Anticancer dihydropyran-3-one compounds

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 technical FIELD

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

The LEVEL of TECHNOLOGY

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

(+)-Discodermolide

This connection is a powerful anticancer agents (Hung DT et al. Chem. Biol. 1996, 3, 287-293 and ter Haar E, et al. Biochemistry 1996, 35, 243-250), with action similar to the action 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, promote the formation of microtubules and have the same inhibitory effect on breast cancer (IC50of 2.4 nm and 2.1 nm, respectively).

On the other hand, some unusual linear dipeptides containing functional group N-tilename, were isolated from mycobacteria belonging to the genusChondromyces(Kunze B et al. J. Antibiot. 1994, 47, 881-886, and Jansen R et al. J. Org. Chem. 1999, 1085-1089). More specifically, these compounds are crocetinate A, B, C and D are the group of inhibitors of electron transport.

Cu is kazini A-D moderately inhibit the growth of some gram-positive bacteria and are potent inhibitors of animal cell cultures, and some yeasts and fungi. The most active is crocetin D, which shows the MIC of 1.4 ng/ml against fungiSaccharomyces cereυisiaeand strong toxicity (IC500.06 mg/l) to the cell culture of fibroblasts of mouse L929.

Cancer is the leading cause of death in animals and humans. Huge attempts are made to obtain an antitumor agent, active and safe for administration to patients suffering from cancer. The problem solved by this invention is to obtain compounds which are useful for the treatment of cancer.

The INVENTION

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

where R1selected from hydrogen ORa, OCORa, OCOORa, NRaRb, NRaCORband NRaC(NRa)NRaRb;

each R2and R3independently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil;

each R41, R42, R43, R44, R45, R46, R47and R48independently selected from hydrogen, substituted or unsubstituted C -C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2- C12the quinil;

each R5, R6and R7independently selected from hydrogen, CORa, COORasubstituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil, or R5and R48together with the corresponding N atom and C atom to which they are attached, may form a substituted or unsubstituted heterocyclic group;

each Raand Rbindependently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12the quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and

each dotted line represents an optional additional bond.

In another aspect, this invention relates to compounds of the formulaIor their pharmaceutically acceptable salts, derivatives, tautomers, prodrugs or stereoisomers for use as pharmaceuticals, in particular as a drug for cancer treatment.

In another aspect, the invention also relates to the use of compounds of the formula Ior their pharmaceutically acceptable salts, derivatives, tautomers, prodrugs or stereoisomers for cancer treatment or to obtain medicines, preferably for the treatment of cancer. Other aspects of this invention are the treatment methods and compounds for use in these methods. Therefore, this invention also relates to a method of treating any mammal, in particular human cancer, which includes the introduction of a cancer patient a therapeutically effective amount of the compound defined above.

In another aspect, this invention relates to pharmaceutical compositions containing a compound of the formulaIor their pharmaceutically acceptable salts, derivatives, tautomers, prodrugs or stereoisomers, together with a pharmaceutically acceptable carrier or diluent.

This invention also relates to the separation of compounds of the formulaIfrom sponges of the family Raspailiidae, genusLithoplocamia,lithistoides, method of their production and the formation of derivatives of these compounds.

A DETAILED description of the PREFERRED OPTIONS

This invention relates to compounds of General formulaI,as explained above.

In these compounds, the substituents can be selected according to the following principles.

Alkyl groups can be OSVETLENIE or unbranched and preferably have from 1 to about 12 carbon atoms. One more preferred class of alkyl groups containing from 1 to about 6 carbon atoms. Even more preferred alkyl groups contain 1, 2, 3 or 4 carbon atoms. Methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl, sec-butyl, isobutyl, are particularly preferred alkyl groups in the compounds in accordance with this invention. Another preferred class of alkyl groups contains 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 in accordance with this invention can be branched or unbranched, contain one or more unsaturated linkages and from 2 to about 12 carbon atoms. One more preferred class alkenyl and etkinlik group contains from 2 to about 6 carbon atoms. Even more preferred are alkeneamine and alkyline group containing 2, 3 or 4 carbon atoms. Another preferred class alkenyl and etkinlik group contains 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 atom is in carbon.

Suitable aryl groups in the compounds in accordance with this invention include compounds with one or more rings, including compounds with several rings that contain separate and/or condensed aryl group. Typical aryl groups contain from 1 to 3 separate or condensed rings and from 6 to about 18 carbon atoms in the ring. Preferably, the aryl groups contain from 6 to about 10 carbon atoms in the ring. 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.

Suitable heterocyclic groups include heteroaromatic and heteroalicyclic group containing from 1 to 3 separate or condensed rings and from 5 to about 18 atoms in the ring. Preferably, heteroaromatic and heteroalicyclic groups contain from 5 to about 10 atoms in the ring. Suitable heteroaromatic groups in the compounds in accordance with this invention contain one, two or three heteroatoms selected from N, O or S atoms and include, for example, kumaril, including 8-coumaryl, hinely, including 8-chinolin, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, satyasai, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazoles, indolizinyl, phthalazine, pteridine, purinol, oxadiazolyl, thiadiazolyl, furutani, pyridazinyl, triazinyl, cinnoline, benzimidazolyl, benzofuranyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properity. Suitable heteroalicyclic group in the compounds in accordance with this invention contains 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, azetidine, oxetane, 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, ditional, dithiolane, dihydropyran, dehydration, dihydrofurane, pyrazolidine, imidazoline, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and finalizing.

These groups may be substituted at one or more available positions by suitable groups such as OR', =O, SR', SOR', SO2R', NO2That other', N(R')2, =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, Galaga is, COR', COOR', OCOR', OCONHR', OCON(R')2protected OH, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R' groups is independently selected from the group including hydrogen, OH, NO2, NH2, SH, CN, halogen, SON, Isoalkyl, CO2H, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. If such groups substituted by themselves, the substituents can be selected from the list above.

Suitable halogen substituents in the compounds in accordance with this invention include F, Cl, Br and I.

Suitable protective group for OH well-known to the person skilled in the art. Overview of protective groups in organic chemistry are presented in Wuts, PGM and Greene TW Protecting Groups in Organic Synthesis, 4thEd. Wiley-Interscience, and Kocienski PJ Protecting Groups, 3rdEd. Georg Thieme Verlag. In these reference sections that describe the protective group for OH. All these sources incorporated by reference in full. Examples of such protected OH include ethers, similarity, esters, sulfonates, sulfonate and sulfinate, carbonates and carbamates. Using simple ester protective group for OH can be the ü selected from the group includes 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)methyl, guaiacolate, [(p-phenylphenyl)oxy]methyl, tert-butoxymethyl, 4-pentyloxide, cilexitil, 2-methoxyethoxymethyl, 2-cyanoethoxy, bis(2-chloroethoxy)methyl, 2,2,2-trichloroacetyl, 2-(trimethylsilyl)ethoxymethyl, methoxymethyl, o-bis(2-acetoacetate)methyl, tetrahydropyranyl, fluoride tetrahydropyranyl, 3-bromotetradecane, tetrahydrothiopyran, 1-methoxycyclohexyl, 4-methoxyestradiol, 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,4,5,6,7,7α-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-foretel, 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 is)ethyl, tert-butyl, cyclohexyl, 1-methyl-1'-cyclopropylmethyl, allyl, prenyl, cinnamyl, 2-finally, propargyl, p-chlorophenyl, 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, pentadecanedioic, galamensis, 2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-diferensial, p-cyanobenzyl, benzyl fluoride, 4-fluoride alkoxybenzyl, trimethylsilylmethyl, p-phenylbenzyl, 2-phenyl-2-propyl, n-acylaminoalkyl, p-azidobenzoyl, 4-azido-3-Chlorobenzyl, 2-trifloromethyl, 4-trifloromethyl, p-(metroliner)benzyl, p-siltakylantie, 4-acetoxyphenyl, 4-(2-trimethylsilyl)ethoxymethylene, 2-naphthylmethyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, 2-hyalinella, 6-methoxy-2-(4-were-4-rhinoliner, 1-pirinelli, diphenylmethyl, 4-methoxybiphenyl, 4-phenyldiethanolamine, p,p'-dinitrobenzamide, 5-dibenzosuberyl, difenilmetan, Tris(4-tert-butylphenyl)methyl, α-naphthylmethyl, p-methoxyphenylalanine, 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-(imidazol shall later)carbarnoyl]trityl, bis(4-methoxyphenyl)-1'-pirinelli, 4-(17-tetrabenzo[a,c,g,i]fertility)-4,4"-dimethoxytrityl, 9-antrel, 9-(9-phenyl)xantener, 9-phenylthiomethyl, 9-(9-phenyl-10-oxo)antril, 1,3-benzodithiol-2-yl and 4,5-bis(etoxycarbonyl)-[1,3]-dioxolane-2-yl, benzisothiazolin S,S-dioxide. In the case of silylation, a protective group for OH can be selected from the group including trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, dimethylhexylamine, 2-norbornadiene, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-silisili, triphenylsilane, diphenylmethylsilane, di-tert-butylmethylether, bis(tert-butyl)-1-perenedootsenili, Tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilane, (2-hydroxystyryl)diisopropylzinc, tert-butylperoxybenzoate, tert-butoxyphenyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethane)ethoxy]disiloxane-1-yl and fluoride silyl. In the case of the use of esters as a protective group for OH, they can be selected from the group comprising formate, benzoylformate, acetate, CHLOROACETATE, dichloroacetate, trichloroacetate, trichloroacetamide, triptorelin, methoxyacetate, triphenylmethane, phenoxyacetyl, p-chlorophenoxyacetate, phenylacetate, diphenylacetate, 3-phenylpropionate, bistritei chain propanol, 4-pentenoate, 4-oxopentanoate, 4,4-(Atlantic is about)pentanoate, 5[3-bis(4-methoxyphenyl)hydroxymethylene]levulinate, pivaloate, 1-adamantoyl, crotonate, 4-mitoxantrone, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoic, 4-bromobenzoate, 2,5-differentat, p-nitrobenzoate, picolinate, nicotinate, 2-(azidomethyl)benzoate, 4-azidomethyl, (2-azidomethyl)phenyl acetate, 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)phenyl acetate, 2-(prenylacetic)benzoate, 6-(levelingacheter)-3-methoxy-2-nitrobenzoate, 6-(levelingacheter)-3-methoxy-4-nitrobenzoate, 4-benzyloxyphenol, 4-triallylisocyanurate, 4-acetoxy-2,2-dimethylbutyl, 2,2-dimethyl-4-pentenoic, 2-identit, 4-nitro-4-methylpentanoate, o-(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, jordivericat, isobutyrate, mononuclear, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-aftout, nitrate, alkyl N,N,N',N'-tetramethylphosphonium and 2-chlorobenzoate. In the case of the sulfonates, sulfonato and sulfinate, protective GRU is PA to OH can be selected from the group including sulfate, arylsulfonate, methanesulfonate, bansilalpet, toilet, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-triftoratsetilatsetonom, 4-monomethoxypolyethylene, alkyl 2,4-dinitrobenzenesulfonic, of 2.2.5.5-tetramethylpyrrolidine-3-one-1-sulfinate, Borat and dimethylphosphinic. In the case of carbonates, a protective group for OH may be selected from the group including methylcarbonate, methoxyethylamine, 9-fertilitycaretm, ethylcarbonate, bromadiolone, 2-(methylthiomethyl)ethylcarbonate, 2,2,2-trichlorethylene, 1,1-dimethyl-2,2,2-trichlorethylene, 2-(trimethylsilyl)ethylcarbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethylcarbonate, 2-(phenylsulfonyl)ethylcarbonate, 2-(triphenylphosphonio)ethylcarbonate, CIS-[4-[[(methoxytrityl)sulfenyl]oxy]tetrahydrofuran-3-yl]oxycarbonate, isobutylamine, tert-BUTYLCARBAMATE, vinylcarbenes, allylcarbamate, cinnamonbear, propylenecarbonate, p-chlorpheniramine, p-nitrophenylarsonic, 4-ethoxy-1-aftercurrent, 6-bromo-7-hydroxycoumarin-4-ylmethylboronic, benzylcarbamoyl, o-nitrobenzylamine, p-nitrobenzylamine, p-methoxybenzylamine, 3,4-dimethoxybenzophenone, anthraquinone-2-ylmethylboronic, 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-femilet carbonate, 2-(2-pyridyl)amino-1-phenylethylamine, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethylamine, pencilsharpener, 3',5'-dimethoxybenzophenone, methyl dithiocarbonate and S-benzoylthiourea. In the case of carbamates, a protective group for OH may be selected from the group including dimethylthiocarbamate, N-phenylcarbamate, N-methyl-N-(o-nitrophenyl)carbamate. The mention of these groups should not be considered as limiting the scope of the present invention, as they are shown only as an illustration of a protective group for OH, but other groups, having the specified function can be well-known specialist in this field of technology, and they are also considered as included in the scope of this invention.

The term "pharmaceutically acceptable salt, derivative, prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES, hydrate or any other compound which, when administered to a patient is able to give (directly or indirectly) described here is the link. However, it should be clear that non-pharmaceutical acceptable salts also fall within the scope of this invention because they can be used to obtain pharmaceutically acceptable salts. Obtaining salts, prodrugs and derivatives can be carried out by methods known in the art.

For example, pharmaceutically acceptable salts present is here compounds are synthesized from the parent compound, which contains a basic or acidic group, conventional chemical methods. Typically, such salts are, for example, is produced by interaction of the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or mixtures thereof. Usually the preferred aqueous medium, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the acid additive salts include mineral acid additive salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid additive salts such as, for example, acetate, triptorelin, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate. Examples of primary additive salts include inorganic salts such as, for example, salts of sodium, potassium, calcium and ammonium, and organic basic additive salts such as, for example, salts of Ethylenediamine, ethanolamine, N,N-dialkylacrylamide, triethanolamine, and salts of basic amino acids.

Compounds in accordance with 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 assumes that both forms are included in the scope of this invention. How is alvarezii widely known in this technical field.

Any compound that is a prodrug of compounds of formula I, falls within the scope and essence of the present invention. The term "prodrug" is used in its broadest sense, and it covers such derivatives, which are converted in vivo into compounds in accordance with this invention. Such derivatives are easily recognized experts in the art and include, for example, compounds in which the free hydroxy-group converted into a derivative of ester.

Any connection specified here represents a particular connection, as well as certain ways or forms. In particular, these compounds may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of these compounds and their mixtures are included in the scope of this invention. Thus, any given connection specified here represents any racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomers forms and their mixtures. In particular, the compounds in accordance with this invention represented by the above formulaImay include enantiomers depending on their asymmetry or diastereoisomer. Stereoisomeric about the double bond is also possible, therefore, some of the s cases, the molecule may exist as (E)-isomer or (Z)-isomer. If the molecule contains several double bonds, each of the double bond will have its own isomerism, which may be the same or different from stereoisomeric other double bonds in the molecule. Individual isomers and mixture of isomers fall within the scope of this invention.

Further, these compounds may exist as geometric isomers (i.e.CISandTRANSisomers), in the form of the tautomers or atropisomers. More specifically, the term "tautomer" refers to one of the two or more structural isomers compounds that exist in equilibrium and are readily converted from one isomeric form to another. Normal tautomeric forms include amine-Imin, amide-imide, keto-enol, lactam-lactim etc. Additionally, any specified here, the connection is a hydrate, solvate and polymorph, mixtures thereof, where such forms exist in the environment. In addition, these compounds can exist in the labeled isotope forms. All geometric isomers, tautomers, atropisomers, hydrate, solvate, polymorph, and labeled isotopes forms of these compounds fall within the scope of this invention.

For more specific descriptions, some quantitative expression data here, not indicated by the term "about". It is clear that regardless of whether used the term "about" nedum Lenno or not, every this number refers to the actual given value, and also refers to the approximate values of such given value that are reasonably assumed to be a specialist in the art, including equivalents and approximate values resulting from experimental and/or measurement conditions for such given value.

In the compounds of General formulaIespecially preferred R1is hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted C1-C12the alkyl. Special preferred Rais hydrogen and substituted or unsubstituted C1-C6alkyl; and even more preferred is hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, OH and methoxy are preferred R1groups.

Particularly preferred R2and R3are hydrogen and substituted or unsubstituted C1-C12alkyl. More preferred R2and R3are hydrogen and substituted or unsubstituted C1-C6alkyl, and even more preferably, hydrogen.

Particularly preferred R41, R42, R43, R44, R45, R46, R47and R48are hydrogen and substituted or unsubstituted C1-Csub> 12alkyl. More preferred R41, R42, R43, R44, R45, R46,R47and R48are hydrogen and substituted or unsubstituted C1-C6alkyl, and even more preferred is 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 of these groups are OR', =O, SR', SOR', SO2R', NO2That other', N(R')2, =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCON(R')2protected OH, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each R' is independently selected from the group including hydrogen, OH, NO2, NH2, SH, CN, halogen, SON, Isoalkyl, COOH, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. If such groups are substituted, the substituents can be selected from the list above. D. the more preferred substituents of the above groups are OH, 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 R41, R42, R43, R44, R45, R46, R47and R48groups. More specifically, particularly preferably R42, R44, R45, R46and R47are hydrogen. Particularly preferably R41and R43are the stands. And particularly preferably R48is isopropyl, tert-bootrom or benzyl.

Particularly preferred R5and R6are hydrogen and substituted or unsubstituted C1-C12alkyl. More preferred R5and R6are hydrogen and substituted or unsubstituted C1-C6alkyl; and even more preferred are hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen is most preferred.

