CS178691A3 - Heterocyclic anthracyclinone and anthracycline analogs - Google Patents

Description

anthracyclinone-a -afttrooykl v

> O

O <O Network

- <mN

Heterocyclic

FIELD OF THE INVENTION The present invention relates to improved anthracycline derivatives, a process for the preparation of such derivatives and intermediates thereof, pharmaceutical compositions containing such derivatives, and the use of such derivatives as antitumor agents in mammals. Background Art

Anthracycline antibiotics including doxorubicin and dauno-rubicin are important chemotherapeutic agents in the treatment of a wide range of tumor conditions. While daunorubicin formula I is clinically used mainly against acute leukemia and adults, doxorubicin of formula II, also known as α-driamycin, has wider among all chemotherapeutic agents (spectrum of antitumor activity Weiss R. · Sar, Sarosa G.,

Clagett-Carr K., Russo and Leylan-Jones B .: Chemother. Pharmacol. 18, 185-197 (1986). Arcamone P, Doxorubicin, Academic Press, New York 1980. J.

The usefulness of known anthracycline antibiotics is reduced by the fact that the dosage is limited due to toxicity, such as myelosuppression (Crooke SK: Anthracyclines} Current Status and New Developments, Academic Press, New York 1980) and cardiotoxicity (Olson ED et al. Proc. Natl., Acad. Sci., USA 85: 5585-5559 (1988) and references therein, and also because of the resistance of treated tumors (Mimnaugh EG et al., Cancer Research 49: 8-15 (1989), McGrath T et al., Biochemical Pharmacology 58: 497-51 (1989) ·) Due to the proven efficacy of known anthracyclines in the treatment of cancer, efforts have been made to develop anthracycline analogues with either improved therapeutic index or reduced cross resistance.

Biosynthesis (from streptomyces) or semi-synthetic modification of known natural anthracycline antibiotics (Arcamone F .: Doxorubicin, Academic Press, New York 1980, Thomson EH: Naturally Occuring Quinones III: Recent Ad-vances, Chapman and Hali, New York 1987, Anthracycline : Current Status and New Developments, Academic Press, New York 1980, Brown JR and Iman S · H. Recent Studies on Doxorubicin and its Analogues, Prog. Med., 21, 170-256 (1984); Several thousand anthracycline derivatives have been obtained by Adriamycin and Elated Anthracycline Antibiotics, Prog. Med., Chem., 15: 125-164 (1978). Most known anthracyclines exhibit two types of structural differences: i) substitution of the aglycone tetracycline ring system; and ii) the structure and number of glycosides attached to the C-7 or C-10 (doxorubicin numbering) atom. Some examples of structural diversity of anthracycline antibiotics are shown in Figure 1.

I,.-.-- -.1. t ·> Τ / '·

KOSMOMYCIN Á

Figure 1

In contrast to the large number of derivatives that were obtained based on these two kinds of structural modifications, little effort was devoted to the synthesis and biological evaluation of heteroantracycline derivatives with a heteroatom in ring A. Some 9-oxa-heteroantracyclines (III to V) were prepared by Kochem et al. its antitumor activity was not significant. (Heterooycles 26 (2), 541-545 (1987) Heterocycles 26 (4), 879-882 (1987).). Mitsher et al. found that N- (trifluoroacetyl) -4-demethoxy-9-azadaunorubicin (VI) had no antitumor activity at all (J. Med. Chem. 29 (7): 1277-1281 (1986)).

IV, H 1 = sugar, R 2 = H, CH 5

Pyranonaftoohinones such as nanaomycin A (VII) and calafungin (VIII) are found in nature. These agents exhibit potent antibacterial and fungicidal activity (Moore H.W. and Czerniak R.t. Medicinal Research Reviews 1 (5), 249-280 (1981) and references therein). Granatin (IX) has been reported to have antitumor activity (Chang C.J.

Floss, H.G., Soong, P., and Chang, C.Ti, J. Antibiot. 28, 156

SUMMARY OF THE INVENTION

The present invention relates to heteroantracyclines which are structurally distinct from the compounds known from the literature of the A-ring of the anthraoyclinone system. In particular, the compounds of this invention differ structurally from those known in the art in that they have a heteroatom at the 8-position in the A ring. This structurally different class of compounds exhibits therapeutic activity, particularly anti-cancer and anti-tumor activity, which compounds are active against some adriamycin-resistant tumor cells may also exhibit less myelosuppression.

In one aspect of the present invention, compounds of Formula X are obtained

wherein Χχ and X2 are each independently selected from the group consisting of oxygen, sulfur, C NN (R), wherein R is a group selected from hydrogen, alkyl of one to sixteen carbon atoms, acyl carbon atoms and one to sixteen carbon alkylamino groups, X1 is O, S, SO, SO2, NO or NR, where R is C1 -C6 alkyl, alkyl C 1 -C 16 groups, C 1 -C 16 aryl groups, C 1 -C 16 haloacyl groups or H, R 8, R 8, R 8, H 8, and R 8 represent a group independently selected from each other from the group consisting of hydrogen,

fr-N, N-6-hydroxyl groups, alkyl groups of one to sixteen carbon atoms, alkoxy groups of one to sixteen carbon atoms, cycloalkyl groups of three to eight carbon atoms, tosyl groups, triflate groups, trifluoroacetate groups, halogen atoms , nitro groups, cyano groups, acyl groups of one to sixteen carbon atoms, arylacyl groups of one to sixteen carbon atoms, aminoalkylaminoalkoyl groups of the general formula JSH (CH2) nNH (CH2) mOH, in which they independently represent m from 1 to 4, amino-alkylaminoalkyl and a new moiety of the formula NHCCH 3), NH (CH 2) mX, wherein n and n are independently 1 to 4 and X is a halogen atom, an amino group which may be unsubstituted or may be carry one or two substituents which may be an alkyl group of one to eight carbon atoms, a cycloalkyl group of three to eight carbon atoms, and cyclic group, trifluoroacyl group, ar-alkyl group or aryl group, alkenyl group of one to eight carbon atoms, or alkynyl group of one to eight carbon atoms, haloalkylnitrosoureide group of general formula NH (CO) N (NO) (CH 2) n CH 2 X, in wherein n is zero to four and X is halogen, thiol and -OC (R) = O, wherein R is hydrogen, alkyl of one to sixteen carbon atoms, cycloalkyl of three to eight carbon atoms, an alkoxyalkyl group, an aralkyl group, an araloxyalkyl group, and a ryloxyalkyl group or an aryl group,

R8 is hydrogen, C1 -C16 alkyl, C3 -C10 cycloalkyl, -C (R) = One, or dioxolane or dioxane ketal, wherein R is hydrogen, alkyl of one to sixteen a carbon atom, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an araloxyalkyl group, an acyloxyalkyl group, an amino group which is not substituted or is mono- or di-substituted by an alkyl group of one to eight carbon atoms a cycloalkyl group having from 3 to 8 carbon atoms, -7 - an acyl group, a trifluoroacyl group, an aralkyl or an aryl group, a naturally occurring amino acid, for example alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like; a synthetic amino acid, R 8 can also be a group of the formula-C (R) (Oalkyl with one C1 to C5, where R is as defined above, -C (OR) = O, wherein R is hydrogen, C1 -C6 alkyl, C3 to C8 cycloalkyl, hydroxyalkyl, alkoxyalkyl , an aryloxyalkyl group, an araloxyalkyl group, an aryl group and an aralkyl group -CH 2 C (OR) = O wherein R is hydrogen, alkyl of one to sixteen carbon atoms, cycloalkyl of three to eight carbon atoms, hydroxyalkyl group , an alkoxyalkyl group, an aryloxyalkyl group, an araloxyalkyl group, an aryl group, an aralkyl group which is unsubstituted or is mono- or di-substituted by an alkyl group of one to eight carbon atoms, a cycloalkyl group of three to eight carbon atoms, acyl, trifluoroacyl, aralkyl or aryl ,

R 8 represents a hydrogen atom, an alkyl group of from one to sixteen carbon atoms, a halogen atom, an amino group, a hydroxyl group, an alkoxy group of one to sixteen carbon atoms, a thiol group, a cyano group, a sulfide group, an acyl group of the formula - C (R) = O, wherein R represents a hydrogen atom, a C1 -C16 alkyl group, a three to eight carbon cycloalkyl group, a hydroxyalkyl group, an araloxyalkyl group, an alkoxyalkyl group, an acyloxyalkyl group, an amino group which is unsubstituted or mono or di-substituted with one to eight carbon atoms, cycloalkyl with three to eight carbon atoms, acyl, trifluoroacyl, aralkyl or aryl, a naturally occurring amino acid such as alanine, arginine , cysteine, glycine, - 8 - leucine, lysine, methionine and the like, or by synthetic amino- an acid of the formula -C (OR) = O wherein R is a hydrogen atom, an alkyl group having from 1 to 16 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an aryloxyalkyl group, an araloxyalkyl group, an aryl group, an aralkyl group and an alkenyl group having from 1 to 16 carbon atoms, Ϊ and R 1 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy of one to sixteen carbon atoms, alkyl groups of one to sixteen atoms, acetylenyl groups of two to sixteen atoms, cycloalkyl groups of three to eight carbon atoms, alkenyl groups of two to sixteen carbon atoms, cyano groups, groups of the formula -OC (R) = O wherein R is one to sixteen alkyl, hydrogen, cycloalkyl three to eight carbon atoms, and alkoxy and alkyl and aryl, acyl groups having the formula -C (R) = O, wherein R is hydrogen, thiol, thioalkyl of one to sixteen carbon atoms, alkyl of one to sixteen carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an araloxyalkyl group, an acyloxyalkyl group, an amino group which is not substituted or substituted by one or two substituents, an amino acid as defined above or a synthetic amino acid of the formula -C (OR) = O wherein R is hydrogen, an alltyl group of one to sixteen carbon atoms and a cycloalkyl group of three to eight carbon atoms, mono or oligosaccharides usually present in other anthracyclines, for example one or two sugars selected from the group consisting of of rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose-A, amicetose, aculose, redness, rhodinosine and 2-deoxyfucose, asaccharide of formula

E 9 and R 10 independently represent a group selected from the group consisting of hydrogen, halogen, hydroxyl, acetoxy, alkoxy of one to sixteen carbon atoms, alkyl groups of one to sixteen carbon atoms, cycloalkyl groups of three to six carbon atoms and thiol groups means an amino group, which is either not substituted or mono- or di-substituted with an alkyl group of from one to eight carbon atoms, a cycloalkyl group of from three to eight carbon atoms, an acyl group, a trifluoroacyl group, an aralkyl group or an aryl group a natural amino acid such as alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like, a synthetic amino acid, a mono or dibenzylated amine group, an acylated amino group, a trifluoroacylated amine group, a morpholino group, a cyano substituted morpholino group, a mono- , di-, tri- or tetra-me thio-substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, alkoxy of one to sixteen carbon, cycloalkyl of three to eight carbon atoms , a thiol group, a sulfide group, a group of the general formula ΝΗζΟΗ ^^ ΟΗζΟΕ), wherein R is an alkyl group of one to sixteen carbon atoms, an acyl group of one to sixteen carbon atoms, or an aroyl group of seven to sixteen carbon atoms and n is a number from zero to five or chloroalkylnitrosoureide groups of the general formula ΝΗ (00) Ν (Ν0) ζ0Η2) CHgCl in which n represents a number from zero to four, - 10 represents a hydrogen atom, a hydroxyl group or a tetrahydropyranyl ether (—OTHP), a halogen atom, a mono- or di— carbohydrates usually present in other anthracyclines, such as those mentioned above for an R 6, an amino group, a mono- or di-alkylamino group, wherein each alkyl group is a group of one to sixteen carbon atoms, an alkoxy group having one to sixteen carbon atoms, a cycloalkyl group three to eight carbon atoms, the benzoate which is either unsubstituted or substituted with a nitro group, for example p-nitrobenzoate, acetoxy group, trifluoroacetoxy group and chloroalkyl-nitrosoureido group as defined above for R 1. Preferred compounds of formula (X) are those wherein χ and Xg are each independently selected from the group consisting of oxygen, sulfur, and RH, X ^ is oxygen, sulfur, SO, R5, R6 and R5, R6, R6, R6, R6, R6, R6 and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, alkoxy with one C 4 -C 4, tosyl groups, triflate groups, fluorine atoms, chlorine atoms, aminoalkylaminoalcohol groups of the formula RH (CH 2) n NH (CH 3 OH, where n is one to three independently of one another, aminoalkyl aminoalkyl chloride) a group of the formula NHCCH 3) NHCCH 3 GlG 1 in which n and n are independently of one another, an amine group, a chloroalkylnitrosoureide group of the general formula RH (CO) R (RO) (CHg) CHgCl wherein n is a number from nu to four and groups of the formula -O-C (R) = O, wherein R is hydrogen, alkyl of one to six carbon atoms and aryl,

R8 is an alkyl of one to four carbon atoms, a hydrogen atom, an acyl group having the formula-C (R) = O, wherein R is hydrogen, alkyl of one to eight carbon atoms, hydroxyalkyl, alkoxyalkyl an acyloxyalkyl group and an amino group which is either unsubstituted or mono- or di-substituted with a one- and eight-carbon alkyl group, a cycloalkyl group having three to eight carbon atoms, an acyl group, a trifluoroacyl group, an aralkyl group, or an aryl group furthermore, θθ is a group of the formula -C (OR) = O, wherein R is a hydrogen atom, an alkyl group of from one to eight carbon atoms, an aryl group, an aralkyl group, or a general group -05 ^ 0 ((^) = O, in which R represents a group selected from a group consisting of hydrogen, a straight-chain or branched alkyl group having from one to eight carbon atoms and amine groups y which is either unsubstituted or is mono- or di-substituted by a C 1 -C 6 alkyl group, a C 3 -C 8 cycloalkyl group, an acyl group, a trifluoroacyl group, an aralkyl group or an aryl group, Εθ is a hydrogen atom , a fluorine atom, an amino group, an alkoxy group having from one to four carbon atoms, a sulfide group, an acyl group of the formula -C (R) = O, in which R is a hydrogen atom, an alkyl group having from one to eight carbon atoms, a hydroxyalkyl group, an acyloxyalkyl group a group, an amino group or a cyano group, a group of the general formula -C (OR) = O, wherein R is hydrogen, alkyl of one to eight carbon atoms, aryl group, al-kenyl group of one to five carbon atoms, eight carbon atoms, Y and Br, independently represent a group selected from the group consisting of a halogen atom, a hydrogen atom, a hydroxyl group, an alkoxy group having one to one atom, and carbon atoms, two to eight carbon acetylenyl groups, two to eight carbon alkenyl groups, cyano groups, -OC (R) = O, wherein R is hydrogen or alkyl having one to five carbon atoms, acyl groups of formula -C (R) = O, wherein R is a hydrogen atom, a thiol group, an alkyl group of one to eight carbon atoms, a hydroxyalkyl group, or an amino group, groups of the formula-C (OR) = O, wherein R is hydrogen, alkyl of one to eight carbon atoms, or a carbohydrate of formula

wherein R 1 and R 1-Q independently represent a group selected from the group consisting of hydrogen, fluoro, chloro and hydroxyl, R 4 'represents an amino group which is either unsubstituted or mono- or di-substituted by one to eight carbon atoms, cycloalkyl by up to eight carbon atoms, acyl, trifluoroacyl, aralkyl or aryl, morpholino, cyano-substituted morpholino, mono-, di-, a tri- or tetra-methoxy-substituted morpholino group, a hydroxyl group, a mono- or di-alkylated amine group having one to 16 carbon atoms, an alkoxy group having one to eight carbon atoms, a group of the formula wherein R is an alkyl group of one to eight carbon atoms, an acyl group of one to eight carbon atoms or an aroyl group of seven to twelve carbon atoms a number of one to five, a chloro-rosoureido group of the general formula NH (CO) N (NOXCHg) CHCl, wherein n is a number from zero to four, or a fluorine atom, and R 2 is a hydroxyl group or a tetrahydropyranyl ether, atom halogen, mono- or oligosaccharide customary in other anthracyclines, for example one or more sugars such as rhodosamine, cinerulose-B, L-cinnamose, L-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine and trifluoroacetyldaunosine, amine group, mono- or dimethylamino group, - 13 - one to eight carbon alkoxy group, benzoate, p-nitrobobenzoate, acetoxy group and trifluoroacetoxy group. More preferred compounds of formula X are those compounds wherein χ and X X are each independently selected from the group consisting of oxygen and NH,

X 1 represents an oxygen atom, a sulfur atom, a SO group, a group NH, or a group NO, R 1, R 2, R 5 and R 8, and independently represent a group selected from the group consisting of hydrogen, hydroxyl, methoxy, aminoethylaminoethanol, aminoethylaminoethyl chloride, chloroalkylnitrosoureido NH (CO) N (NO). (CH 3 CH 2 Cl 2 wherein n is a number from zero to two, amino and fluorine,

R 8 is an alkyl group of from one to four carbon atoms, an acyl group of the formula -G (R) = O, wherein R 1 is a methyl group, a hydroxymethyl group, an acyloxymethyl group, and an amino group, the -C (OR) group. = O, wherein R is a hydrogen atom, a methyl group or an ethyl group, a group of the formula -CH2COROR2, wherein R is hydrogen, methyl or ethyl, Ηθ is hydrogen, fluoro, amino, methoxy , an acyl group of the formula -C (R) = O, wherein R is hydrogen, a C1 -C5 alkyl group, a hydroxyalkyl group, an amino group, or a cyano group, a group of the formula-C (OR) = O wherein R is hydrogen, C 1 -C 5 alkyl, aryl or C 1-4 alkenyl, Y and R y are each independently selected from the group y consisting of a hydrogen atom, a halo gene atom, a hydroxyl group, a methoxy group, a cyano group, an acetate group, an acetyl group and a saccharide of the formula u

AND

wherein R 9 and R 10 independently represent a group selected from the group consisting of hydrogen and fluoro, R 1 represents an amino group, a dimethylamino group, a trifluoroacetamide group, a morpholino group, a cyano-substituted morpholino group, a mono-, di-, a tri- or tetra-methoxy-substituted morpholino group of the formula NH (CH 2) n CH (OR) 2 wherein R is an alkyl group having one to four carbon atoms, an acyl group having one to four atoms carbon or aroyl of seven to eight carbon atoms and n is a number, from two dopes, of a chloroalkylnitrosoureido group of the general formula NH (CO) N (NO) (CH 2) n CH 2 Cl, where n is a number from zero to four, and a hydroxyl group and R ^ 2 are hydroxyl a group, a tetrahydropyranyl ether, a benzoate, a p-nitrobenzoate, an amino group or a fluorine group.

Even more preferred compounds of formula X are those wherein X 1 and X 2 are oxygen, X 1 is oxygen, sulfur, SO, NH, or NO, R 5, R 2, R 4, R 6 is hydrogen, and Rq is independently selected from the group consisting of hydrogen, hydroxyl, amino, and aminoethylaminoethanol, Ηθ is methyl, ethyl, acyl, -C (R) = O or a dioxolane or dioxane ketal thereof, wherein R is methyl, hydroxymethyl, acetoxymethyl or amino-15, C (OE) = O wherein R is hydrogen or methyl or a group of the general formula -CH2CKOR6O, wherein R is hydrogen or methyl, θθ is hydrogen, fluorine, amino, cyano or -C (OR) = O, wherein R is zn and one to four-carbon alkyl, Y and R? independently represent a group selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and saccharide of the formula

S9 and R1 are fluorine, R1 is amino, dimethylamino, trifluoroacetamide, morpholino, cyano substituted morpholino, mono-, di-, tri- or tetra-methoxy substituted morpholino, in which R is methyl, acyl or non-benzoyl and n is from 3 to 5, or chloroalkylnitrosoureido NH (CO) N (NO),. zero to four, and B12 is hydroxyl, benzoate or p-nitrobenzoate.

