°C for 120 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (dichloromethane/Meon = from 100:1 to 20:1)to give a pure compound81(38 mg, yield: 54%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 9,00 (d, 1H, J=10,8 Hz), for 6.81 (t, 1H, J=9.6 Hz), 6.73 x (d, 1H, J=9.6 Hz), 6,38 (d, 1H, J=12.0 Hz), 5,63-5.56mm (m, 5H), of 5.45 (d, 1H, J=11.7 Hz), 5,43 and 5.36 (m, 1H), 4,90-to 4.81 (m, 1H), and 4.40 (d, 1H, J=9,3 Hz), 4,40-to 4.33 (m, 1H), 4,24-4,17 (m, 1H), to 3.64 (s, 3H), 2,90-2,82 (m, 1H), 2,42-2,31 (m, 5H), 2,18-of 2.09 (m, 1H), 2,09 (s, 3H), of 1.62 (d, 3H, J=6.6 Hz)and 1.15 (d, 3H, J=6.6 Hz), a 1.01 (s, 9H).

Example 17

Figure 17 shows the synthesis of some compounds according to this invention.

The synthesis of compound 82

To a solution of alkenylbenzene21A(1.1 g, of 1.47 mmol) and compound9(0,62 g, 1.77 mmol) in 1-methyl-2-pyrrolidinone (NMP) (14.7 ml), at 0°C, add thiophencarboxylic copper (CuTC) (422 mg, 2.2 mmol). The reaction mixture was stirred at 0°C for 45 min is t and within 20 minutes at room temperature. Then the crude mixture is filtered through a bed of neutral alumina, washed with a mixture of EtOAc/diethyl ether (50:50) and the combined filtrates washed with 0.5 n HCl solution (3 x 15 ml). The organic solution is dried and evaporated, to give crude product, which was purified by column chromatography (hexane/EtOAc = 5:1 to 1:1)to give triene82(0.66 g, yield: 66%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 7,89 (d, 1H, J=10,8 Hz), 7,22 (DD, 1H, J=12,3, and 11.4 Hz), 6,86 (DD, 1H, J=11,7, and 11.4 Hz), 6,70 (DD, 1H, J=9,9, and 9.3 Hz), 6.35mm (d, 1H, J=9.3 Hz), 6,13 (d, 1H, J=11,4 Hz), to 5.66 (d, 1H, J=11.4 in Hz), the ceiling of 5.60 (DD, 1H, J=5,4, 3,9 Hz), 5,55 (Ust, 1H, J=7.8 Hz), 5,26 (d, 1H, J=10,2 Hz), 4,84 was 4.76 (m, 1H), 4,3 (d, 1H, J=9.3 Hz), 4,20-4,16 (m, 1H), of 3.77 at 3.69 (m, 1H), 3,63 (s, 3H), 2,89-2,77 (m, 1H), 2,41 is 2.33 (m, 2H), 2,19-to 2.13 (m, 4H), from 2.00 (s, 3H), equal to 1.82 (s, 3H), of 1.13 (d, 3H, J=6.9 Hz), of 1.02 (s, 9H), 0,86 (s, 9H), 0,4 (s, 3H), of 0.03 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 168,5, 166,4, 161,8, 145,4, 140,3, 137,3, 134,4, 134,3, 131,0, 124,3, 124,1, 122,4, 121,2, 108,7, 108,4, 82,0, 71,6, 60,6, 55,6, 37,5, 36,5, 35,1, 33,8, 26,5, 26,0, 21,3, 18,3, 17,4, 16,9, -4,3, -4,4.

Synthesis of compound 83

To a solution of compound82(275 mg, 0.41 mmol) in anhydrous THF (6 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (of 0.82 ml, 0.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. Together the major organic phase is dried over anhydrous Na 2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 3:1 to 1:2)to give alcohol83(175 mg, yield: 76%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 9,00 (d, 1H, J=10,2 Hz), 7,25 (DD, 1H, J=12,0, to 11.4 Hz), 6,86 (DD, 1H, J=11,7, and 11.4 Hz), 6,72 (DD, 1H, J=9,6, and 8.7 Hz), of 6.68 (d, 1H, J=8.7 Hz), 6,13 (d, 1H, J=11.7 Hz), of 5.68 (d, 1H, J=11,4 Hz), 5,63-5,58 (m, 2H), 5,27 (d, 1H, J=10,2 Hz), 4,85 was 4.76 (m, 1H), 4,42 (d, 1H, J=9.3 Hz), 4,25-4,17 (m, 1H), 3,70 at 3.69 (m, 1H), 3,63 (s, 3H), 3,48 (USS, 1H), 2,89 is 2.75 (m, 1H), 2,42-of 2.36 (m, 2H), 2,22-2,11 (m, 4H), 2,04 (, 3H), equal to 1.82 (s, 3H), 1.14 in (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

Synthesis of compound 84

To a solution of compound83(300 mg, of 0.53 mmol) in anhydrous DCM (7.5 ml), at 0°C, add trichlorotriazine (TCAI) (76 μl, 0.64 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then add neutral alumina. The mixture is stirred for 5 to 30 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of DCM/Meon = 50:1. The filtrate is evaporated in vacuum to give crude product, which was purified by column chromatography (hexane/EtOAc = 2:1 to 1:2)to give compound84(0.26 g, yield: 81%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 8,78 (d, 1H, J=10,8 Hz), 7,30 (DD, 1H, J=11,6, the 11.6 Hz), 6,91 (DD, 1H, J=11,6, the 11.6 Hz), 6,84 (USD, 1H, J=10,8, 9.7 Hz), 6,51 (d, 1H, J=9.5 Hz), ,17 (d, 1H, J=11,6 Hz), 5,70 (d, 1H, J=11,6 Hz), 5,63 (DD, 1H, J=6,5, and 2.6 Hz), 5,61 (Ust, 1H, J=6,8 Hz), from 5.29 (d, 1H, J=9.8 Hz), 4,80 (m, 1H), to 4.41 (m, 1H), to 4.41 (d, 1H, J=9.5 Hz), 4,24 (DDD, 1H, J=11,5, 7,1, 4,1 Hz), 3,66 (s, 3H), 2,85 (ddcv, 1H, J=9,8, 7,1, 6,7 Hz), 2,46 (m, 1H), 2,45 (DDD, 1H, J=17,3, 11,5, and 2.6 Hz), is 2.37 (DDD, 1H, J=17,3, 6,5, 4,1 Hz), 2,33 (m, 2H), 2,09 (DDD, 1H, J=14,1, and 8.4 and 8.1 Hz), to 2.06 (s, 3H), equal to 1.82 (s, 3H), 1,15 (d, 3H, J=6,7 Hz), was 1.04 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 168,2, 166,3, 161,6, 157,2, 145,2, 140,2, 137,6, 134,1, 133,7, 132,0, 124,6, 124,5, 122,4, 120,7, 108,2, 105,0, 81,9, 74,9, 60,8, 55,4, 37,1, 34,7, 33,0, 30,7, 26,7, 26,1, 21,0, 17,1, 16,3.

Synthesis of compound 85

It cooled down to -78°C solution of compound84(10 mg, to 0.016 mmol) in anhydrous dichloromethane (0.3 ml)in an argon atmosphere, was added 1 M solution of diisobutylaluminium (DIBAL) in toluene (0,02 ml, 0.02 mol) and the mixture was stirred at -78°C. After 2 hours, the reaction mixture was quenched with saturated aqueous solution of NH4Cl and diluted with dichloromethane (2 ml). The mixture is stirred for 0.5 hours at room temperature and then the organic layer decanted. The aqueous residue is extracted with additional dichloromethane (2 x 4 ml), the combined organic layers are dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is purified by column chromatography (hexane/EtOAc = 2:1 to 1:2)to give compound85(5 mg, yield: 50%) as a colourless oil.

1H NMR (CDC 3, 300 MHz) δ: to 8.57 (d, 1H, J=10,9 Hz), 7,19 (t, 1H, J=11.3 Hz), 6,92 (t, 1H, J=11,4 Hz), PC 6.82 (t, 1H, J=9.3 Hz), 6,38 (d, 1H, J=9.5 Hz), 6,18 (d, 1H, J=11.5 Hz), 5,64 (d, 1H, J=11.2 Hz), the ceiling of 5.60 (m, 1H), 5,35 (d, 1H, J=10.0 Hz), 5,27 (d, 1H, J=3.1 Hz), to 4.81 (m, 2H), 4,46 (m, 1H), and 4.40 (d, 1H, J=9.5 Hz), 3,85 (m, 1H), only 3.57 (s, 3H), 3,21 (d, 1H, J=3.1 Hz), 2,61 (m, 1H), 2,46-to 2.29 (m, 3H), 2,14-of 2.08 (m, 3H), 2.06 to (s, 3H), of 1.81 (s, 3H), of 1.08 (d, 3H, J=6,7 Hz)of 1.05 (s, 9H).