In another embodiment of the invention, it is also preferred that R5and R48together with the corresponding N atom and C atom to which they are attached, form a substituted or unsubstituted heterocyclic group. Preferred heterocyclic group is pyrrolidinyl, including 1-, 2 - and 3-pyrrolidinyl.

<> Particularly preferred R7is hydrogen, substituted or unsubstituted C1-C12alkyl and substituted or unsubstituted C2-C12alkenyl, and more preferred is hydrogen, substituted C1-C12alkyl and substituted C2-C12alkenyl. Preferred substituted alkyl and substituted alkenyl may be present not only in one but in two or more substituents. More preferred alkyl groups are those which contain 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 which contain from 6 to about 10 carbon atoms; and even more preferably 7, 8 or 9 carbon atoms. OCTA-1,6-Ventil, 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. Preferred substituents for the above alkyl and alkenyl groups are OR', =O, SR', SOR', SO2R', NO2That other', N(R')2, =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCON(R')2, Conn the hydrated OH, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each of the R' groups is independently selected from the group including hydrogen, OH, NO2, NH2, SH, CN, halogen, SON, Isoalkyl, COOH, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12quinil, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. If such groups are substituted, the substituents can be selected from the list above. More preferred substituents for the above alkyl and alkenyl groups are halogen, OR', =O, OCOR', OCONHR', OCON(R')2and protected OH, where each of the R' groups are preferably selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12the quinil and substituted or unsubstituted aryl. Even more preferred substituents for the above alkyl and alkenyl groups are halogen, OR', =O, OCONHR', OCON(R')2and protected OH, where the protective group for OH is preferably selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine, d is methylhexanamine, 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 fluoride Silla and where each of the R' groups is more preferable selected from hydrogen, unsubstituted C1-C6of alkyl and substituted or unsubstituted aryl. Cl, OH, =O, OCONH2, OCONH and protected OH, where the protective group for OH is preferably selected from 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-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 fluoride silila are the most preferred is entrusted substituents for these alkyl and alkenyl groups.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of additional relationships in all areas marked with a dashed line. In addition, the stereochemistry of each double bond can exist as (E) or (Z). Individual isomers and mixture of isomers fall within the scope of this invention.

More specifically, this invention is represented by compounds of General formulaIIor their pharmaceutically acceptable salts, derivatives, tautomers, prodrugs or stereoisomers

where R1selected from hydrogen ORa, OCORa, OCOORa, NRaRb, NRaCORband NRaC(NRa)NRaRb;

each R41, R43and R48independently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil;

each R5, R6and R7independently selected from hydrogen, CORa, COORasubstituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil, or R5and R48VM is the extent with the corresponding N atom and C atom, to which they are attached, may form a substituted or unsubstituted heterocyclic group;

each Raand Rbindependently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12the quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and

each dotted line represents an optional additional bond.

In the compounds of General formulaIIespecially preferred R1is hydrogen, ORaand OCORawhere Raselected from hydrogen and substituted or unsubstituted C1-C12the alkyl. Particularly preferred Rais hydrogen and substituted or unsubstituted With1-C6alkyl; and even more preferred is hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen, OH and methoxy are preferred R1.

Particularly preferred R41, R43and R48are hydrogen and substituted or unsubstituted C1-C12alkyl. More preferred R41, R43and R48are hydrogen and substituted or unsubstituted With1-C6alkyl, and even more preferable is what I 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 of these groups are OR', =O, SR', SOR', SO2R', NO2That other', N(R')2, =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCON(R')2protected OH, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each group R' is independently selected from the group including hydrogen, OH, NO2, NH2, SH, CN, halogen, SON, Isoalkyl, COOH, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. If such groups substituted by themselves, the substituents can be selected from the list above. Even more preferred substituents of the above groups are OH, SCH3, SH, NH2, NHC(=NH)NH2, CONH2, COOH, phenyl, p-, m - or o-hydroxyphenyl, indolyl, 1-, 2 - and 3-indolyl, imidazolyl, including 4 - and 5-imidazolyl. The waters of the genus, methyl, isopropyl, tert-butyl and benzyl are preferred R41, R43and R48groups. More specifically, particularly preferred R41and R43are methyl, and especially preferred R48is isopropyl, tert-butyl or benzyl.

Particularly preferred R5and R6are hydrogen and substituted or unsubstituted C1-C12alkyl. More preferred R5and R6are hydrogen and substituted or unsubstituted With1-C6alkyl; and even more preferred are hydrogen, methyl, ethyl, propyl, isopropyl and butyl, including tert-butyl. Hydrogen is most preferred.

In another embodiment, the present invention also preferably, R5and R48together with the corresponding N atom and C atom to which they are attached, form a substituted or unsubstituted heterocyclic group. Preferred heterocyclic group is pyrrolidinyl, including 1-, 2 - and 3-pyrrolidinyl.

Particularly preferred R7is hydrogen, substituted or unsubstituted C1-C12alkyl and substituted or unsubstituted C2-C12alkenyl and, more preferably, is hydrogen, substituted C1-C12alkyl and substituted C2-C12alkenyl. More predpochtitel is different alkyl groups are, which contain 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 which contain 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. Preferred substituents for the above alkyl and alkenyl groups are OR', =O, SR', SOR', SO2R', NO2That other', N(R')2, =N-R', NHCOR', N(COR')2, NHSO2R', NR'r C(=NR')NR'r R', CN, halogen, COR', COOR', OCOR', OCONHR', OCON(R')2substituted OH, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group, where each group R' is independently selected from the group including hydrogen, OH, NO2, NH2, SH, CN, halogen, SON, Isoalkyl, COOH, substituted or unsubstituted C1-C12alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group. If what these groups are substituted, the substituents can be selected from the list above. More preferred substituents for the above alkyl and alkenyl groups are halogen, OR', =O, OCOR', OCONHR', OCON(R')2and protected OH, where each group R' is preferably selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12the quinil and substituted or unsubstituted aryl. Even more preferred substituents for these alkyl and alkenyl groups are halogen, OR', =O, OCONHR', OCON(R')2and protected OH, where the protective group for OH is preferably selected from 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-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 fluoride Silla and where each group R' more predpochtitel is but selected from hydrogen, unsubstituted With1-C6of alkyl and substituted or unsubstituted aryl. Cl, OH, =O, OCONH2, OCONH and protected OH, where the protective group for OH is preferably selected from 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-perenedootsenili, 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 fluoride silila are the most preferred substituents for these alkyl and alkenyl groups.

Especially preferred is the presence of one or more links in the positions indicated by the dotted line. More preferred is the presence of additional relationships in all areas marked with a dashed line. In addition, the stereochemistry of each double bond can exist as (E) or (Z). Individual isomers and mixture of isomers fall within the scope of this invention.

Particularly preferred compounds according the this invention are the following:

Connection 1
Connection 2
Connection 3

Connection 4
Connection 5
Connection 6
Connection 7
Compound 8

Compounds 1-8 isolated from sponges of the family Raspailiidae, genusLithoplocamia,lithistoides.

SampleLithoplocamia lithistoidesstored in the "Instituto de Ciencias del Mar y Limnologia" Universidad Nacional Autόnoma de Mexico in Mazaltan in Mexico, with a serial number LEB-ICML-UNAM-11-2004. This sponge is collected manually swimmers diving in Madagascar (S 17° 06,071'/E 49° 51,385') at a depth of from 6 to 20 m, and it has the following description.

The family Raspailiidae: Raspailiidae Hentschel, 1923 represent is a sponge, have crusted, massive, lobed, fan-shaped or branched growth form, usually with a very bristly surface. There is normally adapted ectosomal skeleton, consisting of a brush or a small fine needles (Hooper &Wiedenmayer 1994: Fig. 17) or ocean (Hooper &Wiedenmayer 1994: Fig. 5)surrounded by a separate long thick needles or okeanami. Choanosomal skeleton varies from compressed axial skeleton to pinnate-reticulate or solely mesh structures. Fiber spongin usually completely surrounded by a hollow spines (choanosomal needle, oxiana or both). A special category of thorn needles (Hooper &Wiedenmayer 1994: Fig. 22) or modification of needles (e.g., Fig. 22-25, 28), covered with thorns fibers sticking out at right angles to the fibers. Microcline are usually absent, although in some genera may be separate rafidi (Hooper &Wiedenmayer 1994: Fig. 109) or bundles (trichodragmata; Hooper &Wiedenmayer 1994: Fig. 110). Reaility widespread in depth from shallow water to at least 2460 m (Hartman 1982).

The genusLithoplocamia,lithistoidesrepresents crusted massive growth form, choanosomal skeleton is a dense sticciano or unevenly substentially mesh structure cantastorie, 1 or 2 dimensional categories, without axial compression, without prickly akintoye, with extra what avimi radial plots of smooth needles and usually without specialized ectosomal skeleton RASPAIL (although, if they are present, actosonline spikes are long, thin oxiana); microcline missing.

SamplesLithoplocamia lithistoidesalso collected in Kenya (S 04°40'5,5"/E 39°26'4.3", S 03°38'is 36.5"/E 39°53'53,8") and Tanzania (S 08°55'31,7"/E 39°34'53,5" and S 05°24,200'/E 39°47,730') at a depth of 30 to 40 meters

In addition, the compounds in accordance with this invention can be obtained by synthesis. For example, compound 1 may be obtained by combining various fragments, as shown in figure 1.

Scheme 1

where R, RI, RII, RIII, RIV, RV, RVI, RVIIand RVIIIare the desired group or a suitable protecting group, if necessary.

This method may include the following key stages:

a) amidation yodaiken derived (fragment D) a fragment of C followed by the application of standard techniques (Kozawa Y et al. Tetrahedron Lett. 2002, 43, 111) for receiving a corresponding enamide (fragment CD);

b) reaction of a combination of still between fragment a and fragment B, followed by the application of known methods of organic synthesis (Scott WJ et al. J. Am. Chem. Soc. 1984, 106, 4630; Labadie J W et al. J. Org. Chem. 1983, 48, 4634-4642; Farina V et al. Organic Reactions 1998, Wiley) to obtain the linear polyene (fragment AB);

c) fragments AB and CD can be connected using standard techniques (Bodanszky M and Bodanszky A, The Practice of Peptide Synthesis, Sringer-Verlag, 1993) to obtain the carbon skeleton of compound 1;

d) removing protection from alcohol ORIIwith the subsequent lactonization can be conducted by known methods of organic synthesis (Greene and Wuts, Protective Groups in Organic Synthesis, 3rded., 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);

e) finally, removing protection from alcohol ORIIIwith the subsequent formation of carbamate can be performed by standard methods (Love B et al. Organic Syntheses, Coll. Vol. 5, p. 162; Vol. 48, p. 32; Muller E et al. Methods der Organischen Chemie (Houben-Weyl), 4thed., Vol. 8, G. Thieme, Stuttgart, 1952, p. 137) to obtain compound 1.

The sequence of stages can be changed to obtain the final compounds. For example, the segment BC can be obtained at the first stage then attached to the fragments A and D to obtain the carbon skeleton of compound 1. The compound 1 may be obtained by the serial combination of fragments A, B, C and D in any order. Another option includes obtaining lactoovo group fragment And prior to its combination with any other fragment.

Analogs of compound 1 can be synthesized by a method equivalent to that described for compound 1, by suitable choice of the substituents in the intermediate compounds in each case.

Optionally the substituents may apply appropriate Samaniego for so were not affected by the reactive group. The synthesis can be carried out using a precursor substituents which can be converted to a suitable stage in the desired Deputy. Saturation or unsaturation of the ring structure can be introduced or removed as part of the synthesis. Starting materials and reagents can be modified if desired to provide a synthesis of the desired compounds. In addition, from compound 1 can also be synthesized analogs of conventional methods of synthesis in organic chemistry which are known to experts in this field of technology.

The above path synthesis can be modified on request to obtain stereospecific compounds as well as mixtures of stereoisomers. It is possible to synthesize certain stereoisomers or certain mixtures of different methods, including the use of stereospecific reagent or the introduction of chiral centers in the compounds during synthesis. It is possible to introduce one or more stereocentres during synthesis, as well as to invert the existing stereocenter. In addition, it is possible to separate the stereoisomers immediately after synthesis of the compounds using conventional separation techniques known to the person skilled in the technical field.

An important characteristic described in the above compounds of formulas IandIIis their bioactivity and, in particular, their cytotoxic and antimitoticescoe effect.

This invention presents new pharmaceutical compositions of compounds of General formulaIandIIthat possess cytotoxic and antimitoticheskim action, their use as antitumor agents. Thus, the present invention also presents a pharmaceutical composition containing the compound in accordance with this invention, its pharmaceutically acceptable salt, derivative, tautomer, prodrug or stereoisomer, and a pharmaceutically acceptable carrier.

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 in accordance with this invention may be conducted in any suitable way, such as intravenous infusion, oral drugs and intraperitoneal and intravenous administration. Preferably, the time of infusion was up to 24 hours, more preferably 1 to 12 hours, most preferably 1-6 hours. Particularly preferably shorter infusion, which can be treated without having ostabat is camping in the hospital overnight. However, if necessary, the injection may be performed within 12 to 24 hours or even longer. The infusion can be carried out with suitable intervals, for example from 1 to 4 weeks. Pharmaceutical compositions containing the compounds in accordance with this invention, can be delivered with the use of liposomal or nanoferrites encapsulate, in compositions with delayed release or other standard means of delivery.

The exact dose of the compounds varies in accordance with the specific composition, method of administration and the particular site of impact, the patient and treat the tumor. Should also be taken into account other factors such as age, body weight, sex, diet, time of administration, rate of excretion, condition of the patient, the combination of drugs, reaction sensitivities and severity of the disease. The introduction can be carried out continuously or intermittently, with the use of the maximum tolerated dose.

Compounds and compositions in accordance with this invention can be used with other drugs for combined modality therapy. Other medicines may be part of a single composition or may be a separate composition for administration at the same time or at another time.

The antitumor action of these the compounds includes, but not limited to, the impact on lung cancer, colon cancer, breast cancer and cervical cancer.

EXAMPLES

EXAMPLE 1: DESCRIPTION of MARINE ORGANISM AND the GATHERING PLACE

Lithoplocamia lithistoidespicked swimmers diving in Madagascar (S 17°06,071'/E 49°51,385') at a depth of from 6 to 20 m Animal material identified Jose Luis Carballo (Universidad Autόnoma de Mejico). The sample deposited in the Instituto de Ciencias del Mar y Limnologia" Universidad Nacional Autόnoma de Mexico in Mazaltan in Mexico, with a serial number LEB-ICML-UNAM-11-2004.

EXAMPLE 2: ISOLATION of COMPOUNDS 1

A frozen sample of example 1 (61 g) cut and extracted with H2O (3×200 ml) and then with a mixture of MeOH:dichloromethane (1:1, 3×200 ml) at room temperature. The combined organic extracts are concentrated with the receipt of 1.11 g of the crude product. This material is subjected to VLC on Lichroprep RP-18 with a stepped gradient from H2O to MeOH.

Connection1(1.6 mg) was isolated from fractions, buervenich MeOH using prepreparation HPLC with reversed phase (SymmetryPrep C18, 7 μm, and 7.8×150 mm, gradient of H2O:MeCN from 35 to 100% MeCN in 30 min, UV determination, flow 2.5 ml/min, CT of 14.4 min).

Compound 1: white amorphous substance. (+)HRESIMS m/z 606,2940 [M+H]+(RASSC. for C31H4535ClN3O7606,2946);1H (500 MHz) and13C NMR (125 MHz), see table 1.

29
Table 1
Data1H and13C NMR for compound 1 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,6186,84 (userid, 10,8, 9,7)124,5
2-145, 2mm194,80 (m)105,0
35,63 (DD, 6,5, 2,6)to 108.2202,46 (m) of 2.09 (DDD, 14,1, 8,4, 8,1)30,7
4of 2.45 (DDD, 17,3, 11,5, 2,6) is 2.37 (DDD, 17,3, 6,5, 4,1)26,121to 4.41 (m)74,9
54,24 (DDD, 11,5, 7,1, 4,1)81,922 of 2.33 (m, 2H33,0
62,85 (ddcv., 9,8, 7,1, 6,7)37,1235,61 (ushort, 6,8)122,4
7of 5.29 (d, 9,8)134,124-132,0
8-133,725to 2.06 (C), 3H21,0
9of 6.17 (d, 11,6)140,2263,66 (s), 3H55,4
107,30 (DD, 11,6, 11,6)124,627to 1.15 (d, 6,7), 3H16,3
116,91 (DD, 11,6, 11,6)137, 6mm281,82 (s), 3H17,1
125,70 (d, 11,6)120,7-34,7
13-166,3301,04 (s), 3H26,7
146,51 (d, 9,5)-311,04 (s), 3H26,7
15to 4.41 (d, 9,5)60,8321,04 (s), 3H26,7
16-168,233-157,2
178,78 (d, 10,8)-

Connection 1

EXAMPLE 3: ISOLATION of COMPOUNDS 2, 3, 4, 5, 6 AND 7

The second group of samplesLithoplocamia lithistoides(7.66 kg), pounds and carefully extracted with a mixture of MeOH:dichloromethane (1:1, 14 l, 2×5 l, 4 l). The solvent is removed vacuume and the remaining aqueous solution extracted with EtOAc (12 l, 3×8 l). The organic layer is evaporated to obtain the crude residue 21,71,

This material is subjected to chromatography on a column of RP-18 with a stepped gradient from H2O:MeOH (4:6) to MeOH. Faction, erwerbende H2O:MeOH (2:8, 430 mg), combined and subjected to preparative HPLC (Atlantis dC18, OBD, 5 μm, 19×150 mm, isocratic H2O:MeOH (39:61), flow: 20 ml/min, UV determination) to obtain the pure compounds1(160,8 mg),2(13.2 mg) and7(1.8 mg) and mixtures3and4(11.4 mg) and5and6(10.0 mg). Net connection3(5.1 mg) and4(2.6 mg) obtained after the final purification of the mixture prepreparation HPLC (X-Terra Prep RP-18, 10 μm, 10×150 mm, gradient of H2O:MeOH to 50 to 70% MeOH at 70 min, flow: 2.5 ml/min, UV definition). Connection5(3.6 mg) and6(1.0 mg) divided by the same method prepreparation HPLC (X-Terra Prep RP-18, 10 μm, 10×150 mm, isocratic H2O:MeOH (45:55), flow: 2.5 ml/min, UV definition).