The term "alkyl" as used herein means straight or branched chain groups of up to sixteen carbon atoms, for example methyl, ethyl, 16-propyl, isopropyl, butyl, tert-butyl, iso- butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, variously branched isomers and also those which contain one or more halogen substituents such as fluorine, chlorine, bromine, iodine or trifluoromethyl, alkoxy, aryl, alkylaryl, haloaryl, cycloalkyl or alkylcycloalkyl.

As used herein, the term "cycloalkyl" means a cycloalkyl group having three to eight carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and cyclooctyl group.

The term "aryl" as used herein means a monocyclic or bicyclic aromatic group containing from six to ten carbon atoms in the ring moiety, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein the substituent on the phenyl or naphthyl group may be, for example, one to four carbon atoms, an atom of halogen, one to four carbon atoms, or a nitro group.

The term "halogen atom" as used herein means a chlorine atom of a bromine atom, a fluorine atom, or an iodine atom.

As used herein, the term "aralkyl" means an alkyl group as defined above with an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl and triphenylmethyl. - 17 -

As used herein, the term "aroyl" refers to a group of the general formula -COAr, where aar is an "aryl group" as defined above.

As used herein, the term "alkoxy" or "aralkoxy" refers to any of the above alkyl and aralkyl groups attached to the oxygen atom.

As used herein, the term " alkoxyalkyl " means any alkyl group mentioned above attached to an alkoxy group, such as a methoxymethyl group.

As used herein, the term "aryloxyalkyl" means any alkyl group mentioned above linked to an aryl group by the aforementioned oxygen atom, for example a phenoxymethyl group.

As used herein, the term "araloxyalkyl" refers to an aralkyl group as above linked to an alkyl group as defined above through an oxygen atom, for example a benzyloxymethyl group.

As used herein, the term "acyloxyalkyl" refers to an acyl group having one to eight carbon atoms attached to an alkyl group by the above-mentioned oxygen atom, for example an acetoxymethyl group.

As used herein, the term "hydroxyalkyl" means an alkyl group bound to a hydroxyl group, such as a hydroxymethyl group.

It will be apparent to those skilled in the art that when R 1, R 8 is a hydroxyl group and X 1 is an oxygen atom, then the compounds of formula X exist in the thermodynamic form. The preferred tautomers of Formula XI are therefore within the scope of the present invention.

X XI (X 1 = X 2 = O and R 5 = R q = OH)

The present invention also relates to all possible isomers and mixtures thereof including diastereoisomeric mixtures and racemic mixtures resulting from the possible combinations of R and S stereochemical centers at carbon atoms 0-7 »C-9 and 0-10 as well as at all chiral oentres in the sugar moiety.

The present invention also encompasses novel compounds which have been prepared as intermediates or precursors to compounds of formulas X and XI. These intermediates are further described herein in conjunction with the preparation of compounds of formula X and XI.

Compounds of formula X may be prepared by a process as illustrated in reaction chemistry I.

The heterocyclic esters of formula (X) in which Y is sa-charide are best prepared according to Reaction Schemes I. - 19 -

The aglycone of formula (XII) in which E @ 1 to E @ 8 is as defined above is reacted with a sugar derivative of formula (XIII) in which E @ 1 to R @ 5 are as defined above and L is a displaceable atom or a displaceable group. Suitable groups I include halogen, for example iodine, bromine or chlorine, unsubstituted or substituted benzoyl groups such as p-nitrobenzoyl, and -OR or -SE, wherein E is unsubstituted or a substituted alkyl group such as an alkyl group of from one to sixteen carbon atoms, such as a methyl, ethyl or butyl group, or R is an unsubstituted or substituted acyl group such as an acyl group of one to sixteen carbon atoms such as an acetyl group, and or R is an unsubstituted or substituted aryl group. erivatizing known carbohydrates from the anthracycline anti-biotics family available from commercial or natural sources. See, for example, Monneret C, Martini A., Pais M .: Carbo-drate Research 166: 59-70 (1987);

Acton E.M., Tong G, L., Mosher, C.W. and Wolgemuth, R.L., J. Med. Chem. 27: 658-645 (1984) and references therein, Arcamone P.i Cancer Research 45, 5995-5999 (1985) and references therein.1.

The aglycone of formula XII is reacted with the corresponding sugar derivative of formula XIII typically in a compatible solvent such as methylene chloride using Lewis acids such as thiobutyl chloride, stannic chloride or trimethylsilyl trifluoromethanesulfonate. It is also known to those skilled in the art of anthracycline chemistry that the moiety leaving the sugar moiety is halogen, and that in this case Koenigs-Knor's glycosylation or modification thereof can be used. Processes for the preparation of compounds of Formula XII wherein X 1, X 2, and X 2 are both O and R 1 is hydrogen are illustrated in Reaction Scheme II,

XIV

XV

XVII

XVIII

xxt

Reaction Scheme II - 21 -

According to Reaction Scheme II, trimethylene acetal of dimethoxybenzaldehyde (XV) can be prepared by reacting 2,5-dimethoxybenzaldehyde (XIV) by boiling under reflux with 1,3-pentanediol in benzene or another suitable solvent in the presence of an acid catalyst, as for example p-toluenesulfonic acid. The trimethylene acetal XV can then be reacted with an alkyllithium such as butyllithium. The lithium salt is reacted with the appropriate alkyl halide of formula R 1 CH 2 X, wherein X is a halogen atom, a R 2 is halogen. means as described above, however, it is necessary to maintain compatible reaction conditions. Where R? it is not compatible to exchange functional groups at a later stage in a manner known to those skilled in the art of organic synthesis. Subsequent aqueous acid treatment may result in the corresponding 2,5-dimethoxy-6-alkylbenzaldehyde, such as e.g. XVI; in the photochemical irradiation of an intermediate (such as XVI) in a sulfur dioxide solution in an aryl solvent such as benzene, a dihydrothiophene-2,2-dioxide of formula XVII is obtained, which can then be reacted with the hydride borate. Subsequent acid treatment can then be obtained (T-symmetric formula XVIII. This intermediate can then be condensed by cyclo-condensation with an appropriately functionalized aldehyde of formula XIX to form dimethoxyisochroman intermediate products XX. These intermediates of formula XX are then further chlorinated with hypochlorite, e.g. The oxidative demethylation of compounds of formula XXI with an adequate oxidizing agent, such as ammonium nitrate, may give rise to the chloropyranoquinones of formula XXII. condensate with the corresponding functionalized homophthalic anhydrides, such as the compound of formula XXIII, to form pyranonquine tetracyclic derivatives of general formula XXIV: The free phenol is then protected to form the tetracyclic compound of formula XXV. The XXV is then brominated with a free-radical brominating agent such as N-bromosuccinimide in the presence of an initiator such as ultraviolet light, and in a chlorinated solvent such as carbon tetrachloride. The resulting volatile bromides can then be reacted directly with the aqueous ether solvent to form pyranotetracyclic aglycone of formula XII. The aglycones of formula XII can then be further transformed into various structures by synthetic methods well known to those skilled in the art of anthracyclines. Any changes in functional groups or deprotection groups are preferably carried out under neutral or basal conditions at this stage or at later stages of the synthesis, whichever is appropriate.

Another possibility for preparing compounds of formula XII is illustrated in Reaction Scheme III. According to this scheme, dimethoxyisochroman intermediates, such as, for example, a compound of formula XX, can be directly oxidized with a oxidizing agent, such as nitric oxide, in a polar solvent system such as acetonitrile in water. The resulting pyranoquinones of general formula XXVI are then condensed with an appropriately functionalized homophthalic anhydride of formula XXIII in an aprotic solvent under basic catalysis, preferably lithium diisopropylamide or sodium hydride. The tetracyclic derivative of formula XXVII is separated from the compound of formula XXIV. The free phenol is then protected to form a compound of formula XXV. The above-described bromination of asolvolysis provides aglycones of formula XII. Preferred processes for the preparation of compounds of formula XII are illustrated in Reaction Scheme IV. In Reaction Scheme IV, the lithium salt obtained by reacting the 2,5-dimethoxybenzaldehyde dioxane acetal (XV) with alkyllithium is reacted with an epoxide of formula XXXI, optionally in the presence of a Lewis acid such as boron trifluoride etherate. An adduct is obtained

Reaction Scheme III

- 24 -> 1-Jat

ZsivfK, ii .- * .’zz. and formula XXXII ·

Route b in Scheme IV represents an alternative route for the preparation of adduct XXXII · Addition of aldehyde XXVIII to the lithium salt of 2,5-dinethoxybenzaldehyde dioxane acetal (XV) yields the adduct of formula XXIX, in the aldehyde of formula XXVIII means the protecting group (but not limited) methoxymethyl, methoxyethyl, methyl, benzyl, trityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or other groups preferably used in the protection of alcohols in organic synthesis. The hydroxyl group of formula XXIX can be converted into a variety of functional groups by conventional methods known to those skilled in the art of organic synthesis. Thus, the compounds of formula XXX can be obtained after removal of the protected secondary alcohol protecting group by known methods. The resultant substituted dioxanacetal adduct of the benzaldehyde of the formula XXXII is obtained in a desired manner.

The adduct of formula (XXXII) is then cyclized to the 1-hydroxyisochroman of general formula XXXIII in the presence of a mild acid.

Tetracyclic aglycones XXXIX and XL can be prepared by procedure c according to Reaction Scheme IV. The pyranoquinones of general formula XXXIV are prepared by oxidizing the isochromanes of the general formula (XXXIII) with an agent such as silver or ammonium nitrate. Quinones of formula XXXV wherein the hydroxyl group is protected by a K 2 group selected from (but not limited to) methyl, ethyl, methoxymethyl, methoxyethyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl, p-nitrobenzyl, and trityl groups may then be added to the homophthalic anhydride of formula XXIII in the presence of a strong base or to a benzomonoketene of formula XXIII * under IR irradiation conditions (Krohn K. et al. -Λίλ .-. '··' Λ, · <'' '' -'r Λ. Lik -25 -

-► r7ch2x

XXXII

Reaction Scheme IV> 1 L f-26-bigs Ann. Chem. 943-948 (1988). Thus, after deprotection, aglycones of formulas XXXIX and XL are obtained.

The tetracyclic aglycones of formula (XXXIX) and (XL) can also be prepared according to procedure d from the isochroman of formula XXXIII, which, when chlorinated twice with such a reagent as tert-butyl hypochlorite, affords the iso-chromates of formula XXXVI. Subsequent oxidation with an oxidizing agent, such as ammonium nitrate, affords the benzopyranoquinones of formula XXXVII. Addition of these quinones to o-quinodimethanes generated by thermolytically benzosulfones such as benzosulfone (XXXVIII) yields tetracyclic aglycones of general formulas (XXXIX) and (XL). The compounds of formula XII are then available from these aglycones by substituting the phenolic group with another functional group.

A process for the preparation of compounds of formula XII in which R represents a hydrogen atom is illustrated in Scheme V. In Scheme V, a cyclo-addition reaction occurs between the o-quinodimethane reactive intermediate of formula XLII, which can be generated by heating the recombinant reagent, such as is, for example, <RTIgt; f-sultin </RTI> of formula XLI (prepared as described for compound of formula XVIII in Reaction Scheme II) and pyranoquinone such as compound of formula XXVI. After silica gel treatment, pyranoquinone structures such as the structure of Formula XLIII are obtained. By bromination and solvolysis as described above for the intermediate of Formula XXIII, pyranoquinone aglycones without substituents on the C ring are obtained, e.g. Formula XLIV.

The process for the preparation of the compound Rq represents the hydroxyl of the formula X in which the moiety 5 - 2.7 -

XLIV (xii, r8 = r5 = h)

Scheme V is converted to compounds of Formula XI and is illustrated in Flow Diagram VI. In the reaction scheme VI, by reacting the pyranoquinone derivatives, such as compounds of the formula XLV, prepared by the method described above for the compound of the formula XXIV, with the lead acetate in glacial acetic acid, the acetoxylated pyranoquinones of the formula XLVI can be obtained. These may be acetylated by reaction with acetic acid or with acetic acid chloride in the presence of a base such as pyridine. The resulting tetracycline intermediates of formula XLVII can be brominated and solvolysed. The glycosidation then gives the bisacetoxypyranoquinone glycosides of the general formula XLIX. Alkaline removal of the acetyl groups of the bisacetoxypyranoquinone glycosides of general formula XLIX yields the glycosides of formula L which exist preferably in the tautomeric form illustrated by the structure of formula XI. - 28 -

XI Y = carbohydrate, X y = O) - 29 - A preferred process for the preparation of compounds of formula XIa XLIV is illustrated in Reaction Scheme VII. In this scheme, pyranoquinones such as Formula XXXIV can be added to o-quinodimethanes (obtained by thermolysis of the S-sultin of Formula XLI as described in Reaction Scheme V). Thus, pyrano anthraquinone aglycones of the general formula XLIV are obtained directly. The cycloaddition reaction of the bisbenzoketene derivative of the general formula LI1 preferably obtained from the benzocyclobutanedione of the general formula LI in the manner described by Krohnem Liebigs Ann. 943-948 (1988)] in the presence of general formula XXXIV by ultraviolet radiation, may provide tetracyclic derivatives of general formula Lili, which in tautories will be converted to a more preferred structure of formula LIV. can obtain general formula glycosides XI ·

An alternative procedure for the preparation of compounds of Formula XII is shown in Scheme VIII. According to Reaction Scheme VIII, the 2,5-dimethoxybenzoic acid is converted to the benzamide of formula LV by first converting the acid chloride to the oxalic acid chloride in the presence of a base such as pyridine in a solvent such as dichloromethane followed by diethylamine in ether. The lithium salt of the compound of formula (LVase) is prepared by treatment with a strong base such as sec-butyllithium in a suitable solvent such as tetrahydrofuran in the presence of TMEDA and reacted with an electrophilic reagent of the formula L-CH 2 R 2 in which R 5 is hydrogen. is as defined above and L is a substitutable or substitutable group such as halogen. The resulting benzoderivative of formula LVb is then reacted with a strong base such as lithium diisopropylamide or butyllithium in a solvent such as tetrahydrofuran. It is then added to the carbonyl electrophilic agent of formula LVI. - 30 -

Reaction Scheme VII-31 provides the adduct of Formula LVII. This sepak adduct cyclizes to the isochroman derivative of formula (LV) by reaction with an acid. Reduction of a derivative of formula (LVIII) with a hydride such as DIBAL in a compatible solvent such as dichloromethane affords the general formula XXXIII isochroman hydroxylated at position 1. Formula XXXIII in a solvent system such as acetonitrile / water, for example, ammonium nitrate, affords the iso-chromandion of Formula XXXIV, which is then converted to a natetracyclic derivative such as Formula XII as As explained in Scheme IV, a change in the hydroxyl group of a compound of Formula XII on Group Y can be readily accomplished by methods customary to those skilled in the art of organic synthesis.

For example, glycosidation as described in Scheme I, the tetracyclic derivative of Formula XII can be obtained by the structure of Formula X wherein Y is saccharide Acetylation or benzoylation of Formula XIIe may afford structures of Formula X wherein Y is O-COR and R is an alkyl or aryl group. The alkylation of the hydroxyl group of the compound of formula (XII) can be carried out by treatment with various known electrophilic agents, for example, alkyl halides, orthoformates or other agents, in the presence of catalysts or without catalysts. Compounds of formula X are thus obtained wherein Y is alkoxy. The hydroxyl group of formula X can be converted into a substitutable atom or a substitutable group L, wherein L is a substitutable group, such as a halide, which can be obtained, for example, by reacting an alcohol with triphenylphosphine in the presence of carbon tetrachloride, tetrabromomethane or iodine. or sulfonates, such as mesylate, tosylate or triflate, which can be obtained, for example, by reaction of the alcohol with mesyl chloride, with tosyl chloride, with anhydride

Scheme VIII - 33 - trifluoroacetic acid or the like, in the presence of a base such as pyridine or triethylamine, in an appropriate solvent such as benzene or dichloromethane, or L may be any suitable substitutable group. of formula X with different functional groups Y. For example, Y represents a CN group when L is substituted with a cyanide, Y represents an alkyl group, an alkenyl group or an alkyne group when the substitution is carried out with a carbanion. The above examples are not intended to limit the invention in any way. Where this method is incompatible with other substituents R 1 to E 8 of the tephracyclic structure of formula XII, the quinone of formula XXXIV is converted to the isochromanedione of formula LIX with the desired group Y (as discussed above) by the application of readily available organic chelating techniques. mie. By reacting the homophthalic anhydride of formula (XXIII) with an isochroman of formula (LIX) in the presence of a strong base such as lithium diisopropylamide or hydrosodium in a solvent such as tetrahydrofuran, a tetracyclic intermediate of formula (LX) can be obtained. various functional groups by methods available to organic chemists to obtain the tetracyclic of Formula X.

A more general procedure for the preparation of compounds of Formula X is shown in Reaction Scheme IX. According to this reaction, compounds of formula LXI in which L is a substitutable atom or a substitutable group such as a halogen atom or a mesylate, a tosylate or a triflate can be reacted with an intermediate of formula LXII in the presence of a base. The desired acyclic compounds of formula LXII are either known or readily available. The cyclization of a compound of formula (LXIII) to a compound of formula (LXIV) can be carried out in an aprotic solvent such as e.g.

OMe t

R4 O HO Y

XI

Scheme IX-35-tetrahydrofuran or ether, in the presence of a non-nucleophilic base such as sodium hydride or lithium diisopropyl amide. The ester moiety of the compound of Formula LXIV can be converted into the various moieties listed in Εθ by known methods. The intermediates of formula LXV can then be used to prepare the desired tetracyclic of formula X by the procedure of a. Thus, quinones of formula LXVI should be obtained by oxidative demethylation of a compound of formula LXV with an oxidizing agent such as ammonium nitrate, which can then be condensed with various acid anhydrides homophthalic formula XXIII. Thus, tetracyclic heteronaphthalenediones of the general formula LXVIII are obtained. Oxidation of a compound of formula LXVIII with, for example, radical bromination with N-bromosuccinamide or bromine in tetrachloromethane or other compatible solvents and the subsequent bromide-water reaction results in the general formula XII. Depending on the nature of X 1, it may be necessary to use alternative oxidation procedures. For example, when X1 is a sulfur atom, it is desirable to oxidize the sulfur heteroatom with a sulfoxide (X1 is SO) and then carry out a mercury shift and subsequent treatment with a hydroxide. These procedures are common and are well described in the literature. The conversion of the compound of formula XII to the compound of formula X can be carried out as described herein in other schemes.

The intermediate of formula LXV can also be used to prepare the tautomeric form of formula X below b when E 1 and E 2 are hydroxyl. If the path b is followed, electrochemical reduction of the product of formula LXV in methanol with the presence of sodium methoxide yields the bisulfite intermediate of the general formula LXIX. Removal of one ketal group in the presence of a weak acid yields a monocetalquinone of the general formula LXX in aqueous medium. This intermediate can then condense with known benzofurans of the general formula - 6 - formula IXXI under strong basic conditions (e.g. sodium hydride in an aprotic medium). wherein Z is an electron-withdrawing moiety such as cyano or phenylsulfone moiety. The resulting heteronaphthalenediones of formula (LXXII) can then be converted to the desired tautomer of formula (XI) in the same manner as described herein for compound (XXV or LXVIII).

Another method for the preparation of key bicyclic intermediates of formula LXV is shown in Scheme X. Under Scheme X below, dioxane acetal 2,5-dimethoxybenzaldehyde is reacted with a strong base such as butyllithium in an aprotic solvent such as diethyl ether. The resulting lithium salt is alkylated with formaldehyde which is preferably prepared from p-formaldehyde. The resulting hydroxyl group in the intermediate of formula LXXIII is then converted into a substitutable group, such as mesylate, by mesylation with mesyl chloride in the presence of a base such as pyridine, in a vaprotic environment. an agent such as LXII, as described in Scheme IX, yields key intermediates of Formula LXXV. The aldehyde protecting group of the intermediate of formula LXXV is then removed in an acidic aqueous medium. Thus, benzaldehyde of general formula LXXVI is obtained. These intermediates are then cyclized by bases, such as methoxide, carbonate, sodium hydride, or lithium diisopropylamide in compatible (i.e., to dissolve, but do not interfere with, re-action) solvents. Intermediates of general formula LXXVII can be further converted to the desired key compounds of general formula LXV by the procedure a or b in reaction scheme X.