Example 18

Figure 18 presents the synthesis of some compounds according to this invention.

Synthesis of compound 86

To a solution of alkenylbenzene63(780,4 mg, 0,904 mmol) and the product9(377,4 mg, 1,085 mmol) in NMP (9 ml)at 0°C, add thiophencarboxylic copper (258,5 mg of 1.36 mmol). The reaction mixture was stirred at 0°C for 45 minutes and for 20 minutes at room temperature. Then the crude mixture is filtered through a bed of neutral alumina, washed with a mixture of EtOAc/diethyl ether (50:50) and the combined filtrates washed with 0.5 n HCl solution (3 x 10 ml). The organic solution is dried and evaporated, to give crude product, which was purified by column chromatography (hexane/EtOAc = 5:1 to 1:1)to give triene86(459,7 mg, yield: 66%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 7,66-to 7.64 (m, 4H), 7,43-to 7.32 (m, 7H), of 7.23 (t, 1H, J=11.7 Hz), 6,85 (t, 1H, J=11.7 Hz), 6,62 (DD, 1H, J=10,5, and 9.3 Hz), 6,41 (d, 1H, J=9,3 Hz), 6,11 (d, 1H, J=11.7 Hz), to 5.66 (d, 1H, J=11.4 in Hz), the ceiling of 5.60 (DD, 1H, J=5,7, 5,1 Hz), 5,49-5,41 (m, 1H), 5,32 at 5.27 (m, 1H), 5.25 in (d, 1H, J=9.9 Hz), a 4.83-4.75 in (m, 1H), 4,32 (d, 1H, J=9.3 Hz), 4,22-to 4.15 (m, 1H), 3,83-of 3.78 (m, 1H), 3,62 (s, 3H), 2,86-2,78 (m, 1H), 2.40 a to 2.35 (m, 2H), 2,20-2,04 (m, 4H), of 1.81 (s, 3H), of 1.40 (d, 3H, J=6.9 Hz), of 1.13 (d, 3H, J=6.9 Hz), of 1.03 (s, 9H), of 0.97 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 168,3, 166,3, 161,8, 145,4, 140,2, 137,3, 136,1, 134,8, 134,4, 134,3, 129,9, 127,8, 126,4, 126,1, 124,4, 121,7, 121,2, 108,4, 109,1, 82,0, 72,6, 60,6, 55,6, 37,5, 35,2, 32,7, 31,1, 27,2, 26,8, 26,5, 19,5, 17,4, 16,9, 13,1.

Synthesis of compound 87

To a solution of compound86(586 mg, from 0.76 mmol) in anhydrous THF (7.5 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (1,53 ml, 2 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 3:1 to 1:2)to give alcohol87(320 mg, yield: 80%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 8,95 (d, 1H, J=10,2 Hz), 7,25 (t, 1H, J=12.0 Hz), 6,85 (t, 1H, J=11.7 Hz), 6.73 x (t, 1H, J=9.6 Hz), to 6.57 (d, 1H, J=8.7 Hz), 6,12 (d, 1H, J=11A Hz), 5,67 (d, 1H, J=11A Hz), 5,61 (DD, 1H, J=5,4, 3,9 Hz), 5,63-to 5.58 (m, 1H), 5,44 to 5.35 (m, 1H), 5,26 (d, 1H, J=9.9 Hz), a 4.86 (q, 1H, J=8.1 Hz), to 4.38 (d, 1H, J=9.3 Hz), 4,24-4,16 (m, 1H), 3,81-3,71 (m, 1H), to 3.64 (s, 3H), 2,96 of 2.92 (m, 1H), 2,86-and 2.79 (m, 1H), 2,41-is 2.37 (m, 2H), 2,28-2,14 (who, 4H), equal to 1.82 (s, 3H), of 1.61 (d, 3H, J=6.6 Hz), 1.14 in (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 168,7, 166,6, 161,8, 145,4, 140,3, 137,5, 134,4, 134,3, 127,7, 126,0, 124,4, 123,7, 121,1, 108,9, 108,4, 82,0, 72,1, 60,9, 55,7, 37,6, 35,0, 34,8, 33,2, 26,9, 26,5, 17,4, 16,9, 13,3.

Synthesis of compound 88

To a solution of the product87(56 mg, 0,105 mmol) in anhydrous DCM (1 ml), at 0°C, add trichlorotriazine (15 μl, 0,126 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then add neutral alumina. This mixture is stirred for 5 to 30 minutes and then applied, when the impregnation, the layer of aluminum oxide. Product wash using a mixture of DCM/Meon (50:1). The filtrate is evaporated in vacuum to give crude product, which was purified by column chromatography (hexane/EtOAc = 3:1 to 1:2)to give compound88(57.6 mg, yield: 96%) as a white foam.

1H NMR (CDCl3, 300 MHz) δ: 8,69 (d, 1H, J=10.4 Hz), 7,31 (DD, 1H, J=11,6, the 11.6 Hz), 6.90 to (DD, 1H, J=11,6, the 11.6 Hz), PC 6.82 (DDD, 1H, J=10,4, 9,1, 0.9 Hz), 6,53 (d, 1H, J=9.6 Hz), x 6.15 (d, 1H, J=11,6 Hz), 5,72 (USD, 1H, J=11,6 Hz), 5,63 (DD, 1H, J=6,6, 2.7 Hz), the ceiling of 5.60 (m, 1H), 5.40 to (m, 1H), from 5.29 (d, 1H, J=9.9 Hz), 4,82 (m, 1H), 4,45 (m, 1H), of 4.44 (d, 1H, J=9.6 Hz), 4,25 (DDD, 1H, J=11,3, 7,0, 4.0 Hz), 3,66 (s, 3H), 2,85 (ddcv, 1H, J=9,9, 7,0, 6,7 Hz), 2,46 (m, 1H), 2,44 (m, 1H), 2,39 (m, 1H), 2,35 (m, 2H), 2,12 (DDD, 1H, J=14,1, to 8.0, 8.0 Hz), equal to 1.82 (s, 3H), and 1.63 (DD, 3H, J=6.8 cm, 1.0 Hz)and 1.15 (d, 3H, J=6,7 Hz), was 1.04 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 168,2, 166,3, 161,6, 157,6, 145,2, 140,2, 137,5, 134,1, 133,8, 27,1, 124,9, 124,4, 124,2, 120,8, 108,2, 105,8, 81,9, 75,6, 60,7, 55,4, 37,1, 34,8, 31,4, 30,9, 26,7, 26,1, 17,1, 16,4, 13,0.

Synthesis of compound 89

It cooled down to -78°C solution of compound88(15 mg, 0,0262 mmol) in anhydrous dichloromethane (0.5 ml)in an argon atmosphere, was added 1 M solution of diisobutylaluminium (DIBAL)in toluene (0,03 ml 0,034 mol)and the mixture stirred at -78°C. After 2 hours, the reaction mixture was quenched with saturated aqueous solution of NH4Cl and diluted with dichloromethane (2 ml). The mixture is stirred for 0.5 hours at room temperature and then the organic layer decanted. The aqueous residue is extracted with additional dichloromethane (2 x 4 ml), the combined organic layers are dried (anhydrous Na2SO4) and the solvent is evaporated, receiving the connection89(12 mg, yield: 80%)without further purification.

1H NMR (CDCl3, 500 MHz) δ: 8,67 (d, 1H, J=10,7 Hz), 7,17 (m, 1H), 6,92 (t, 1H, J=11.4 in Hz), for 6.81 (t, 1H, J=9.6 Hz), 6,44 (d, 1H, J=9.5 Hz), 6,18 (d, 1H, J=11.5 Hz), the 5.65 (d, 1H, J=11,4 Hz), 5,59 (m, 1H), 5.40 to (m, 1H), 5,35 (d, 1H, J=10.0 Hz), 5,27 (s, 1H), a 4.83 (q, 1H, J=8,3 Hz), 4,80 (m, 1H), 4,46 (m, 1H), and 4.40 (d, 1H, J=9.6 Hz), 3,85 (m, 1H), only 3.57 (s, 3H), 3.27 to (s, 1H), 2,61 (m, 1H), 2,42 (m, 2H), 2,15 of 1.99 (m, 4H), to 1.83 (s, 3H), and 1.63 (d, 3H, J=6,7 Hz), a 1.08 (d, 3H, J=6.6 Hz), was 1.04 (s, 9H).