Connection 2: amorphous white solid. MS (ER) m/z 606,3 [M+H]+, 628,3 [M+Na]+;1H (500 MHz) and13C NMR (125 MHz), see table 2.

Connection 3: amorphous white solid. (+)HRESIMS m/z 628,2774 [M+Na]+(RASSC. for C31H4435ClN3O7Na 628,2760);1H (500 MHz) and13C NMR (125 MHz), see table 3.

Compound 4: amorphous white solid. (+)HRESIMS m/z 594,3152 [M+Na]+(RASSC. for C31 45N3O7Na 594,3150);1H (500 MHz) and13C NMR (125 MHz), see table 4.

Connection 5: amorphous white solid. MS (ER) m/z 592,3 [M+H]+, 614,3 [M+Na]+;1H (500 MHz) and13C NMR (125 MHz), see table 5.

Compound 6: amorphous white solid. MS (ER) m/z 592,3 [M+H]+, 614,3 [M+Na]+;1H (500 MHz) and13C NMR (125 MHz), see table 6.

Compound 7: amorphous white solid. (+)HRESIMS m/z 427,2207 [M+Na]+(RASSC. for C22H32N2O5Na 427,2203);1H (500 MHz) and13C NMR (125 MHz), see table 7.

Table 2
Data1H and13C NMR for compound 2 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,5186,83 (DDD, 10,8, 8,9, 1,2)to 124.4
2-145, 2mm194,80 (m) 105,5
35,61 (DD, 6,4, 3,1)108,1202,43 (m) 2,12 (m)30,6
4to 2.41 (DDD, 17,1, 11,3, 3,0) 2,34 m26,6214,50 (m)74,9
54,18 (DDD, 11,3, 7,8, 4,3)81,622of 2.36 (m, 2H33,2
62,88 (ddcv., 10,0, 7,8, 6,7)37,4235,61 (ushort, 6,5)122,2
75,46 (userd, 10,0)136,524-132,1
8-135,6252,07 (l, 1,0), 3H21,0
96,41 (d, 15,5)145,0the 3.65 (s), 3H55,4
10of 7.60 (DD, 15,5, 11,4)124,227of 1.16 (d, 6,7), 3H16,5
11of 6.49 (DD, 11,4, 11,3)142,528to 1.86 (d, 1,0), 3H13,1
125,63 (d, 11,3)119,029-34,6
13-KZT 166.5301,05 (s), 3H26,6
14to 6.39 (d, 9,4)-311,05 (s), 3H26,6
15of 4.44 (d, 9,4)60,7321,05 (s), 3H26,6
16- 33-157,0
178,50 (userd, 10,8)-

Connection 2

Table 3
Data1H and13C NMR for compound 3 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,5186,83 (userid, 10,7, 9,6)to 124.4
2-145,319to 4.81 (m)105,4
35,61 (DD, 6,3, 3,0) 108,1202,47 (m) 2,10 (m)30,8
42,39 (m) 2,37 (m)26,3214,43 (m)75,0
5is 4.21 (DDD, 10,9, 7,6, 4,7)81,722of 2.34 (m, 2H33,0
62,90 (ddcv., 10,0, 7,6, 6,6)37,4235,62 (ushort, 6,5)122,4
75,46 (userd, 10,0)to 136.424-132,0
8-135,1252,07 (s), 3H21,0
96,51 (d, 15,3)144,126the 3.65 (s), 3H55,4
10 6,27 (DD, 15,3, 11,1)125,227to 1.15 (d, 6,6), 3H16,6
11of 7.25 (DD, 14,8, 11,1)141,928to 1.83 (d, 1,0), 3H12,9
125,96 (d, 14,8)122,929-35,1
13-166,030of 1.03 (C), 3H26,6
14to 6.39 (d, 9,3)-31of 1.03 (C), 3H26,6
154,43 (d, 9,3)60,832of 1.03 (C), 3H26,6
16-168,333-157,9
17 8,82 (d, 10,7)-

Connection 3

2,44 (m) 2,39 (m)
Table 4
Data1H and13C NMR for compound 4 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,618PC 6.82 (DDD, 10,4, 9,1, 0,9)124,2
2-145, 2mm194,82 (m)105,8
35,63 (DD, 6,6, 2,7)to 108.2202,46 (m) a 2.12 (DDD, 14,1, 8,0, 8,0)30,9
426,1214,45 (m)75,6
5of 4.25 (DDD, 11,3, 7,0, 4,0)81,922to 2.35 (m, 2Hof 31.4
62,85 (ddcv., 9,9, 7,0, 6,7)37,123of 5.40 (m)124,9
7of 5.29 (d, 9,9)134,124the ceiling of 5.60 (m)127,1
8-133,8251,63 (DD, 6,8, 1,0), 3H13,0
9x 6.15 (d, 11,6)140,2263,66 (s), 3H55,4
107,31 (DD, 11,6, 11,6)to 124.427to 1.15 (d, 6,7), 3H16,4
11make 6.90 (DD, 11,6, 11,6)137,5281,82 (s), 3H17,1
125,72 (userd, 11,6)120,829-34,8
13-166,3301,04 (s), 3H26,7
146,53 (d, 9,6)-311,04 (s), 3H26,7
15of 4.44 (d, 9,6)60,7321,04 (s), 3H26,7
16-168,233-157,6
178,69 (d, 10,4)-

Connection 4

Table 5
Data1H and13C NMR for compound 5 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-of 161.7178,69 (d, 10,7)-
2-RUB 145.118at 6.84 (DDD, 10,7, or 9.8, 0,9)124,5
35,64 (DD, 6,6, 2,6)108,3194,80 (m)105,2
42,48 (DDD, 17,4, 12,0, 2,6) is 2.37 (DDD, 17,4, 6,6, 3,9)26,0202,45 (m) of 2.10 (DDD, 15,0, 7,1, 6,2)30,7/td>
5to 4.28 (DDD, 12,0, 6,6, 3,9)81,921of 4.44 (m)74,8
62,85 (ddcv., 9,7, 6,6, 6,7)37,022of 2.33 (m, 2H33,0
75,31 (d, 9,7)134,123the ceiling of 5.60 (ushort, 7,1)122,4
8-133,624-132,0
9of 6.17 (d, 11,5)140,325to 2.06 (C), 3H21,0
107,31 (DD, 11,5, 11,5)124,5263,66 (s), 3H55,4
116,93 (DD, 11,5, 11,5)137, 6mm27 to 1.15 (d, 6,7), 3H16,2
125,73 (d, 11,5)of 120.5281,82 (users), 3H17,1
13-KZT 166.5292,22 (m)31,1
14is 6.54 (d, 9,2)-301,00 (l, 6,8), 3H19,3
15to 4.46 (DD, 9,2, 6,4)58,531of 0.96 (d, 6,8), 3H18,0
16-169,132-157,4

Connection 5

Table 6
Data1H and13C NMR for compound 6 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,5178,59 (d, 10,8)-
2-145, 2mm186,84 (userid, 10,8, 8,7)124,5
35,61 (DD, 6,8, 2,8)to 108.219to 4.81 (m)105,5
4to 2.41 (m, 2H26,6202,42 (m) to 2.13 (DDD, 14,1, 7,5, 7,2)30,6
54,18 (DDD, 11,6, 7,7,4,2)81,6214,49 (m)74,7
62,88 (ddcv., 10,0, 7,7, 6,6) 37,422to 2.35 (m, 2H33,1
75,47 (userd, 10,0)136,5235,61 (m)122,3
8-135,524-132,1
96,41 (d, 15,4)145,0252,07 (s), 3H21,0
10to 7.61 (DD, 15,4, 11,3)124,226the 3.65 (s), 3H55,4
11of 6.49 (DD, 11,3, 11,3)142,527to 1.15 (d, 6,6), 3H16,5
125,63 (d, 11,3)118,9281,86 (s), 3H13,1
13 -166,6292,20 (m)30,9
146,34 (h, 8,9)-30a 1.01 (d, 6,7), 3H19,3
15was 4.42 (DD, 8,9, 7,1)58,6310,98 (l, 6,8), 3H18,2
16-169,032-157,0

Connection 6

Table 7
Data1H and13C NMR for compound 7 (CDCl3)
No.1N (Multipletness, J)13C
1-161,5
2-35,62 (DD, 6,1, 3,2)108,1
42,43 (m) 2,38 (m)26,3
5is 4.21 (DDD, 12,0, 7,0, 4,8)81,8
62,86 (ddcv., 9,9, 7,0, 6,6)37,4
7of 5.29 (d, 9,9)134,2
8-134,1
9of 6.17 (d, 11,6)140,2
107,26 (DD, 11,6, 11,5)of 124.1
11make 6.90 (DD, 11,5, 11,5)137,4
125,67 (d, 11,5)120,8
13-to 166.2
14to 6.22 (d, 9,2)-
154,34 (d, 9,2)16-172,5
173,66 (s), 3H55,4
181,17 (l, 6,6), 3H16,7
191,85 (s), 3H17,2
20-34,5
211,05 (s), 3H26,6
221,05 (s), 3H26,6
231,05 (s), 3H26,6

Connection 7

EXAMPLE 4: ISOLATION of COMPOUND 8

The fraction containing the compound 1 (61,6 mg)obtained by the method of extraction described in example 3, then clean prepreparation HPLC (Symmetryprep C-18, 7 μm, and 7.8×150 mm, isocratic H2O:CH3CN (55:45), flow rate: 2.3 ml/min, UV definition) and 0.9 mg connection8get in purified form.

Compound 8: amorphous white firmly the substance. MS (ER) m/z 606,2 [M+H]+, 628,3 [M+Na]+;1H (500 MHz) and13C NMR (125 MHz), see table 8.

Table 8
Data1H and13C NMR for compound 8 (CDCl3)
No.1N (Multipletness, J)13CNo.1N (Multipletness, J)13C
1-161,6186,83 (DDD, 10,8, 8,7, 1,0)to 124.4
2-145, 2mm194,80 (m)105,2
35,66 (ushort, 4,6)108,4202,11 (DDD, 14,2, 8,1, 7,8) 2,45 (m)30,7
4of 2.45 (m, 2H26,6214,46 (m)75,0
5 is 4.21 (DDD, 7,7, 7,7, 7,7)81,722of 2.34 (t, 6,7), 2H33,0
62,85 (ddcv., 10,0, 7,7, 6,7)37,423the ceiling of 5.60 (dt, 7,8, 1,2)122,3
7to 5.35 (d, 10,0)135,124-132,0
8-134,625to 2.06 (C), 3H21,0
96,16 (d, 11,7)140,6263,66 (s), 3H55,4
10the 6.06 (DD, 11,7, 11,7)125,6271,17(y, 6,7), 3H16,6
117,71 (DD, 14,7, 11,7)137,928at 1.91 (d, 0.7)and 3H170
125,95 (d, 14,7)124,529-34,8
13-166,0301,04 (s), 3H26,6
146.35mm (d, 9,5)-311,04 (s), 3H26,6
154,47 (d, 9,5)61,0321,04 (s), 3H26,6
16-168,333-157,1
178,65 (d, 10,8)-

Compound 8

EXAMPLE 5: SYNTHESIS of FRAGMENT A

Figure 2 presents a few examples of the synthesis of fragment AB accordance with the nomenclature, presented in figure 1.

Scheme 2

Synthesis of intermediate compound (9)

It has a temperature of 0°C. solution of (2S,3S) - for 3,5-bis{[(tert-butyl)dimethylsilane]oxy}-4-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) Et3N (96,1 ml, 0.69 mol) is added by adding a funnel. After 10 minutes SO3·Pyr (54,8 g, 0.34 mol) is added in portions and the solution stirred for another 2 h at 0°C. Then it was diluted with dichloromethane (800 ml) and quenched with HCl (0,5N, 800 ml). The organic layer is decanted, dried over MgSO4and concentrated in vacuo. Purification by chromatography on a column (hexane/EtOAc 100:0 to 10:1) to give 45 g (yield: 90%) of aldehyde9.

1H NMR (CDCl3, 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,GC), 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 intermediate compound 10

In a solution of aldehyde9(45 g, 0.12 mol) in toluene (625 ml) add carbomethoxyamino-triphenylphosphorane (113 g, 0.31 mol) and the mixture is heated at 60°C for more than 17 hours and Then the solvent is removed under reduced pressure, the remaining oil purified by chromatography on a column (EtOAc 100:0 to 10:1) to obtain the level of 53.3 g (yield: 96%) complex essential connection 10.

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 intermediate compound (11)

It cooled down to -78°C solution of ester10(46,7 g, 0,105 mol) in anhydrous THF (525 ml) in an argon atmosphere add hydride diisobutylaluminum (DIBAL) 1 M in toluene (231 ml, 0,231 mol) over 10 minutes and the mixture was stirred at -78°C. After 4 hours the reaction is quenched with MeOH (10 ml), add a saturated solution of tartrate of potassium-sodium (800 ml) and diluted with EtOAc (1000 ml). This mixture is stirred for 2 h and then the organic layer decanted. The aqueous residue is extracted with additional EtOAc (2×400 ml), the combined organic layers are dried (Na2SO4) and the solvent is evaporated. The resulting oil purified by chromatography on a column (hexane/EtOAc 20:1 to 10:1) obtaining of 32.5 g (yield: 77%) of alcohol11.

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 intermediate compound 12

To a solution of alcohol11(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 EtOAc (3 l)and the resulting solution was dried under reduced pressure obtaining of 29.1 g (yield: 94%) of aldehyde12.

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, 12H).

13C NMR (CDCl3, 75 MHz) δ: 195,4, 157,8, 138,3, 134,5, 72,0, 59,5, 36,7, 37,5, 25,8, 18,2, 18,1, 14,3, 9,4, -4,4, -4,5, -5,4.

Synthesis of intermediate compound 13

To a suspension of iodide iodocyclization (Gilbert Stork, KZ.Tetrahedron letters1989, 30(17), 2173) (96,3 g 181,7 mmol) in THF (727 ml) at a temperature of 0°C. is slowly added a 1 M solution hexamethyldisilazane sodium (NaHMDS) (181,7 ml 181,7 mmol) via adding funnel within 10 minutes. After stirring for a further 5 min the solution is cooled to a temperature of -78°C and then added 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (43,9 ml, 363,4 mmol) via cannula, followed by the addition of aldehyde12(29,1 g, 72,7 mmol)dissolved in THF (727 ml). The temperature of the support at the level of -78°C while stirring the reaction mixture for 2 hours. Add hexane (1 l) and who received the 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 chromatography on a column (hexane/EtOAc 100:0 to 20:1) to give 32 g (yield: 84%) of iodide13.

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, 38,1, 37,9, 26,0, 18,3, 18,2, 15,7, 15,7, -4,4, -5,2, -5,2.

Synthesis of intermediate compound 14

To a solution of iodide13(12 g, to 22.9 mmol) in EtOH (114 ml) is added p-toluensulfonate pyridinium (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 chromatography on a column (hexane/EtOAc 10:1) to give 8.7 g (yield: 93%) of alcohol14.

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 intermediate compound 15

It has a temperature of 0°C solution of alcohol14(8.7 g, of 21.2 mmol) in a mixture of dichloromethane/DMSO (50,9 ml/22,9 ml) was added Et3N (of 14.8 ml, 106 mmol) through a funnel. the via 10 minutes SO 3·Pyr (8,43 g, to 53.0 mol) is added in portions and the solution stirred for another 2 h at 0°C. Then it was diluted with dichloromethane (800 ml) and quenched with HCl (0,5N, 50 ml). The organic layer is decanted, dried over MgSO4and concentrated in vacuo. Purification by chromatography on a column (hexane/EtOAc 10:1) to give 6.9 g (yield: 80%) of aldehyde15.

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 intermediate compound 16a

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 dry THF (390 ml), stirred in an argon atmosphere at -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 aldehyde15(5.9 g, accounted for 14.45 mmol) in dry THF for 30 min and stirred at -78°C for 90 min and Then the reaction quenched with saturated solution of NH4Cl (200 ml), warmed to room temperature and diluted with dichloromethane (1000 ml). The organic phase is dried (Na2SO4) and evaporated under reduced pressure. Purification by chromatography on a column (hexane/Et2O 20:1) gives pure 42 g (59%) (E)-16a.

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, 75 MHz) δ: 163,7, 145,9, 142,1, 137,3, 132,1, 110,4, 75,4, 74,8, 55,4, 51,9, 38,1, 32,3, 25,9, 18,1, 16,5, 15,7, -4,3, -4,5.