According to procedure a, the hydroxyl group of the benzoderivative formula LXXVII is converted to the functional group R? the introduction of a compound of formula (LXIV) and subsequently LXV by simple derivatizations commonly used by those skilled in the art of organic synthesis. Procedure b is used if - 57 -

Reaction Scheme X-38 - that θθ represents a hydrogen atom. In this case, the dehydrated compound of general formula LXXVTI on LXXVIII can be made either basic or acidic. Conversion of the ester function of structure LXXVIII to the above-mentioned substituent βθ is possible by known methods. The resulting derivatives of formula (LXXIX) can then be oxidized by known oxidation methods to compounds of formula (LXV). A preferred process for the preparation of compounds of formula X is shown in Reaction Scheme XI. In Scheme XI, compounds of Formula LXI are condensed with basic intermediates of Formula LXXX under basic conditions in a suitable solvent such as benzene or tetrahydrofuran. Such adducts of general formula LXXXI are obtained. Compounds of formula (XXXXX) wherein Pg is a protecting group such as benzoyl, and Rg or Εθ are preferably electron acceptor moieties are available by derivatization of known compounds. Removal of the protecting group Pg in the compound of general formula LXXXI with sodium hydride in a protic solvent provides intermediates of general formula LXXXII. These can then be cyclized in a basic environment in an aprotic solvent to obtain the bicyclic intermediates of formula LXV. While the key intermediates of Formula LXV are readily available (as described above), it is best to use the compounds of Formula LXXXV to prepare the quinone derivatives of Formula LXXXV or LXXXVII. Thus, the compounds of general formula LXXXI are oxidized by known methods to a compound of general formula LXXXIII. For example, benzyl bromides can be oxidized by treatment with sodium bicarbonate in dimethylsulfoxide or other known agents that provide aromatic aldehydes. Removal of the protecting group of the compound of general formula LXXXIII, for example by hydrolysis of the benzoate with hydroxide water, can give directly the hydroxylated heterocyclic compounds of general formula LXXXIV. These compounds are readily oxidized by the action of agents such as ammonium nitrate. This will give the quinones - 39 -

LXXXIII LXV

/

Reaction Scheme XI-40 - Formula LXXXV. The compounds of formula X are readily prepared from the quinones of formula LXXXV by the methods described herein in other schemes.

In a known manner, a hydroxyl group in a quinone of formula (LXXXV) or a benzoderivative of formula (XXXXIV) can be converted to a group Y to give compounds of formula (LXXXVI). Compounds of formula (X) may be obtained from a compound of formula (LXXXVI) as described above for compound of general formula (LXXXIV). Reaction Scheme XII provides a shorter and more straightforward process for the preparation of compounds of Formula XI, which is a tautomeric formula of Formula X when i is a hydroxyl group. According to Reaction Scheme XII, a known quinizari derivative of formula LXXXVIII is converted to an anthraquinone of formula XC wherein OP8 is a protected phenolic group and L is a substitutable atom or a substitutable group, protecting a hydroquinone of formula LXXXVIII as an alkoxy group, an acyl group, a silyl group, or an ether group known to those skilled in the art. ways. The resulting protected isizarin of formula (LXXXIX) is then reacted with, for example, N-bromosuccinamide or bromine in a solvent such as carbon tetrachloride, catalysed by a free radical catalyst. The compound of formula XC is then converted to the compound of formula XI by the method described above in other schemes. For example, a compound of formula XC can be converted to a compound of general formula XI via compounds of formula XCI, XCVI and XCV as described for converting a compound of formula XI to a compound of formula LXXXVI in Scheme XI · A compound of formula XC can be converted to a compound of formula XCIII via a compound of formula XCI according to the method described for converting a compound of formula LXI to a compound of formula LXV in Scheme XI. Compound (XCIV) can be obtained from - 41 -

## STR4 ## The compound of formula XCIV can be converted into the compound of formula XC via the compounds of formula XCII and XCIII as described for converting compound of formula XXI to compound of formula LXV in Scheme IX. the compound of general formula XI.

It is preferred that the anthracyclines of the formulas X and XI can be converted into other structures of the substituents X1 and X2 by synthetic methods known to those skilled in the art. Furthermore, it is preferred that the compounds of formula X in which X5 is SO or SO2 can be obtained by oxidation of any intermediate in which X5 is atomisers, whichever is the best. Suitable reagents for this oxidation are m-chloroperbenzoic acid, hydrogen peroxide or any other known reagents · Compounds in which X 1 is a group of NO can be obtained from compounds in which X 1 is a group ΝΗ? oxidation.

It is also preferred that the following reactions may require. the use (or conventionally can be used for) of starting materials which have functional groups protected. Thus, removal of the protecting groups may be required as one of the intermediate steps or as a final step for obtaining the desired compound. Protection of functional groups and deprotection groups can be carried out by conventional methods. For example, amino groups may be protected with an aralkyl group (e.g., benzyl), an acyl group, or an aryl group (e.g., 2,4-dinitrophenyl), followed by removal of the protecting group, if desired, by hydrolysis or hydrogenolysis, as appropriate for standard conditions. The hydroxyl groups can be protected by any conventional hydroxyl protecting group, for example as described in "Protective Reagents in Organic Chemistry", red. J. F. W. 'McOmie (Plenum - 43 -

Press, 1973) or in "The Protective Groups in Organic Synte-sis" by Theodor W. Green (John Wiley and Sons, 1931) ·

Examples of suitable hydroxyl protecting groups include alkyl groups (e.g., methyl, tert-butyl or methoxymethyl), aralkyl (e.g., benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl a group (e.g., acetyl or benzoyl) and silyl groups such as a trialkylsilyl group (e.g., a tert-butyldimethylsilyl group). Protecting groups of the hydroxyl group can be removed by conventional means. For example, an alkyl group, a silyl group, an acyl group, and a heterocyclic group may be removed by solvolysis, for example, by hydrolysis under acidic or basic conditions. Aralkyl groups such as the triphenylmethyl group may also be removed by solvolysis, for example by hydrolysis of acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by reaction with boron trifluoride ether and acetic anhydride, followed by removal of the acetate groups.

In the above processes, the compounds of general formula X and Π are usually obtained as a mixture of diastereoisomers. These isomers can be separated by conventional chromatography or fractional crystallizations.

If it is desired to have a compound of formula X or XI as a single isomer, this isomer may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting materials or stereo-isomerically pure any suitable intermediate.

The cleavage of the final product or its intermediate starting material can be carried out by any suitable method known to those skilled in the art, see, for example, E. L. Eliel et al., "Stereochemistry of Carbon Compounds" (McGraw Hill, 1962) and S. H. Wilen: "Tables of Resolving Agents".

The compounds of formula (X) and (XI) have anticancer and antitumor activity. These compounds are believed to have antibacterial, fungicidal, and antiviral activity. While it is possible to administer one or more compounds of the present invention as a raw chemical, it is preferred to administer (administer) the active ingredient (s) as a pharmaceutical composition.

In another aspect, the present invention provides pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable prodrug thereof in association with one or more pharmaceutically acceptable carriers and optionally other therapeutic agents. and / or prophylactic components. All pharmaceutically acceptable salts, such as the hydrochloric acid and tartaric acid salts of these compounds, which are useful as antitumor agents in mammals, including humans, are part of this invention.

It will be appreciated by those skilled in the art of oncology that the compound (s) of the present invention can be used in combination with other therapeutic agents including chemotherapeutic agents Cancer: Principles and Practices of Oncology, Third Edition, VT DeVito Jr., S. Hellman and SAEosenberg; Antineoplastic Agents, red. W. A. Remers, John Wiley and Sons (New York 1984).]. It is to be understood that these compounds or pharmaceutical compositions of the present invention may be formulated with a therapeutic agent to provide a composition to be administered to a patient. Or, the compounds or compositions and the therapeutic agent may be administered separately, as appropriate to the drug, by assessing the condition to be treated. - 45 -

Thus, for therapeutic purposes, a compound or composition of the invention may be used in association with one or more therapeutic agents belonging to any of the following groups: 1) Alkylating agents such as: 2-haloalkylamines (e.g., mefalan and chlorambucil), 2-haloalkylsulfides, N-alkyl-N-nitrosoureas (eg carmustine, lomustine or semustine), aryltriazines (eg decarbazine), mitomycins (eg mitomycin C), methylhydrazines (eg procarbazine), bifunctional alkylating agents (eg mechlorethamine), carbinolamines (e.g., sibiromycin), streptozotocin and chlorozotocin, phosphoramides (e.g., cyclophosphamide), urethanes, and hydantoins. 2) Antimetabolites such as: mercaptopurines (eg 6-thioguanine and 6-methylthioJpurine), azapyrimidines and pyrimidines, hydroxyureas, 5-fluorouracil, folic acid antagonists (eg ametopterin), cytarabines, prednisones, diglycoaldehydes. 5) Intercalators such as:

Bleomycins and similar glycoproteins, anthracyclines (eg, doxorubicin, daunorubicin, epirubicin, esorubicin, idarubicin, aclacinomycin A), acridines (eg, m-AMSA), hycantones, ellipticins (eg, 9-hydroxyelipticine), actinomycins (eg, actinocin ), anthraquinones (e.g., 1,4-bis (aminoalkyl) -aminol-9,10-anthracenediones),

- 46 - anthracene derivatives (eg pseudourea and bisantrene), phleomycins, aureolic acids (eg mitramycin and olivomycin) ^ 4) Mitosis inhibitors such as: dimeric catharantine alkaloids (eg vincristine, vinblastine and vindesine) colchicine (eg, trimethylcolchicine acid), epipodophyllotoxins and podophyllotoxins (eg, etoposide and thieniside), maytansinoids (eg, maytansine and colubrinol), terpenes (eg, helenaline, tripdiolide and taxol), steroids (e.g., 43-hydroxywithanolide E) , quassinoids (eg, bruceantin), pipobroman, 3 / methylglyoxals (eg, methylglyoxalbis (thiosemil)?). 5) Hormones (eg, estrogens, androgens, tamoxifen, naphoxidine, progesterone, glucocorticoids, mitotane, prolactin). 6) Immunostimulatory agents (eg, human interferons, leva- misol and tilorane). 7) Monoclonal and polyclonal antibodies. 8) Hadiosensitizers and radioprotectives (eg metronidazole and misonidazole). 9) Other various cytotoxic agents such as: camptothecins, quinolinquinones (eg, streptonigrin and isopropylidene-azastreptonigrin), cis-platinum and similar platinum complexes, tricotecans (eg, trichodermol or vermicarin A), cephalotoxins (eg, haringtonin). 10) Cardioprotectants such as (+) - 1,2-bis (3,5-dioxopiperazin-1-yl) propane, commonly called ICRF-187, and ICEP-198. 11) Drug-dependent compounds such as p-glycoprotein inhibitors such as Verapamil. 12) Cytotoxic cells, such as lymphokine-activated killer cells or T-cells. -V7- 13) Immunostimulatory agents, such as interleukin factors or antigens. 14) Natural or artificial polynucleotides. 15) Polynucleotides capable of forming triple helices with DNA or PNA. 16) Polyether ethers. Distamycin and analogs.

The above list of therapeutic agents is not intended to limit the invention in any way.

The pharmaceutical compositions of this invention may be in forms suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal or parenteral (including intra-arterial, intraperitoneal, intramuscular, subcutaneous, and intravenous) administration by inhalation or insufflation. If appropriate, the compositions may be advantageously prepared and administered in discrete dosage units. The preparation is carried out by methods well known to those skilled in the art of pharmacy. All methods include the step of combining the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, forming a formulation in the desired shape.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of a sterile solution or dispersion for injection. In all cases, this form must be liquid so that it can be administered a sterile syringe and of course it must be sterile. It must also be stable to the conditions of manufacture and storage, and the anti-infestation of micro-organisms such as bacteria or fungi must be protected. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., chlorophorel, twin 80, glycerol, dimethylsulfoxide, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof and oil). coating the composition with, for example, lecithin, preserving the required particle size in the case of dispersion and using surfactants, by treating the various microorganisms with the addition of various antibacterial and fungicidal agents, for example, parabens, chlorobutanol, phenol, acid sorbic acid, thimerosal, and the like; In many cases, it is preferred that the composition contain isotonic agents, for example, sugars or sodium chloride, by prolonging the absorption of the injectable compositions by the use of agents that delay absorption, e.g. o gelatin.

Sterile injectable solutions are prepared by mixing the active ingredient (s) in the required amount in the appropriate solvent with the various other ingredients as desired. The solution is then sterile filtered. Usually, dispersions are prepared by mixing the various sterilized active ingredients with a sterile liquid containing a basic dispersion medium and the desired other ingredients listed above. A preferred method for preparing sterile powders for the preparation of sterile injectable solutions is vacuum drying and freeze-drying to obtain a powder of the active ingredient and any other desired ingredients from a previously sterile-filtered solution.

The pharmaceutical compositions for oral administration are preferably prepared as discrete units, such as tablets, powders or tablets, each containing a predetermined amount of the active ingredient as a powder, granule, solution, suspension or emulsion, the active ingredient being me as a bolus, potion or paste. Tablets and capsules for oral administration may contain conventional adjuvants such as binding agents, fillers, lubricants, disintegrating agents or wetting agents. The tablets may be coated by methods well known to those skilled in the art. Oral liquid compositions may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. Or they can be prepared as dry pre-use products when mixed with water or other suitable solvents (vehicles). Such liquid compositions may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous solvents (for example, edible oils) or preservatives.

The term "pharmaceutically acceptable carrier" refers to any solvent, dispersing media, coating materials, antibacterial agents, fungicidal agents, isotonic agents, absorption delaying agents, and the like. According to the present invention, any conventional media or agents which are not incompatible with the active ingredient may be used.

For ease of administration and uniformity of dosage, it is particularly preferred that the compositions be formulated in unit dosage form. The unit dosage form in this specification refers to a physical discrete unit designed to uniformly dispense a composition upon administration to treated animals, wherein each component, each unit, contains a predetermined amount of active material that is calculated to obtain the desired therapeutic effect. -nek. This amount is mixed with the desired pharmaceutical carrier. The unit dosage forms are determined and dependent upon: a) the properties of the active material and its therapeutic effect; and b) the limitations of the effective material, where the health of the treated organism would be damaged in the treatment of the disease. The dosage of the main active ingredient for the treatment of these conditions depends on the age, weight and condition of the subject being treated, the form of the active ingredient, the activity of the active ingredient and the mode of administration. For the treatment of most of the conditions in which the novel compounds are effective and substantially non-toxic, daily doses of from about 0.001 to about 100 mg / kg body weight are administered in one single dose. dose or divided up to five-times a day or by continuous infusion. For a subject weighing 75 kg this is about 0.075 to about 75 mg / day. For example, if the dosage is divided into three individual doses, these doses will range from about 0.025 to about 2500 mg of the active ingredient. Preferred is from about 0.1 to 50 mg / kg body weight per day, more preferably from about 0.2 to about 3 mg / kg body weight per day.

For convenient and effective administration, an effective amount of the main active ingredient is mixed with a pharmaceutically acceptable carrier in unit dosage form as described above. For example, the unit dose may contain a major active ingredient in an amount of from about 0.1 to about 1000 mg, more preferably 1.0 to 5 mg mg. from about 0.1 to about 500 mg / ml carrier. In the case of compositions which contain the additional active ingredients, the dosage is determined according to the usual dosage and the method of administration of the ingredients.

Antitumor treatment is characterized in that any of the compounds of the invention are administered in a pharmaceutically acceptable composition at an effective therapeutic dose. It is to be understood that chemotherapy may require the use of any of the compounds of the invention bound to a vehicle that facilitates targeting of the compound to tumor cells. The agent can be, for example, monoclonal or polyclonal antibodies, proteins and liposomes. The compounds of this invention may also be administered as monomeric, dimeric or oligomeric metal chelate complexes containing, for example, iron, magnesium or calcium.

The compounds of this invention exhibit antitumor or anticancer activity in breast cancer, leukemia, gastric cancer, lung cancer, renal cancer, 51-ovarian cancer, CNS cancer, and melanoma. However, this list is incomplete. The compounds of this invention are believed to exhibit activity on other tumors and cancers, such as pancreatic or gallbladder cancer.

Also, some of the above-described intermediates used in the synthesis of the compounds of the present invention are of pharmacological interest. Compounds having antibacterial, fungicidal, antiviral, antitumor and anticancer activity are believed to include the compounds listed above in the various reaction schemes of the following general formulas: X, XI, as well as the general formulas XII, XVII, XVIII , XX, XXI, XXII, XXV, XXVI, XXVII, XXIX, XXX, XXXII through XLI, XLIII through L, LIII, LIV, LVIII, LIX, LX, LXIV through LXX, LXXII, LXXVII through LXXIX, LXXXIII through LXXXVII , XLI to XLVI. Like the compounds of Formulas X and XIi, these products are preferably administered as a pharmaceutical composition for the treatment of the above conditions. They may be administered in the amounts indicated above for compounds of formulas Xa XI. In addition, such intermediates may be administered as pharmaceutically acceptable salts or as chelate complexes with metals, as appropriate. They may also be administered as mixtures with other intermediates and / or with compounds of Formula X or XI and / or with one or more therapeutic agents targeted to cancer or tumor cells. EXAMPLES OF THE INVENTION

The invention will be further illustrated by the following examples. Example 1

Step 1: 2,5-Dimethoxybenzaldehyde trimethyleneacetal (2,5-dimethoxybenzaldehyde dioaneacetal)

A solution containing 200 g (1.2 mmol) of 2,5-dimethoxybenzaldehyde, 150 g (2.0 mmol) of 1,5-propanediol and 1.0 g of 52-p-toluenesulfonic acid in 1.0 liter benzene, the cooker was heated under reflux with a Dean-Stark trap for six hours until water was separated. The reaction mixture is cooled, washed with 400 ml of saturated aqueous sodium hydrogen carbonate solution, 200 ml of water and 200 ml of saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate. The solvent was distilled off in vacuo. Distillation of the residue under reduced pressure (b.p. 167 DEG C. @ 13 mm Hg) gave 263.7 g (98% yield) of pale yellow oil, which was trimethylene acetal 2,5-dimethoxybenzaldehyde. 1 H NMB spectrum (200 MHz, CDCl 3, δ): 1.40 (dm, 1H, HCH 3), 2.24 (m, 1H, HCH 2), 3.77 (s, 3H, OCH 2), 3, 78 (s, 3H, OCH2), 4.00 (dt, 2H, O-HCHa), 4.24 (dd, 2H, O-HCHe), 3.84 (s, 1H, O-CH-O- ), 6.82 (dd, 2H, ArH), 7.19 (d, 1H,

ArH). '

Step 2: 2,5-Dinethoxy-6-methylbenzaldehyde To a cooled solution containing (cooled to -40 ° C) 84.0 g (0.37 mmol) of 2,5-dimethoxybenzaldehyde trimethylene acetal in 2.0 L of dry diethyl ether, 240 ml of a 2.5 M solution of butyllithium in hexanes was added under stirring and under argon. The mixture was stirred for four hours at -25 ° C, then for twenty-four hours at -10 ° C. 90.0 g of methyl iodide are added under argon to the cooled (at -25 ° C) stirred reaction mixture and the mixture is allowed to stand overnight at room temperature. This solution was then washed twice with 300 mL of water, once with 3 mL of saturated sodium chloride, and dried over magnesium sulfate. The organic solvent is evaporated and the evaporation is dissolved in 5 ml of ether. The mixture is stirred for one and a half hours with 5 ml of 1N aqueous hydrochloric acid. The organic layer was separated and washed twice with 200 mL of water, once with 200 mL of brine, and dried over magnesium sulfate. Evaporation of the solvent gave a yellow oil which was chromatographed (flash chromatography) eluting with 2.5 7 ° ethyl acetate in toluene. 45 g (yield: 67%) of 2,5-dimethoxy-6-methylbenzaldehyde are obtained (m.p. 61-61.5 ° C). B NMB spectrum (200 MHz, CDCl 3, δ): 2.46 (s, δ-3H, CH 3, 5.78 (s, 5H, OCH 2), 5.83 (s, 3H, OCH 2), 6 90 (d, 2H, ArH), 10.58 (s, 1H, CHO).