Example 19

Figure 19 presents the synthesis of some compounds according to this invention.

Synthesis of intermediate product 90A

A solution of (E)-Penta-2-EN-4-OIC acid (52 mg, 0.54 mmol), amine62(232 mg, 0.47 mmol) in anhydrous DCM (5 ml) cooled to 0°C. in an argon atmosphere, and add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (100 mg, 0.52 mmol). The reaction mixture was stirred at 0°C for 10 minutes and then at a temperature of 23°C within 90 minutes, quenched with saturated aqueous solution of NH4Cl and extracted with dichloromethane. The combined organic layers are dried (anhydrous Na2SO4), filtered and concentrated, obtaining the product90A(223 mg, yield: 83%) as colorless foamy solid, which is used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 7,69-to 7.67 (m, 4H), 7,44 and 7.36 (m, 6H), 7,11 (d, 1H, J=10,8 Hz), 6,72-6,60 (m, 2H), 6.42 per (d, 1H, J=8.1 Hz), 6,41 (d, 1H, J=15.6 Hz), 5,54-of 5.45 (m, 1H), are 5.36 at 5.27 (m, 1H), 4,89-to 4.81 (m, 1H), 4,30 (d, 1H, J=9,3 Hz), 3,89-with 3.79 (m, 1H), 3,25 (USS, 1H), 2,25-2,02 (m, 4H), of 1.45 (d, 3H, J=6.3 Hz), of 1.05 (s, 9H), of 0.97 (s, 9H).

MS (ES) [m/z] = 593,3 [M+Na]+.

13C-NMR (CDCl3, 125 MHz) δ: 167,7, 164,1, 135,8, 134,4, 134,1, 129,7, 129,7, 127,6, 127,6, 126,4, 125,8, 121,4, 121,1, 109,2, 84,6, 80,5, 72,3, 60,7, 35,3, 33,8, 32,4, 29,7, 27,0, 26,5, 19,3, 12,9.

Synthesis of intermediate product 90b

To a solution of amine20A(96,04 mg, 0.24 mmol) and (E)-Penta-2-EN-4-OIC acid (27.4 mg, 0.28 mmol) in anhydrous mixture on Harmattan/DMF (10:1, 3,3 ml)in an argon atmosphere and at 0°C, add DIPEA (0,049 ml, 0.28 mmol), HOAt (38,11 mg, 0.28 mmol) and HATU (106,4 mg, 0.28 mmol) and after 30 minutes the ice bath put aside. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous solution of NH4Cl, poured into water and extracted with dichloromethane. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 20:1 to 10:1)to give amide90b(81,9 mg, yield: 71%) as a white foam.

1H NMR (CDCl3, 300 MHz) δ: to $ 7.91 (d, 1H, J=10,2 Hz), 6,74-6,63 (m, 3H), 6.48 in (d, 1H, J=15.6 Hz), 5,58-of 5.53 (m, 1H), 4,89-to 4.81 (m, 1H), 4,48 (d, 1H, J=9.3 Hz), of 3.77-to 3.73 (m, 1H), 3,25 (d, 1H, J=9.3 Hz), 2,18-of 2.09 (m, 4H), 2,01 (s, 3H), of 1.02 (s, 9H), of 0.87 (s, 9H), 0.06 to (s, 3H), of 0.04 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 168,3, 164,4, 134,7, 131,7, 133,9, 122,5, 121,3, 109,1, 84,8, 80,8, 71,6, 61,0, 36,5, 35,4, 33,8, 26,8, 26,0, 21,2, 18,3, -4,3, -4,4.

The synthesis of compounds a

To a solution of the product45(56,2 mg of 0.182 mmol) in IPA (1.6 ml)at a temperature of 23°C, add Pd(Ph3P)4(15.7 mg, 0.014 mmol) and CuI (5.2 mg, 0,028 mmol). Then add connection90A(114,6 mg, 0,200 mmol)in 0.4 ml of IPA, and the reaction mixture was stirred at 23°C for 90 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4A(96 mg, yield: 70%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 7.68 per-7,66 (m, 4H), 7,46-7,35 (m, 6H), 7,11 (d, 1H, J=10,8 Hz), for 6.81 (DD, 1H, J=15,3 and 2.1 Hz), 6.30-in (DD, 1H, J=10,2, and 9.3 Hz), 6,32 (d, 1H, J=9.3 Hz), and 6.25 (d, 1H, J=15.3 Hz), 6,15 6,32 (DD, 1H, J=15,9, 8,4 Hz), 5,74 (d, 1H, J=15,9 Hz), 5,62 (DD, 1H, J=6,3, 3.0 Hz), 5,54-5,46 (m, 1H), 5,30 at 5.27 (m, 1H), 4,84-4,82 (m, 1H), 4,30 (d, 1H, J=9.3 Hz), 4,28-is 4.21 (m, 1H), 3,86-3,82 (m, 1H), the 3.65 (s, 3H), 2,68-2,62 (m, 1H), 2,43-of 2.36 (m, 2H), 2,22-2,04 (m, 4H), USD 1.43 (d, 3H, J=6.6 Hz), of 1.18 (d, 3H, J=6.9 Hz), was 1.04 (s, 9H), is 0.96 (s, 9H).

13C-NMR (CDCl3, 125 MHz) δ: 167,7, 164,3, 161,3, 145,5, 145,2, 135,2, 134,1, 131,8, 129,8, 129,7, 127,6, 127,6, 126,4, 125,8, 122,2, 121,4, 111,3, 109,1, 108,0, 95,1, 86,7, 80,8, 72,3, 60,7, 55,4, 41,5, 35,2, 33,8, 32,4, 29,7, 27,0, 26,5, 25,9, 19,3, 15,5, 12,9.

Synthesis of compound 91b

To a solution of the product45(30,2 mg, 0,098 mmol) in IPA (0.5 ml)at a temperature of 23°C, add Pd(Ph3P)4(8 mg, to 0.007 mmol) and CuI (3 mg, 0.014 mmol). Then add connection90b(47,6 mg, 0,098 mmol) in 0.5 ml of DIPA and the reaction mixture was stirred at 23°C for 90 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (EtOAc/hexane = 1:4 to 1:1)to give a pure compound91b(41,2 mg, yield: 64%) as a colourless oil.

1H NMR (CDCl3300 MG what) δ: of 7.70 (d, 1H, J=10,2 Hz), PC 6.82 (DD, 1H, J=15,3, 2.4 Hz), 6,72 (t, 1H, J=9.5 Hz), 6,28 (d, 1H, J=9.0 Hz), and 6.25 (d, 1H, J=15.3 Hz), x 6.15 (DD, 1H, J=15,9, 8.1 Hz), 5,74 (d, 1H, J=15,9 Hz), 5,63 (DD, 1H, J=6,3, 3.0 Hz), 5,62-of 5.55 (m, 1H), 4,89-to 4.81 (m, 1H), to 4.38 (d, 1H, J=9.6 Hz), 4,30-to 4.23 (m, 1H), 3,79 of 3.75 (m, 1H), the 3.65 (s, 3H), 2,69-2,61 (m, 1H), 2,44 of-2.32 (m, 2H), 2,20-2,14 (m, 4H), 2,02 (s, 3H), of 1.18 (d, 3H, J=6.6 Hz), 1,02 (s, 9H), of 0.87 (s, 9H), of 0.07 (s, 3H), of 0.05 (s, 3H).

13C-NMR (CDCl3, 75 MHz) δ: 168,1, 164,6, 161,5, 145,7, 145,4, 132,1, 131,2, 123,9, 122,4, 111,5, 108,9, 108,2, 95,4, 86,9, 81,0, 71,7, 61,0, 55,7, 41,7, 36,5, 35,4, 33,8, 29,9, 26,8, 26,2, 26,1, 21,3, 18,3, 15,7, -4,3, -4,4.