Synthesis of intermediate compound 16b

To a solution of ethyl[bis(2,2,2-triptoreline)phosphinyl]acetate (0.16 ml, 0.66 mmol) and 18-crown-6 (350 mg, 1,32 mmol) in dry THF (2.4 ml), stirred in an argon atmosphere at 0°C., added dropwise KHMDS (1.23 ml of 0.62 mmol). After 30 minutes, added dropwise to the aldehyde15(180 mg, 0.44 mmol) in dry THF and stirred at -78°C for 60 minutes

Then the reaction quenched with saturated solution of NH4Cl, warmed to room temperature and diluted with EtOAc. The organic phase is dried (Na2SO4) and evaporated under reduced pressure. Purification by chromatography on a column (hexane/EtOAc 100:1 to 15:1) to give 172 mg (yield: 82%)(Z)-16b.

1H NMR (CDCl3, 300 MHz) δ: 6,70 (d, 1H, J=8.7 Hz), 6,44-6,36 (m, 1H), 6,09 (d, 1H, J=8.7 Hz), 5,86-of 5.81 (m, 1H), vs. 5.47 (d, 1H, J=9.9 Hz), 4,14 (q, 2H, J=7,2 Hz), 3,69-to 3.64 (m, 1H), 3,06-3,00 (m, 1H), 2,85 is 2.75 (m, 1H), 2,59 is 2.51 (m, 1H), of 1.84 (s, 3H), of 1.28 (t, 3H, J=7,2 Hz), and 1.00 (d, 3H, J=6.6 Hz), to 0.89 (s, 9H), 0.06 to (s, 3H), of 0.05 (s, 3H).

MS (ER) m/z 501,0 [M+Na]+.

Synthesis of intermediate compound 17a

To a solution of the false air of 16a(4.15 g, 8,39 mmol) in MeOH (125 ml) at room temperature add HCl 37% (1,04 ml) and the reaction mixture is stirred for 6 hours. The mixture is then neutralized with saturated solution of NaHCO3(pH 7-8) and the organic solvent is evaporated under reduced pressure. The resulting suspension is extracted with dichloromethane (3×200 ml), dried and evaporated. Filtration chromatography on a column (hexane/EtOAc 10:1 to 2:1) to give 2.76 g (yield: 94%) of lactone17a.

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 (DK, J=1H, 3,0, 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.

Synthesis of intermediate compound 17b

To a solution of ester16b(172 mg, 0.36 mmol) in MeOH (4.5 ml) at room temperature add HCl 37% (0,03 ml) and the reaction mixture is stirred for 3 hours. The mixture is then neutralized with saturated 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. Purification by chromatography on a column (hexane/EtOAc 10:1 to 5:1) to give 70 mg (yield: 61%) of lactone17b.

1H NMR (CDCl3, 300 MHz) δ: 6,91-6,85 (m, 1H), of 6.68 (d, 1H, J=8,4 Hz), 6,62 (d, 1H, J=8,4 Hz), of 6.02 (DD, 1H, J=2,7 9,6 Hz), the 5.45 (d, 1H, J=9.9 Hz), 4,19 (m, 1H), the 3.65 (s, 3H), 4.26 deaths-4,18 (m, 1H), 2,92-and 2.79 (m, 1H), 2.57 m-2,48 (m, 1H), 2,39-of 2.28 (m, 1H), of 1.88 (s, 3H), of 1.17 (d, 3H, J=6.6 Hz).

EXAMPLE 6: SYNTHESIS of FRAGMENT D

Figure 3 presents some examples of the synthesis of fragment D in accordance with the nomenclature presented in figure 1.

Scheme 3

Synthesis of intermediate compound 19

To a solution of intermediate compound18(72,3 g) in dichloromethane (DHM) (918 ml) at room temperature portions add 3-chloroperbenzoic acid (m-CPBA) (100 g, of 0.58 mol) and the mixture is stirred at room temperature for 18 hours a White precipitate quenched with saturated solution of NaHCO3, extracted DHM (3×250 ml) and again washed with saturated aqueous NaHCO3(3×250 ml). The organic layers are combined, dried over Na2SO4and concentrated in vacuo. The resulting oil purified on silica gel (hexane-AcOEt; 15:1) to give the epoxide as a colorless oil (64,5 g, 82%). To a solution of racemic epoxide (30 g) in anhydrous THF (7.5 ml) of type complex(R,R)Co(II) (448 mg, of 0.74 mmol), and then AcOH (0,14 ml). The solution is cooled to 0°C and added dropwise water (1.2 ml). The reaction mixture is heated to room temperature and stirred for 18 hours then volatiles concentrated in vacuo and the crude residue load C is directly in a column with silica gel. Flash chromatography using hexane/EtOAc (15:1 to 12:1) as eluent gives the chiral epoxide(+)-19(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.

Synthesis of intermediate compound 20

Propyne condense at a temperature of -78°C and dissolved in anhydrous THF (165 ml). Added dropwise n-utility in an atmosphere of Ar for more than 30 min and the resulting white suspension is stirred for additional 30 min at -78°C. and Then added dropwise a solution of (+) (R)-2-[2-(tert-butyldimethylsilyloxy)ethyl]oxirane19(23.7 g) in anhydrous THF (125 ml) and then adding BF3OEt2. The mixture is stirred for 1 h at -78°C and for a further one hour at 0°C. the Reaction is quenched with saturated aqueous NH4Cl (150 ml) and extracted with Et2O (3×150 ml). The combined organic layers dried over NaSO4filter and concentrate. Flash chromatography (hexane/EtOAc 10:1 to 1:1) gives an increase of 22.7 g (yield: 80%) of alcohol20in the form of a colorless oil.

[α]D=+5,6 (c=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 (ER)m/z243,2 [M+H]+, 265,2 [M+Na]+.

Synthesis of intermediate compound 21a

A solution of intermediate compound20(22,7 g) and p-methoxyphenylacetamide (PMBTCA) in DHM treated with Sc(OTf)3. The mixture is stirred at room temperature for 2 h (TLC test) and the reaction was concentrated in vacuo and purified by chromatography on a column (hexane/EtOAc 50:1 to 15:1) to obtain the connection21ain the form of a yellow oil (18.3 g; yield: 55%).

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 compound 21b

A solution of alcohol20(2,88 g, to 11.9 mmol), tert-butyldiphenylsilyl (4,39 ml, 16,89 mmol) and 4-(dimethylamino)pyridine (43,6 mg) in N,N-dimethylformamide (DMF) (14 ml) is stirred overnight at room temperature. The mixture is diluted with water and extracted with Et2O and the organic phase is washed with saturated salt solution, dried over Na2SO4filter and concentrate. Flash chromatography (hexane/EtOAc, 95:1) gives silloway ether21b(5,3 g, yield: 93%) as a colourless liquid.

1H NMR (CDCl3, 300 MHz) 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 compound 22a

To a solution of compound21ain anhydrous toluene in an atmosphere of Ar and at a temperature of 0°C, add the reagent Schwartz hydride chloride (bis(cyclopentadienyl)zirconium(IV), Cp2ZrHCl) and the reaction mixture stirred for 5 min at room temperature. The reaction temperature was raised to 50°C for 20 min and stirred at 50°C for 2,30 o'clock In the course of this time the reaction solution becomes orange. The reaction is cooled to 0°C. and add N-chlorosuccinimide in one piece. Stirring is continued for 30 min at room temperature and the reaction mixture was diluted with hexane/EtOAc (95:5; 500 ml). Remove the solids by filtration and evaporation of volatiles gives compound22ain the form of a yellow oil which is 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 (75 MHz, CDCl3) 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 compound 22b

The flask containing the mixture of compounds21b(4,73 g, 9,85 mmol), quinoline (0,582 ml, to 4.92 mmol) and Lindlar catalyst (2,18 g) in ethyl acetate, vacuum and washed with H2. The reaction mixture was stirred at room temperature in an atmosphere of H2(1 ATM) for 2 h and then filtered through a layer of celite. Layer washed with ethyl acetate and the combined filtrates washed with 0.1% HCl. The organic layer is dried over Na2SO4filter and concentrate to obtain the intermediate compound22b(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 compound 23a

To a solution of compound22a(23 g) in anhydrous THF in an atmosphere of Ar and at a temperature of 0°C is added dropwise a fluoride of tributylamine (TBAF) for 20 min (the solution becomes red). The reaction mixture was stirred at room temperature for 2 h and then quenched with a saturated aqueous solution of N 4Cl (200 ml). The combined layers are separated and the aqueous phase was thoroughly extracted with EtOAc (3×150 ml). The combined organic layers dried over NaSO4filter and concentrate. Flash chromatography (hexane/EtOAc 4:1 to 1:1) gives23ain 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 intermediate compound 23b

PPTS (837,7 mg of 3.33 mmol) added in one portion to a solution of22b(4 g, with 8.33 mmol) in ethanol (80 ml). The reaction mixture was stirred at room temperature for 7 h and then concentrated. The residue was diluted DHM and washed with saturated solution of NaHCO3. The organic layer is extracted, dried over Na2SO4filter and concentrate. Flash chromatography (Hexane/EtOAc, 95:1) gives silloway ether23b(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 compound 24a

(Diacetoxy)benzene (BAIB) (11.5g, to 35.7 mmol) are added to races is the thief of alcohol 23a(9.2 grams, 32,4 mmol) and 1-oxyl 2,2,6,6-tetramethylpiperidine (TEMPO) (515 mg, 3.3 mmol) in anhydrous dichloromethane (92 ml). The reaction mixture was stirred at room temperature for 20 h before until no longer be determined alcohol (TLC), and the mixture is then quenched with saturated aqueous NH4Cl and extracted with DHM (3×100 ml). The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 4:1 to 1:1) to obtain the connection24ain the form of a colorless oil (6.3 g; yield: 70%).

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 compound 24b

BAIB (1.97 g, 6,11 mmol) are added to a solution of alcohol23b(2,05 g, to 5.56 mmol) and TEMPO (86,87 mg, 0,56 mmol) in 25 ml DHM. The reaction mixture was stirred at room temperature for 16-18 h before until the alcohol no longer be detected (TLC), and then quenched with saturated aqueous NH4Cl and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/DHM 5:1 to 1:2) to obtain the connection is of 24b(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 compound 25a

To a suspension of iodide iodocyclization (16.6 g; 31 mmol) in anhydrous THF (126 ml) at room temperature is slowly added 1 M solution of NaHMDS in THF (31,27 ml). After stirring for 2 min yellow mixture is cooled to -78°C and then add a solution of24a(6.3 g, 22 mmol) in THF (82 ml). The reaction mixture was stirred at -78°C for 2 h and at room temperature for 5 min, diluted with hexane and filtered through a layer of celite. Layer washed with hexane, and the combined filtrates evaporated under reduced pressure and the resulting oil purified by chromatography on a column (hexane/EtOAc 12:1 to 8:1) to obtain the25ain the form of a yellow oil (5.6 g; yield: 62%)

1H NMR (CDCl3, 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 compound 25b

To a suspension of iodocyclization (of 3.32 g, 6.38 mmol) in THF (60 ml) and anatoy temperature slowly add 6,83 ml of 1 M solution of NaHMDS (6.38 mmol) in THF. After stirring for 2 min yellow mixture is cooled to a temperature of -78°C and then add24b(1,67 g, 4,56 mmol) in THF (40 ml). The reaction mixture was stirred at -78°C for 90 min, then at room temperature for 5 min, diluted with hexane and filtered through a layer of celite/SiO2. Layer washed with hexane/EtOAc (10:1 to 5:1) to obtain the connection25b(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 compound 25c

2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ) (3.6 g, 16 mmol) are added to a solution of compound25a(5 g; 12 mmol) in DHM-H2O (20:1) in an atmosphere of Ar at room temperature. After 1:30 h (TLC hexane/EtOAc 4:1) shows the absence of starting material), the reaction mixture was quenched by pouring in Et2O (200 ml) and washing with 1 M NaOH (3×50 ml) and saturated salt solution (50 ml). The organic phase is dried over Na2SO4filter and concentrate. Chromatographic separation of n-methoxybenzaldehyde conducted through the restoration to the p-methoxybenzylthio alcohol is. In the end the solution of the residue obtained in MeOH with NaBH4in the atmosphere of Ar, keep at room temperature for 1 h Then the reaction mixture was quenched by pouring in Et2O (100 ml) and washing with 1 M HCl (40 ml) and saturated salt solution (40 ml). The organic phase is dried over Na2SO4filter and concentrate. 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 DHM in Ar atmosphere and at a temperature of 0°C is added dropwise 2,6-lutidine followed by the addition of tert-butyldimethylchlorosilane (TBSOTf) (TLC hexane/DHM 4:1 shows the absence of starting material). At this point, the crude mixture was quenched with 0.5 M HCl (25 ml) and extracted with DHM (2×25 ml). The combined organic layers washed with saturated aqueous NaHCO3and a saturated solution of salt. The organic phase is dried over NaSO4filter and concentrate. Flash chromatography (hexane/EtOAc 100:1 to 20:1) gives compound25cin 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.

EXAMPLE 7: SYNTHESIS of FRAGMENT BCD

On the Hema 4 presents several examples of the synthesis of fragment BCD in accordance with the nomenclature, presented in figure 1.

Scheme 4

Synthesis of intermediate compound 26a

Reseal the tube Slinka download 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 in Pozdnev, V. F., Tetrahedron Letters 1995, 36, 7115-7118) (0.96 g, 4,15 mmol), vacuum and filled with argon.N,N'-dimethylethylenediamine (DMEDA) (0,166 ml, 1.55 mmol), vinylite25c(1.04 g, at 2.59 mmol) and dry DMF (15 ml) is added in an argon atmosphere. Tube Slinka, sealed, heated to a temperature of 90°C for 16-18 h 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 Na2SO4. The solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (hexane/EtOAc, 20:1 to 15:1). The intermediate connection26a(670 mg, yield, 53%) was obtained as oil.

1H NMR (CDCl3, 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), 0,971 (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 compound 26b

Reseal the tube Slinka download 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), vacuum and filled with argon.N,N'-dimethylethylenediamine (DMEDA) (0,26 ml, 2.45 mmol), vinylite25b(2 g, 4,08 mmol) and dry DMF (35 ml) is added in an argon atmosphere. Tube Slinka, sealed, heated to a temperature of 90°C for 16-18 h 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 Na2SO4. The solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (hexane/EtOAc, 20:1 to 15:1). The intermediate connection26b(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 compound -26 C

Reseal the tube Slinka download iodide copper (I) (40,4 g, 0,213 mmol), potassium carbonate (294 g, 2,13 mmol) and Boc-Val-CONH2(obtained by the procedure described in Pozdnev, V. F., Tetrahedron Letters 1995, 36, 7115-7118) (230 mg, 1.06 mmol), vacuum and filled with argon.N,N'-dimethylethylenediamine (DMEDA) (45 μl, 0,426 mmol) vinylite 25c(283 mg, 0.71 mmol) and dry DMF (35 ml) is added in an argon atmosphere. Tube Slinka, sealed, heated to a temperature of 90°C for 16-18 h 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 Na2SO4. The solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (hexane/EtOAc, 7:1 to 3:1). The intermediate connection26C(270 g, yield, 77%) was obtained as oil.

1H NMR (CDCl3, 300 MHz) δ: 7,80 (d, 1H, J=9,3), 6,79-of 6.73 (m, 1H), 5,58 (t, 1H, J=7.5 Hz), 5,02 (users, 1H), 4,85 was 4.76 (m, 1H), 3,93 (DD, 1H, J=8,4, 6,0 Hz), 3,80-to 3.73 (m, 1H), 2,12-2,22 (m, 5H), 2,02 (s, 3H), 1,45 (s, 9H), of 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).

13C NMR (CDCl3, 75 MHz) δ: 169,3, 131,1, 124,0, 122,7, 108,9, 71,6, 36,5, 33,8, 30,6, 28,5, 26,1, 21,3, 19,6, 18,3, 17,9, -4,3, -4,4.

Synthesis of intermediate compound 26d

Reseal the tube Slinka download iodide copper (I) (14,2 mg of 0.075 mmol), potassium carbonate (104 mg, 0.75 mmol) and Fmoc-Phe-CONH2(obtained by the procedure described in Pozdnev, V. F., Tetrahedron Letters 1995, 36, 7115-7118) (145 mg, the 0.375 mmol), vacuum and filled with argon.N,N'-dimethylethylenediamine (16 μl, 0.15 mmol), vinylite25c(100 mg, 0.25 mmol) and dry DMF (2.5 ml) is added in an argon atmosphere. Tube Slinka, sealed, heated to pace the atmospheric temperature of 90°C for 16-18 h 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 Na2SO4. The solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (hexane/EtOAc, 4:1 to 1:1). The intermediate connection26d(46 mg, yield, 42%) are obtained in the form of oil.

1H NMR (CDCl3, 300 MHz) δ: 9,19 (d, 1H, J=11.1 in Hz)of 7.36-7,21 (m, 5H), 6,77 (DDD, 1H, J=10,2, 9,3, 0,9), 5,60 (ushort, 1H, J=7.8 Hz), 4,82-4,78 (m, 1H), 3,79-3,71 (m, 1H), to 3.67 (DD, 1H, J=9,6, 3,9 Hz), 3,32 (DD, 1H, J=13,8, a 3.9 Hz), 2,69 (DD, 1H, J=13,8, 9.6 Hz), 2,20-2,11 (m, 4H), of 1.99 (s, 3H), of 0.89 (s, 9H), of 0.05 (s, 3H), of 0.04 (s, 3H).

13C NMR (CDCl3, 75 MHz) δ: 171,9, 137,9, 130,9, 129,5, 129,1, 127,2, 124,1, 122,5, 107,9, 71,4, 56,6, 40,9, 36,3, 33,6, 26,1, 21,3, 18,3, -4,4, -4,5.

MS (ER) m/z 437,1 [M+H]+, 459,0 [M+Na]+.