Step 3i 5,8r-Dimethoxy-1-hydroxy-1,3-dihydrobenzothiophene-2,2-dioxide

Procedure 1: Under an argon atmosphere, the desiccant solution containing 1.60 g (8.9 mmol) of 2,5-dimethoxy-6-methylbenzaldehyde, 11.0 g of sulfur dioxide in 100 ml of thiophene benzene was irradiated. hours at 350 nm. Precipitated crystals (2.01 g, 93%) were filtered off. These crystals were sufficiently pure for further use.

Procedure 2: On a larger scale, the oxygen-free argon solution containing 10.0 g (55.5 mmol) of 2,5-dimethoxy-6-methylbenzaldehyde, 50 g of sulfur dioxide in 600 ml of thiophene-free benzene, irradiates a four-day, mid-pressure mercury lamp with a Pyrex filter. The resulting mixture was extracted three times with 400 ml of 1N sodium hydroxide.

The combined aqueous layers were washed twice with 200 mL of methylene chloride. The aqueous layer was then neutralized with concentrated aqueous hydrochloric acid. The resulting mixture was then extracted three times with 500 ml of methylene chloride. The combined organic layer is then washed once with 200 ml of water, 200 ml of saturated sodium bicarbonate, 200 ml of water, 200 ml of brine and dried over magnesium sulfate. Subsequent evaporation of the solvent gave 11.2 g (83%) of pure 5,8-dimethoxy-1-hydroxy-1,3-dihydrobenzoic acid, thiophene-2,2-dioxide (m.p. 140 ° C with decomposition). . NME spectrum (200 MHz, CDCl 3, δ): 3.57 (s, 3H, OCH 2), 3.60 (s, 3H, OCH 2), 4.44 (dd, 2H, CH 2), 5.65 (s, 1H, CH), 6.85 (dd, 2H, Ar H).

Step 4: 4,7-Dimethoxy-3,8-dihydrobenzoylb-1,2-oxathiamine 2-oxide

The procedure was slightly modified as described by Charlton J.L. and DurstT .: Tetr. Letters 25 (46), 529-1984. To a stirred and cooled solution (at 0 ° C) of 7.30 g (30 mmol) of 1-hydroxysulfone, prepared according to step 3, - 54 - is added portionwise in 275 ml of methanol , 5.65 g of sodium borohydride over fifteen minutes. The mixture was stirred for one hour and then heated to 50 ° C for five minutes. The reaction mixture was then evaporated to dryness. 200 ml of concentrated hydrochloric acid are added to the residue. After heating to 5 ° C for five minutes, 500 mL of water was added. The aqueous mixture was extracted three times with 500 ml of dichloromethane. The combined organic layer was washed twice with 200 mL of water, once with 200 mL of brine, and dried over magnesium sulfate. After evaporation of the solvent, a substance is obtained which is found to be so pure that it can be used directly for the next step. Temperature: 90.0 ° C. @ 1 H NMR spectrum (200 MHz, DMSO-d6, .delta.): 5.65 (d, 1H, J = 16 Hz, CH2SO4), 5.80 (s, 5H, OCH2), 5.81 (s, 5H , 4.15 (d, 1H, J = 16Hz, CH2SO4), 5.14 (dd, 2H, CH2O-), 6.78 (s, 2H, aryl-H).

Step 5: (5,8) -Dimethoxyisochroman) -5-formic acid ethyl ester

In a 250 ml three-necked round bottom flask with a Dean-Starco tip, a solution containing 5 g (0.5 mmol) of ethyl glyoxalate is refluxed [Kelly et al.

Synthesis 544 (1972) .J in 100 ml of benzene. The cooking is continued until the water is separated. Then a solution containing 4.59 S (19.2 mmol) of the sultin prepared according to step 4 in 75 ml of benzene was added dropwise over three hours. Argon was bubbled through the reaction mixture during the addition. Reflux was continued overnight. After cooling, excess glyoxalate is extracted with four 200 ml portions of water. The benzene layer was dried and evaporated. This gave a residue which was flash chromatographed, eluting with ethyl acetate: toluene, to give 5.15 S (61%) of dimethoxyisochroman, mp 59.8 ° C. 1 H NMR spectrum (200 MHz, CDCl 3, δ): 1.54 (s, 5H, J = 7.1 Hz, CHβ, 2.78 (broad dd, 1H, J = 17.0 Hz, 10.8 Hza) 1.5 Hz, HGHaCHC = O), 5.10 (ddd, 1H, J = 16.9 Hz, 5.9 Hza 1.44 Hz, HCHe, CHC = O), 5.77 (s, 5H, OCH) 5.80 (s, 5H, OCH2), 4.26 (dd, 1H, J = 10.8 Hz, 5.9 Hz, OCHC-O), 4.50 (quartet, 2H, J = 7.1 Hz, -OCH2), 4.68 (broad dt, 1H, 1H) and [alpha] -55-J = 16.0 Hz, 1.4 Hz, 1.3 Hz, ArHCl3O-), 5.0 ? (broad d, J = 16.0 Hz, ArHCH? O-), 6.66 (dd,? = 8.9 Hz, ArH).

Step 6 i (7-Chloro-5,8-dimethoxyisochroman-3-yl) formic acid ethyl ester To a stirred solution containing 1.975 S (7.4 mmol) of isochroman prepared according to step 5 in 75 mL of anhydrous dichloromethane under argon 0.820 g (7.6 mmol) of tert-butyl iron (II) is added dropwise. The reaction mixture is stirred for three hours. Then the reaction mixture was washed successively with 25 ml of saturated aqueous sodium thiosulfate, water and brine. After drying over sodium sulfate, the organic layer was evaporated. The residue was flash chromatographed, eluting with 2.5% ethyl acetate in toluene. The title compound was obtained in 46% yield (1.02 g), m.p. 95 ° C. 1 H NMR spectrum (200 MHz, CDCl 3, δ): 1.35 (t, 3H, J = 7.1 Hz, CH 3), 2.95 (broad dd, J = 16.8 Hz and 10, 3 Hz, HCHaCHC-O), 3.16 (broad d, J = 16.9 Hz, 3.2 Hz, HCHeGHC-O), 3.78 (s, 3H, OCH3), 3.81 ( s, 3H, OCH 2), 4.27 (dd, J = 10.2 Hz, 3.5 Hz, -GH), 4.31 (q, 2H, J = 7.1 Hz, OCH 2), 4, 63 (broad doublet, 1H, J = 16.2 Hz, HCHaO), 5.01 (d, 1H, J = 16.2 Hz, HCHeO), 6.73 (s, 1H, ArH).

Step 7 '(7-Chloro-5,8-dioxo-5,8-dihydroisochroman-3-yl) formic acid ethyl ester To a stirred solution of 1.0 g (3.7 mmol) chloro isochr isomer prepared according to Step 6 in 20 mL acetonitrile was added dropwise to a solution containing 6.25 S (H, 4 mmol) of ammonium nitrate in 20 mL of water. The mixture was stirred overnight. It is then diluted with 50 ml of dichloromethane. The organic layer was separated and the aqueous phase was extracted twice with 25 mL of dichloromethane. The combined organic layer is washed once with 5 ml of water, 50 ml of brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed by flash chromatography, eluting with a gradient of 5 to 20% ethyl acetate in toluene. There was thus obtained 495 mg (55%) of the title compound, m.p. 83.5 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3): 1.27 (triplet, 3H, J = 7.1 Hz, CH 2), 2.58 (ddt, 1H, J = 19.0 Hz, 8.8) Hz and 3.2 Hz, - 56 - HCHaCHC = O), 2.8? (d multiplets, 1H, HCHeCHC = O), 4.17 (dd, 1H, J = 8.7 Hz, 3.3 Hz, OCHC = O), 4.20 (q, 2H, J = 7.0 Hz 4.44 (dt, 1H, J = 18.8 Hz, '3.4 Hz, HCHaO), 4.78 (dmultiplets, 1H, J = 18.8 Hz, 2.6 Hz and 1, 7 Hz, HCH 2 O), 6.95 (s, 1H, C = CH).

Step 8: Ethyl 11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-3-carboxylic acid ethyl ester To a cooled (0 ° C) and stirred solution of 203 mg of sucrose 0.74 ml of a 2.5M solution of butyllithium in hexanes is added to dry diisopropylamine in 7 ml of dry tetrahydrofuran by subargon. The mixture is cooled to -78 ° C and stirring is continued for half an hour. A solution containing 325 mg (2.0 mmol) is added slowly over five minutes. of homophthalic anhydride in 7 ml of tetrahydrofuran. Then a solution containing 5θ mg (1.85 mmol) of chloroquinone prepared according to Step 7 in 9 ml of tetrahydrofuran is added in one portion. The reaction mixture was then stirred for 20 minutes at -78 ° C, allowed to warm to room temperature and stirred for one hour. The reaction was then quenched with 10 mL of saturated ammonium chloride and partitioned between 10 mL of 5% aqueous hydrochloric acid and 100 mL of dichloromethane. The organic layer was then separated, washed with 25 ml of water, 25 ml of brine and dried over anhydrous sodium sulfate. Evaporation of the solvents gave crude pyranoanthracyclinone which was immediately acetylated in 90 ml of dichloromethane at room temperature for 10 hours with anhydride. acetic acid (1.25 ml) in the presence of 100 mg dimethylaminopyridine and 1.5 ml pyridine. To this reaction mixture was added 50 g of ice. The separated organic layer was washed successively with 25 ml of 5% aqueous hydrochloric acid, water and brine. The organic solution was then dried over sodium sulfate and evaporated to a flash chromatographed with 5% ethyl acetate / toluene . 351 mg (34% yield) of the title compound are obtained, m.p. 171-173 ° C. H NMR Spectrum (300 MHz, CDCl3): 1.32 (t, 3H, J = 7.1 HzCH2), 2.64 (s, 3H, COCH3), 2.80 (dd, 1H, J). = 19.1 Hz, 9.0 Hz and 3.0 Hz, HCHaCHC = 0), 3.07 (dm, 1H, J = 18.9 Hz, - 57 - HCHeCHC = O), 4.29 (dd, 1H, J = 9.0 Hz, 4.8 Hz, OCHC = O), 4.28 (quartet, 1H, J = 7.1 Hz, OCH2), 4.59 (dt, 1H, J = 18.9 Hz and 5.2 Hz, HCHaO), 4.97 (broad doublet, 1H, J = 18.9 Hz, CH2CH2), 7.72 (m, 2H, ArH), 8.20 (m, 2H, ArH) 8.58 (s, 1H, ArH). &Lt; 15 &gt; C-NMR spectrum (75.44 MHz, CDG1, [delta]): 15.9 (CH2), 20.9 (CH5), 24.6 (CH2), 61.6 (00¾), 71.1 (OCH), 125.9, 127.4, 150.5, 150.5, 15θ, β (aryl CH), 117.9, 128.6, 150.4, 155.6, 140.9, 144.4, 148.2 (aryl C), 166.7 and 170.4 (ester 0 = 0), 181.7 and 182.5 (quinone C = O). (CDCl 3, Vmax): 1774 (acetate 0 = 0), 1750 (ester 0 = 0), 1667, 1645 (chi-nonone 0 = 0) Mass spectra (HR): for G22H18 ° 7 (m + ') at “Climbed: 594,1067, calculated 594,1055 ·

Stage 95 (1S, 5S) and (1R, 5R) -11-acetoxy-1-hydroxy-5,12-dioxo-5,4,5,12-tetrahydro-anthraceno [2,5-c] pyran-5-yl formate acid

A mixture containing 257 mg (0.65 mmol) of pyranotetracycl, obtained as described in Example 1, step 8, 121 mg of N-bromosuccinimide and 15 mg of AIBN in 25 ml of carbon tetrachloride was refluxed for two hours. After cooling, the solvent was removed by distillation in vacuo. The residue is not reacted for one hour with 40 ml of a 1: 1 mixture of tetrahydrofuran-water solvent. Most of the tetrahydrofuran is then removed by distillation on a rotary evaporator. The remaining aqueous mixture is extracted three times with 50 ml of dichloromethane. The combined organic layers were washed with 25 mL of water and brine. After drying over sodium sulfate, the solvent is removed and the residue is chromatographed by flash chromatography. 178 mg (67%) of the title aglycone were obtained, m.p. Mp 190-192 ° C. · NMR spectrum (500 MHz, CDCl 3, δ "): 1.25 (t, J = 7.1 Hz, j" "CH 3), 2.54 (s, 5H, 0000¾), 2.59 (dd, 1H, J 1 = 11.5 Hz and 19.1 Hz, HCHa), 2.89 (dd, 1H, J = 4.0 Hz and 19.1 Hz, HCHe), 4.21 (quartet , 2H, J = 7.1 Hz, OCH 2), 4.75 (dd, 1H, J = 4.1 H 2 and 11.6 Hz, OCH), 5.89 (broad singlet, 1H, OCH-OH), 7 54 (broad singlet, 1H, exchangeable OH), 7.84 (m, 2H, ArH), 8.25 (m, 1H, Ar H), 8.54 (m, 1H, Ar H), 8.65 (s , 1H, ArH). 15 C NMR spectrum (75.44 MHz, LMSO-d 6, δ): 14.0 (0¾), S - 58 - 20.9 (CH 2), 61.0 (OCH 2), 64.4 (OCH) , 85.9 (O-CH-OH), 120.0, 126.8, 150.8, 150.9, 155.1 (aryl CH), 118.0, 128.5, 150.0, 142, 1, 142.7, 147.7 (aryl C), 169.5 and 170.5 (ester 0 = 0), 180.8 and 185.2 (quinone O = O). IR spectrum (FT, CDCl3, vmax) with 5575 (broad band) (hydroxyl), 1774 and 1750 (ester = 0), 1670 (quinone 0 = O). Mass spectrum (HR) calcd for C22H18N18O [M +, J: 410.1002, found! 410,1010.

Step 10: Ethyl ester (1S, IR, 5S) and (1'S, 1S, 5R) -1'-acetoxy-1 (2 ', 5', 4'-tricyxy-5'-trifluoroacetamido-4'-O-p- Nitrobenzoyl-L-lyxohexopyranoso) -5,12-dioxo-5,4,5,12-tetrahydroanthraceno- (2,5-c) pyran-5-yl] formic acid For stirred and cooled (at -40 ° C) 222 mg. (0.41 mmol) 2,5,6-trideoxy-5-trifluoroacetamido-1,4-di-O-p-nitrobenzyl-α- (or 3) -L-lyxohexapyranose in 20 ml solvent mixture (dichloromethane / ether 5.11) is added 0.15 ml of trimethylsilyl trifluoromethanesulfonate under subargon and in the presence of molecular sieve (4A). The mixture is stirred for one hour at -5 ° C. The solution is then cooled to -15 DEG C. A solution containing 121 mg (0.50 mmol) of pyranoaglycone prepared according to step 9 in 10 ml of dichloromethane is added. The mixture was stirred for 20 hours at -15 ° C. The reaction mixture is then poured into 50 ml of ethyl acetate and saturated sodium bicarbonate solution (1: 1), filtered and the organic layer is separated, washed with 10 ml of water, 10 ml of brine and dried over magnesium sulphate. After removal of the solvents, the residue was chromatographed by flash chromatography eluting with 10% ethyl acetate in toluene. The desired title pyranoantracycline glycosides were obtained as a 1: 1 mixture of diastereomers in 65% yield (259 mg). Melting point: 60 DEG-162 DEG C. with decomposition. Nuclear Magnetic Resonance Spectrum (200 MHz, CLCl 3) (1 S, 1 S, 5 R) diastereomers (TT): 1.24 (d, 5H, J = 6.5 Hz, CH 6 *), 1.57 (t, 5H) , J = 7.1 Hz, CH2 -, 2.06 (m, 2H, H-2 '), 2.58 (s, 5H, acetyl, CH3), 2.74 (dd, 1H, J) = 17.5 Hz and 12 Hz, HCH a CHC = O), 5.17 (dd, 1H, J = 19.4 H a of 5.8 Hz, HGHeCHC = O), 4.52 (quartet, 2H, J = 7 , 0 Hz, .fwdarw.-59-OCH2CH3, 4.42 (broad quartet, 1H, J = 7.1 Hz, HC-5 *), 4.66 (m, 1H, HC) -3 '), 4.74 (dd, 1H, J = 11.9 Hz and 3.8 Hz, OCHC = O), 5.47 (broad singlet, 1H, HC-4Z), 5.75 (broadsinglet, 1H, HC-1 ', 6.05 (s, 1H, O-CH-O), 6.31 (d, 1H, J = 6.6 Hz, NH), 7.76 (m, 2H, Ar H) 8.14 (dm, 2H, ArH), 8.31 (dd, 4H, p-nitrobenzoyl-H), 8.60 (s, 1H, arylH). @ 1 H NMR spectrum (200 MHz, .delta. CDCl3) (.delta.S, .delta., 3S) -diastereomer (.delta.): 1.26 (d, 3H, J = 6.5 Hz, H-C-6 "), 1.35 (t, 3H, J = 7.1 Hz, OCH 2 CH 5), 2.06 (m, 2H, H 2 C-2Z), 2.59 (s, 3H, acetyl-CH 2), 2.76 (dd, 1H, J '). = 18.8 Hz, 12 Hz, HCHaCHC = O), 3.15 (dd, 1H, J = 19.4 Hz and 4.1 Hz, HCHeCHC = O), 4.31 (quartet, 2H, J = 7) , 4 Hz (m, 2H, HC-3'a overlap and HC-5 '), 4.76 (dd, 1H, J = 11.9 Hz and 4.0 Hz, 0CHC = Q ), 5.44 (broadsinglet, 1H, HC-4Z), 5.65 (broad singlet, 1H, HC-1Z), 6.42 (d, 1H, J = 7.4 Hz, NH), 7.76 (m, 2H, ArH), 8.14 (d-muliple). (2H, ArH), 8.32 (dd, 4H, p-nitrobenzyl-H), 8.60 (s, 1H, ArH) 13 C NMR spectrum (75.44 MHz, CDCl 3, δ): 13.9 and 14.0 (COOCH 2 CH 3), 16.6 and 16.8 (δ'-ΟΗ), 20.9 (acyl CH 5) ), 24.1 and 24.6 (2'-CH 2), 29.4 and 29.8 (4-CH 2), 45.4 and 45.5, (CHNH), 61.7 and 61.8 (esterified). 00¾), 65.6 and 66.3 (5 * - OCH), 66.5 (4z-0CH), 71.8 and 72.4 (3-OCH), 87.9 and 92.7 '(1 -O-CH-O), 92.7 and 98.0 (1'-O-CH-O), 115.6 (quartet, J = = 289.2 Hz, CP3), 124.0, 127.57 , 127.64, 130.5, 130.6, 130.7, 131.18, 131.22 and 135.6 (aryl CH), 118.0, 128.4, 134.6, 134.7, 141, 0, 141.5, 142.2, 143.1, 148.3, 151.10, 151.14 (aryl C), 157.1 (quartet, J = 37.7 Hz, COCP1), 164.8, 165.2, 169.2, 169.8 and 170.2 (ester 0 = 0), 181.2 and 183.2 (quinone 0 = O). IR spectrum (PT, CDCl 3, V max) · 1775, 1737 (broad band, ester = 0), 1670 (quinone 0 = 0).