The synthesis of compounds 91p

To a solution of the product27(58 mg, 0,188 mmol) in IPA (1.6 ml)at a temperature of 23°C, add Pd(Ph3P)4(of 16.3 mg, 0.014 mmol) and CuI (5.3 mg, 0,028 mmol). Then add connection90A(118,2 mg, 0,207 mmol)in 0.4 ml of IPA, and the reaction mixture was stirred at 23°C for 90 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (EtOAc/hexane = 1:4 to 6:1)to give a pure compound91p(92 mg, yield: 65%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 7.68 per-7,66 (m, 4H), 7,46-7,35(m, 6H), to 7.15 (d, 1H, J=10.5 Hz), 6,85 (DD, 1H, J=15,3 and 2.1 Hz), only 6.64 (DD, 1H, J=10,5, and 9.3 Hz), to 6.39 (d, 1H, J=9.0 Hz), 6.30-in (d, 1H, J=15.3 Hz), 5,88 (t, 1H, J=10.5 Hz), 5,71 (DD, 1H, J=10,5, and 2.1 Hz), 5,69-5,61 (m, 1H), of 5.53-vs. 5.47 (m, 1H), 5,35-and 5.30 (m, 1H), 4,88-4,80 (m, 1H), or 4.31 (d, 1H, J=9.6 Hz), 4,28-4,19 (m, 1H), a 3.87-3,82 (m, 1H), the 3.65 (s, 3H), 3,143,06 (m, 1H), 2,58-2,47 (m, 1H), 2,41 of-2.32 (m, 1H), 2,23-2,04 (m, 4H), USD 1.43 (d, 3H, J=6.6 Hz), of 1.18 (d, 3H, J=6.9 Hz), of 1.05 (s, 9H), and 0.98 (s, 9H).

13C-NMR (CDCl3, 300 MHz) δ: 167,9, 164,5, 161,7, 145,5, 145,4, 136,1, 134,3, 132,4, 130,0, 129,9, 127,9, 127,8, 126,7, 126,1, 122,2, 121,6, 110,7, 109,4, 108,4, 93,2, 91,8, 81,0, 72,6, 61,0, 55,6, 39,6, 35,4, 34,0, 32,7, 29,8, 27,2, 26,8, 23,5, 19,5, 15,8, 13,2.

The synthesis of compounds 91d

To a solution of the product27(26,2 mg of 0.085 mmol) in DIPEA (4 ml), at -20°C, add Pd(Ph3P)2Cl2(6 mg, 0,0085 mmol) and CuI (5 mg, of 0.025 mmol). Then add connection90b(45 mg, 0,094 mmol) and the reaction mixture was stirred at 23°C for 90 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (EtOAc/hexane = from 1:10 to 2:1)to give compound91d(44,5 mg, yield: 79%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: of 7.75 (d, 1H, J=11.1 in Hz), for 6.81 (DD, 1H, J=15,6, 2.4 Hz), of 6.68 (t, 1H, J=9.3 Hz), 6,37 (d, 1H, J=9.3 Hz), 6,34 (d, 1H, J=11.7 Hz), by 5.87 (t, 1H, J=10,8 Hz), 5,70 (DD, 1H, J=10,8, 2.4 Hz), 5,62-to 5.57 (m, 2H), around 4.85 (q, 1H, J=8,1 Hz)to 4.41 (d, 1H, J=9.3 Hz), 4,28-4,18 (m, 1H), 3,81-and 3.72 (m, 1H), to 3.64 (s, 3H), 3,16-of 3.06 (m, 1H), 2,56 is 2.46 (m, 1H), 2,40 of-2.32 (m, 1H), 2.26 and and 2.13 (m, 4H), 2,04 (s, 3H), of 1.17 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H), of 0.87 (s, 9H), of 0.07 (s, 3H), of 0.05 (s, 3H).

Synthesis of compound 92A

To a solution of the productA(78,2 mg, 0.104 g mmol) in anhydrous THF (2 ml), the atmosphere is nitrogen and at 0°C, add a 1 M solution of TBAF in THF (0.2 ml, 0,208 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:2)to give alcohol92A(17.9 mg, yield: 34%) in the form of oil pale yellow color.

1H NMR (CDCl3, 500 MHz) δ: 8,89 (d, 1H, J=10.0 Hz), to 6.80 (DD, 1H, J=15,0, 2.0 Hz), 6.75 in (DD, 1H, J=10,0, 9.0 Hz), 6,50 (d, 1H, J=9.5 Hz), 6,28 (d, 1H, J=15,5 Hz), 6,14 (DD, 1H, J=15,5, 8.0 Hz), 5,74 (DD, 1H, J=16,0, 2,5 Hz), 5,68-65 (m, 1H), 5,63 (DD, 1H, J=6,5, 2,5 Hz), 5,42 of 5.39 (m, 1H), 4.92 in-the 4.90 (m, 1H), 4,37 (d, 1H, J=9.0 Hz), 4,28-to 4.23 (m, 1H), 3,79-to 3.73 (m, 1H), the 3.65 (s, 3H), 2,67-2,62 (m, 1H), 2,47-is 2.37 (m, 2H), 2,34-of 2.15 (m, 4H), of 1.64 (d, 3H, J=7.0 Hz), of 1.18 (d, 3H, J=6.5 Hz), a 1.01 (s, 9H).

Synthesis of compound 92b

To a solution of the product91b(41,2 mg, 0.061 mmol) in anhydrous THF (1 ml), under nitrogen atmosphere and at 0°C, was added 1 M solution of TBAF in THF (0,12 ml, 0,122 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexa is/EtOAc = 4:1 to 1:2), getting alcohol92b(14,7 mg, yield: 65%) as oil pale yellow color.

1H NMR (CDCl3, 500 MHz) δ: cent to 8.85 (d, 1H, J=10,2 Hz), 6,84-of 6.73 (m, 2H), is 6.61 (d, 1H, J=9.3 Hz), 6,27 (d, 1H, J=15.6 Hz), x 6.15 (DD, 1H, J=15,9, and 8.4 Hz), of 5.75 (d, 1H, J=15,9 Hz), 5,63-the ceiling of 5.60 (m, 2H), 4.92 in-4,84 (m, 1H), to 4.41 (d, 1H, J=9,3 Hz), 4,29-to 4.23 (m, 1H), 3,79 is 3.76 (m, 1H), the 3.65 (s, 3H), 3,10 (USS, 1H), 2,69-2,61 (m, 1H), 2,46-is 2.37 (m, 2H), 2,20-2,14 (m, 4H), 2,04 (s, 3H), of 1.18 (d, 3H, J=6.9 Hz), of 1.02 (s, 9H).

The synthesis of compounds s

To a solution of the product91p(71,5 mg, 0,095 mmol) in anhydrous THF (2 ml), under nitrogen atmosphere and at 0°C, was added 1 M solution of TBAF in THF (0,19 ml to 0.19 mmol). The reaction mixture was stirred at room temperature for 4 hours and then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:2)to give alcoholS(18,1 mg, yield: 37%) as oil pale yellow color.

1H NMR (CDCl3, 300 MHz) δ: to 8.94 (d, 1H, J=9.6 Hz), 6,83 (DD, 1H, J=15,3 and 2.1 Hz), 6.75 in (t, 1H, J=9.6 Hz), to 6.57 (d, 1H, J=9.6 Hz), 6,32 (d, 1H, J=15.3 Hz), 5,88 (d, 1H, J=10,2 Hz), 5,74-5,70 (m, 1H), 5,67-5,62 (m, 2H), 5,44 and 5.36 (m, 1H), 4.95 points-a 4.86 (m, 1H), to 4.38 (d, 1H, J=9.3 Hz), 4,28-to 4.23 (m, 1H), of 3.77-to 3.73 (m, 1H), the 3.65 (s, 3H), 3,14-of 3.06 (m, 1H), 2,59-2,11 (m, 6H), and 1.63 (d, 3H, J=6.9 Hz), 1,19 (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

The synthesis of compounds 92d

To a solution of PR the product 91d(40 mg, 0.06 mmol) in anhydrous THF (0.6 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (of 0.12 ml, 0.12 mmol). The reaction mixture was stirred at room temperature for 18 hours, then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:2)to give alcohol92d(20 mg, yield: 61%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 8,90 (d, 1H, J=9.9 Hz), PC 6.82 (DD, 1H, J=15,6, 2.4 Hz), 6,74 (t, 1H, J=9.6 Hz), of 6.66 (d, 1H, J=9.3 Hz), 6,33 (d, 1H, J=9.3 Hz), 5,88 (t, 1H, J=10.5 Hz), 5,71 (DD, 1H, J=10,8, 2.4 Hz), 5,64-5,59 (m, 2H), 4,84 (kV, 1H, J=7.8 Hz), and 4.40 (d, 1H, J=9.3 Hz), 4,28-4,20 (m, 1H), and 3.72 (m, 1H), to 3.64 (s, 3H), 3,13-of 3.06 (m, 2H), 2,58-2,47 (m, 1H), 2,41 is 2.33 (m, 1H), 2,31-of 2.15 (m, 4H), of 2.05 (s, 3H), of 1.18 (d, 3H, J=6,9 Hz)of 1.02 (s, 9H).