Synthesis of intermediate compound 27a

A solution of amino-protected derivative26a(670 mg, of 1.33 mmol) in ethylene glycol (30 ml) is heated at 200°C for 10-20 minutes Then the reaction mixture is cooled at room temperature, diluted with DHM, quenched with a saturated solution of salt and pour in the water. A few drops of 3 M NaOH add up until the pH of the solution becomes equal to 14, and is then thoroughly extracted DHM. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo to obtain the primary amine27a(510 mg, yield: 95%) as a yellow oil, katareena 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 compound 27b

A solution of amino-protected derivative26b(847 mg, 1,43 mmol) in ethylene glycol (50 ml) is heated at 200°C for 10-20 minutes Then the reaction mixture is cooled at room temperature, diluted with DHM, quenched with a saturated salt solution is poured into water. A few drops of 3 M NaOH add up until the pH of the solution becomes equal to 14, and is then thoroughly extracted DHM. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo to obtain the primary amine27b(435 mg, yield: 62%) as a white foam after purification with 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.

Synthesis of intermediate compound 27c

A solution of amino-z is Semenovo derived 26C(255 mg, 0.52 mmol) in ethylene glycol (15 ml) is heated at 200°C for 10-20 minutes Then the reaction mixture is cooled at room temperature, diluted with DHM, quenched with a saturated solution of salt and pour in the water. A few drops of 3 M NaOH add up until the pH of the solution becomes equal to 14, and is then thoroughly extracted DHM. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo to obtain the primary amine27(170 mg, yield: 85%) as a yellow oil which is used without further purification.

1H NMR (CDCl3, 300 MHz) δ: 9,27 (d, 1H, J=10,2), 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 (users, 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, 36,5, 33,7, 30,8, 26,0, 21,3, 20,0, 16,1, -4,3, -4,4.

Synthesis of intermediate compound 28a

To a solution of amine27a(918 mg, of 2.27 mmol) in DHM/DMF (10:1, 39,6 ml) add a solution of (Z)-3-tributylstannyl acid (1028 mg, 2,84 mmol) in dry DHM in an argon atmosphere and then cooled at 0°C. Diisopropylethylamine (DIPEA) (0.6 ml, 3.4 mmol), 1-hydroxy-7-asobancaria (HOAt) (310 mg, of 2.27 mmol) and hexaphosphate N,N,N',N'-tetramethyl-O-(7-asobancaria-1-yl)Urania (HATU) (860 mg, of 2.27 mmol) is added is to the solution and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 20:1 to 15:1) to give the amide28a(1110 mg; 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 compound 28b

To a solution of amine27b(575 mg, 1,17 mmol) in DHM/DMF (4:1, 12.5 ml) add a solution of (Z)-3-tributylstannyl acid (505,6 mg, 1.4 mmol) in dry DHM in an argon atmosphere and then cooled to 0°C. 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) is added to the solution and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 20:1 to 15:1) to give the amide (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.

Synthesis of intermediate compound 28c

To a solution of amine27c(170 mg, 0,437 mmol) in DHM/DMF (10:1, and 7.7 ml) add a solution of (Z)-3-tributylstannyl acid (197,2 mg, 0,546 mmol) in dry DHM in an argon atmosphere and then cooled at 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 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 20:1 to 15:1) to give the amide28c(250 mg, yield: 78%) as a white foam.

1H NMR (CDCl3, 300 MHz) δ: 7,94 (d, 1H, J=10,8 Hz), 7,00 (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, 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, 29,4, 27,6, 26,1, 21,3, 19,5, 18,5, 18,3, 14,0, 11,8, -4,3, -4,4.

Synthesis of intermediate compound 28d

To a solution of amine26d(44 mg, 0.1 mmol) in DHM/DMF (10:1, 1.3 ml) add a solution of (Z)-3-tributylstannyl acid (45 mg, 0.125 mmol) in dry DHM in an argon atmosphere and then cooled at 0°C. To the solution was added DIPEA (26 μl, 0.15 mmol), HOAt (to 13.6 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 20:1 to 15:1) to give the amide28d(60 mg, yield: 80%) as oil.

1H NMR (CDCl3, 300 MHz) δ: the 7.43 (d, 1H, J=10,8 Hz), 7,34-7,22 (m, 5H), 7,02 (d, 1H, J=12.3 Hz), 6,70 (d, 1H, J=12.3 Hz), of 6.66 (DD, 1H, J=9,9, and 9.3 Hz), 6,34 (d, 1H, J=7.8 Hz), the 5.51 (DD, 1H, J=8,1, 7.5 Hz), 4,81-4,71 (m, 2H), 3,68-3,59 (m, 1H), 3,18 (DD, 1H, J=13,5, 6 Hz), 2,69 (DD, 1H, J=13,5, and 8.4 Hz), 2,11-2,04 (m, 2H), a 2.01 (s, 3H), 1,96-to 1.87 (m, 1H), 1,80 is 1.70 (m, 1H), 1,53 was 1.43 (m, 8H), 1,31-of 1.24 (m, 10H), 0,89-0,85 (m, 9H), 0.88 to (s, 9H), of 0.04 (s, 3H), of 0.01 (s, 3H).

13C NMR (CDCl3, 75 MHz) δ: 168,, 166,5, 154,4, 136,7, 135,9, 131,0, 129,5, 129,1, 127,4, 124,0, 122,3, 108,8, 71,5, 55,1, 38,8, 36,6, 33,3, 29,5, 29,4, 27,6, 26,0, 21,3, 18,2, 14,0, 11,8, -4,3, -4,5.

MS (ER) m/z 781,2 [M+H]+, 803,2 [M+Na]+.

Synthesis of intermediate compound 28e

To a solution of amine27A(30 mg, of 0.075 mmol) in DHM/DMF (10:1, 1 ml) add a solution of (E)-3-tributylstannyl acid (33,5 mg, 0,095 mmol) in dry DHM in an argon atmosphere and then cooled at 0°C. To the solution was added DIPEA (19 μl, 0.11 mmol), HOAt (10 mg, of 0.075 mmol) and HATU (27.5 mg, of 0.075 mmol) and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 6:1) to give the amide28th(25 mg, yield: 45%) as oil.

1H NMR (CDCl3, 300 MHz) δ: to 7.68 (d, 1H, J=9,2 Hz), 7,52 (d, 1H, J=18,9 Hz), 6.73 x (t, 1H, J=9,2 Hz), 6,28 (d, 1H, J=10,8 Hz), and 6.25 (d, 1H, J=18,9 Hz), the ceiling of 5.60 (t, 1H, J=7,2 Hz), a 4.83 (q, 1H, J=9,2 Hz), and 4.40 (d, 1H, J=9.6 Hz), of 3.77 (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).

EXAMPLE 8

Figure 5 presents a synthesis of several compounds in accordance with this invention.

Scheme 5

Sin is ez connect 29a

To a solution of alkenylbenzene28a(1.1 g, of 1.47 mmol) and compound17a(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 and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0,5N (3×15 ml). The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 5:1 to 1:1) to obtain the triens29a(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 (user. t, 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 and 2.13 (m, 4H), from 2.00 (s, 3H), is 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 29b

To a solution of alkenylbenzene28b(780,4 mg, 0,904 mmol) and the program 17a(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 min and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0,5N (3×10 ml). The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 5:1 to 1:1) to obtain the triens29b(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-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 29c

To a solution of alkenylbenzene28C(250 mg, 0.34 mmol) and compound17a(142 mg, 0,409 mmol) in NMP (2.5 ml) at 0°C add thiophencarboxylic copper (97 mg, 0.51 mmol). The reaction to shift the ü is stirred at 0°C for 45 min and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0,5N (3×10 ml). The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 10:1 to 6:1) to obtain the triens29s(150 mg, yield: 67%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 8,21 (d, 1H, J=10,8 Hz), 7,28 (t, 1H, J=11.7 Hz), to 6.88 (DD, 1H, J=11,7, and 11.4 Hz), 6,72 (DD, 1H, J=10,2, and 9.3 Hz), 6.42 per (d, 1H, J=8,4 Hz), x 6.15 (d, 1H, J=11.7 Hz), to 5.66 (d, 1H, J=11,4 Hz), 5,61 (DD, 1H, J=5,7, and 3.6 Hz), 5.56mm (ushort, 1H, J=8.1 Hz), 5,27 (d, 1H, J=9.9 Hz), 4,85-of 4.77 (m, 1H), 4,30 (DD, 1H, J=8,1, 7.5 Hz), 4,24-4,16 (m, 1H), 3,79-and 3.72 (m, 1H), 3,66 (s, 3H), 2,88 is 2.80 (m, 1H), 2,42-is 2.37 (m, 2H), 2,18-and 2.14 (m, 5H), from 2.00 (s, 3H)and 1.83 (s, 3H), 1.14 in (d, 3H, J=6.9 Hz), of 0.97 (d, 3H, J=6.6 Hz), is 0.96 (d, 3H, J=6.6 Hz), 0,86 (s, 9H), 0,4 (s, 6H).

13C NMR (CDCl3, 75 MHz) δ: 169,2, 166,8; 161,8; 145,4; 140,5, 137,7; 134,6; 134,3; 131,0, 124,3; 124,2, 122,6; 121,2; 108,6; 108,4; 82,0; 71,5; 58,9; 55,6; 37,5; 36,4; 33,8; 30,8, 26,5; 26,1; 21,3, 19,6, 18,5, 18,3, 17,4, 16,9, -4,3, -4,4.

Synthesis of compound 29d

To a solution of alkenylbenzene28d(60 mg, 0.08 mmol) and compound17a(32.4 mg, 0.09 mmol) in NMP (1 ml) at 0°C add thiophencarboxylic copper (22 mg, 0.12 mmol). The reaction mixture was stirred at 0°C for 45 min and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 0:50 and the combined filtrates washed with HCl 0,5N (3×10 ml). The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 4:1 to 1:1) to obtain the triens29d(13 mg, yield: 25%) as oil.

1H NMR (CDCl3, 300 MHz) δ: to 7.59 (d, 1H, J=11,1 Hz), 7,33-of 7.24 (m, 5H), of 7.23 (t, 1H, J=11.7 Hz), 6.90 to (DD, 1H, J=11,7, and 11.4 Hz), of 6.66 (DD, 1H, J=10,5, 9 Hz), 6,24 (d, 1H, J=7,2 Hz), 6,17 (d, 1H, J=12.0 Hz), 5,63-to 5.58 (m, 2H), the 5.51 (dt, 1H, J=7,8, 1.2 Hz), 5,28 (d, 1H, J=10,8 Hz), 4,79-of 4.67 (m, 2H), 4,24-4,17 (m, 1H), 3,66 (s, 3H), 3,65-3,62 (m, 1H), up 3.22 (DD, 1H J=13,5, 6.3 Hz), 3.04 from (DD, 1H, J=13,8, and 8.4 Hz), 2,89-of 2.81 (m, 1H), 2,43-2,37 (m, 2H), 2,11-2,04 (m, 2H), from 2.00 (s, 3H), of 1.84 (s, 3H), 1.93 and-1,72 (m, 2H), of 1.16 (d, 3H, J=6.9 Hz), 0,86 (s, 9H), 0.03 in (s, 3H), of 0.01 (s, 3H).

13C NMR (CDCl3, 75 MHz) δ: 168,4, 166,5, 161,7, 145,5, 140,8, 138,1, 136,8, 134,5, 134,3, 131,0, 129,5, 129,1, 127,4, 124,2, 124,1, 122,3, 120,4, 108,7, 108,3, 82,0, 71,4, 55,7, 54,9, 38,3, 37,5, 36,6, 33,4, 26,5, 26,0, 21,3, 18,2, 17,4, 16,9, -4,3, -4,4.

MS (ER) m/z 711,2 [M+H]+.

Synthesis of compound 29e

To a solution of alkenylbenzene28th(50 mg, 0,067 mmol) and compound17a(28 mg, 0.08 mmol) in NMP (1 ml) at 0°C add thiophencarboxylic copper (19.1 mg, 0.10 mmol). The reaction mixture was stirred at 0°C for 45 min and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0,5N (3×10 ml). The organic solution is dried and evaporated to obtain the crude is of the product, which is purified by chromatography on a column (hexane/EtOAc 5:1 to 1:1) to obtain the triensE(33 mg, yield: 50%) as oil.

1H NMR (CDCl3, 300 MHz) δ: 7,73 (d, 1H, J=11.4 in Hz)of 7.70 (DD, 1H, J=14,1, 11.7 Hz), of 6.71 (DD, 1H J=a 9.9, 9.7 Hz), 6.30-in (d, 1H, J=9.3 Hz), 6,13 (d, 1H, J=12.9 Hz), 6,04 (DD, 1H, J=11,7, and 11.4 Hz), to 5.93 (d, 1H, J=15,0 Hz), 5,63 (ushort, 1H, J=4.5 Hz), 5,58-of 5.53 (m, 1H), of 5.34 (d, 1H, J=9.9 Hz), 4,85-4,78 (m, 1H), to 4.41 (d, 1H, J=9,3), 4,24-4,16 (m, 1H), of 3.77-and 3.72 (m, 1H), to 3.64 (s, 3H), 2,90-2,78 (m, 1H), 2,45-to 2.41 (m, 2H), 2,19-2,12 (m, 4H), a 2.01 (s, 3H), 1.91 a (s, 3H), of 1.16 (d, 3H, J=6.6 Hz), 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: 168,5, 166,1, 161,8, 145,4, 140,7, 138,0, 135,3, 134,9, 131,1, 125,8, 124,9, 124,0, 122,4, 108,7, 108,5, 81,9, 71,6, 60,9, 55,6, 37,6, 36,5, 35,2, 33,8, 29,9, 26,8, 26,1, 21,3, 18,3, 17,3, 16,9, -4,3, -4,4.

Synthesis of compound 29f

To a solution of alkenylbenzene28a(60 mg, 0,083 mmol) and compound17b(29 mg, 0.09 mmol) in NMP (0.9 ml) at 0°C add thiophencarboxylic copper (24 mg, 0.12 mmol). The reaction mixture was stirred at 0°C for 45 min and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0,5N (3×10 ml). The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 5:1 to 1:1) to give the amide29f(27 mg, yield: 50%) as oil.

1H I Is R (CDCl 3, 300 MHz) δ: a 7.62 (d, 1H, J=10.5 Hz), 7,25 (DD, 1H, J=12,6, and 11.4 Hz), 6,94-6,84 (m, 2H), 6.73 x (DD, 1H, J=10,5, 9.0 Hz), 6,23 (d, 1H, J=9.3 Hz), 6,17 (d, 1H, J=11,4 Hz), 6,06-6,01 (m, 1H), to 5.66 (d, 1H, J=11,4 Hz), the ceiling of 5.60-of 5.55 (m, 1H), from 5.29 (d, 1H, J=9.9 Hz), 4,88-4,80 (m, 1H), 4,34 (d, 1H, J=9.3 Hz), 4,27-4,19 (m, 1H), 3,79-and 3.72 (m, 1H), 2,90-of 2.81 (m, 1H), 2,36-of 2.30 (m, 2H), 2.21 are to 2.13 (m, 4H), 2,03 (s, 3H), of 1.85 (s, 3H), of 1.17 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H), to 0.89 (s, 9H), and 0.08 (s, 3H), 0,06 (s, 3H).

Synthesis of compound 30a

To a solution of29a(275 mg, 0.41 mmol) in THF (6 ml) in an atmosphere of N2and at room temperature is added 1 M 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 NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30a(175 mg; yield: 76%) as a white solid.

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 (users, 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).

Isomer(21S)connection 30aget with the synthesis starting from racemic fragment D. the Final mixture of the Mer [(21S)connection 30a and (21R)-connection 30a] share prepreparation HPLC with reversed phase (SymmetryPrep C18, 7 μm, of 7.8×150 mm, gradient of H2O:MeCN from 50 to 60% MeCN in 30 min, UV determination, flow 2.5 ml/min [CT ((21S)-30a): 15,4 min CT ((21R)-30a): 14,7 min]) and(21S)connection 30aget in pure form:

1H NMR (CDCl3, 300 MHz) δ: to 8.62 (d, 1H, J=10,2 Hz), 7,28-22 (m, 1H), 6,93-6,86 (m, 1H), for 6.81-6.75 in (m, 1H), 6,32 (d, 1H, J=9.0 Hz), 6,17 (d, 1H, J=11.7 Hz), 5,68-to 5.58 (m, 3H), 5,28 (d, 1H, J=10,2 Hz), 4,93-4,84 (m, 1H), 4,32 (d, 1H, J=9.3 Hz), 4,25-4,17 (m, 1H), 3,78-to 3.67 (m, 1H), 3,66 (s, 3H), 2,89-of 2.81 (m, 1H), 2,43-of 2.38 (m, 2H), 2,28-of 2.20 (m, 4H), of 2.08 (s, 3H), of 1.84 (s, 3H), of 1.16 (d, 3H, J=6.9 Hz), of 1.02 (s, 9H).

Synthesis of compound 30b

To a solution of compound29b(586 mg, from 0.76 mmol) in THF (7.5 ml) in an atmosphere of N2and at room temperature is added 1 M 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 NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30b(320 mg, yield: 80%) as a white solid.

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=11,4 Hz), 5,67 (d, 1H, J=11,4 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-,79 (m, 1H), 2,41-is 2.37 (m, 2H), 2,28 with 2.14 (m, 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 30c

To a solution of compound29c(150 mg, 0.23 mmol) in THF (4.8 ml) in an atmosphere of N2and at room temperature add TBAF 1M in THF (0.45 ml, 0.45 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30c(90 mg, yield: 73%) as a white solid.