Step 11: (2R, 1R, 3S) and (1 * S, 1S, 3R) -11-Hydroxy-1R, 3 *, 6Z-trideoxy-3 * -trifluoroacetamide-L-lxohexapyranoso) methyl ester -5,12-Dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] 5'-anil-3-yl-naphthalic acid was dissolved in an atmosphere of argon at room temperature. mg (0.13 mmol) of glycosides, prepared as described in step 10 above, in 10 ml of dry methanol with 0.16 ml of 1.0 M sodium methoxide (methanolic solution) over two hours. The reaction mixture was then quenched by the addition of three drops of saturated aqueous ammonium chloride solution. The solvent is distilled off to dryness. The residue is stirred with pentane for five hours and then filtered. The portion which did not dissolve in pentane was extracted into ether and filtered. The residue is chromatographed by flash chromatography, eluting with a gradient of solvents: from 5% ethyl acetate in toluene to 20% methanol in ethyl acetate. The resulting heteroantracycline glycoside was obtained in a yield of 74% (56 mg) as a mixture (1: 1), m.p. 147-150 ° C. 1 H NMR spectrum (300 MHz, CDCl 3, δ): (1'S, 1R, 3S) -diastereomer: 1.50 (d, 5H, J = 6.9 Hz, H 2 C-6 '), 1.88 (m , 1H, HaC-2 '), 2.04 (m, 1H, HeC-2'), 2.72 (dd, 1H, J = 19.0 Hz and 12.0 Hz, HCHaCHC = O), 3, 18 (doublet of doublets, 1H, J = 19.0 Hz and 3.9 Hz, HCHeCHC = O), 3.66 (broad singlet, 1H, HC-3 '), 3.36 (s, 3H, OOHp, 4 , 33 (m, 2H, HC-4 ' and HC-5 '), 4.73 (dd, 1H, J = 11.8 HZ3.9 Hz, O-CHC = O), 5.50 (broad singlet) , 1H, HC-1 '), 5.88 (singlet, 1H, O-CH-O), 6.74 (broad doublet, 1H, NH), 7.74 (m, 2H, ArH), 7.98 (m, 1H, Ar H), 8.18 (s, 1H, Ar H), 8.50 (m, 1H, Ar H) .1 H NMR spectrum (300 MHz, CDCl3, δ): (1S, 1S, 3R) diastereomer: 1.3 (d, 3H, J = 7.0 Hz, H-C-6), 1.88 (m, 1H, HaC-2 '), 2.04 (m, 1H, HeC-) 2 '), 2.72 (dd, 1H, J = 19.0 Hz and 12.0 "Hz, HCHaCHC = O), 3.18 (dd, 1H, J = 19.0 Hz and 3.9 Hz, HCHeCHC = 0), 3.66 (broad singlet, 1H, HC-3 '), 3.87 (s, 3H, OCH 2', 4.33 (m, 1H, HC-4 '), 4.59 (broad quartet, 1H, J = 7.1 Hz, HC-5 '), 4.73 (dd, 1H, J = 11.8 Hz and 3.9 Hz, O-CHC-O), 5.60 (broad singlet, 1H, HC-1 '), 6.04 (s, 1H) , O-CH-O), 6.74 (broad doublet, ΙΕ, NH), 7.74 (m, 2H, Ar H), 7.98 (m, 1H, Ar H), 8.18 (s, 1H, ArH), 8.50 (m, 1H, Ar H).

Mass spectrum (HR) calculated for G28H26F3N010: 579.1353, found: 579.1358. - 61 - ο

ΟΡΝΒζ

AND"

H3C

h3c Ηό nhcocf3 BCH 242

HO nhcocf3

Example 1 Preparation of BGH-242; me [11-hydroxy-1- (2,5-hexohexopyrrolidine) - [2,3-c] pyrimidine and n-J-yl] ester. (L # S, 1R, 5S) and (1 s, 1 S, 5 R), 6-trideoxy-5-trifluoroacetamido-L-12-dioxo-3,4,5,12-tetrahydro-anthracene-formic acid; «V / · * - - 62 - Example 2

Step 5 (5,8-Dimethoxyisochroman-5-yl) formic acid p-nitrobenzyl ester

The same procedure as in Step 5 of Example 1 was followed except that 40 g (0.18 mmol) of p-nitrobenzylglyoxalate was used as the hydrate. Flash chromatography gave 58% (4.1 g) of the title compound, m.p. 140-141 ° C. @ 1 H NMR spectrum (200 MHz, CDCl3, .delta.) 2.84 (dd, 1H, J = 16.5 Hz and 10.5 Hz, HCHaCHC = O), 5.09 (dd, 1H, J). = 16.2 Hz and 4.0 Hz, HCHeCHC = O), 3.77 (s, 5H, OCH3), 5.80 (b, 5H, OCH2), 4.59 (dd, 1H, J = = 10.5 Hz and 4.0 Hz, OCHC = O), 4.70 (d, 1H, J = 16.0 Hz, HCHaO), 5.07 (d, 1H, J = 15.9 Hz, CH2O) ), 5.36 (broadsinglet, 2H, C 1-6), 6.67 (broad singlet, 2H, ArH), 7.54 (d, 2H, ArH), 8.24 (d, 2H, ArH).

Step 2: (5,8-Dimethoxyisochroman-5-yl) formic acid methyl ester To a cooled solution (0 ° C) containing 5 ° 0 mg (1.54 mmol) of the p-nitrobenzyl ester prepared in step 1 at 10 ° C. 15 ml of a 0.1 M solution of sodium methoxide in methanol are added to the tetrahydrofuran (15 ml) under an inert atmosphere. A few drops of saturated aqueous ammonium chloride are added under stirring for about 10 minutes. The solvent was removed. Flash chromatography of the residue gave 282 mg (84%) of the desired iso-chromate, mp 89-90 ° C. 1 H NMR spectrum (200 MHz, CDCl 3, δ) δ 2.80 (broad doublet of doublets, 1H, J = 16.9 Hz and 10.8 Hz, HCH 2 CHC = O), 5.12 (ddd, 1H, J = 17.0 Hz, 5.9 Hz and 1.4 Hz, HCHeCHC = O), 5.78 (s, 3H, OCH3, 5.81 (s, 5H, OCH3), 3.84 (s, 5H, COOCHp, 4.50 (dd, 1H, J = 10.8 Hz, 5.9 Hz, OCHC = O), 4.70 (dt, 1H, J = 15.2 Hz and 1.5 Hz, HCHaO), 5.08 (d, 1H, J = 16.2 Hz, CH2CH2), 6.67 (dd, 2H, ArH).

Step 5 (5,8-Dioxo-5,8-dihydroisochroman-5-yl) formic acid methyl ester To a solution containing 265 mg (1.0 mmol) of isochroman from step 2 above in 5 mL of acetonitrile is added a solution of 1.726. g Ammonium nitrate in 5 ml of water »» / - Amino. % Λ f * * 1 Λ * · - 63 - at room temperature. After stirring for 10 min, the mixture was diluted with 5 mL of methylene chloride. The organic phase is separated and the aqueous layer is extracted twice with 25 ml of dichloromethane. The combined organic extract was washed once with water, once with brine, and dried over magnesium sulfate. Evaporation of the solvents gave 228 mg (98%) of the residue which was found to be about 95% pyranoquinone, m.p. 55-58 ° C. @ 1 H NMR spectrum (200 MHz, .delta., .Delta.): 2.68 (dddd, 1H, J =. = 19.0 Hz, 9.0 Hz, 3.7 Hz and 2.8 Hz, CH2CHC = O), 2.93 (septet dub-year, 1H, J = 19.0 Hz, HCHeCHC = O), 3.84 (br, 3H, OCHp, 4.31 (dd, 1H, J = -9.0 Hz and 4.4 Hz, CH), 4.52 (dt, 1H, J = 18.7 Hz, J '= Hz, HCHaO), 4.86 (ddd, 1H, J = 18.9 Hz, 2.8 Hz and 1.6 Hz, HCHeO), 6.78 (dd, 2H, HC = CH).

Step 4: 6- and 11-Hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl} morpholinic acid methyl ester

A solution of 2.5M butyllithium (0.20 mmol) was added in an argon atmosphere at 0 ° C to a stirred solution of 0.07 mL diisopropylamine in two. ml of tetrahydrofuran. The mixture was stirred at -78 ° C for half an hour. A solution of 73 mg (0.45 mmol) of homophthalic anhydride in 2 ml of tetrahydrofuran and then 100 mg (0.45 mmol) of pyranoquinone from step 3 dissolved in 3 ml of tetrahydrofuran were added dropwise to LHA over a few minutes. The resulting mixture was stirred at -78 ° C for 20 minutes, allowed to warm to room temperature and stirred for an additional 1 hour. The reaction was quenched by the addition of 5 mL of saturated aqueous ammonium chloride. Then the mixture was shaken with 5 ml of 5% hydrochloric acid and 50 ml of dichloromethane. The organic layer was separated, washed with 10 ml of brine and dried over sodium sulfate. Evaporation of the solvents gave a residue which was chromatographed by flash chromatography to give pyranotetracyclide in 54% yield. The less polarregioisomer had m.p. 202 to 204 ° C, NMR spectrum (30 ° MHz, CDCl 3): 2.80 (ddy, 1H, J = 19.1 Hz, 9.1 Hz and 3.1 Hz, HCH a CHC = O), 3, 11 (dm, 1H, J = 19.1 Hz, HCHeCHC = O), 3.84 (s, 3H, OCH 2, 4.35 (dd, J = 9.1 Hz and 4.3 Hz, OCHC = O) 'ϋ · ί λ t ϋ λ t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t , 0 Hz and 3.3 Hz, HCHa-O), 5.06 (broad d, 1H, J '= 18.9 Hz, HCHe-O), 7.71 (m, 2H, ArH), 7.95 (m, 1H, Ar H), 8.13 (s, 1H, Ar H), 8.46 (m, 1H, Ar H), 13.70 (s, 1H, exchangeable of "OH", C-NME spectrum (75, 44 MHz, CDCl 3, δ ": 25.7 (CH 2), 53.1 (CH 2 O), 63.3 (CH 2 O), 72.2 (CHO), 122.7, 125.4, 129.8, 131.1 and 131.9 (aryl CH), 127.6, 128.2, 136.4, 143.0 and 143.4 (aryl C), 163.1 and 171.0 (arylCOH ester CO), 182, 4 and 187.1 (quinone CO) Mass Spectrum (HR) calculated for ^Ο ^ ΗΗ Η^ 339.0869, found: 339.0853 · The polar isomer had mp 225-235 (dec) ° C, 1H NMR (300 MHz, CDCl 3, δ): 2.85 (ddt, 1H, J = 19.0 Hz and α 9.2 Hz, HCHαCHC = O), 3.13 (dm, 1H, J = 19.0 Hz, HC HeCHC = O), 3.86 (s, 1H, OCH3), 4.37 (dd, J = 9.1 Hz and 4.3 Hz, OCHC = O), 4.68 (dt, 1H, J = 19.0 Hz and 3.4 Hz, HCHa-O), 5.04 (broad d, 1H, J = 21.1 Hz, HCHe-O), 7.73 (m, 2H, ArH), 7.97 ( m, 1H, ArH), 8.12 (s, 1H, Ar H), 8.50 (m, 1H, Ar H), 13.85 (s, 1H, exchangeable OH proton).

Step 5: 6-Acetoxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-formic acid methyl ester

A mixture of 60 mg (0.18 mmol) of pyranotetracyclone of Step 4 above, 0.25 ml of acetic anhydride, 0.3 ml of pyridine and 6 mg of dimethylaminopyridine in 20 ml of dichloromethane was stirred overnight at room temperature in an argon atmosphere. The mixture was then diluted with 25 ml of dichloromethane and washed successively twice with 15 ml of water, twice with 10 ml of 1N hydrochloric acid, once with 15 ml of water and dried over sodium sulfate. Flash chromatography of the residue gave 55 mg (81%) of the title acetylated pyranotetracycl, m.p. Mp 196-198 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ): 2.60 (singlet, 3H, COCH 3), 2.81 (ddt, 1H, J = 18.7 Hz, -9.1 Hz, and 3.3 Hz, HCHaCHC = O), 3.10 (dm, 1H, J = 19.0 Hz, HCH 2 CHC = O), 3.85 (s, 3H, OCH 2), 4.31 (dd, 1H, J = 9) , 3 Hz and 4.2 Hz, CH), 4.64 (dt, 1H, J = 19.0 Hz and 3.2 Hz, HCHa-O), 5.02 broad d, 1H, J = 19.0 Hz 7.73 (m, 2H, ArH); 8.05 (m, 1H, ArH); 8.13 (m, 1H, ArH); 8.58 (s, 1H, ArH). - 65 -

Step 6: (1S, 3S) and (1R, 3R) -? - acetoxy-1-hydroxy-5,12-dioxo-3,4,5,12-tetrahedroantraceno [2,3-c] pyran-3-yl methyl ester ] formic acid

A mixture containing 47 mg (0.12 mmol) of acetylated pyranotetracycl of step 5, 0.23 mg of N-bromosuccinimide and 0.1 mg of AIBN in 5 ml of carbon tetrachloride was refluxed for two hours. The solvent was removed by distillation in vacuo. To the residue was added 10 mL of a 3: 1 mixture of tetrahydrofuran and water. The mixture was stirred at room temperature for one hour. The mixture was then extracted with three 10 ml portions of dichloromethane. The combined organic extracts are washed once with 10 ml of water and dried over sodium sulfate. Flash chromatography of the residue and removal of the solvents from the appropriate fractions gave 35 mg (71%) of the title pyranotetracyclic aglyde, m.p. I90 ° G (decomposition). Nuclear Magnetic Resonance Spectrum (200 MHz, DMSO-d 6, δ): 2.60 (dd, 1H, J = 19.6 Hz and 11.8 Hz, HCH 2 CHC = O), 3.15 (dd, 1H, J = 19, 6 Hz and 4.3 Hz, HUHeCHC = O), 5.74 (s, 3H, OCH 3), 4.86 (dd, 1H, J = 11.5 Hz, 4.5 Hz, OCHC = O), 6 , 21 (d, 1H, J = 6.2 Hz, CHOH), 7.34 (d, 1H, J = 6.3 Hz, exchangeable hydroxyl proton), 7.75 (multiplet, 2H, ArH), 8.1 (m, 2H, ArH), 8.61 (singlet, 1H, ArH).

Step 7s Methyl ester (1S, 1R, 3S) and (1 * S, 1S, 3R) - 6-acetoxy-1- (2 ', 3', δ-trideoxy-3'-trifluoroacetamido-4'-O- β-hitrobene β-L-lyxohexopyranoso) -5,12-dioxo-3,4,5,12-tetrahydroanthracene ,32,3-c 3 -propan-3-yl formic acid

Glycosidation of pyranoantraquinone from step 6 could be accomplished as described in step 10 of Example 1 above. isomer 1S, 1R, 3S). TH NMR spectrum (200 MHz, CDCl 3, δ) (1 S, 1 S, 3 R) -isomer: 1.25 (d, 3H, J = 6.8 Hz, H 2 C-6 '), 2.06 ( m, 2H, H2C-2 '), 2.62 (s, 3H, acetyl methyl group), 2.77 (dd, 1H, J = 19.5 Hz and 11.3 Hz, HCHaCHC = O), 3 , 19 (dd, 1H, J = 19.3 Hz - 66 - and 5.7 Hz, HCHeCHC = O), 5.89 (s, 5H, OCH2), 4.42 (broadquartet, 1H, J = 6 , 9 Hz, HC-5 *), 4.65 (m, 1H, HC-5 '), 4.78 (dd, 1H, J = 11.4 Hz and 5.7 Hz, OCHC = O), 5 , 48 (broad singlet, 1H, HC-4 '), 5.76 (broad singlet, 1H, HC-1'), 6.05 (s, 1H, O-CH-O), 6.55 (d, 1H, J = 6.4 Hz, NH), 7.76 (m, 2H, ArH), 8.12 (m, 2H, ArH), 8.51 (dd, 4H, p-nitrobenzoyl protons), 8, 65 (s, 1H, Ar H). 1 H UME spectrum (200 MHz, CDCl 3, (δ) (1 S, 1 R, 5 S) - diastereoisomer 1.40 (d, 5H, J = 6.6 Hz, H 2 C-6 '), 2.06 (m, 2H, U2 C-2 '), 2.61 (s, 5H, acetyl CH3 group), 2.81 (dd, 1H, J = 19.0 Hz and 11.7 Hz, HCHaCHC = O), 5.19 (dd, 1H, J = 19.4 Hz at 5.9 Hz, HCHeCHC.dbd.O), 5.89 (s, 5H, OCH2), 4.72 (broad mul tiplet, 5H, overlapped HC-5 * and HC-5's OCHC = O), 5.46 (broadsinglet, 1H, HC-4 '), 5.67 (broad singlet, 1H, HC-1'), 6.26 (s, 1H, O-CH-O), 6.41 (d, 1H, J = 8.0 Hz, NH); 7.72 (m, 2H, ArH), 8.18 (dm, 2H, ArH), 8.55 (dd, 4H, p-nitrobenzyl protons), 8.67 (s, 1H, ArH).

I f - 67 -

Example 2: Preparation of methyl ester (1S, 1R, 3S) and (1'S, 1S, 3R) - [6-acetoxy-1- (2 *, 3 *, 6-trideoxy-3 '' trifluoroacetamido-4 ') -Op-nitrobenzoyl-L-lyxohexopyranoso) - 5,12-dioxo-3, 4,5,12-tetrahydroanthracene-2,3,3-c] pyran-3-yl formic acid, ul. 84Ž.-čL4 // * c2JLL.r. <CJt.; Í ». * F-ž ·. · ^> · · · Ι-5ί ·· 3> .., ιΛζ..λ · ι ' .ι <· Λ2 · .. · · ώ <stbr ^ v>., - 68 - Example 5