Example 20

Figure 20 shows the synthesis of the following compounds according to this invention.

Synthesis of compound 93

To a solution of compound92d(6.5 mg, 0.012 mmol) in anhydrous DCM (0.2 ml)at a temperature of 23°C, add trichlorotriazine (TCAI) (1,7 μl, 0.014 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add neutral aluminium oxide (120 mg). This mixture AC who're asked for 30 minutes and then applied, during impregnation, the layer of aluminum oxide. Product wash using a mixture of dichloromethane/Meon = 50:1. The filtrate is evaporated under reduced pressure to give crude product, which was purified by column chromatography (dichloromethane/Meon = from 100:1 to 40:1)to give compound93(3 mg, yield: 42%) as a solid white color.

1H NMR (CDC13, 300 MHz) δ: 8,83 (d, 1H, J=10.5 Hz), 6.89 in-for 6.81 (m, 2H), 6,62 (d, 1H, J=9.9 Hz), 6,32 (d, 1H, J=15.3 Hz), by 5.87 (t, 1H, J=9.0 Hz), 5,73 (DD, 1H, J=10,5, 2.4 Hz), 5,65-to 5.57 (m, 2H), 5,38 (USS, 2H), 4,84 was 4.76 (m, 1H), 4,48 (d, 1H, J=9.3 Hz), 4,40-to 4.33 (m, 1H), 4,28-is 4.21 (m, 1H), 3,66 (s, 3H), 3,19-3,10 (m, 1H), 2,58-to 2.42 (m, 3H), 2,35-of 2.30 (m, 2H), 2,14-to 2.06 (m, 1H), 2,08 (s, 3H), of 1.20 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

13C-NMR (CDCl3, 125 MHz) δ: 167,9, 164,3, 161,4, 157,6, 145,1, 145,0, 132,3, 132,0, 124,5, 122,3, 121,9, 110,6, 108,3, 104,9, 92,9, 91,7, 80,8, 75,1, 61,2, 55,5, 39,3, 35,0, 32,9, 30,9, 26,7, 26,4, 21,0, 15,9.

MS (ES) [m/z]: 590,2 [M+H]+.

Example 21

Figure 21 presents the synthesis of some compounds according to this invention.

Synthesis of intermediate 94

A solution of (Z)-iodically acid (365 mg, of 1.84 mmol) (obtained as described Takeuchi R., Tanabe K., Tanaka, S., J. Org. Chem., 2000, 65, 1558-1561), Amin62(700 mg, of 1.42 mmol) in anhydrous DCM (12 ml) cooled to 0°C. in an argon atmosphere, and add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) (340,8 mg, 1.78 mmol). The reaction mixture was stirred at t is mperature 0°C for 10 minutes and then at a temperature of 23°C - within 3 hours, quenched with saturated aqueous NaCl and extracted with dichloromethane. The combined organic layers are dried (anhydrous Na2SO4), filtered and concentrated. The residue is purified using flash chromatography (EtOAc/hexane = 1:10 to 1:1)to give the product94(675 mg, yield: 71%) as colorless foamy solid.

1H NMR (CDCl3, 300 MHz) δ: 7,69-7,66 (m, 4H), 7,44 and 7.36 (m, 6H), from 7.24 (d, 1H, J=9.6 Hz), 7,06 (d, 1H, J=9.3 Hz), 6.90 to (d, 1H, J=9.0 Hz), 6,68-of 6.61 (m, 2H), 5,55-5,43 (m, 1H), 5,35-of 5.26 (m, 1H), 4,89-to 4.81 (m, 1H), to 4.38 (d, 1H, J=9,3 Hz), 3,88-of 3.80 (m, 1H), 2,23-to 2.06 (m, 4H), USD 1.43 (d, 3H, J=6.9 Hz), of 1.05 (s, 9H), is 1.01 (s, 9H).

13C-NMR (CDCl3, 125 MHz) δ: 167,4, 164,3, 135,8, 134,1, 133,0, 129,7, 129,6, 127,6, 127,5, 126,4, 125,8, 121,4, 109,1, 88,3, 72,3, 60,4, 35,1, 33,8, 32,5, 27,0, 26,7, 19,3, 12,9.

MS (ES) [m/z]: 695,2 [M+Na]+.

Synthesis of compound 95

To a solution of the product94(304,4 mg, 0.45 mmol) in IPA (5.5 ml)at a temperature of 23°C, add Pd(Ph3P)4(39,3 mg 0,034 mmol) and CuI (12.9 mg, 0,068 mmol). Then add connection56(100 mg, 0.45 mmol) and the reaction mixture was stirred at 23°C for 45 minutes. The crude mixture was quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue is purified using flash chromatography (EtOAc/hexane = 1:4 to 3:1)to give a pure compound95(300 mg, yield: 87%) as bestv the private foamy solid.

1H NMR (CDCl3, 300 MHz) δ: of 7.82 (d, 1H, J=9.3 Hz), 7.68 per-the 7.65 (m, 4H), 7,46-7,29 (m, 7H), 6,62 (DD, 1H, J=10,2, and 9.3 Hz), 6,14 (d, 1H, J=12.3 Hz), between 6.08 (DD, 1H, J=10,5, and 9.3 Hz), equal to 6.05 (d, 1H, J=12.3 Hz), the ceiling of 5.60 (DD, 1H, J=6,3, 3,0 Hz), 5,52-5,43 (m, 1H), 5,33-a 5.25 (m, 1H), 4,85-of 4.77 (m, 1H), of 4.44 (d, 1H, J=9.3 Hz), 4,24-to 4.23 (m, 1H), 3,88-of 3.80 (m, 1H), to 3.64 (s, 3H), 2.91 in-and 2.79 (m, 1H), 2,54-of 2.34 (m, 2H), 2.23 to-2,04 (m, 4H), of 1.92 (s, 3H), of 1.42 (d, 3H, J=6.9 Hz), of 1.13 (d, 3H, J=6.6 Hz), was 1.04 (s, 9H), 0,99 (s, 9H).

13C-NMR (CDCl3, 125 MHz) δ: 167,9, 164,6, 161,7, 145,5, 136,1, 134,3, 132,5, 129,9, 127,8, 126,7, 126,1, 121,7, 118,9, 116,4, 108,9, 108,4, 104,5, 98,8, 82,8, 81,6, 72,6, 60,9, 55,7, 38,0, 35,5, 34,0, 32,7, 27,2, 26,9, 26,5, 19,5, 17,3, 16,5, 13,1.

Synthesis of compound 96

To a solution of the product95(250 mg, 0,326 mmol) in THF (3.3 ml), under nitrogen atmosphere and at 0°C, was added 1 M solution of TBAF in THF (0,65 ml of 0.65 mmol). The reaction mixture was stirred at room temperature for 3 hours, then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 4:1 to 1:3)to give alcohol96(150 mg, yield: 87%) as a colourless oil.

1H NMR (CDC13, 300 MHz) δ: 8,76 (d, 1H, J=9.9 Hz), 7,83 (d, 1H, J=9.0 Hz), 6,74 (t, 1H, J=9.3 Hz), 6,17 (d, 1H, J=12.0 Hz), 6,15-6,09 (m, 1H), 6,07 (d, 1H, J=12.0 Hz), 5,74-the ceiling of 5.60 (m, 1H), 5,61 (DD, 1H, J=6,3, 3.0 Hz), 5,44-lower than the 5.37 (m, 1H), 4,94-is 4.85 (m, 1H), to 4.41 (d, 1H, J=9.3 Hz), 4,25-4,17 (m, 1H), 3,76 (m, 1H), the 3.65 (s, 3H), 2,92 is 2.80 (m, 1H), 2,55-2,11 (m, 6H), of 1.93 (s, 3H), of 1.62 (d, 3H, J=6.6 Hz), 1.14 in (d, 3H, J=6.6 Hz), a 1.01 (s, 9H).

Example 22

Figure 22 presents the synthesis of some compounds according to this invention.