1H NMR (CDCl3, 300 MHz) δ: 9,16 (d, 1H, J=10,2 Hz), 7,26 (DD, 1H, J=12,0, to 11.1 Hz), 6.87 in (DD, 1H, J=11,7, and 11.4 Hz), 6,79-6,70 (m, 2H), 6,14 (d, 1H, J=11.7 Hz), of 5.68 (d, 1H, J=11.7 Hz), 5,63-to 5.58 (m, 2H), 5,27 (d, 1H, J=9.6 Hz), 4,85 was 4.76 (m, 1H), 4,35 (DD, 1H, J=8,4, 7.5 Hz), 4,24-4,17 (m, 1H), 3,70 at 3.69 (m, 1H), 3,63 (s, 3H), 3.43 points (users, 1H), 2,89 was 2.76 (m, 1H), 2,42-of 2.36 (m, 2H), 2.21 are to 2.14 (m, 4H), 2,03 (s, 3H), equal to 1.82 (s, 3H), of 1.13 (d, 3H, J=6.9 Hz), is 0.96 (d, 6H, J=6.6 Hz).

13C NMR (CDCl3, 75 MHz) δ: 169,7, 167,1, 161,8, 145,4, 140,5, 137,8, 134,6, 134,2, 131,6, 124,4, 123,9, 123,8, 120,7, 108,5, 108,4, 82,0, 59,1, 55,7, 37,5, 36,4, 33,5, 31,0, 26,5, 21,3, 19,5, 18,7, 17,4, 16,8.

MS (ER) m/z 549,0 [M+H]+, 571,1 [M+Na]+.

Synthesis of compound 30d

To a solution of compound29d(11 mg, 0.02 mmol) in THF (0,32 ml) in an atmosphere of N2and at room temperature is added 1 M TBAF in THF (of 0.03 ml, 0.03 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30d(6 mg, yield: 65%) as a white solid.

1H NMR (CDCl3, 300 MHz) δ: 8,54 (d, 1H, J=9.9 Hz), 7,34-of 7.23 (m, 5H), 7,20 (t, 1H, J=11.7 Hz), 6.89 in (DD, 1H, J=11,7, and 11.4 Hz), 6,72 (DD, 1H, J=9,9, and 9.3 Hz), 6,27 (d, 1H, J=8.1 Hz), 6,17 (d, 1H, J=11.7 Hz), 5,63-of 5.53 (m, 3H), 5,28 (d, 1H, J=10,2 Hz), 4,84 was 4.76 (m, 1H), 4.75 V-and 4.68(m, 1H), 4,25-4,17 (m, 1H), 3,66 (s, 3H), 3,67-the 3.65 (m, 1H), 3,18 (DD, 1H, J=13,8, 6.3 Hz), 3,06 (DD, 1H, J=13,8, 8.1 Hz), 2,89-of 2.81 (m, 1H), 2,43-of 2.38 (m, 2H), 2,15-2,10 (m, 3H), of 2.06 (s, 3H), 1,92-to 1.87 (m, 1H), of 1.84 (s, 3H), of 1.16 (d, 3H, J=6.6 Hz).

13C NMR (CDCl3, 75 MHz) δ: 168,6, 166,6, 160,8, 145,8, 140,8, 138,1, 136,8, 134,6, 134,2, 129,6, 129,0, 127,2, 124,1, 124,0, 123,4, 120,4, 108,3, 108,2, 82,0, 71,6, 55,7, 55,0, 38,4, 37,5, 36,4, 33,0, 26,5, 21,3, 17,4, 16,9.

MS (ER) m/z 597,2 [M+H]+.

Synthesis of compound 30e

To a solution of compoundE(32 mg, 0,047 mmol) in THF (1 ml) in an atmosphere of N2and at room temperature is added 1 M TBAF in THF (0,094 ml, 0,094 mmol). The reaction mixture was stirred at room temperature for 18 hours and the ATEM quenched with saturated aqueous NH 4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30e(14 mg, yield: 55%) as a white foam.

1H NMR (CDCl3, 500 MHz) δ: 8,97 (d, 1H, J=10,2 Hz), 7,71 (DD, 1H, J=14,7, 11.7 Hz), 6,74 (DD, 1H, J=9,3, 9.9 Hz), to 6.57 (d, 1H, J=9.0 Hz), x 6.15 (d, 1H, J=11.7 Hz), 6,03 (DD, 1H, J=11,7, and 11.4 Hz), 5,95 (d, 1H, J=14,7 Hz), 5,65-5,58 (m, 2H), 5,35 (d, 1H, J=9.9 Hz), 4,87-4,78 (m, 1H), 4,42 (d, 1H, J=9,3), 4,25-4,18 (m, 1H), 3.72 points-3,68 (m, 1H), the 3.65 (s, 3H), 3,25 (users, 1H), 2,87-and 2.79 (m, 1H), 2,45-to 2.40 (m, 2H), 2.23 to-2,12 (m, 4H), 2,04 (s, 3H), 1,89 (s, 3H)and 1.15 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

13C NMR (CDCl3, 75 MHz) δ: 168,8, 166,5, 161,68, 145,3, 140,9, 138,2, 135,4, 134,7, 132,0, 125,68, 124,6, 123,9, 123,6, 108,6, 108,4, 81,9, 71,7, 61,3, 55,7, 37,5, 36,5, 36,3, 34,9, 33,3, 26,9, 26,7, 21,3, 17,0, 16,7.

MS (ER) m/z 563,3 [M+H]+, 585,2 [M+Na]+.

The synthesis of compounds 30f

To a solution of compound29f(28 mg, 0.04 mmol) in THF (1 ml) in an atmosphere of N2and at room temperature is added 1 M TBAF in THF (0,09 ml, 0.09 mmol). The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol30f(17 mg, yield: 75%) as a white solid.

sup> 1H NMR (CDCl3, 300 MHz) δ: 9,05 (d, 1H, J=10,2 Hz), 7,35 (m, 2H), 7,0 (DD, 1H, J=11,7, and 11.4 Hz), 6.73 x (DD, 1H, J=9,6, and 8.7 Hz), 6,56 (d, 1H, J=8.7 Hz), equal to 6.05 (m, 3H), 5,63-to 5.58 (m, 2H), and 5.30 (d, 1H, J=10,2 Hz), 4,78 (m, 1H), 4,50 (d, 1H, J=9.3 Hz), 3,68 (m, 1H), 3,48 (users, 1H), 2,45 (m, 1H), 2,42-of 2.36 (m, 2H), 2,22-2,11 (m, 4H), 2,04 (s, 3H), equal to 1.82 (s, 3H), 1.14 in (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

Synthesis of compounds 1

To a solution of compound30a(300 mg, of 0.53 mmol) in dichloromethane (7.5 ml) at 0°C add trichlorotriazine (TCAI) (76 μl, 0.64 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 2:1 to 1:2).Connection 1(0.26 g, yield: 81%) was obtained as white solids and receive physical and spectroscopic characteristics (1H,13C NMR and MS)equivalent to those described in example 2.

Isomer(21S)-link 1receive one of two ways:

A) using the same techniques from a mixture of isomers(21R)-and(21S)connection 30aand to the Department of(21S)-link 1prepreparation HPLC with reversed phase (Symmetry Prep C18 7 μm, and 7.8×150 mm, gra is ient H 2O:MeOH from 50 to 100% MeOH for 30 min, UV determination, flow 2.5 ml/min [CT ((21S)-1): 19,2 min CT ((21R)-1): 19,8 min]).

B) according to the method described for compound 1, but starting with a clean(21S)connection 30a.

(21S)connection 1

1H NMR (CDCl3, 500 MHz) δ: 8,69 (d, 1H, J=10.5 Hz), 7,30 (t, 1H, J=11.5 Hz), 6.90 to (t, 1H, J=11.5 Hz), 6,86-PC 6.82 (m, 1H), 6,34 (d, 1H, J=9.0 Hz), 6,17 (d, 1H, J=11.5 Hz), to 5.66 (d, 1H, J=11.5 Hz), 5,64-5,62 (m, 1H), 5,59-5,56 (m, 1H), from 5.29 (d, 1H, J=9.5 Hz), 4,81-of 4.77 (m, 1H), 4,50 is 4.45 (m, 1H), 4,42 (d, 1H, J=9.5 Hz), 4,25-4,20 (m, 1H), 3,66 (s, 3H), 2,89-of 2.81 (m, 1H), 2,44-2,31 (m, 5H), 2,24-2,17 (m, 1H), 2.06 to (s, 3H), 1,84 (, 3H), of 1.16 (d, 3H, J=6.5 Hz), was 1.04 (s, 9H).

13C NMR (125 MHz, CDCl3) δ: 168,4, 166,1, 157,2, 148,3, 145,2, 140,2, 137,4, 134,1, 134,0, 132,0, 124,7, 124,2, 122,4, 120,7, 108,1, 104,7, 81,8, 75,0, 60,8, 55,4, 37,2, 34,8, 32,5, 30,3, 26,7, 26,2, 21,0, 17,1, 16,6.

The synthesis of compounds 4

To a solution of compound30b(56 mg, 0,105 mmol) in dichloromethane (1 ml) at 0°C add trichlorotriazine (15 μl, 0,126 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product, which cleans the HRO what ecografia in column (hexane/EtOAc 3:1 to 1:2). Connection 4(57.6 mg, yield: 96%) was obtained as a white foam and receive physical and spectroscopic characteristics (1H,13C NMR and MS)equivalent to those presented in example 3.

Synthesis of compound 5

To a solution of compound30s(115 mg, 0.21 mmol) in dichloromethane (2 ml) at 0°C add trichlorotriazine (27 μl, 0.23 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 3:1 to 1:2).Connection 5(71 mg, yield: 57%) was obtained as a white foam and receive physical and spectroscopic characteristics (1H,13C NMR and MS)equivalent to those presented in example 3.

The final mixture of isomers (15 mg) share prepreparation HPLC with reversed phase (SymmetryPrep C18, 7 μm, and 7.8×150 mm, gradient of H2O:MeOH 50 to 70% MeOH for 75 min, UV determination, flow 2.5 ml/min [CT ((15R)-7): 18,15 min CT ((15S)-7)]: 19,62 min) and receive 3.1 mg pure(15-R)-compound 7and 2.9 mg of pure(15S)-connection 7.

Isomer(21S)-link 5highlight PR is the purification of the connection 5prepreparation HPLC with reversed phase (Symmetry Prep C8, gradient H2O:MeCN from 45% to 50% MeCN in 30 min, UV determination, the flow of 4.7 ml/min [CT ((21S)-5): 21,6 min CT ((21R)-5)]: 23,6 min). Starting with a sample (50 mg), which contains both isomers, after the above separation receive 39 mg of pure (21R)-connection 5 and 6.1 mg of pure (21S)connection 5.

(21S)connection 5

1H NMR (CDCl3, 500 MHz) δ: a total of 8.74 (d, 1H, J=10.5 Hz), 7,29 (DD, 1H, J=11,7, and 11.4 Hz), 6,94 (DD, 1H, J=11,7, and 11.4 Hz), at 6.84 (DD, 1H, J=10,5, and 9.3 Hz), to 6.22 (m, 2H), of 5.68 (d, 1H, J=11.5 Hz), 5,63 (m, 2H), 5,42 (d, 1H, J=9.3 Hz), 4,81 (m, 1H), to 4.52 (m, 1H), to 4.41 (m, 1H), 4,23 (m, 1H), 3,66 (s, 3H), 2.91 in (m, 1H), 2,49-of 2.38 (m, 3H), 2,35-2,31 (m, 2H), 2,24-2,17 (m, 2H), 2.05 is (s, 3H), equal to 1.82 (s, 3H)and 1.15 (d, 3H, J=6.6 Hz), 0,99 (d, 3H, J=6,9 Hz) to 0.96 (d, 3H, J=6.9 Hz).

MS (ER) m/z 592,3 [M+H]+.

Synthesis of compound 31

To a solution of compound30d(5 mg, 0,008 mmol) in dichloromethane (0.7 ml) at 0°C add trichlorotriazine (1,1 μl, 0,009 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product is and, which is purified by chromatography on a column (hexane/EtOAc 3:1 to 1:2).The connection 31(3.5 mg, yield: 66%) are obtained in the form of a white solid.

1H NMR (CDCl3, 300 MHz) δ: 8,43 (d, 1H, J=10.5 Hz), 7,29-7,19 (m, 6H), 6,91 (DD, 1H, J=11,7, and 11.4 Hz), 6,77 (user. DD, 1H, J=10,2, 9.6 Hz), 6,51 (d, 1H, J=8.1 Hz), 6,16 (d, 1H, J=11,4 Hz), 5,69-5,63 (m, 2H), 5,59 is 5.54 (m, 1H), 5,31 (d, 1H, J=9.3 Hz), 5,12 (users, 1H), 4,91-4,84 (m, 1H), 4,76-4,70 (m, 1H), or 4.31 is 4.13 (m, 2H, CH-5), 3,66 (s, 3H), 3,20 (DD, 1H, J=13,5, 6,9 Hz)to 3.09 (DD, 1H, J=13,5, and 6.6 Hz), 2,89-of 2.81 (m, 1H), 2,48 to 2.35 (m, 2H), 2,28-of 2.23 (m, 3H), of 2.05 (s, 3H), 2,01-1,90 (m, 1H), is 1.81 (s, 3H)and 1.15 (d, 3H, J=6.6 Hz).

13C NMR (CDCl3, 75 MHz) δ: 168,9, 166,5, 161,9, 157,1, 145,4, 140,6, 137,9, 136,4, 134,4, 133,9, 132,1, 129,7, 128,8, 127,2, 124,6, 124,6, 122,7, 120,7, 108,5, 105,6, 82,1, 74,8, 55,7, 54,6, 38,7, 37,2, 33,1, 30,5, 26,2, 21,2, 17,3, 16,4.

Synthesis of compound 8

To a solution of compound30e(13 mg, is 0.023 mmol) in dichloromethane (1.7 ml) at 0°C add trichlorotriazine (3 µl of 0.025 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 3:1 to 1:2).Compound 8(14.3 mg, yield: 100%) are obtained in the form of a white solid substance and get physical and spec is roscopically characteristics ( 1H,13C NMR and MS)equivalent to those shown in example 4.

EXAMPLE 9

Figure 6 depicts a method of synthesis of several compounds in accordance with this invention.

Scheme 6

Synthesis of intermediate compound 32

To a solution of triethyl 4-phosphonocrotonate (3.7 g, 14,66 mmol) and 18-crown-6 (6.2 g, 23,46 mmol) in dry THF (59 ml), stirred in an argon atmosphere at -78°C, are added dropwise KHMDS (28,1 ml, 14,07 mmol). After 15 minutes, added dropwise to the aldehyde12(2.35 g, 5,86 mmol) and stirred for 20 hours at room temperature. Then the reaction mixture was quenched with saturated solution of NH4Cl (200 ml) and diluted with EtOAc. The organic phase is dried (Na2SO4) and evaporated under reduced pressure. Purification by chromatography on a column (hexane/EtOAc 20:1 to 10:1) to give 2.7 g (yield: 93%) of triens32.

1H NMR (300 MHz, CDCl3) δ: 7,31 (DD, 1H, J=11,2, 15.3 Hz), 6,53 (d, 1H, J=15,0 Hz), 6,21 (DD, 1H, J=11,7, to 13.8 Hz), of 5.84 (d, 1H, J=15.1 Hz), 5,61 (d, 1H, J=9.6 Hz), 4,17 (m, 2H), and 3.72 (m, 1H), 3,63 (m, 2H), 2,61 (m, 1H), 1,78 (s, 3H), to 1.67 (m, 2H), 1.26 in (m, 3H), were 0.94 (d, 3H, J=6,7 Hz)of 0.87 (s, 18H), of 0.01 (m, 12H).

Synthesis of intermediate 33

To a solution of compound32(3.75 g, rate of 7.54 mmol) in EtOH (38 ml) is added p-toluensulfonate pyridinium (663 mg, of 2.64 mmol). The reaction mixture is peremeshivayte at room temperature for 17 hours. Then the solvent is removed under reduced pressure, the resulting oil purified by chromatography on a column (hexane/EtOAc 4:1 to 1:1) to obtain 2,11 g (yield: 73%) of alcohol33.

1H NMR (300 MHz, CDCl3) δ: 7,31 (DD, 1H, J=10,8, 15,0 Hz), of 6.52 (d, 1H, J=15.3 Hz), 6,23 (DD, 1H, J=11,1, 15,0 Hz), 5,86 (d, 1H, J=15.3 Hz), 5,52 (d, 1H, J=9.9 Hz), 4,18 (q, 2H, J=7.5 Hz), and 3.72 (m, 3H), 2,73 (m, 1H), equal to 1.82 (s, 3H), by 1.68 (m, 2H), 1.28 (in t, 3H, J=7,2 Hz), and 0.98 (d, 3H, J=6.6 Hz), to 0.88 (s, 9H), and 0.08 (m, 6H).

Synthesis of intermediate compound 34

Alcohol33(130 mg, 0.34 mmol) was stirred at room temperature in DHM (3.4 ml) under inert atmosphere and one portion add periodinane (DMP) (288,5 mg of 0.68 mmol). The reaction mixture is stirred until completion of the reaction (TLC, about 1 hour and then quenched with NaHCO3(saturated solution), extracted with DHM, washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was then purified by chromatography on a column elwira EtOAc/hexane 1:4 with getting about 125 mg (yield: 96%) of aldehyde34in the form of a colorless oil.