Step 1: Ethyl η 6 - and 11-hydroxy-5,12-dioxo-5,4,5,12- in tetrahydroanthraceno [2,5-a] β-pyran-5-yl] uroic acid To a stirred solution of 0.07 ml of dry diisopropylamine in two milliliters of tetrahydrofuran a solution of 2.5M butyllithium (0.20 mmol) is added in an argon atmosphere at 0 ° C. The mixture is stirred for half an hour at -7 ° C. A solution of 75 mg (0.45 mmol) of homophthalic anhydride in 2 ml of tetrahydrofuran and then 100 mg (0.45 mmol) of pyranoquinone (from the previous step) dissolved in three ml of tetrahydrofuran were added dropwise to the LDA over several minutes. The resulting mixture was stirred for 20 minutes at -78 ° C, then allowed to warm to room temperature and stirred at this temperature for one hour. The reaction is stopped by the addition of 5 ml of saturated aqueous ammonium chloride. The mixture was partitioned between 5 mL of 5% hydrochloric acid and 50 mL of dichloromethane. The organic layer was separated, washed with 10 ml of brine and dried over sodium sulfate. The residue was chromatographed by flash chromatography (eluting with 10% ethyl acetate in toluene). This gives a polar component which has been randomly labeled as 6-hydroxytetracycl. Yield 15%. mp 150-152 ° C. NMR spectrum (200 MHz, CDCl 3, δ T) δ 1.56 (t, 5H, J = 7.1 Hz, CH 3), 2.84 (ddt, 1H, J = 19.1 and 9.1) Hz, J '= 5.2 Hz, HCHaCHC = O, 5.15 (dm, 1H, J = 19.1 Hz, HCHeCHC = O), 4.52 (quartet, 2H, J = 7.1 Hz , OCHg), 4.54 (dd, J = 9.1 Hz, 4.5 Hz, OCHC = O), 4.67 (dt, 1H, J = 19.0 and 5.5 respectively, HCHaO), 5.06 (broad doublet, 1H, J = 19.0 Hz, HCH 2 O), 7.71 (multiplet, 2H, ArH), 7.94 (multiplet, 1H, ArH), 8.11. (s, 1H, ArH), 8.47 (multiplet, 1H, ArH), 15.7 (s, 1H, exchangeable proton proton group). 1 H NMR spectrum (75.44 MHz, CDCl 3, δ): 14.0 (CH 3), 24.4 (CH 3), 61.6 and 65.2 (OCH 2), 71.7 (OCH), 121.9, 125.0, 129.4, 150.7, 151.5 (aryl CH), 127.2, 127.6, 151.0, 156.0, 141.7, 144.2, 162.7 (aryl C), 170.4 (ester 0 = 0), 185.5 and 187.5 (quinone = 0). IR spectrum (PT, CDCl 3, γ y) δ 5405 (broad δ, OH), 1 (λ, LV 1 1 '(λ 1 · 1 ii - 69 - 1748 (ester C = O), 1660, 1644 (quinone C = O), 1609 (C.dbd.C.dbd.) Mass spectrum (HR) calcd for C20H16O6N + M + @ +, 352.0947, found: 352.0997. -hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno-1,2,3-c] pyran-3-yl-formic acid, "was obtained in a yield of 32%. m.p. 149-150 ° C. NMR (300 MHz, CDCl 3, δ): 1.35 (t, 3H, J = 7.1 Hz, CH 3), 2.78 (ddt, 1H, J = 3.4 Hz, 9.1 Hz and 19.0 Hz, HCHa), 3.07 (dm, 1H, J = 19.0 Hz, HCHe), 4.31 (overlapped with dd, 3H, OCH3, and OCH), 4.65 (dt, 1H) , J = = 3.3'Hz and 18.8Hz, HCHa), 5.04 (bd, 1H, J = 18.8Hz, HCHe), 7.71 (m, 2H, ArH), 7.93 (dd, 1H, J = 1.3 Hz and 7.3 Hz, ArH), 8.07 (s, 1H, ArH), 8.43 (dd, 1H, J = 1.2 Hz and 7.2) &Lt; 1 &gt; C NMR spectrum (75.44 MHz, CDCl3, [delta]): 13.9 (CH2), 24.8 (CH2), 61.6 (OCH2), 71.6 (OCH), 122, 1, 124.8, 129.3, 130.6, 131.4 (aryl CH), 106.1, 127.0, 127.6, 135.7, 142.6, 143.0, 162.6 (CH), 170.3 (ester C = O), 182 , 0 and 186.0 (C = O quinone). IR spectrum (FT, CDCl3, Vmax): 3590 (broad band, OH), 1748 (ester C = O), 1662, 1645 (C = 0 quinoline), 16O7. (C = C). Mass spectrum: (HR): for Ο ^ Η ^ θΟθ calculated MM * ·]: 352,0947 »found:. 352.0946. In addition, (5,12-dihydroxy-6,11-dioxo-3,4,6,11-tetrahydro-anthraceno [2,3-a] pyran-3-yl) formic acid ethyl ester, BCH-650, was isolated in 10% yield. . Melting point: 153-154 ° C. @ 1 H NMR Spectrum (300 MHz, CDCl3, .delta.): 1.36 (triplet, 3H, J = 6.0 Hz, .delta.) / 2.96 (ddt, 1H, J = 2.0 Hz, &apos; 10, 1 Hz and 18.2 Hz, HCHa), 3.26 (ddd, 1H, J = 1.8 Hz, 4.0 Hz and 18.3 Hz, HCHe), 4.33 (quartet, 2H, J) = 6.2 Hz, OCH 2, 4.37 (dd, 1H, J = 4.0 Hz and 10.0 Hz, OCH), 4.82 (dt, J = 2.0-H 2a of 17.6 Hz, O -HCHa), 5.23 (d, 1H, J = 17.5 Hz, O-HCHe), 7.85 (m, 2H, ArH), 8.35 (m, 2H, ArH), 13, 17 (s, 1H, ArOH), 13.34 (s, 1H, ArOH).

Step 2: Ethyl 16-acetoxy-5,12-dioxo-3,4,5,12-tetrahydro-danoantraceno [2,3-c] pyran-3-yl] naphthenic acid

A mixture containing 60 mg (0.18 mmol) of a more polar pyranotetracycl of the previous step, 0.25 ml of acid anhydride acetic acid, 0.5 ml of pyridine and 6 mg of dimethylaminopyridine in 20 ml of dichloromethane are stirred overnight at room temperature under argon, then diluted with 25 ml of dichloromethane and washed successively with 15 ml of water, twice with 10 ml. 1N hydrochloric acid, once with 15 ml of water and dried over sodium sulfate, flash chromatography of the residue to give 55 mg (81%) of the title acetylated pyranotetracycl, mp 196-198 ° C. 1 H NMR spectrum (500 MHz, CDCl 3, δ): 1.34 (t, 5H, J = 7.2 Hz, CH2), 2.65 (s, 3H, COCH3), 2.78 (ddt, 1H, J = 5.5 Hz, 9.1 Hz) and 18.7 H, HCHa), 5.10 (dm, 1H, J = 19.0 Hz, HCHe), 4.29 (quartet, 2H, J = 7.2 Hz, OCHg), 4.51 ( dd, 1H, J = 4.2 Hz, 9.5 Ηζ, ΌΟΗ), 4.61 (dt, 1H, J = 5.2'Hz and 19.0 Hz, HCHa-O), 5.02 ( bd, 1H, J = 19.0 Hz, HCHe-O), 7.75 (rn, 2H, ArH), 8.05 (m, 1H, ArH), 8.15 (m, 1H, ArH), 8.58 (br, 1H, ArH) .C spectrum (FT, CDCl3, .nu.max) J1775, 1751 (O = O ester), 1667 and 1644 (C = O quinone), 1618 (C = C). Mass spectrum (HR): for θ22 22 18θ7 Ό'Ρθθββη 1M + 3: 594.1055, found: 594.1020.

Step 5: Ethyl ester of (1S, 5S) and (1R, 5R) 16-acetoxy-1-hydroxy-5,12-dioxo-5,5,5,12-tetrahydro-anthrano-12,5-c 3-pyran-5 -yl 3-formic acid

A mixture containing 47 mg (0.12 mmol) of acetylnopyranote tracyl, 0.25 mg of N-bromosuccinimide and 0.1 mg of AIBN in 5 ml of carbon tetrachloride was refluxed for 2 hours. The solvent is then removed by distillation in a vacuum. To the residue was added 10 ml of tetrahydrofuran mixture in a ratio of: 1. After stirring for one hour at room temperature, the mixture was extracted with three 10 ml portions of dichloromethane. The combined organic extracts are washed once with 10 ml of water and dried over sodium sulfate. Flash chromatography of the residue afforded pyranotetracyclic aglycone (55 mg, 71%) after distilling off the appropriate fractions, m.p. 215-220 ° C (dec). @ 1 H NMR spectrum (500 MHz, CDCl3, .delta.): 1.55 (t, 5H, J = 7.1 Hz, CHp, 2.61 (s, 5H, OGOCH2), 2.71 (dd, 1 H, J = 19.6 Hz and 11.8 Hz, HCHaCHC = O), 5.15 (dd, 1H, J 1 · · · · 71 - 71 - j = 19.6 Hz and 4 , 5 Hz, HCHeCHC = O), 4.52 (quartet, 2H, J = 7.1 Hz, OCH2), 4.86 (dd, 1H, J = 11.5 &apos; Hz and 4.5 Hz, ' OCHO = O), 6.22 (s, 1H, CHOH), 7.74 (m, 2H, Ar H), 8.12 (m, 2H, Ar H), 8.61 (s, 1H, Ar H) 15CHMR spectrum (75.44 MHz, DMSO-d 6, δ): 15.9 (OH p, 20.9 (CH 3), 24.7 (CB 2), 60.9 µ (OCH 2), 64.6 (OCH) ), 85.9 (O-CH-O), 124.1, 126.7, 150.8, 150.9 and 151.0 '(aryl CH), 118.1, 126.6, 129.7, 155.5, 141.1, 145.9 and '147.6 (aryl C), 169.5, 170.5 (0 = O-ester), 181.5 and 182.6 (0 = 0 IR spectrum (PT, CDCl3, V): 5565 (broad band, OH), 1774 and 1748 (O = O ester), 1668 (O = O quinone). [.alpha.] D @ 20 g [M @ +] +: Calculated: 410.1002, Found: 410.1009

Step 4: Ethyl ester (1ZS, 1R, 5S) and (1'S, 1S, 5E) - 16-acetoxy-1- (2 ', 5', δ-trideoxy-5'-trifluoroacetamido-4'-O-p-nitrobenzoyl) -L-lyxohexopyranoso) -5,12-dioxo-5,4,5,12-tetrahydroanthraceno [2,5-] pyran-5-yl] formic acid

The glycosidation of the pyrano anthraquinone from step 5 above can be carried out as described in step 10 of Example 1. The overall pyrazine anthraquinone glycoside yields a total yield of 77%, m.p. 158-160 ° C (1S, 1S, 5R) and 225-227 ° C (1S, 1R, 5S). 1 H NMR spectrum (500 MHz, CDCl 3, δ): (1'S, 1S, 5R) -diastereoisomer: 1.25 (Γ, 5H, J = 6.8 Hz, CH5-6z), 1.56 (t , 5H, J = 7.0 Hz, CH 2), 2.06 (m, 2H, CH 2 - 2 '), 2.62 (s, 5H, acetyl CH 2), 2.77 (dd, 1H, J) = 19.5 Hz and 11.5 Hz, HCHaCHC = O), 5.19 (dd, 1H, J = 19.5 and 5.7 Hz, HCHeCHC = O), 4.51 (quartet, 2H, J = 7) , 0 Hz, OCH 2), 4.42 (broad quartet, 1H, J = 6.9 Hz, HC-5 '), 4.65 (m, 1H, HC-5'), 4.78 (dd, 1H) , J = 11.4 Hz and 5.7 Hz, OCHC = O), 5.48 (broad s, t, 1H, HC-4Z), 5.76, (broad singlet, 1H, HC-1 '), 6, 05 (s, 1H,, O-CH-O), 6.55 (d, 1H, J = 6.4 Hz, NH), 7.76 (m, 2H, Ar H), 8.12 (m, 2H) , 8.5H (doublet of doublets, 4H, 'p-nitrobenzoyl protons), 8.65 (s, 1H, ArH). NMR Spectrum (5θ MHz, CDCl 3) (1 / S, 1R, 5S) -diastereoisomer: 1.40 (d, 5H, J = 6.6 Hz, CH 3 -6 '), 1.57 (t, 5H) , J = 7.0 Hz, CHp, 2.06 (m, 2H, - 5, rVVHrc '' '' '' '>' ·> AmiRiiiii 'Altii ίίιΛ & Lieďttti jfe-) iLjk <^ ΚΧηΑύΛ «> /' 2.61 (s, 3H, acetic CH 2 group), 2.81 (dd, 1H, J = 19.0 Hz)? and 11.7 Hz, HCHaCHC = O), 3.19 (dd, 1H, J = 19.4 Hza at 3.9 Hz, HCHeCHC = O), 4.31 (quartet, 2H, J = 7.0 Hz , OCH 2, 4.72 (broad multiplet, 3H, overlapped HC-5 *, HC-3'aOCHC = O), 5.46 (broad singlet, 1H, HC-4 "), 5.67 (broad shingle, 1H, HC-1 &apos;), 6.26 (s, 1H, O-CH-O), 6.41 (d, 1H, J = 8.0 &lt; + &gt;,.), 7.72 (m, 2H, ArH), 8 , 18 (dm, 2H, ArH), 8.35 (dd, 4H, p-nitrobenzoyl protons), 8.67 (s, 1H, .RTM.), .Delta. C NMR spectra of diastereomeric mixture (75.44 MHz, CDCl 3, (δ): 14.3 and 14.5 (COOCH 2 CH 3), 17.0 and 17.2 (6'-CH 2), 21.4 (acyl CH 2, 24.9 and 25.4 (2 H); -CH 2), 29.9 and 30.0 (4-0¾), 45.9 and 46.0 (CHNH), 62.1 and 62.2 (ester CH 2 O), 66.2 and 66.8 ( 5 * -00 Η), 66.9 and 67.1 (4'-OCH), 72.2 and 72.8 (3-OCH), 88.0 and 92.7 (1-O-CH-O), 92, 8 and 98.7 (1'-O-CH-O), 113.1 (quartet, J = 287.1 Hz, 0¾), aromatic CH: 124.5, 127.8, 128.1, 131, 0, 131.2, 131.6, 131.7, 135.0, aromatic carbon atoms: 118.5, 128.9, 130.9, 131.0, 131.2, 134.97, 138.16, 138, 23, 139.5, 140.0, 144.9, 145.8, 148.85, 148.94, 151.7, 157.5, (quartet, J = 37.3 Hz, COCFp, 165.4, 165.7, 169.6, 169.7, 170.1 and 170.5 (O = O ester), 182.0, 182.3, 182.7 (O = O quinone). IR spectrum (PT, CDCl3, 1774, 1737 (broad ester ester O = O), 1669 (O = O quinone), 1532 (amide).

Step 5: Ethyl ester of 16-acetoxy-11-hydroxy-5,12-dioxo-3,4,5,13-tetrahydro-anthracene-2,3-c] pyran-3-yl-formic acid and ethyl ester of l-acetoxy-6-hydroxy- . 5.12-Dioxo-3,4,5,12-te trahydro-nitro-12,3-o-pyran-3-yl-formic acid

A mixture containing 387 mg (1.1 mmol) of non-acetylated hopyranotetracycline obtained according to Step 1 above, 2.5 g of lead dioxide, 60 ml of acetic acid and 30 ml of dichloromethane was stirred under argon at room temperature for 48 hours. The mixture is diluted with 100 ml of dichloromethane, extracted twice with 50 ml of water and dried over sodium sulfate. After removal of the solvent, a residue is obtained which contains the title compound. @ 1 H NMR spectrum (75.44 MHz, CDCl3, .delta.): 13.94, 20.66, 20.80, 24.98,. - 25.68, 61.57, 61.70, 65.60, 65.67, 71.97, 73.07, 126.76, 126.82, 127.48, 127.53, 154.19, 135.04 , 157.10, 159.05, 170.46, 170.52, 181.57, 188.78, 188.82. IC spectrum (FT, CDCl3, Vmax) with 1759.8 and 1754.5 (O = O ester), 1671.7 and 1654.7 (0 = O quinone).

Step 6: 16,11-Diacetoxy-5,12-dioxo-3,4,5,12-tetrahydroanthracene-1,2,3-cpyran-5-yl-3-morpholinic acid ethyl ester X

The residue from step 5 above is added to a solution containing 5 ml of acetic anhydride, 6 ml of pyridine and 60 mg of dimethylaminopyridine in 50 ml of dichloromethane. The mixture was stirred at room temperature overnight under argon. Then 50 g of ice are added. The aqueous layer was separated and extracted twice with 50 mL of dichloromethane. The combined organic extracts are then washed sequentially with 25 ml of water, twice with 25 ml of 1N hydrochloric acid, 25 ml of water, 25 ml of brine and dried over sodium sulfate. After evaporation of the solvents, the residue was chromatographed by flash chromatography. There was obtained 175 mg (55%) of the title bisacetylated pyranoanthraquinone, m.p. 205-205 ° C. Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl 3, δ T): 1.56 (t, 5H, J = 7.1 Hz, GH 3), 2.50 (br, 3H, COCH 3), 2.54 (s, 5H , COCH 3), 5.05 (broad multiplet, 2H, CH 2 CHC = O), 4.55 (matrix doublet of doublets, 1H, OCHC = O), 4.52 (quartet, 2H, J = 7.1) Hz, OCHgCHp, 4.75 (broad doublet, 1H, J = 16.7 H, HCHa-O), 5.11- (broad doublet, 1H, J = 16.5 Hz, HCHe-O), 7.75 (m, 2H, Ar H), 8.16 (m, 2H, Ar H) IR spectrum (FT, CDCl3, V1): 1771 (broad CO ester ester), 1677 (C = O'quinone), 1591 ( C = C) Mass spectrum (HR): for G24 1919 ° 19 v 7 Calculated: 451.1029, found: 451.1061. Eň Step 7i Ethyl ester (1S, 3S) and (1R, 3H) -tll-acetoxy- 1,6-dihydroxy-5,12-dioxo-5,4,5,12-thihydro-naphthalene-1,2,3-cypran-3-yl formic acid

A mixture containing 75 mg (0.17 mmol) of the preceding step 6 pyranotetracyclosil, 32 mg (0.17 mmol) of N-bromosuccinimide and 1 mg of AIBN in 15 ml of carbon tetrachloride was boiled for 2.5 hours.

74% under reflux in an argon atmosphere. After removal of the solvent, 25 ml of tetrahydrofuran / water (4: 1) was added to the residue and the residue was stirred for 0.5 hour.

The mixture was then extracted three times with 25 ml of dichloromethane. The combined extracts are washed with 25 ml of water, 25 ml of sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed by flash chromatography. There was thus obtained 61 mg (77%) of the desired bisacetylated tetracyclic glycone, m.p. 220-250 ° C, decomp. @ 1 H NMS spectrum (500 MHz, DMSO-d6, .delta.): 1.25 (t, 5H, J = 7.1 Hz, CH2 -), 2.42 (s, 3H, COCH2), 2, 55 (broad multiplet, 1H, HCHa), 2.47 (broad mulletlet, 1H, HCHe), 4.21 (quartet, 2H, J = 7.1 Hz, OCH2), 4.42 (m, 1H, OCH), 6.11 (d, 1H, J = 5.8 Hz, O-CH-OH), 7.42 (doublet, 1H, J = 5.8 Hz, exchangeable hydroxyl proton), 7.95 ( m, 2H, ArH), 8.12 (m, 1H, Ar H), 8.22 (m, 1H, Ar H), 15.5 (s, 1H, exchangeable hydroxyl proton on ArOH). IR spectra (FT, CDCl 3, ν max): 5690 (OH), 5500 and 5700 (broad band OH), 1764 and 1750 (O = O ester), 1668 and 1656 (C = O-quinone), 1601 ( C = C). Mass spectrum (HR) δ for δ 22: 18θ9 calculated: 425.0951, found: 425.0948.

Step 8: Ethyl ester (1S, 1R, 5S) and (1'S, 1S, 5R) 11-hydroxy-6-acetoxy-1- (2z, 5z-6z-trideoxy-5'-trifluoro-acetamido-4-O-) nitrobenzoyl 1-L-lyxohexapyrano-so-5,12-dioxo-5,4,5,12-te-triazine, 12,5-c 3-pyran-5-yl formic acid

These compounds were obtained in a yield of 61% by a procedure substantially similar to that described in Step 10 in Example 1, using aglycone from the above-mentioned Step 7 procedure. Melting point: 155-158 ° C (1S, 1S, 5R) isomer and 182-184 ° C (1 'S, 1E, 5S) -isomethyl. NME spectrum (200 MHz, CDCl 3,) less polar (2S, 1S, 5R) -isomer: 1.26 (d, 5H, J = 6.5 Hz, H 2 C-6Z), 1.59 (t 5H, J = 7.1 Hz, CHp, 2.21 (m, 2H, H 2 C-2Z), 2.54 (s, 5H, O = C-CH 2, 2.88 (m, 1H, HCHaCHC = 0), 5.15 (m, 1H, HCHeCHC = O), 4.57 (quartet, 2H, J = 7.1 Hz, OCHg), 4.49 (broad quartet, 1H, J = 6.5 Hz) , -75-HC-5 '), 4.67 (m, 1H, HC-3'), 4.83 (dd, 1H, J = 11.6 Hz and 4.45 Hz, OCHC = O), 5 , 49 (broad singlet, 1H, HC-4 '), 5.77 (broad singlet, &lt; 1 &gt; H, &lt; 6 Hz, HC-1 '), 6.21 (s, 1H, O-CH- O), 6.24 (d, 1H, J = 9.1, ΝΗ), 7.84 (m, 2H, Ar H), 8.60 (m, 2H, Ar H), 8.33 (dd). , 4H, p-nitroarboxylic acid H), 13.54 (s, 1H, interchangeable hydroxyl group proton) 1 H NMR spectrum (200 MHz, CDCl 3, cT) (1'S, 1R, 3S) -diastereomer 1.29 (d, 3H, J = 6.5 Hz, H 1 C-6 *), 1.37 (t, 3H, J = 7.1 Hz, CH 3), 2.08 (m, 2H, H 2 C-2 *), 2.88 ( wide multiplet, 1H, HCHaCHC = O), '3.11 (broad multiplet, 1H, HCHeCHC = O), .45 (quartet, 2H, J = 7.0 Hz, OCH2), 4.67 <(m , 1H, HC-3 '), 4.81 (m, 1H, HC-5'), 4.85 (m, 1H, OC HC = O), 5.45 (broadsletlet, 1H, HC-4 '), 5.71 (broad singlet, 1H, 1H-C-1'), 6.37 (broad doublet, 1H, J) = 9 Hz, NH), 6.39 (s, 1H, O-CH-O), 7.85 (m, 2H, ArH), 8.30 (m, 2H, ArH), 8.35 (dd, 4H, p-nitroaryl protons, 13.66 (s, 1H, exchangeable OH proton). Spectrum (FT, CLCl 3, Vmax) * 5431 (OH), 1737 (broad signal, C = O ester), 1674 (C = O quinone), 1595 (C = C).