Synthesis of intermediate 97

To a solution of the product40(200 mg, 0.38 mmol) and 4-ethylpropylamine acid (48 mg, 0.49 mmol) in anhydrous DCM (3.8 ml), at 0°C, add EDC (91 mg, 0.47 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then for 2 hours at room temperature. Then the crude mixture was hydrolized with water and extracted with dichloromethane (3 times 5 ml). After drying and evaporation of the solvent under reduced pressure, the crude product is purified by column chromatography (hexane/EtOAc = 6:1)to give a pure compound97(105 mg, yield: 47%) as a colourless oil.

1H NMR (CDCl3, 300 MHz) δ: 7,66 (m, 4H), 7,43 (m, 6H), 7,14 (d, 1H, J=a 10.6 Hz), of 6.65 (t, 1H, J=9.3 Hz), 6,40 (d, 1H, J=9.1 Hz), 5,52 (t, 1H, J=7,2 Hz), and 4.75 (q, 1H, J=7,6 Hz), the 4.29 (d, 1H, J=9,2 Hz), 3,81 (m, 1H), 2.63 in-to 2.40 (m, 4H), 2,19-2,03 (m, 5H), to 1.86 (s, 3H), of 1.05 (s, 9H), and 0.98 (s, 9H).

Synthesis of compound 98

To a solution of iodotope connection9(52 mg, 0,148 mmol) in Diisopropylamine (0.75 ml), under nitrogen atmosphere and at room temperature, add Pd(Ph3P)4(2.3 mg, 0.002 mmol) and CuI (1.0 mg, of 0.005 mmol). Then, piece by piece, add with the Association of 97(90 mg, 0,148 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The crude product is quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/EtOAc = 3:1 to 1:2)to give a pure compound98(105 mg, yield: 86%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 7,66 (m, 4H), 7,41 (m, 6H), 7,26 (d, 1H, J=a 10.6 Hz), only 6.64 (t, 1H, J=10.1 Hz), 6.42 per (d, 1H, J=9.3 Hz), the 6.06 (d, 1H, J=12.0 Hz), 5,61 (m, 1H), 5,48 (m, 2H), 5,35 (d, 1H, J=11.8 Hz), 4,74 (kV, 1H, J=8,3 Hz), 4,28 (d, 1H, J=9,2 Hz), 4,16 (m, 1H), 3,81 (m, 1H), to 3.64 (s, 3H), of 2.81 (m, 1H), 2,66 (m, 2H), 2,47-of 2.36 (m, 4H), 2,18-to 2.06 (m, 4H), 2,04 (s, 3H), of 1.85 (s, 3H), of 1.12 (d, 3H, J=6.6 Hz), was 1.04 (s, 9H), and 0.98 (s, 9H).

Synthesis of compound 99

To a solution of compound98(75 mg, 0.09 mmol) in anhydrous THF (1.5 ml), under nitrogen atmosphere and at room temperature, was added 1 M solution of TBAF in THF (of 0.18 ml, 0.18 mmol). The reaction mixture was stirred at room temperature for 4 hours, then quenched with saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified using flash chromatography (hexane/EtOAc = 3:1 to 1:3)to give alcohol99(35 mg, yield: 67%) as a solid white color.

1 H NMR (CDCl3, 300 MHz) δ: of 8.92 (d, 1H, J=10.1 Hz), 6,74 (t, 1H, J=9.5 Hz), to 6.67 (d, 1H, J=9.1 Hz), the 6.06 (d, 1H, J=12.0 Hz), 5,62 (m, 2H), vs. 5.47 (d, 1H, J=9.8 Hz), of 5.34 (d, 1H, J=11,9 Hz), 4,84 (kV, 1H, J=8.5 Hz), 4,32 (d, 1H, J=9.1 Hz), 4,18 (m, 1H), to 3.73 (m, 1H), to 3.64 (s, 3H), 3,20 (d, 1H, J=4.0 Hz), 2,82 (m, 1H), 2,66 (m, 2H), 2,49-of 2.36 (m, 4H), 2,24 with 2.14 (m, 4H), of 2.05 (s, 3H), 2,02 (s, 3H), of 1.12 (d, 3H, J=6.6 Hz), to 1.00 (s, 9H).

13C-NMR (CDCl3, 75 MHz) δ: 171,3, 168,4, 161,7, 145,1, 142,1, 135,5, 134,4, 131,7, 123,6, 123,4, 108,4, 108,2, 106,1, 94,3, 81,8, 80,2, 71,4, 60,9, 36,7, 36,1, 35,3, 34,5, 33,0, 29,6, 26,5, 26,3, 21,0, 16,4, 16,1, 15,5.

Synthesis of compound 100

To a solution of compound99(30 mg, 0.05 mmol) in anhydrous DCM (3.15 ml), at room temperature, add trichlorotriazine (TCAI) (6 μl, 0.06 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then add neutral alumina (375 mg). The mixture is stirred for 1 hour and then applied, impregnation, on the layer of aluminum oxide. Product wash using a mixture of dichloromethane/Meon = 50:1. The filtrate is evaporated under reduced pressure to give crude product, which was purified by column chromatography (hexane/EtOAc)to give compound100(26 mg, yield: 82%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 8,87 (d, 1H, J=10,7 Hz), for 6.81 (t, 1H, J=9.8 Hz), 6,62 (d, 1H, J=9.5 Hz), the 6.06 (d, 1H, J=12.0 Hz), 5,75 (USS, 2H), 5,61 (m, 2H), of 5.45 (d, 1H, J=10.1 Hz), to 5.35 (d, 1H, J=11,9 Hz), 4,80 (kV, 1H, J=and 8.4 Hz), 4,37 (m, 1H), 4,33 (d, 1H, J=9.3 Hz), 4,18 (m, 1H), 3,64 (who, 3H), and 2.83 (m, 1H), 2,66 (m, 2H), 2,50-of 2.27 (m, 8H), was 2.05 (s, 3H), 2,03 (s, 3H), of 1.12 (d, 3H, J=6.6 Hz), 0,99 (s, 9H).

Example 23

In scheme 23 presents a synthesis of some compounds according to this invention.

Synthesis of compound 101

To a solution of iodotope connection51(70 mg, 0,217 mmol) in Diisopropylamine (1.1 ml), under nitrogen atmosphere and at room temperature, add Pd(Ph3P)4(5 mg, 0.004 percent mmol) and CuI (1.7 mg, 0,008 mmol). Then, piece by piece, add connection97(132 mg, 0,217 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The crude product is quenched with water and extracted with EtOAc. The organic phase is dried (anhydrous Na2SO4) and evaporated under reduced pressure. Purified by column chromatography (hexane/EtOAc = 3:1 to 1:2)to give a pure compound101(80 mg, yield: 50%) as a solid white color.

1H NMR (CDCl3, 300 MHz) δ: 7,66 (m, 4H), 7,41 (m, 6H), 7,25 (d, 1H, J=a 10.6 Hz), of 6.65 (t, 1H, J=10.1 Hz), 6,44 (d, 1H, J=9.3 Hz), 5,63-of 5.48 (m, 3H), 4,78 (kV, 1H, J=8,3 Hz), 4,32 (d, 1H, J=9,2 Hz), 4,14 (m, 1H), 3,81 (m, 1H), to 3.64 (s, 3H), of 2.81 (m, 1H), 2,62 (m, 2H), 2,46 is 2.33 (m, 4H), 2,18-2,05 (m, 4H), 2,02 (s, ZN), of 1.85 (s, MN), by 1.12 (d, 3H, J=6.6 Hz), was 1.04 (s, 9H), and 0.98 (s, 9H).

Example 24

The bioanalysis to determine the antitumor activity

The purpose of this analysis is to evaluate in vitro cytotoxic activity (the ability to slow or stop the growth of tumor is th cells) or cytotoxic activity (ability to destroy tumor cells) of the tested samples.

Cell line

NameNo. of ATSClothFeatures
ACCL-185peopleeasycarcinoma of the lung (NSCLC)

NTNTV-38peoplethe coloncolorectal adenocarcinoma
MDA-MB-231HTB-26peoplemammary glandbreast adenocarcinoma

Evaluation of the cytotoxic activity using colorimetric analysis with SBR

For the quantitative determination of growth and viability of cells was adapted colorimetric type of analysis using the reaction sulforhodamine B (SRB) (following the method described by P. Skehan and others, J. Natl. Cancer Inst., 1990, 82, 1107-1112).

In the case of this type of analysis using SBS-standard 96-well microplates for CL the exact culture (Faircloth et. al., Methods in cell science, 1988, 11(4), 201-205; Mosmann et. al., Journal of Immunological. Methods, 1983, 65(1-2), 55 to 63). Used in this study, all cell lines derived from different types of human cancer, were obtained from the American type culture collection (ATSS).