1H NMR (300 MHz, CDCl3) δ: 9,79 (s, 1H), 7,31 (DD, 1H, J=11,1, 15.3 Hz), of 6.52 (d, 1H, J=15.3 Hz), and 6.25 (DD, 1H, J=11,1, 15.3 Hz), by 5.87 (d, 1H, J=15.3 Hz), of 5.48 (d, 1H, J=10.5 Hz), 4,19 (q, 2H, J=7,2 Hz), a 4.03 (m, 1H), 2,69 (m, 1H), of 2.54 (m, 2H), 1,80 (s, 3H), of 1.29 (t, 3H, J=6.9 Hz), a 1.01 (d, 3H, J=6.9 Hz), to 0.88 (s, 9H), 0.06 to (m, 6H).

Synthesis of intermediate compound 35

Crestore phosphonate (170 mg, 0.67 mmol) and 18-crown-6 (357 mg, 1.35 mmol) in dry THF (10 ml), stirred in an argon atmosphere at -78°C, are added dropwise KHMDS (of 1.34 ml, 0.67 mmol). After 15 min added dropwise a solution of aldehyde34(170 mg, 0.45 mmol) in dry THF (8.5 ml) for 30 min and stirred at -78°C for 90 minutes Then the reaction mixture was quenched with saturated solution of NH4Cl, warmed to room temperature and diluted with dichloromethane. The organic phase is dried (Na2SO4) and evaporated under reduced pressure. Purification by chromatography on a column (hexane/EtOAc 20:1 to 10:2) to give 170 mg (yield: 82%)(E)-35.

1H NMR (300 MHz, CDCl3) δ: 7,29 (DD, 1H, J=10,8, 15.3 Hz), 6,50 (d, 1H, J=15.3 Hz), to 6.19 (DD, 1H, J=10,8, 15,0 Hz), of 5.83 (d, 1H, J=15.3 Hz), of 5.48 (d, 1H, J=10,2 Hz), 5,33 (t, 1H, J=7,2 Hz), 4,17 (m, 2H), 3,71 (s, 3H), 3,61 (m, 1H), to 3.58 (s, 3H), 2,73 (m, 1H), 2.57 m (m, 2H), 1,71 (s, 3H), 1,25 (m, 3H), of 0.97 (d, 3H, J=6,7 Hz)to 0.88 (s, 9H), 0.03 in (m, 6H).

Synthesis of intermediate compound 36

LiOH (15.8 mg, 0.66 mmol) are added to a solution of ester35(140 mg, 0.30 mmol) in 20% water/dioxane (7 ml) and the mixture is stirred for 4 hours at 60°C. the Mixture is cooled, diluted with DHM and washed with HCl (0,5N, 10 ml). The aqueous phase is re-extracted with DHM and the combined organic layers dried over Na2SO4, filtered and evaporated to obtain the crude di-acid, which is used in the next stage without further purification.

Concentrated HCl (43 ml) are added to a solution of the crude product in MeOH (5.2 ml) and the resulting mixture is stirred for 1 hour at room temperature. Then the solvent is removed under reduced pressure, the resulting oil purified by chromatography on a column (hexane/EtOAc 1:4 to EtOAc/MeOH 5:1) to give 72 mg (yield: 70%) acid36in the form of a colorless oil.

1H NMR (300 MHz, CDCl3) δ: 7,40 (DD, 1H, J=10,8, 15,0 Hz), to 6.57 (d, 1H, J=15,0 Hz), of 6.31 (DD, 1H, J=11,4, 15.3 Hz), of 5.89 (d, 1H, J=15,0 Hz), the ceiling of 5.60 (m, 1H), 5,52 (d, 1H, J=10,2 Hz), 4,22 (m, 1H), to 3.64 (s, 3H), 2,90 (m, 1H), of 2.38 (m, 2H,), of 1.84 (s, 3H)and 1.15 (d, 3H, J=6.9 Hz).

Synthesis of compound 37

To a solution of amine27E(37.6 mg, 0,093 mmol) in DHM/DMF (10:1, 1.3 ml) add a solution of acid36(30 mg, 0,103 mmol) in dry DHM in an argon atmosphere and then cooled at 0°C. To the solution was added DIPEA (26 μl, 0.14 mmol), HOAt (12.7mm mg, 0,093 mmol) and HATU (35.4 mg, 0,093 mmol) and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 2:1 to 1:4) to give the amide37(34.7 mg, yield: 55%) as oil.

1H NMR (CDCl3, 500 MHz) δ: 7,88 (d, 1H, J=10.5 Hz), 7,26 (the d, 1H, J=14,4, and 11.4 Hz), 6,72 (DD, 1H, J=a 9.9 and 9.6 Hz), 6,50 (d, 1H, J=15.3 Hz), of 6.31-to 6.22 (m, 2H), 5,94 (d, 1H, J=14,7 Hz), 5,61 is 5.54 (m, 2H), 5,44 (d, 1H, J=9.9 Hz), 4,87-rate 4.79 (m, 1H), 4,45 (d, 1H, J=9,3), 4,24-of 4.16 (m, 1H), of 3.77-3,44 (m, 1H), to 3.64 (s, 3H), 2,96-2,2,81 (m, 1H), 2,39 to 2.35 (m, 2H), 2,16-of 2.15 (m, 4H), for 2.01 (s, 3H), equal to 1.82 (s, 3H), 1.14 in (d, 3H, J=6.6 Hz), of 1.02 (s, 9H), of 0.87 (s, 9H), 0.06 to (s, 3H), 0,05 (, 3H).

Synthesis of compound 38

To a solution of compound37(28 mg, 0.04 mmol) in THF (0.6 ml) in an atmosphere of N2and at room temperature is added 1 M TBAF in THF (83 μl, 0.08 mmol). The reaction was stirred at room temperature for 18 hours and then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 3:1 to 1:2) to give alcohol38(22 mg, yield: 96%) as a white solid.

1H NMR (CDCl3, 500 MHz) δ: 9,06 (d, 1H, J=9.9 Hz), 7,24 (DD, 1H, J=14,7, 10.5 Hz), 6,76 (d, 1H, J=9.6 Hz), 6,74 (DD, 1H, J=a 9.6, 9.6 Hz), 6,50 (d, 1H, J=15.3 Hz), and 6.25 (DD, 1H, J=15,3 and 11.1 Hz), of 5.99 (d, 1H, J=14,7 Hz), 5,65-the ceiling of 5.60 (m, 2H), of 5.45 (d, 1H, J=9.9 Hz), 4,87-to 4.81 (m, 1H), 4,45 (d, 1H, J=9,3), 4,24-4,16 (m, 1H), 3,74-to 3.64 (m, 1H), to 3.64 (s, 3H), 3,22-3,17 (m, 1H), 2.95 and-2,2,82 (m, 1H), 2.40 a to 2.35 (m, 2H), 2,23-of 2.16 (m, 4H), 2,05 (s, 3H), of 1.81 (s, 3H), of 1.13 (d, 3H, J=6.6 Hz), of 1.03 (s, 9H).

Synthesis of compound 3

To a solution of compound38(20 mg, 0.04 mmol) in dichloromethane (0.35 ml) at 0°C add trichloroacetimidate the NAT (5,1 μl, 0.04 mmol). The reaction mixture was stirred at 0°C for 30 min and then add neutral alumina. The mixture is stirred for 5-30 min and then soaked in a layer of aluminum oxide. The product is washed with a blend of DHM/MeOH 50:1. The filtrate is evaporated in vacuum to obtain the crude product, which was purified by chromatography on a column (hexane/EtOAc 1:1 to 1:3). Connection3(13,6 mg, yield: 63%) was obtained as a white foam and receive physical and spectroscopic characteristics (1H,13C NMR and MS)equivalent to those presented in example 3.

EXAMPLE 10

Figure 7 depicts a method of synthesis of compound 7.

Scheme 7

Synthesis of intermediate compound 40

To a solution of Boc-tert-LeuCONH239(obtained by the procedure described in Pozdnev, V. F., Tetrahedron Letters 1995, 36, 7115-7118) (1.9 grams, compared to 8.26 mmol) in MeOH added 66 ml of 1.25 M HCl in MeOH. The reaction mixture is stirred for 2 hours at room temperature and then concentrated under reduced pressure. The solid is then suspended in MeOH and neutralized with concentrated ammonium hydroxide. The solvent is removed on a rotary evaporator and the crude residue dissolved in dichloromethane. The solution is dried over Na2SO4, filtered and conc is the shape with the getting 730 mg (yield: 68%) of intermediate compound 40 as a white solid.

1H NMR (CDCl3, 300 MHz) δ: 6,65-6,55 (users, 1H), 5,65-5,55 (users, 1H), 3,18 (s, 1H), 1,65-1.55V (users, 2H), of 1.05 (s, 9H).

Synthesis of intermediate compound 41

To a solution of amine40(100 mg, 0.77 mmol) in DHM/DMF (10:1, and 7.7 ml) add a solution of (Z)-3-tributylstannyl acid (306 mg, 0.85 mmol) in dry DHM in an argon atmosphere and then cooled at 0°C. To the solution was added DIPEA (with 0.27 ml, 1.54 mmol), HOAt (115,6 mg, 0.85 mmol) and HATU (323 mg, 0.85 mmol) and after 30 min the cold bath removed. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NH4Cl, poured into water and extracted with DHM. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 10:1 to 1:1) to give the amide41(228 mg, yield: 63%) as a white foam.

1H NMR (CDCl3, 300 MHz) δ: 6,99 (d, 1H, J=12.3 Hz), 6,77 (d, 1H, J=12.3 Hz), 6,47 (d, 1H, J=9.6 Hz), 6,38 (users, 1H), 6,12 (users, 1H), 4,46 (d, 1H, J=9.9 Hz), 1,48-of 1.40 (m, 6H), 1,31-1,19 (m, 12H), and 1.00 (s, 9H), 0,89-of 0.83 (m, 9H).

13C NMR (CDCl3, 75 MHz) δ: 173,4, 166,6, 153,4, 136,6, 60,0, 35,0, 29,6, 27,6, 26,8, 14,0, 11,7.

Synthesis of compound 7

To a solution of alkenylbenzene41(227,6 mg, 0.48 mmol) and compound17a(200,9 mg of 0.58 mmol) in NMP (5 ml) at 0°C add thiophencarboxylic copper (19.1 mg, 0.10 mmol). The reaction mixture was stirred at 0°C for 45 minutes and 20 min at room temperature. Then the crude mixture is filtered through a layer of neutral aluminum oxide, washed with EtOAc/simple ether 50:50 and the combined filtrates washed with HCl 0.1 percent. The organic solution is dried and evaporated to obtain the crude product, which was purified by chromatography on a column (dichloromethane/MeOH 100:1 to 10:1) to obtain compound 7 (and 65.7 mg, yield: 34%) as a white foam. This product synthesis demonstrates the physical and spectroscopic characteristics (1H,13C NMR and MS)equivalent to those presented in example 3.

Isomer(15R)-link 7get if racemic mixture of amino acids (Boc-tert-LeuCONH2) used for these reactions. The final mixture of isomers (15 mg) share prepreparation HPLC with reversed phase (SymmetryPrep C18, 7 μm, and 7.8×150 mm, gradient of H2O:MeOH 50 to 70% MeOH in 75 min, UV determination, flow 2.5 ml/min [CT ((15R)-7): 18,15 min CT ((15S)-7)]: 19,62 min) and receive 3.1 mg pure(15-R)-Compound 7and 2.9 mg of pure(15S)-Link 7:

(15R)-connection 7

1H NMR (MeOD, 500 MHz) δ: 7.23 percent (DD, 1H, J=12,5, and 11.5 Hz), 6,94 (DD, 1H, J=12,5, and 11.5 Hz), 6,18 (d, 1H, J=12.0 Hz), 5,91-5,88 (m, 1H), 5,86 (t, 1H,J=4.5 Hz), of 5.34 (d, 1H, J=10.0 Hz), 4,33-to 4.28 (m, 1H), to 3.64 (s, 3H), 2,92-is 2.88 (m, 1H),2,47 is 2.44 (m, 2H), of 1.85 (s, 3H), of 1.17 (d, 3H, J=6.6 Hz), of 1.02 (s, 9H).

13C NMR (MeOD, 125 MHz) δ: 175,3, 168,6, 164,0, 146,0, 140,8, 138,2, 135,4, 135,4, 125,5, 121,9, 111,1, 83,5, 61,8, 55,9, 38,4, 35,0, 27,2, 27,1, 17,3, 16,8.

EXAMPLE 11

Figure 8 illustrates methods of preparing compounds 42 and 43.

Scheme 8

Synthesis of compound 42

To a solution of alcohol30a(5 mg, 8,8 mmol) in pyridine (0.45 ml) add phenylisocyanate (29 ml, 0.27 mmol). The reaction mixture was stirred at room temperature for 20 hours and then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases are dried over Na2SO4filter and concentrate. The residue is purified with flash chromatography (hexane/EtOAc 20:1 to 1:1) to obtain the connection42(2.7 mg, yield: 44%) as a white solid.

1H NMR (CDCl3, 300 MHz) δ: 8,81-8,77 (m, 1H), 7,46-the 7.43 (m, 2H), 7,34-of 7.23 (m,3H), 7,11-7,06 (m, 2H), 6,88-6,77 (m, 2H), to 6.39 (d, 1H, J=9.9 Hz), 6,10 (d, 1H, J=11.7 Hz), 5,67-to 5.57 (m, 3H), 5,27 (d, 1H, J=9.9 Hz), 4,85-4,78 (m, 1H), 4,62-4,56 (m, 1H), 4,54 (d, 1H, J=9.3 Hz), 4,25-4,17 (m, 1H), 3,66 (s, 3H), 2,87 is 2.80 (m, 1H), 2,41-of 2.38 (m, 5H), 2.21 are to 2.13 (m, 1H), 2,08 (s, 3H), equal to 1.82 (s, 3H), of 1.16 (d, 3H, J=6.6 Hz), with 1.07 (s, 9H).

Synthesis of compound 43

Alcohol30a(5 mg, 8,88 mmol) was stirred at room temperature in DHM (0.1 ml) in an inert atmosphere and add periodinane(7.5 mg, 0.018 mmol) in one portion. The reaction mixture is stirred until completion of the reaction (TLC, about 1 hour and then quenched with NaHCO3(saturated solution), extracted with DHM, washed with saturated salt solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was then purified by chromatography on a column elwira EtOAc/hexane 1:1 to obtain about 4.5 mg (yield: 90%) of ketone43in the form of a colorless oil.

1H NMR (CDCl3, 300 MHz) δ: 8,32 (d, 1H, J=9.9 Hz), 7,31-of 7.23 (m, 1H), 6,91 (DD, 1H, J=11,7, and 11.4 Hz), at 6.84 (DD, 1H, J=9,9, to 8.7 Hz), of 6.26 (d, 1H, J=8.7 Hz), 6,18 (d, 1H, J=11,4 Hz), 5,78-5,73 (m, 1H), of 5.68 (d, 1H, J=11,4 Hz), 5,64-5,61 (m, 1H), 5-30-5,27 (m, 1H), 4,94-a 4.86 (m, 1H), to 4.41 (d, 1H, J=9.0 Hz), 4,25-4,17 (m, 1H), 3,66 (s, 3H), 3,18 (DD, 4H, J=18,3, 7,2 Hz), 2,89 is 2.75 (m, 1H), 2,44-of 2.38 (m, 2H), 2,04 (s, 3H), of 1.84 (s, 3H), of 1.16 (d, 3H, J=6.9 Hz), of 1.05 (s, 9H).

EXAMPLE 12: BIOASSAYS TO determine the ANTITUMOR ACTIVITY

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

CELL LINE

NameNo. ATCCTypesClothFeatures
A549 CCL-185humaneasycarcinoma of the lung (NSCLC)
HT29HTB-38humancoloncolorectal adenocarcinoma
MDA-MB-231HTB-26humanmammary glandbreast adenocarcinoma

EVALUATION of the CYTOTOXIC ACTIVITY USING COLORIMETRIC ANALYSIS SBR

Colorimetric type of analysis using the reaction sulforhodamine B (SRB) adapted for the quantitative measurement of growth and viability of cells (using methods described by Skehan P, et al. J. Natl. Cancer Inst. 1990, 82, 1107-1112).

In this kind of analysis applied SBS-standardized 96-well microplates for cell 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). All cell lines used in this study are obtained from various types of human cancer, taken from the American Type Culture Collection (ATCC).

Cells incubated in modified according to the method of Dulbecco environment Needle (DMEM) supplemented with 10% fetal those who Yak serum (FCS), 2 mm L-glutamine, 100 Units/ml penicillin and 100 U./ml streptomycin at 37°C, 5% CO2and 98% humidity. For experiments, cells collected from subconfluent crops using trypsinization and re-suspended in fresh medium before counting and placing them in tablets.

Cells seeded in 96-well title microplate in an amount of 5×103cells per well in 150 μl aliquot and allowed to attach to the tablet surface for 18 hours in not containing medicines environment. One control (untreated) tablet for each type of fixed cells (as described below) and used as reference values for the zero time value. Then the test samples added to the culture ten serial dilutions, aliquot 50 ál, 10 to 0,00262 µg/ml After 48 hours of processing antitumor activity assessed by the SRB method: briefly, cells are washed twice FRFB, fixed for 15 min in 1% solution of glutaraldehyde, washed twice in RFB and stained in 0.4% SRB solution for 30 min at room temperature. The cells are then washed several times with 1% acetic acid solution and air-dried. Then the SRB is extracted in 10 mm main trizma solution and the absorbance was measured in an automated spectrophotometric tablet reader at 490 nm. The survival of cells expressed the t as a percentage of the growth of control cells. The final action of the test specimen is assessed using an algorithm NCI (Boyd and MR Paul KD. Drug Dev. Res. 1995, 34, 91-104).