Step 9: Methyl ester (1S, 1S, 3R) and (1 * S, 1R, 3S) 1 H -hydroxy-1- (2 ', 3'-β-trideoxy-3'-trifluoroacetamide-4'-propyl) L-lyxohexopyranoso) -5,12-dioeo-3,4,5,12-tetrachydroantraceno [2,3-c] pyran-3-yl] acid, BCH-692 and BCH-691

Removal of the protecting group described in Step 11 of Example 1 (conducted at room temperature) gave the title compounds in 65% yield. A less polar compound was assigned the BCH-692 structure. @ 1 H NMR spectrum (3θ MHz, CDCl3, .delta.) With 1.31 (d, 3H, J = 6.6 Hz, CH5), 1.87 (dt, 1H, J = 3.8 H at position 13, 5 Hz, 2'-HCHa), 2.04 (dd, 1H, J = 5.2 Hz and 13.4 Hz, '2'-HCHe), 2.76 (dd, 1H, J = 11.8) Hz and 19.5 Hz, HCHa), 3.18 (dd, 1H, J = 3.9 Hz and 19.5 Hz, HCHe), 3.04 (broad singlet, 1H, 4'-CH), 3, 87 (s, 3H, OCH3), 4.23 (broad quartet, 1H, J = 6.6 Hz, 5'-CH), 4.39 (m, 1H, 3 * -0H), 4.75 ( dd, 1H, J = 3.9 Hz and 11.8 Hz, O-CH), 5.59 (broad doublet, 1H, J = 3.5 Hz, 1'-CH), 6.02 (s) , 1H, O-CH-O), 6.71 (broad doublet, 1H, J = 9.1 Hz, NH), 7.72 (m, 2H, ArH), 7.96 (m, 1H, Ar- H), 8.15 (s, 1H, Ar H), 8.48 (m, 1H, Ar H), 13.75 (s, 1H, ArOH). - 76 -

The more polar compound was designated BCH-691. @ 1 H NMR spectrum (500 MHz, CDCl3, .delta.): 1.40 (d, 5H, J = 6.6 Hz, CH2), 1.88 (m, 2H, 2'-CH2), 2, 75 (dd, 1H, J = 11.7 Hz, 19.7 Hz, HCHa), 5.17 (dd, 1H, J = 4.1 Hz and 19.7 Hz, HCHe), 5, 64 (broad singlet, 1H, 4'-CH), 5.85 (s, 5H, OCH2), 4.51. (m, 1H, 5'-CH), 4.58 (broad quartet, ‘H, J = 6.7 Hz, 5ζ-θΗ). 4.71 (dd, 1H, J = 4.1 Hz and 11.6 Hz, O-CH), 5.49 (broad singlet, 1H, 1 '- CH), 6.19 (s, 1H, O) -CH-O), 6.72 (broad doublet, 1H, J = 7.9 Hz, NH), 7.70 (m, 2H, ArH), 7.97 (broad doublet, 1H, J = 7, 4 Hz, ArH), 8.17 (s, 1H, ArH), 8.47 (broad oak, 1H, J = 7.4 Hz, ArH), 15.8 (s, 1H, ArOH). Small amounts of BCH-675 (5-10%) are obtained. The spectral data were similar to BCH-691 to the presence of the ethyl ester group.

Step 10: Methyl ester (1S, 1S, 5R) and (1 * S, 1R, 5S) (11-hydroxy-6-methoxy-1 H, 5 ', 6-trideoxy-5-trifluoroacetamide) 4z-hydroxy-L-lyxohexopyranoso] -5,12-dioxo-5,4,5,12-tetrahedroantraceno [2, 5-c] pyran-5-yl) formic acid, compounds BCH-674 and BCH-675

Deprotection is performed as described in step 9, at a temperature of -15 ° C. BCH-674 was assigned to the compound with the following data: 1 H NMR spectrum (500 MHz, OD): 1.55 (d, 5H, J = 6.6 Hz, CHβ, 1.89 (m, 2H, 2 ') -CH2), 2.89 (dd, 1H, J = 12.2 and 18.6 Hz, HCH3), 5.51 (dd, 1H, J = 4.2 Hz and 18.6 Hz, HCHe), 5 , 62 (broadsinglet, 1H, 4'-CH), 5.85 (s, 5H, OCH2), 5.92 (s, 5H, OCH2), 4.55 (m, 1H, 5'-CH) , 4.55 (broad quartet, 1H, J = 6.6 Hz, 5Z-CH), 5.49 (broad singlet, 1H, 1'-CH), 6.25 (s, 1H, O- CH-O), 6.76 (broad doublet, 1H, NH), 7.82 (m, 2H, ArH), 8.24 (m, 2H, ArH), 12.54 (s, 1H, ArOH).

The BCH-675 designation was assigned to the compound with the following data: 1 H NMR spectrum (500 MHz, CPCl 3, δ "1.28 (d, 5H, J = 6.6 Hz, CHβ, 1.87 (m, 1H) , 2'-HCHa), 2.04 (m, 1H, 2'-HCHe), 2.86 (dd, 1H, J = 12.1 Hz, 18.4 Hz, HCHa), 5.52-77 - (dd, 1H, J = 5.9 Hz and 18.5 Hz, HCHe), 3.63 (broad singlet, 1H, 4'-CH), 3.86 (s, 5H, OCH2), 3.88 (W, 3H, OCH3), 4.20 (broad quartet, 1H, J = 6.6 Hz, 5'-θ), 4.53 (m, 1H, 5 * -CH), 4.85 (dd, 1H, J = 5.9 Hz, 12.1 Hz, O-CH), 5.51 (broad singlet, 1H, 1'-CH), 6.15 (br, 1H, O-CH-O), 6 , 75 (broad doublet, 1H, J = 8 Hz, NH), 7.27 (m, 2H, ArH), 8.2 (m, 2H, ArH), 15.6 (1H, ArOH). ...

Stage 11: Ethyl ester (1'S, 1R, 3S) and (1'S, 1S, 3R) (6-hydroxy-5,12-dioxo-1- (5'-trifluoroacetamido-1-daunosaminyl) -3,4,5,12-Tetrahydroanthraceno [2,3-c] pyran-3-yl) formic acid Under an argon atmosphere (28 ° C), a solution containing 196 mg (0.25 mmol) The glybside from step 4 above in 50 ml of dry methanol was treated with a total of 5 equivalents (0.25 ml) of 4.37% methanolic sodium methoxide solution, which was added to the reaction mixture according to the reaction. The reaction was then quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with water (2 x 75 mL) and dried over sodium sulfate. Purification by HPLC gave 7.8 mg (5% yield) of 1'S, 1R, 3S-diastereomer BCH-681, m.p. 200 ° C (dec). 1 H NMR spectrum (500 MHz, CDCl 3, δ): 1.55 (t, 3Ξ, J = 7.1 Hz, C 1 H 6 H 2), 1.42 (d, 3H, J = 6.6 Hz, H 3 1.69 (2H, HaC-2 &apos; and HeC-2 '), 2.76 (dd, 1H, J = 19.6 and 11.4 Hz, CH2CHC = O), 5.19 (dd, 1H, J = 19.6 Hz and 4.1 H, HC® CHC = O), 5.64 (broad singlet, 1H, HC-4 '), 4.51 (quartet, 2H, J = 7 2.52 (m, 1H, HC-3 '), &lt; 4.61 &gt; Giro quartet, 1H, J = 6.5 Hz, HC-5 &lt; + &gt;), 4.69 (dd) , 1H, J = II, 8 Hz and 4.2 Hz, O-CH), 5.48 (broad singlet, 1H, HC-1 '), 6.17 (s, 1H, O-CH-O), 6.75 (broad doublet, 1H, NH), 7.74 (m, 2H, ArH), 7.96 (m, 1H, ArH), 8.13 (s, 1H, ArH), 8.51 (m , 1H, ArH), 13.83 (s, 1H, ArOH).

Also obtained was 1S, 1S, 3R-diastereomer labeled BCH-684 in 2% yield (2.9 mg). Melting point: 175 DEG C. (decomposition). 1 H NMR spectrum (300 MHz, CDCl 3, δ): 1.32 (d, 3H, J = 6.6 Hz, - 78 -

H 1 C-6 *), 1.38 (t, 3H, J = 7.2 Hz, OCH 3 CH 2), 1.85 (m, 1H, HaC-2 *), 2.02 (m, 1H, HeC-2) *), 2.62 (dd, -1H, J = 19.5 Hz and 11.8 Hz, HCHaCHC = O), 3.21 (dd, 1H, J '= 19.5 H and 4.0 Hz, H). HCHeCHC = O), 3.65 (broad singlet ', 1H, HC-4'), 4.25 (broadquartet, 1H, HC-5 '), 4.35 (m, 3H, OCH3CH2 and HC-4'). 4.75 (dd, 1H, J = 12.0 Hz and 3.8 Hz, OCHC = O), 5.61 (broad singlet, 1H, HC-1 '), 6.02 (s, H , O-CH-O), 6.72 (broad doublet, 1H, HH), 7.75 (m, 2H, Ar H), 7.98 (m, 1H, Ar H), 8.12 (s, 1H) , ArH), 8.52 (m, 1H, ArH), 13.86 '(s, 1Ξ, Ar-OH). '

BCH-706 could be isolated from HPLC at 2% yield. The NMR spectrum of this compound is similar to that obtained for compound BCH-684 except for the signal prototype of the methoxy ester group at 3.87 PPm instead of the signal of the ethyl ester group.

The BCH-683 compound was also obtained in 17% yield.

This compound has the following physical properties: m.p. 190-215 ° C (dec). @ 1 H NMR spectrum (300 MHz, CDCl3, .delta.): 1.41 (d1, 3H, J1 = 6.6 Hz, CH2), 1.89 (m, 2H, 2'-CH2), 2, 78 (dd, 1Ξ, J = 11.8 Hz and 19.2 Hz, HCHa), 3.20 (dd, 1H, J = 4.0 Hz and 19.6 Hz, HCHe), 3.66 (broad singlet) , 1H, 4 * -CH), 3.87 (s, 3H, OCH 3), 4.54 (m, 1H, 3'-CH), 4.63 (broad quaternary, 1H, H = 6.6 Hz, 5'-CH 3, 4.73 (dd, 1H, J = 4.0 Hz and 11.8 Hz, O-CH), 5.49 (broad singlet, 1H, 1'-CH), 6 18 (s, 1H, O-CH-O), 6.77 (broad d, 1H, J = 7.1 Hz, NH), 7.74 (m, 2H, ArH), 7.98 ( dd, 1H, J = 2.4 Hz and 7.1 Hz, ArH), 8.14 (s, 1H, ArH), 8.52 (dd, 1H, J = 2.4 Hz and 7.1 Hz, ArH), 13.8 (br, 1H, ArOH).

Step 12: Ethyl ester (1'S, 1R, 3S) and (1'S, 1S, 3R) (6-hydroxy-11-methoxy-5'2-dioxo-1- (3-trifluoromethoxy-1-daunosaminyl) -3) 4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl) formic acid

The reaction from step 11 above was carried out at -15 ° C. Yield 20% of a mixture of ethyl esters 1S, 1R, 3S and 1α, 1S, 3R (6-hydroxy-11-methoxy-5,12-dioxo-1- (3'-trifluoroacetamido-1-aunosaminyl) -3,4,5, 12- - 79 - t tetrahydroanthraceno [2,3-d] pyran-3-yl) nirvanoic acid; 176 to. 180 ° C. H NMR spectrum (500 MHz, CDCl3, (R) (1S, 1R, 3S) -diastereomer 1.34 (d, 3H, J = 6.6 Hz, H-C-6 *) , 1.38 (t, 5H, J = 7.1 Hz, OCH2 H6), 1.90 (m, 1H, HaC-2 *), 2.04 (m, 1H, HeC-2 *); ), 2.94 (dd, 1H, J '= 18.7 Hz and 12.2 Hz, HCHaCHC = O), 3.33 (dd, 1H, J = 18.4 Hz and 3.3 Hz, HCHCHCH2 = O), 3.65 (broad singlet, 1H, HC-4 *), 3.95 (broad s, 3H, ArOCH 2, 4.35 (quartet, 2H, J = 7.1 Hz, OC 1 CH 3, 4, 42 (m, 1H, HO-3 '), 4.68 (broad quartet, 1H, HC-5 '), 4.78 (dd, &lt; + &gt;, J = 11.9 &lt; / RTI &gt; CH), 5.53 (broad) 1H, HC-1 '), 6.34' (s, 1H, O-CH-O), 6.76 (broad doublet, IR, NH), 7.83 ( ώ, 2H, ArH), 8.31 (m, 2H, ArHH), 13.70 (s, 1H, ArOH), H HHNMRspectrum (300 MHz, CDClCl, f) (1 * S, 1 S, 3 R) diastereomer: 1.31 (d, 3H, J = 6.6 Hz, H 2 C-6 *), 1.38 (t, 3H, J = 7.1 Hz, CH 2 CH 2), 1.90 (m, 1H, HaC-2 *), 2.04 (m, 1H, HeC-2 *), 2.91 (dd, 1H, J = 18.2 Hz and 12.0 Hz, HCHaCHC = O), 3.34 (dd, 1H, J = 18.3 Hz and 3.7 Hz, HCHeCHC = O), 3.65 (broad sihglet, 1H, HC-4 *), 3.94 (s, 3H , ArOCH 3), 4.28 (broad quart t, 1H, HC-5 '), 4.35 (quartet, 2H, J = 7.1 Hz, OCH2 H6), 4.42 (m, 1H, HC-3 *), 4.81 (dd) , 1H, J = 12.4 Hz and 4.0 Hz, O-CH), 5.59 (broad s-glet, 1H, HC-1 *), 6.14 (s, 1H, O-CH- O), 6.74 (broad doublet, 1H, NH), 7.83 (m, 2H, ArH), 8.31 (m, 2H, ArH), 13.59 (s, 1H, ArOH). ........ - 80 -

as for example lw

+ Diaslercomer

Example

Ji Preparation of Various Pyrano-Heteroanthracones and Heteroanthracyclines * Example 5 (continued)

I - 81 -

10 10 \ t

tiSíiCÓ '- 82 - Example. 5 (continued) OAc o

and

OH O O

+

Example 4

Step 5 (5,8-Dioxo-5,8-dihydroisochloro-3-yl) formic acid p-nitrobenzyl ester (5,8-dimethoxy-isochroman-3-yl) formic acid p-nitrobenzoyl ester is oxidized as described in Step 5 of Example 2, the title compound was obtained in 92% yield. Melting point 133 ° C (decomposition). Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl 3, δ): 2.70 (ddt, J = 18.7 Hz, 9.0 Hz and 3,'Hz, · HCH aCHC = O), 2.95 (doublet of multiplet, 1H, J = 19.0 Hz, HCHeCHC = O), 4.38 (dd, 1H, J = 8.9 Hz and 4.3 Hz, OCHC = O), 4.56 (dt, 1H, J = 17 , 1 Hz and 3.0 Hz, HCHa-O), 4.88 (ddd, 1H, J = 17.3 Hz, 2.8 Hz and 1.7 Hz, HCHe-O), 5.5θ (broad singlet , 2H, CH 2 ArH), 6.79 (dd, 2H, ArH), 7.57 (d, "2H, ArH), 8.29 (d, 2H, ArH).

Step 2: 5,12-Dioxo-3,4,5,12-tetrahydro-anthracene-2,3-cpyran-3-yl) formic acid p-nitrobenzyl ester

A solution containing 669 mg (1.9 mmol) of pyranoquinone of step 1, 485 mg (2.9 mmol) of 3,0-dihydrobenzoylbis-1,2-oxathiine 2-oxide (Charlton UL and Durst T. and Tetra. 25: 5287 (1984) in 50 ml of xylene, boiled overnight under reflux. The solvent is then removed in vacuo. The residue was chromatographed by flash chromatography with ethyl acetate in toluene to give 537 mg (62%) of the title pyranoaniline, mp 214-215 ° C (dec). 1 H NMR Spectrum (200 MHz, CDCl 3, δ): 2.84 (ddt, 1H, J = 18.9 Hz, 9.0 Hz and 2.7'Hz, HCHaCHC = O), 3.12 (broad) doublet, 1H, J = 19.0 Hz, HCHeCHC = O), 4.40 (dd, 1H, J = 9.1 Hz and 4.4 Hz, OCHC = O), 4.67 (dt, 1H, J); = 19.0 H.sub.3.0 Hz, HCHa-O), 5.04 (broad doublet, 1H, J = 18.9 Hz, HCHe-O), 5.33 (broad broad, 2H, ArCH2), 7 , 53 (d, 2H,

ArH), 8.04 (m, 2H, ArH), 8.21 (d, 2H, ArH), 8.58 (s, 1H,

ArH), 8.62 (s, 1H, ArH), 7.6? (m, 2H, Ar H).

Step 3: p-Nitrobenzyl ester of (1S, 5S) and (1R, 3R) 11-Hydroxy-5,12-dioxo-3,4,5,12-tetrafluoroanthenyl-2,3,3-pyran-3-yl formic acid

A mixture containing 164 mg (0.37 mmol) of pyranoanthrone; ~ -x.fet • JÓ -z · /, J. 1 of - 84 - cyclinone from step 2, 65 mg (0.37 mmol) of N-bromosuccinimide and 10 mg of AIBN in 25 ml of carbon tetrachloride, with two hours under reflux. The solvent is then removed and the residue is stirred with 35 ml of tetrahydrofuran-water solution (3: 3) for ten hours. The mixture was then extracted with three 25 mL portions of dichloromethane. The combined organic layers were washed once with 10 mL of water, 10 mL of brine, and dried over sodium sulfate. After evaporation of the solvents, the evaporation is chromatographed by flash chromatography. 118 mg (69%) of the desired pyrano anthraquinone system are obtained. Nuclear Magnetic Resonance Spectrum (200 MHz, DMSO-d 6): 2.68 (doublet, 1 H, J = 19.1 Hz, 11.5 Hz, HCH 2 CHC = O), 3.00 (dd, 1H) , J = 19.4 Hz and 4.4 Hz, HCHeCHC = O), 4.89 (dd, 1H, J = 11.4 Hz and 4.1 Hz, OCHG = O), 5.39 (broad singlet) , 2H, ArCHg), 5.98 (d, 1H, J = 6.3 Hz, CHOH), 7.40 (d, 1H, J = 6.1 Hz, variable hydroxyl proton), 7.7 ( d, 2H, ArH), 7.78 (m, 2H, ArH), 8.27 (d, 2H, ArH), 8.29 (m, 2H, ArH), 8.66 (s, 1H,

ArH), 8.67 (s, 1H, ArH).