Cells were kept in modified according to the method of Dulbecco environment Needle (DMEM), supplemented with 10% fetal calf serum (FBS), 2 mm L-glutamine, 100 µg/ml penicillin and 100 μg/ml streptomycin, at 37°C in presence of 5% CO2and with 98%humidity. For experiments cells were collected from subconfluent cultures using trypsinization, and resuspendable in fresh medium before counting and seeding.

Cells were planted in 96-well titration the microplate 5×103cells per well, in the aliquot of 150 μl, and stood to attach to the tablet surface for 18 hours in not containing medicines environment. One control (untreated) tablet in the case of each cell line were fixed (as described below) and used to help estimate at time zero. After this test, the samples were added to the cultures at 10 serial dilutions, aliquot 50 ál varying from 10 μg/ml to 0,00262 μg/ml After incubation for 48 hours, evaluated the antitumor effect by SRB method: briefly, the cells were twice washed with the aid of the d PBS, were fixed for 15 minutes in a 1%solution of glutaraldehyde, washed twice with PBS and stained with the use of 0.4%SRB solution for 30 minutes at room temperature. The cells are then washed several times with 1%acetic acid solution and dried in air. After that SRB were extracted using a 10 mm solution of Trizma-base, and the optical density was measured using an automated spectrophotometric tablet reader at a wavelength of 490 nm. Cell survival was expressed as a percentage of growth of the control cells. The final effect of the test sample was evaluated by using the NCI algorithm (Boyd MR. and Paul KD., Drug Dev. Res., 1995, 34, 91-104).

Using mean ±SD (standard deviation) of crops in three repetitions, the curve "dose-response" built automatically using nonlinear regression analysis. Counted three basic parameters (NCI-algorithm) by automatic interpolation: GI50= concentration, which causes the inhibition of growth by 50 %; TGI = total growth inhibition (cytostatic effect) and LC50= concentration, which causes the destruction of 50% of the cells (cytotoxic effect).

Table 1 shows data on the biological activity of compounds according to the present invention.

1. The compound of General formula I

where Y is chosen from the group consisting of CHRay- and-CHRay-CRby=CRcy-;
each Ray, Rbyand Rcyindependently selected from hydrogen and unsubstituted C1-C12-alkyl;
each R1, R2, R3, R4and R5independently selected from hydrogen and unsubstituted1-C12-alkyl;
R6choose from NR8R9and OR10;
And means

W means NR7;
R7means hydrogen;
R8means hydrogen;
R10means unsubstituted With2-C12alkenyl;
each dotted line represents an optional additional bond, but when there is a triple bond between carbon atoms, which are attached to R1and R2, R1and R2no, and when there is a triple bond between carbon atoms, which are attached to R3and R4, R3and R4no;
R9selected from substituted C2-C12-alkenyl and replaced With4-C12-alkenyl, where the substituents are selected from the group consisting of halogen, OR', OCONHR', and HE protected simple silyl ether, where R' is hydrogen; provided that when Y represents-CHRay-CR =CRcyand there is a single or double bond between carbon atoms, which are attached to R3and R4then R9means substituted C4-C12-alkenyl; and,
each R16, R17and R18independently selected from hydrogen and ORa;
each Raselected from hydrogen or unsubstituted C1-C12-alkyl; or
its pharmaceutically acceptable salt, tautomer or stereoisomer.

2. The compound according to claim 1, where R16selected from hydrogen and ORawhere Raselected from hydrogen and unsubstituted C1-C6-alkyl.

3. The compound according to claim 2, where R16selected from hydrogen, HE and methoxy.

4. The compound according to any one of claims 1 to 3, where one additional bond is present between carbon atoms, which are attached to R16and R17.

5. The compound according to any one of claims 1 to 3, where R17and R18mean hydrogen.

6. The compound according to any one of claims 1 to 3, where R1, R2, R3and R4independently selected from hydrogen and unsubstituted C1-C6-alkyl.

7. The connection according to claim 6, where R1, R2, R3and R4mean hydrogen.

8. The compound according to any one of claims 1 to 3, where Y is chosen from-CHRay- and-CHRay-CRby=CRcy-, where Ray, Rbyand Rcyindependently selected from hydrogen and unsubstituted C1 -C6-alkyl.

9. The connection of claim 8, where Ray, Rbyand Rcyindependently selected from hydrogen and methyl.

10. The compound according to any one of claims 1 to 3, where R5selected from hydrogen and unsubstituted C1-C6-alkyl.

11. The connection of claim 10, where R5selected from methyl, isopropyl and tertbutyl.

12. The compound according to any one of claims 1 to 3, where R6mean NR8R9and where R8means hydrogen, and R9selected from substituted C2-C12-alkenyl and replaced With4-C12-alkenyl, which is substituted in one or more positions by halogen, OR', OCONHR', and HE protected simple silyl ether, where R' is hydrogen.

13. The compound according to any one of claims 1 to 3, where one additional bond is present between carbon atoms, which are attached to R1and R2and one or two additional relationships are present between carbon atoms, which are attached to R3and R4.

14. The compound according to claim 1, having the following formula
















or

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

15. Pharmaceutical composition having cytostatic or cytotoxic activity containing a compound according to any one of the preceding paragraphs, or its pharmaceutically acceptable salt, tautomer or stereoisomer, and a pharmaceutically acceptable solvent or carrier.

16. The compound according to any one of claims 1, 2, 3, 7, 9, or 14, or its pharmaceutically acceptable salt, tautomer or a stereoisomer, for use as a drug for the treatment of cancer.

17. The connection 15 for use as a drug for the treatment of cancer.

18. The use of compounds according to any one of claims 1 to 14, or its pharmaceutically acceptable salts, tautomers or stereoisomers, in order to obtain drugs for the treatment of cancer.

19. A method of treating any mammal, especially a person stricken cancer, which includes the introduction of the affected individual a therapeutically effective amount of compounds with cytostatic or cytotec the practical activity, according to any one of claims 1 to 14, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

20. A method of treating any mammal, especially a person stricken cancer, which includes the introduction of the affected individual a therapeutically effective amount of the composition according to item 15.

21. Method of preparing compounds having the formula I
,
according to any one of claims 1 to 14, where A, Y, W, R1, R2, R3, R4, R5and R6are as defined in any one of claims 1 to 14, containing the accession of Fragments C and D
,
where R1, R2, R3, R4, R5, R6, A, Y and W denote the desired groups defined in the compound of formula I, or a suitable protective group as required, and L and M indicate the appropriate reactive or delete the group.

22. The method according to item 21, where the compound of formula I is any connection 14.

23. The method according to any of PP-22, where the deleted group L is iodine.

24. The method according to any of PP-22, where the reactive group, M means tributyl tin.

25. The method according to any of PP-22, where the Fragment D means

26. The method according to any of PP-22, where the Fragment D means

27. The connection according to the definition of the Fragm is that D item 21, which is a

28. The connection according to the definition of Fragment D in item 21, which is a

29. The connection according to the definition of Fragment D in item 21, which is a

30. Method of producing compounds of the formula I

according to any one of claims 1 to 14, where A, Y, W, R1, R2, R3, R4, R5and R6are as defined in any one of claims 1 to 14, containing the accession of Fragments a and b

where R1, R2, R3, R4, R5, R6And Y indicate the desired group or a suitable protective group as required, and J and K indicate the appropriate reactive or delete the group.

31. The method according to item 30, where the compound of formula I is any connection 14.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydropyran-2-one of formula

, where R1 is selected from hydrogen, ORa, OCORa, OCOORa, NRaRb, NRaCORb and NRaC(NRa)NRaRb; each R2 and R3 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R41, R42, R43, R44, R45, R46, R47 and R48 are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl; each R5, R6 and R7 are optionally selected from hydrogen, CORa, COORa, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl and substituted or unsubstituted C2-C12 alkynyl, or R5 and R48 together with coupled atom N and atom C whereto attached can form substituted or unsubstituted heterocyclic group; each Ra and Rb are optionally selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and each dashed line means an optional additional bond; to its pharmaceutically acceptable salts, tautomers or stereoisomers.

EFFECT: development of the method for preparing an anticancer composition, and the method of treating cancer.