Applying the mean ± SD from three cultural samples automatically build the curve dose-effect using the analysis of nonlinear regression. Expect three reference parameter (algorithm NCI) using mathematical interpolation: GI50= the concentration that gives 50% inhibition of growth; TGI = total growth inhibition (cytostatic effect) and LC50= the concentration that gives 50% of the total cell killing (cytotoxic effect).

The PROTOCOL ANTIMITOTICESCOY ANALYSIS

Mitotic ratio of cell cultures (percentage of cells arrested in mitosis) estimate using a specific immunoassay using 96-well microplate, which quantitatively defines specific mitotic marker. HeLa cells (h-cervical carcinoma, ATCC# CCL-2) incubated for 18 hours in the presence or in the absence of the test specimen. The cells are then washed RFB and are lysed on ice in 75 ál of freshly prepared lisanova buffer (1 mm EGTC (pH 7.5), 0.5 mm PMSF and 1 mm NaVO3within 30 minutes an Aliquot of the cell extract (60 μl) is transferred into the tablet ELISA with highly-binding surface and dried in a speed vacuum for 2 h at room temperature. Tablets blocks the comfort in 100 μl FRFB - 1% ABS for 30 min at 30°C and then incubated with anti-MPM2 primary mouse monoclonal antibody (Upstate Biotechnology, cat # 05-368) for 18 h at 4°C and the appropriate peroxidase-conjugated secondary antibody for 1 h at 30°C. After extensive washing in 0.02% Tween-20 spend peroxidase reaction using 30 μl of TMB (3,3',5,5'-tetramethylbenzidine) for 30 min at 30°C. the Reaction is stopped by adding 30 μl of a 4% solution of H2SO4. Perform quantitative analysis by measuring the O.D. at 450 nm in a microplate spectrophotometer. The results are expressed as IC50the concentration of the sample, which gives a 50% stop mitosis in the treated cell cultures compared with control, untreated cultures.

In tables 9 and 10 show the data of biological activity of compounds in accordance with this invention.

Table 9
Analysis of cytotoxicity data activity (molar)
Connection 1Connection 2Connection 3Connection 4
MDA-MB-2314,45E-109,85E-099,24E-106,13E-10
TGI9,90E-102,15E-082,47E-091,49E-09
LC502,80E-097,20E-089,57E-098,23E-09
HT29GI504,62E-108,31E-094,45E-10<4,31E-10
TGI6,10E-101,09E-087,59E-109,28E-10
LC509,90E-101.72e-08>1,65E-071,12E-09
A549GI503,79E-108,63E-091,02E-095,95E-10
TGI1,09E-09 2,37E-084,29E-092,45E-09
LC50>1,65E-071,65E-05>1,65E-07>1.64e-06

Table 9
(continued)
Connection 5Connection 6Connection 7Compound 8
MDA-MB-231GI501,03E-104,90E-104,20E-073,46E-09
TGI4,56E-103,21E-098,41E-071,01E-08
LC504,90E-091,55E-082,45E-064,12E-08
HT29GI504,39E-115,91E-10,20E-07 2,14E-09
TGI1,28E-101,01E-095,44E-073,13E-09
LC50>1,69E-074,90E-098,16E-076,27E-09
A549GI506,08E-117,60E-106,18E-073,63E-09
TGI3,21E-10>1.64e-061,19E-061,30E-08
LC50>1,69E-07>1.64e-06>2,47E-06>1,65E-06

Table 9
(continued)
Compound 29AConnection 29dCompound 29eConnection 30a
GI501,18E-061,10E-061,14E-061,95E-09
TGI2,80E-061,39E-061,48E-069,41E-09
LC506,20E-061,83E-062,07E-068,52E-08
HT29GI506,05E-078,29E-072,07E-061,35E-09
TGI1,42E-068,72E-072,21E-062,13E-09
LC504,43E-069,28E-072,36E-061,01E-08
A549GI508,86E-074,64X-071,15E-062,31E-09
TGI 3.40e-068,01E-071,77E-061,37E-07
LC508,56E-061,38E-062,66E-06>1,78E-06

Table 9
(continued)
Compound 30bCompound 30cConnection 30dConnection 30f
MDA-MB-231GI502,08E-089,83E-103,10E-106,94E-07
TGI5,11E-075,83E-097,03E-101,07E-06
LC505,11E-065,28E-08>1,67E-081,61E-06
HT29GI509,84E-09 4,74E-101,32E-104,88E-07
TGI9,27E-088,38E-102,51E-107,13E-07
LC504,73E-06>1,82E-07>1,67E-081,05E-06
A549GI502,27E-087,10E-103,18E-104,88E-07
TGI3,22E-073,10E-091,06E-096,57E-07
LC50>1,89E-05>1,82E-07>1,67E-089,19E-07

Table 9
(continued)
Connection 30eThe connection 31 The connection 37Compound 38
MDA-MB-231GI502,31E-087,50E-113,10E-066,04E-08
TGI6,57E-081,50E-105,61E-06>1,78E-07
LC502,66E-073,59E-10>1,48E-05>1,78E-07
HT29GI501,35E-084,06E-111,92E-063,91E-08
TGI2,13E-081,02E-102,95E-066,39E-08
LC504,44E-08>1,56E-081,00E-05>1,78E-07
A549GI503,55E-089,22E-11 3,54E-064,62E-08
TGI3,02E-072,19E-106,64X-066,75E-08
LC503,55E-06>1,56E-081,39E-05>1,78E-07

Table 9
(continued)
Connection (21S)-1Connection (21S)-5Connection (15R)-7Connection (21S)-30a
MDA-MB-231GI501,65E-094,56E-097,66E-072,49E-09
TGI5,77E-091,86E-082,47E-062,13E-08
LC503,46E-081,03E-07>2,47E-05 2,84E-07
HT29GI508,91E-102,53E-093,46E-072,66E-09
TGI1,63E-092,87E-095,93E-073,02E-09
LC502,31E-083,88E-091,31E-06>1,63E-06
A549GI502,14E-096,92E-091,04E-063,73E-09
TGI4,29E-082,87E-083,46E-061,95E-07
LC50>1,65E-06>1,69E-06>2,47E-05>1,63E-06

Table 10
Antimitoticescoe analysis - activity data (molar)
compounds 1 and 2
IC50
Connection 12,64X-8
Connection 22,64X-8

1. The compound of General formula I

where R1selected from hydrogen ORa, OCORa, OCOORa, NRaRb, NRaCORband NRaC(NRa)NRaRb;
each R2and R3independently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil;
each R41, R42, R43, R44, R45, R46, R47and R48independently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil;
each R5, R6and R7independently selected from hydrogen, CORa, COORasubstituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl and substituted or unsubstituted C2-C12the quinil, or R5and R48together with the corresponding N atom and the atom to which they accession the s, may form a substituted or unsubstituted heterocyclic group;
each Raand Rbindependently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted With2-C12the quinil, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclic group; and
each dotted line represents an optional additional bond;
or its pharmaceutically acceptable salt, tautomer or stereoisomer.

2. The compound according to claim 1, having formula II

where R1, R41, R43and R48, R5, R6and R7such as defined in claim 1, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

3. The compound according to claim 1, where R2and R3each independently selected from hydrogen and substituted or unsubstituted C1-C6the alkyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

4. The compound according to claim 3, where R2and R3are hydrogen, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

5. The compound according to any one of the preceding paragraphs, where R1selected from hydrogen ORaand OCORawhere Raselected from hydrogen and substituted sludge is unsubstituted With 1-C6the alkyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

6. The compound according to claim 5, where R1is hydrogen or methoxy, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

7. The compound according to any one of claims 1 and 3-4, where R42, R44, R45, R46and R47groups independently selected from hydrogen and substituted or unsubstituted With1-C6the alkyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

8. The connection according to claim 7, where R42, R44, R45, R46, R47groups independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted isopropyl and substituted or unsubstituted tert-butyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

9. The connection of claim 8, where R42, R44, R45, R46and R47are hydrogen, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

10. The compound according to any one of claims 1 to 4, where R41, R43and R48groups independently selected from hydrogen and substituted or unsubstituted C1-C6the alkyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

11. The connection of claim 10, where the group R41, R43and R48independently selected from hydrogen, Samusenko is about or unsubstituted methyl, substituted or unsubstituted isopropyl and substituted or unsubstituted tert-butyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

12. Connection to item 11, where R41and R43are the stands, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

13. The connection section 12, where R48selected from isopropyl, tert-butyl and benzyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

14. The compound according to any one of claims 1 to 4, where R5and R6each independently selected from the group comprising hydrogen and substituted or unsubstituted C1-C6alkyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

15. The connection 14, where R5and R6are hydrogen, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

16. The compound according to any one of claims 1 to 4, where R7selected from hydrogen, substituted or unsubstituted C1-C12of alkyl and substituted or unsubstituted C2-C12alkenyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

17. Connection P16, where R7selected from hydrogen and substituted C2-C12alkenyl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

18. The connection 17, where R7is alkenylphenol GRU is sing, which is substituted in one or more positions by halogen, OR', =O, OCOR', OCONHR', OCON(R')2and HE substituted, where each group R' is independently selected from hydrogen, substituted or unsubstituted C1-C12of alkyl, substituted or unsubstituted C2-C12alkenyl, substituted or unsubstituted C2-C12the quinil and substituted or unsubstituted aryl, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

19. The compound according to any one of claims 1 to 4, where additional bond is present in all places, indicated by the dotted line, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

20. The compound according to claim 1 or 2, having the following formula:








or its pharmaceutically acceptable salt, tautomer or stereoisomer.

21. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

22. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or article shall reasoner.

23. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

24. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

25. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

26. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

27. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

28. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

29. The compound according to claim 1 or 2, having the following formula:



























or its pharmaceutically acceptable salt, tautomer or stereoisomer.

30. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

31. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

32. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

33. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

34. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

35. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

36. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

37. The compound according to claim 1 or 2, having the following formula:

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

38. The compound according to claim 1 or 2, having the following formula

or its pharmaceutically acceptable salt, tautomer or stereoisomer.

39. The method of obtaining the connection defined in claim 20, or its pharmaceutically acceptable salt, tautomer or stereoisomer, which includes the stages of extraction and selection of Lithoplocamia lithistoides.

40. Antitumor pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or its pharmaceutically acceptable salt, tautomer or stereoisomer, and a pharmaceutically acceptable diluent or carrier.

41. The compound according to any one of claims 1 to 38, or its pharmaceutically acceptable salt, tautomer or stereoisomer for use in the treatment of cancer.

42. The composition according to p used is in the treatment of cancer.

43. The use of compounds as defined in any one of claims 1 to 38, or its pharmaceutically acceptable salt, tautomer or stereoisomer for the manufacture of a medicinal product for the treatment of cancer.

44. The use of a composition according p for the manufacture of a medicinal product for the treatment of cancer.

45. A method of treating a mammal affected by cancer, which includes the introduction of a cancer patient a therapeutically effective amount of a compound defined in any one of claims 1 to 38, or its pharmaceutically acceptable salt, tautomer or stereoisomer.

46. The method according to item 45, where the mammal is man.



 

Same patents:

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: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, characterised by X-ray powder diffraction pattern with principal peaks either at 2θ = 16.1 ± 0.2, 20.1 ± 0.2, 20.7 ± 0.2, and 24.2 ± 0.2, or at 2θ = 9.0 ± 0.2, 14.7 ± 0.2, 19.6 ± 0.2, 21.6 ± 0.2 and 24.3 ± 0.2. The invention also relates to methods of obtaining the disclosed crystalline forms, a pharmaceutical composition having thyroid beta-receptor agonist properties, a method for selective agonist action on thyroid beta-receptor, use of said forms to produce a medicinal agent and a method of treating mammals suffering from thyroid dysfunction associated conditions.

EFFECT: obtaining novel crystalline forms of 3-[[3,5-dribromo-4-[4-hydroxy-3-(1-methylethyl)phenoxy]phenyl]amino]-3-oxopropanoic acid, having thyroid beta-receptor agonist properties.

19 cl, 3 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used for combination treatment of locally advanced non-small-cell lung cancer. That is ensured by thorax computed tomography to determine an area of parietal and visceral pleura. It is attended by lung reduction with mediastinal lymph node dissection. That is accompanied with intraoperative photoradiation therapy. It is ensured by intravenous introduction of Photoditasine 0.8-1.0 mg/kg of body weight, In 2 hours, a lymph node dissection region, bronchial and vascular stumps are exposed to light stimuli generated by a diode laser at wave length 662 s and power density 40 J/cm2 for a time estimated on account of the area of the lymph node dissection regions, the bronchial and vascular stumps. It is followed by light stimuli covering the parietal and visceral pleura at power density 4 J/cm2 for a time estimated on account of the area of the bronchial and vascular stumps.

EFFECT: method provides improved therapeutic effects ensured by destruction of the lesions both within the lymph node dissection region, and on the periphery of the lung root reduction and tumour cell resorption in the operative wound, prevention of developing recurrent tumour growth within the pleural cavity.

6 cl, 2 dwg, 3 tbl, 2 ex

Drug preparation // 2444362

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns an antineoplastic drug containing a compound of formula

,

a method for treating a tumour and using the compound of formula (1) for preparing the antineoplastic drug.

EFFECT: drug preparation shows high activity and high safety.

54 cl, 435 tbl, 2717 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fluorinated derivatives of 1,4-naphthoquinone of general formula (II), having cytotoxic effect on human cancer cells in a culture. In formula (II) R = NHCH2COOH, NHCH2COOC2H5, NH(CH2)5COOH, NH(CH2)3COOH, NH(CH2)2COOH, OOC(CH2)3NH2.

EFFECT: disclosed compounds can be used in medicine for therapy of malignant growths.

1 dwg, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition for injections contains a mixture of platinum complex of formula II and at least one cyclodextrin and/or at least one cyclodextrin derivative selected from a group comprising alpha-, beta- and gamma-cyclodextrins and their alkylated derivatives in mass ratios within 1:0.1 to 10:1 respectively, and optionally at least one pharmaceutically acceptable excipient. The composition is presented in the form of an aqueous solution prepared by adding an aqueous medium to cyclodextrin or its derivative that is followed by adding the platinum complex of formula ;

or adding the aqueous medium to the mixed platinum complex of formula II and/or at least one cyclodextrin derivative; or adding cyclodextrin or its derivative to the suspension of the platinum complex of formula II in the aqueous medium.

EFFECT: preparing the inclusion complex in the aqueous medium is considerable facilitation of the method for producing the complex and preparing the injected pharmaceutical composition.

3 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly oncology, and can be applied in treating non-muscle invasive bladder cancer. The method involves adjuvant intra-bladder therapy with chemopreparations pre-dissolved in Tisol, aqueous solution. The tumpours with a low risk of relapse and progression require single instillations immediately following the operation of doxorubicine 50 mg or mitomycin 40 mg pre-dissolved in 40% Tisol, aqueous solution 50 ml with the length of exposition 1 h. In the tumours with a medium risk of relapse and progression, the postoperative instillations are added with intra-bladder chemotherapy with doxorubicine 50 mg or mitomycin 40 mg pre-dissolved in Tisol, aqueous solution with the length of exposition 1 h once every 6 weeks.

EFFECT: use of the invention provides higher clinical effectiveness and decreases a degree of side effects due to the adjuvant intra-bladder therapy according to a degree of postoperative risk of relapse and progression of the tumour.

3 tbl, 1 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns a method for treating a proliferative disease associated with PAX/FKHR translocation by introducing N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j[1,7]benzodiazonin-11-yl]-H-methylbenzamide.

EFFECT: invention provides high clinical effectiveness.

4 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered a pharmaceutical combination for treating a proliferative disease containing a) 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-phenyl]benzamide (nilotinib) and b) at least one mTOR kinase inhibitor selected from a group including rapamycin RAD (sirolimus) and its derivatives/analogues, such as everolimus, or RAD001, CCI-779, ABT578, SAR543, ascomycin (ethyl analogue FK506), AP23573 and AP23841, an appropriate method of treating or preventing a proliferative disease, a method of treating leucosis with using such combination, as well as application thereof for treating or preventing a proliferative disease (versions). Synergetic action of the combination in treating cancer is shown. A mechanism of action of the combination is suggested: Bcr-Abl, , or Fit-3 kinase expression inhibition.

EFFECT: preparing the pharmaceutical combination for treating a proliferative disease.

7 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

FIELD: medicine.

SUBSTANCE: invention relates to veterinary. Veterinary composition for prevention and treatment of various form of endometritis contains propanol in combination with antibacterial component, water polymers of polysaccharide class, mixture of fat-soluble vitamins A, D and E and pharmaceutically suitable solvent, as antibacterial component used is either antibiotic, selected from group of macrolides, aminoglycosides, polypeptides, linkosamides, cephalosporins, or sulfanilamide, or antiseptic, selected from group, including benzalkonium chloride, benzethonium chloride, nipagin, nirasol or their combination. Veterinary medication for prevention and treatment of various form of endometritis contains claimed composition and can represent solution or suspension for intrauterine introduction.

EFFECT: invention ensures increase of treatment efficiency.

9 cl, 6 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to suppositories for treating proctologic and gynaecologic diseases. Said suppositories contain a drug in the form of the dehydrated preparation 'Baliz' or a power-predried form of the preparation 'Baliz', or an active substance pre-recovered from the preparation 'Baliz' in the form of comenic acid or its salts, and also a base representing fatty substances, and a food or medicinal emulsifier.

EFFECT: higher therapeutic clinical effectiveness in gynecologic and proctologic diseases by reducing tissue inflammatory processes, hypostasis events, itching, burning and providing longer remission period.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

Up!