46 cl, 10 tbl, 12 ex

The invention relates to new intermediate products-compounds: (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-Piran-2-ONU, [3(R), 6(R)]-5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)propyl] -6-[1-(2-phenyl)ethyl] -6-propyl-2H-Piran-2-ONU, [3(R), 6(R)] -5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl] -6-[1-(2-phenyl)ethyl]-6-propyl-2H-Piran-2-ONU, as well as to improved methods of producing an intermediate product of the formula (CVI), where R1represents C1-C6alkyl, -CH2-CH2-фенилR1-1where R1-1represents H, where R2represents C1-C6alkyl, -CH2-CH2-фенилR1-1where R1-1represents N.

The invention relates to 2,4,5-triple-substituted phenylethanol formula I, in which HET denotes one of the groups(1), (2), (3), (4), (5)

The invention relates to new derivatives of 5H-pyrano[2,3-d:6,5-d']dipyrimidine General formula I possess anti-microbial, antiviral and immunomodulatory effects

The invention relates to new Paramonova compounds useful for the inhibition of retrovirus in human cells infected with the indicated retroviruses

The invention relates to a new catalytic method for obtaining optically active compounds of General formula (I),

< / BR>
where R1and R2denote alkyl, which can be broken by oxygen atom in a different position thanor- position, or optionally substituted benzyl;

R3denotes hydrogen, lower alkyl, optionally substituted benzyl, -CO R4, -COOR4or-CONR24;

R4denotes lower alkyl or aryl,

asymmetric hydrogenation of compounds of formula (II)

< / BR>
where R1, R2, R3have the above values,

asimetricna hydronaut in the presence of a complex of optically active, preferably atropoisomeric of lifestyleand with the metal of group VIII

FIELD: medicine.

SUBSTANCE: there are presented drug derivatives wherein said derivatives contain a H2S-releasing fragment of 4-hydroxythiobenzamide which is either covalently bond with the drug, or forms a pharmaceutically acceptable salt with the antilipidemic drug.

EFFECT: compounds show higher activity, or reduced side effects.

5 cl, 26 ex, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydropyran (tetrahydropyranone), substituted in the beta-position relative to the carbon atom in the ring, as a fragrant substance. This compound has the following formula: where: the substitute R denotes a linear alkyl radical CH3-(CH2)n- in which n=2-10 inclusively, (CH3)2CH- or C6H5-(CH2)m-, where m=0 or 1; or , where: A denotes -CH2- or -CO-, to a method of producing the said compounds and compositions such as perfume, topical, particularly cosmetic compositions and everyday conditioning agents.

EFFECT: wider field of use of the compounds.

12 cl, 6 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns improved method of obtaining mevalonic acid derivatives of the general formula I or its pharmaceutically acceptable salt with base, or lactone, where -CH2-CH2- or -CH=CH-, R is heterocyclical residual of interaction of compound of the general formula IIa , where R1, R2, R3, R4 meanings are described in the invention, with compound of the general formula IIb: R-CH(=O) where R is cyclical residual. Obtained compound is recovered in the presence of recovery agent, preferably a compound of the formula IId , where M is Ru, Rh, Ir, Fe, Co, Ni, L1 - H, L2 - aryl, R5 is aliphatic residual, R8 and R9 are C6H5 or form cyclohexane ring or cyclohexane or cyclopentane ring combined with C atom, to which they are bound, with a number of further stages.

EFFECT: high product output.

4 cl, 1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of discodermolid and its analogs of the formula (V): At the first step method involves the coupling reaction of ketone compound of the formula (I): with aldehyde compound of the formula (II): in the presence of dialkylboron halide or triphlate, amine base and polar organic solvent to yield β-hydroxyketone of the formula (III): at the second step method involves reduction of ketone compound synthesized at the first step by its treatment with boron hydride reagent in polar organic solvent medium and proton solvent to yield 1,3-diol of the formula (IV): at the third step method involves lactonization and removal of free acid-labile hydroxyl protective group of 1,3-diol synthesized at the second step by its treatment with hydrogen halide dissolved in polar solvent or mixture of solvents to yield the end compound of the formula (V) wherein R1 means (C1-C6)-alkyl; R2 means (C1-C6)-alkyl; R3 means hydrogen atom or acid-labile hydroxyl protective group; R3'' means acid-labile hydroxyl protective group; R4 means hydrogen atom or methyl group; X means oxygen atom (O) under condition that when X means O and R3 means acid-labile hydroxyl protective group of compound of the formula (I) then residue -X-R3 in compound of the formula (V) represents hydroxyl group (-OH). Also, invention relates to novel intermediate compounds of formulae (I), (III) and (IV) and to a method for synthesis of compound of the formula (I). Invention provides a new method for synthesis of the valuable compound discodermolid and its analogs with the satisfied yields.

EFFECT: improved method of synthesis.

16 cl, 4 ex

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing derivatives of 2-(6-substituted-1,2-dioxane-4-yl)-acetic acid of the formula (1) or its salt, or acid wherein X means halogen atom, tosylate, mesylate, acyloxy-group, aryloxy- or nitro-substituted benzenesulfonyl group; each R1, R2 and R3 means independently (C1-C3)-alkyl group from compound of the formula (2):

wherein X has abovementioned values by using a suitable acetylation agent in the presence of acidic catalyst and its following conversion, if necessary, to the corresponding salt or acid. These compounds are intermediate substances in synthesis of statins that represent inhibitors of HNG-CoA-reductase. Also, invention relates to new parent compounds of the formula (2) in (4R,6S)-forms and new compounds of the formula (1b) given in the description. Invention provides preparing a valuable intermediate substance with high yield.

EFFECT: improved preparing method.

11 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: biotechnology, organic chemistry, microbiology, pharmacy.

SUBSTANCE: invention describes a new highly productive strain of fungus Aspergillus terreus № 44-62 that is deposited in the Collection of the company Metkinen Oy, Littoinen, Finland, producing lovastatin. Also, invention relates to a method for isolation of lovastatin and a method for lactonization of statins, such as lovastatin and simvastatin. Method for isolation of lovastatin involves its extraction from raw obtained in culturing the above said fungus-producer, concentrating extract, lactonization of lovastatin in the absence of solvent, clearing and crystallization of the end product. The lactonization process of statins carrying out in the absence of solvent provides preparing their lactones in crystalline form directly and practically without impurities of dimmers and acid form. Invention provides highly profitable manufacturing lovastatin and allows preparing the end product corresponding to Pharmacopoeia purity, higher yield (above 70%) and low cost.

EFFECT: improved preparing method and enhanced quality of product.

48 cl, 2 dwg, 10 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

FIELD: biotechnologies.

SUBSTANCE: invention relates to new compounds of the formula I:

or its pharmaceutically acceptable salts, where values R1, R2, R3, R3', R4, R4', X2, X1, X3, X4, X5, R6, R7, R5', R6', R7', R14', R8, R9, R10, R11a, b, c are specified in the clause 1 of the formula.

EFFECT: compounds demonstrate antitumoral activity and may be used to produce a pharmaceutical composition for tumor treatment in a mammal.

14 cl, 18 dwg, 1 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and may be used for the purpose of the integrated treatment of the patients with oncological diseases. For this purpose, a drug preparation of cytostatic group and a drug preparation of fragmented double-stranded DNA with fragments having a biologically active size and making a complete genome of a physiologically and genetically healthy donor in the form of tablets is administered into the patient's body. A tablet containing 5 mg of the active ingredient is used according to the scheme in 30 min and 2, 3 and 5 days after the administration of cyclophosphan in the amount of one tablet in the first 30 minutes after the administration of cyclophosphan. Further on these days, one tablet is taken every 2-3 hours a day while awake, but no more than 30 mg of the active ingredient a day.

EFFECT: use of the given method enables achieving an increase of mature dendritic cell count in the body that allows achieving the maximum development of the retrogressive effect on the tumour.

1 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used for an adjuvant therapy of colorectal cancer. That is ensured by the intraoperative insertion of a microirrigator into an abdominal cavity in a bed of the extracted tumour. On the 7th postoperative day, oxaliplatin 85 mg/m2, and then leukovorin 200 mg/m2 are administered intravenously drop-by-drop on the 1st therapeutic day for 2 hours. Hyalobarrier gel 50 ml is put in a bottle with 5-fluorouracil 1000 mg/m2, incubated for 30 minutes at 37°C, then the incubated gel is introduced into the abdominal cavity through the microirrigator from the bottle. On the 5th therapeutic day, leukovorin 200 mg/m2, then incubated Hyalobarrier gel with 5-fluorouracil are introduced in the patients intravenously drop-by-drop. Further, the microirrigator is removed from the abdominal cavity that is followed by a chemotherapy.

EFFECT: invention provides reducing a rate of remote metastases.

2 ex

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