Stage 4: p-Nitrobenzyl ester (1'S, 1R, 3S) and (1 * S, 1S, 3R) -L1- (2Z, 3 ', 6'-trideoxyacetamido-4' -Op-nitrobenzene-1L-lyxohexopyranose) -5 12-Dioxo-3, 4,5,12-tetrahydro-anthracene-2,3-pyran-3-yl-formic acid The desired glycosides were prepared in the same manner as described above in Step 10 of Example 1 using the aglyconase of Step 3 of this Example. The melting point of (1S, 1S, 3R) -isomer was 192-195 ° C, the melting point of (1'S, 1R, 3S) -isomer was 175-174 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ ") (1'S, 1S, 3R) -diastereomer: 1.12 (d, 3H, J = 6.3 Hz, H 2 C-6 *), 2.09 ( m, 2H, H 2 C-2Z), 2.83 (dd, 3H, J = 19.4 Hz and 11.7 Hz, HCH a CHC = 0), 3.26 (dd, 1H, δ = 19.1 Hz and 3.7 Hz, HCHeCHC = O), 4.4 (broad quartet, 1H, J = 6.1 Hz, HC-5 '), 4.65 (m, 1H, HC-3 *), 4.89 ( doublet of doublets, 1H, J = 11.8 Hz and 3.8 Hz, OCHC-O), 5.42 (broad ether, 3H, HC-4 'and aralCH 2, 5.82 (broad singlet, 1H, W less than 6 Hz, HC-1 '), 6.13 (s, 1H, W is less than 0.7 Hz, OCH-O), 6.40 (d, 1H, J = 7.5 Hz, NH) , 7.28 (d, 2H, p-nitrobenzyl protons), 7.75 (m, 2H, ArH), 8.09 (m, 2H, ArH), 8.29 (d, 2H, p-nitrobenzyl protons), 8 , 31 (dd, 4H, benzoyl protons), 8.64 (s, 1H, ArH), 8.69-85 - (s, 1Η, irH). @ 1 H NMR spectrum (200 MHz, CDCl3, .delta. , 1R, 3S) diastereomer 1.42 (d, 3H, J = 6.4 Hz, H 2 C-6 '), 2.09 (m, 2H, H 2 C-2Z), 2.85 (dd, 1H, J = 19.4 Hz and 11.3 Hz, HCHaCHC = O), 3.25 (dd, 1H, J = 19.4 Hz and 4.3 Hz, HCHeCHC = O), 4.63 (m, 1H, HC-3 '), 4.84 (overlapped signals, m, 2H, HC-5 ' and OC HC = O), 5.4-1 (broad singlet, 2H, aralCH 2), 5.47 (s, 1H, W = 5 Hz, HC-4Z), 5.69 (s, 1H, W is less than 0.7 . H, O-CH-O), 6.57 (d, 1H, J = 7.2 Hz, NH), 7.73 (d, 2H, p-nitrobenzyl protons), 7.75 (ώ, 2H, ArH), 8.11 (m, 2H, ArH), 8.33 (d, 2H, p-nitrobenzyl protons), 8.37 (dd, 4H, p-nitrobenzyl protons), 8.69 (s, 1H, ArH).

Step 5: (L'S, 1S, 3S) - (1-I 2Z, 3 ', 6z-trideoxy-acetamido-4'-hydroxy-L-lxohexopyropyrosine-5,12-dioxo-3,4-, 5,12) methyl ester &lt; tb &gt; ______________________________________ &lt; tb &gt; ______________________________________ &lt; tb &gt; ______________________________________ &lt; tb &gt;

Removal of the protecting groups from the less polar glycoside of Step 4 above as described in Step 11 of Example 1 yields the title compound in a 20% yield. 1 H NMR spectrum (300 MHz, CDCl 3): 1.29 (d, 3H, J = 3.3 Hz, CH 3), 1.85 (dt, 1H, J = 3.8 Hz and 13.3 Hz, 2'-HCHa), 2.00 (dd, 1H, J = 5.4- and 13.4 Hz, 2'-HCHe), 2.76 (dd, 1H, J = 1.0 ' Hz, 11, 8 Hz -19.5 Hz, HCHa), 3.18 (dd, 1H, J = 3.8 Hz and 19.5 Hz, HCHe), 3.63 (broad singlet, 1H, 4Z-CH), 3 86 (s, 3H, OCH 2), 4.23 (broad quartet, 1H, J = 6.6 "Hz, 5,-θ), 4, 35 (m, 1H, 3Z-CH), 4.75 (dd, 1H, J = 3.9 Hz and 11.8 Hz, O-CH), 5.61 (broad d, H, J '= 3.4 Hz, 1Z-CH), 6.04 (s, 1H, O-CHO), 6.71 (broad doublet, 1H, J = 9.0 Hz, NH), 7.70 (m, 2H, 4rH), 8.06 (m, 2H, ArH), 8, 60 (br, 1H, ArH), 8.67 (s, 1H, ArH) The less polar compound, which was provisionally labeled as (1ZS, 1S, 3R) (1R2, 3 ', 6Z-trideoxyacetamido-4 z) methyl ester -Hydroxy-L-lyxohexapyranoso-5,12-dioxo-3,4-, 5,12-tert-transananthracene-2,3,3-cpyran-3-yl) tertiary acid, compound designated as BCH-670, was obtained in a yield of 60% @ 1 H NMR spectrum (300 MHz, CDCl3, .delta.) With 1.25 (d, 3H, J = 6.6 Hz, CH3), 1.86 (d). triplet triplet, 1H, J = 3, 84 Hz and 13.2 Hz, 2z-HCH a), M-J: - 86 - 2.09 (dd, 1H, J = 5.2 Hz and 15.4 Hz , 2'-HCHe), 2.51 (dd, 1H, J = 11.9 Hz and .15.2 Hz, HCHa), 2.88 (give, 1H, J 2,9'Hz and 15.2 Hz, HCHe), 5.61 (broad doublet, 1H, J = 4.2H, 4'-CH), 5.82 (s, 5H, OCH2), 4.21 (broad quartet, 1H, J = 6.8 Hz, 5'-CH, 4.44 (m, 1H, 5'-CH), 4.5? (dd, 1H, J = 2.74 and 11.87H, O-CH), 5.55 (broad doublet, 1H, J = 5.6 Hz, 1'-CH), 6.19 (s, 1H, O-CH-O), 7.67 (broad doublet, 1H, J = 8.6 Hz, NH), 7.71 (m, 2H, ArH), 3.06 (m, 2H, ArH), 8 57 (s, 1H, Ar H), 8.58 (s, 1H, Ar H).

Step 6: (1 ' S, 1R, 5S) (1-12 ', 5 ', 6 ' -trideoxyacetamido-4 &apos; -hydroxy-L-lyxohexapyrose) -5,12-dioxo-5,4,5,12 -Tetrahydroanthracene [2,5-c] pyran-5-yl-formic acid, compound BCH-671

Removal of the protecting group from the more polar Glycoside of Step 4 as described in Step 11 of Example 1 affords BCH-671 in 70% yield. 1 H NMR spectrum (500 MHz, CDCl 3, δ 1.41 (d, 5H, J = 6.6 Hz, CHβ, 1.95 (m, 2H, 2 * -CH 2), 2.51 (dd, 1H) J = 12.0 and 15.1 Hz, HCHa), 2.85 (dd, 1H, J = 5.0 and 15.1 Hz, HCHe), 5.65 (broad singlet, 1H, 4 * - CH), 5.80 (s, 5H, OCH2), 4.46 (overlapped multiplet, 5H, 5 *, 5 * -θΗ and O-CH), '5.42 (wide oak, 1H, J = 5.2 Hz, 1'-CH), 6.52 (s, 1H, O-CH-O), 6.69 (broad doublet, 1H, J = 8.5 Hz, NH), 7, 70 (m, 2H, ArH), 8.05 (m, 2H, ArH), 8.57 (s, 1H, ArH), 8.58 (s, 1H, ArH).

Step 1: 5,8-Dimethoxy-1-methylbenzoic acid, 2, 2-oxathiine-2-oxide Slightly modified by Dursta and Charlton (Aunt.

Letters 25 (46), 5290 (1984)) were used to prepare the title compound by adding 800 mL of a 2.5 M solution of methyl lithium in hexane at room temperature under argon to solutions containing <14.58 g. (59 mmol) of hydroxysulfone from Example 1, Step 3 above, in 2.5 L of anhydrous tetrahydrofuran. After stirring for 16 hours, 400 ml of methanol are added to the mixture. The solvents were removed by distillation in vacuo. w 1 1 4? what Φ P O -P CO fi o o o 2 j j r — 1 • o! Ή ?? * • H Λ P co -P P FV -P «Φ O -P Φ 1, • thi OJ '• H i — 1 P». P IA 1 • k * • 3 "ω« k • fc íA% 1 K - - * H% o Ol • H »—1 'd 1 1 | —1 OJ I-1 · * r >> ex IA Í P4 1 • H tA «-1 rH * o CO Q í Q Q P P P P P P P Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ What K '—1 (AE? H «*>> K K il K K K K K K K K K K K K K 1 1 1 1 1 - - - - - - - - - - - - - - - 1. Φ j. * * 1 1 1 1 1 1 1 1 1 1 3 3 3 3 3 3 P P & & & 4 4 4 'a

CD 2

- 88 -

The residue was treated with 5 ml of 12M hydrochloric acid at 50 ° C for three minutes. The solution is then diluted with 1 liter of water and extracted three times with 300 ml of dichloromethane. The combined organic layer is washed twice with water, once with brine and dried over magnesium sulfate. After removal of the solvents, the chromatograph is flash chromatographed to give the title sultin as a yellow solid in 47% yield. Mp 152-153 ° C. HMR spectrum (200 MHz, CDCl 3): 1.58 (d, 3H, J = 6.2 Hz, CH 3, 3.49 (d, 1H, J = 14.8 Hz, CH), 3, 79 (s, 3H, OCH 3, 3.80 (s, 3H, OCH 2, 4.29 (d, 1H, J = 14.8 Hz, CH), 5.63 (quartet, 1H, J = 6.2 Hz) CH 2 CH 2 6.82 (s, 2H, ArH) 15 C HMR (75.44 MHz, CDCl 3): 15.5 ~ (CHp, 52.2 (CHp, 55.7 ( OCH 3, 59.9 (CH), 110.1 and 110.6 (aryl CH), 123.6, 123.8, 149.8 and 149.9 (aryl C). 137 ° C): m / e 246 (100, M + NH 4).

Step 2: Cis and trans p-Nitrobenzyl (5,8-dimethoxy-1-methyliso-chroman-3-yl) formic acid

These 1-methylated isochromanes were obtained in the same manner as described above for isochroman from step 5 in Example 1. Reaction of 4 g (16.5 mmol) of 1-methylated sultin from step 1 and 18.76 g (83 mmol) ) p-nitrobenzylglyoxalate (as hydrate) resulted in a black residue which flashed chromatography (10% ethyl acetate, 25% toluene and 65% cyclohexane) afforded two title diastereomeric isochromans in a 3: 1 ratio · Trans isomer (2.8 g, yield 44%) had tt 110-111 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ): 1.53 (d, 3H, J = 6.8 Hz, CH 3), 2.85 (dd, 1H, J = 9.8 Hz and 16.8 Hz) , HCHa), 3.07 (dd, 1H, J = 4.4 Hz, 16.7 Hz, HCHe), 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH2, 4 , 69 (dd, 1H, J = 4.7 Hz and 9.9 Hz, OCH), 5.29 (quartet, 1H, J = 6.7 Hz, OCHCH 2, 5.33 (broad singlet, 2H, OCH 2, 6.68 (s, 2H, HC = CH), 7.49 (d, 2H, J = 8.9 Hz, ar H), 8.22 (d, 2H, J = 8.9 Hz, ar H). Nuclear Magnetic Resonance Spectrum (75.1 Hz, CDCl 3, F): 19.6 (CH 2, 25.5 (CH 3 (55.5 and 55.4 (OCH 2, 65.0 (OCH 3, 67.2 and 68.6 ( OCH), 107.8, 123.6, 128.2 (aryl CH), 121.0, 128.0, 142.8, 147.6, 149.2, 15θ, 6 (aryl C), 171, 4 (ester C = O) IR spectrum - 89 - (FT, CDCl 3, V max) * 1756 (C = O ester), 1216 (C-O). / e: 405 (52, M + NH 4), 270 (100, M + ΝΗκ-C 4 H 4 NO 3) · Cis isomer (247) (0.9 g, 14% yield, oil) had -H HMR spectrum (200 MHz, CDCl 3, δ): 1.62 (d, 3H, J = 6.4 Hz, CH 3), 2.75 (ddd, J = 2.1 Hz, 11.4 Hz and 16, 0 Hz, HCH a), 5.17 (dddd, 1H, J = 1.2 Hz, 2.4 Hz, 16.0 Hz, HCHe), 3.79 (s , 3H, OCH 3), 3.80 (s, 3H, OCH 2), 4.23 (dd, 1H, J = 2.4 Hz, 11.4 Hz, OCH), 5.09 (broad quartet, 1H) , J = 6.5 Hz, CHCl 3, 5.56 (broad singlet, 2H, OCH 2), 6.71 (broad singlet, 2H, ArH), δ.80 (d, 2H, J = 8, 9 Hz, ArH), 8.25 (d, 2H, J = 8.9 Hz, ArH). 15 C NMR spectrum (75.44 HHz -, CDCl 3, Z): 21.5 (CH 3), 26.7 (CH 2), 55.2 and 55.6 * (OCH 2), 65.0 (OCH 2) , 71.5 and 72.1 (OCH), 108.4, 123.7 and 128.3 (aryl), 107.9, 122.9, 142.8, 148.1, 149.9 and 150. , 4 (aryl C), 170.8 (C = O ester). IR spectrum (FT, CDCl3, Vmax). 1755 (C = O ester), 1219 (C = O). Mass spectrum (HR) for 20Η21Νθ7, calculated: 387.1318, found: 387.1299 ·

Step 3: Cis p-nitrobenzyl (5,8-dioxo-1-methyl-3,4,5: 8-tetrahydrobenzol-2,3-cypyr-3-yl) formic acid

To 400 mg (1.0 mmol) of cis isochroman from above 2 in 10 ml of acetonitrile, a solution of 1.96 g (3.6 mmol) of nitric ammonium in 10 ml of water was added dropwise over five minutes of stirring. After five minutes, the mixture was diluted with 25 mL of water. It is then extracted three times with 5 ml of methylene chloride. The combined organic layer was washed once with 5 mL of water, once with 25 mL of sodium chloride, and dried over magnesium sulfate. After evaporation of the solvent, the oily residue was found to be pure (95% yield) isochromandione.

Flash chromatography, eluting with 20% ethyl acetate in toluene, significantly reduced the yield (65%) without significant increase in product purity. @ 1 H NMR spectrum (200 MHz, CDCl3, .delta.): 1.57 (d, 3H, J = 6.7 Hz, CH2 -), 2.57 (ddd, 1H, J = 4.3 Hz, 10, 8 Hza 18.4 Hz, HCHa), 2.98 (broad doublet of triplet, 1H, J = 2.8 Hz and 18.4 Hz, HCHe), 4.19 (dd, 1H, J = 2.75 Hz and 10.8 Hz, O-CH), 4.81 (m, 1H, OCHCH2), 5.56 (broad singlet, 2H, OCH2), 6.76 (dd, 2H, J = 10.1 Hz, ArH), 7.57 (d, 2H, [lambda] / [lambda] -1a -90-J = 9.0 Hz, [lambda] ArH), 8.24 (d, 2H, J = 9.0 Hz, ArH) 15 C NMR spectrum (75.44 MHz / CDCl 3, t): 20.2 (CH 2), 25.2 (CH 3), 65.3 (OCH 2), 70.2 and 71.1 (OCH), 123.6 and 128.4 "(aryl CH), 135.7 and 136.8 (CH), 138.4, 142.2, 143.4 and" 147 ^ 6 (quaternaryC), 169.2 ( 185.2 and 185.4 (C = 0 quinoline).

Stage 4: (5,8-Dioxo-1-methyl-5,8-dihydroisochroman-3-yl) -phosphoric acid trans p-nitrobenzyl ester

Oxidative demethylation of (5,8-dimethoxy-1-methylisochroman-3-yl) trans-p-nitrobenzyl ester of 160 mg (0.4 mmol) of trans-p-nitrobenzyl ester with 780 mg (1.4 mmol) of ammonium nitrate as Step 3 above gave 137 mg of isochromandione as yellow. oil. NMR Spectrum: (200 MHz, CDCl 3) δ 1.5 (d, 3H, J = 6.8 Hz, CHβ, 2.67 (ddd, 1H, J = 2.2 Hz, δ, 9 Hz and 19.0 Hz, HCHa), 2.89 (ddd, 1H, J = 1.3 Hz, 4.6 Hz and 19.0 Hz, HCHe), 4.59 (dd, 1H, J '= = 4.7 Hz and 8.9 Hz, OCH), 5.04 (broad quartet, 1H, J = 6.8 Hz, OCHCH2), 5.33 (broad singlet, '2H, OCH2), 6, 75 (dd, 2H, J = 10.1 Hz, HC = CH), 7.54 (doublet, 2H, J = 8.9 Hz, AHH), 8.24 (d, 2H, J = 8.9) Hz, ArH) 15 C NMR spectrum (75.44 MHz, CDCl 3, δ 19.4 (CH 5), 24.4 (CH 2), 65.5 (OCH 2), 65.7 and 67.1 (OCH) ), 123.8, 128.6, 136.0 and 136.5 (aryl CH), 137.3, 142.2, 145.5 and 146.7 (aryl C), 185.0 and 185.3 ( 0 = 0 quinone) ......

Step 5i Cis p-nitrobenzyl ester (1R, 3R) and (1S, 5S) (5,12 * <dioxo-1-methyl-3,4,5,12-tetrahydro-anthraceno-1,2,3-cpyran-3-yl) morphine acid

This compound was obtained as described in Step 2 of Example 4. Reaction of 250 mg (1.5 mmol) of 3,6-dihydrobenzo (b) -1,2-oxathine-2-oxide with 268 mg (0.7 mmol) cis isochromandione from step 3 (above) yielded 157 mg (49% yield) of the title tetracycl, tt 118-120 ° C. Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl 3, Z *): 1.69 (d, 3H, J = 6.5 Hz, CHβ, 2.74 (ddd, 1H, J = 5.7 Hz, 10.8 H 2 O) 5 Hz, HCHa), 3.24 (dt, 1H, J = 2.8 Hz and 18.5 Hz, HCHe), 4.26 (dd, 1H, J = 2.9 Hz and 10.9 Hz, OCH), 5.04 (m, 1H, CHCH 2, 5.38 (broad singlet, 2H, OCH 2), 7.59 (d, 2H, J = 8.9 Hz, ar H), 7.7 (m, 2H) H, 8.05 (m, 2H, ArH), 8.26

ťV n v? 4 ^ 4 / t in J * * ik l

Jj

IN

AND

P-91- (d, 2H, J = 8.9 Hz, ArH); δ s, 1H, ArH), 8.61 (s, 1H, ArH). [15GNMR spectrum (75.44 MHz; CDCl3, [delta]): 20.6 (CH2), 26.2 (CH2), 65.5 (0GH2), 71.0 and 71.4 (OCH), 125 , 9, 128.6, 129.9, 129.7 and 150.2 (aryl CH), 127.8, 127.9, 128.2, 154.7, [141.1, 142.2, 146, 7 and 147.2 (aryl C), 169.7 (O = O ester), 182.2 and 182.5 (O = O quinone). r • t £

Trans, p-nitrobenzyl ester (1S, 5R) and (1R, 5S) (5,12-d dioxo-1-methyl-5,4,5,12-tetrahydro-anthracene-2,5-c3-pyran-5- yl) formic acid?

Following the procedure described in step 2 of Example 4 above, 175 mg (1.1 mmol) of 5,6-dihydrobenzo [b] -1,2-oxathiine-2-oxide were treated with 187 mg (0.5%) of the quinone from step 4 above, 119 mg (52% yield) of the title compound were obtained. Melting point: 151-152 ° C. Nuclear Magnetic Resonance Spectrum> (200 MHz, CDCl 3, δ): 1.62 (d, 5H, J = 6.8 Hz, CH 3), 2.89 (ddd, 1H, J = 2.0 Hz, 8.9) Hz and 19.0 Hz) (HCHa), 5.11 (ddd, 1H, J = 1.0 Hz, 4.6 Hz and 19.1 Hz, HCHe), 4.69 (dd, 1H, J = 4.7 Hz and 8.8 Hz, OCH), 5.50 (broad quartet, 1H, J = c = 6.8 Hz, CHCH 2, 5.55 (broad singlet, 2H, OCH 2), 7, 55 (d, J 2H, J = 8.7 Hz, ArH), 7.7 (m, 2H, ArH), 8.05 (m, 2H, ArH), δ 8.20 (d, 2H, J = 8.7 Hz, ArH), 8.58 (broad singlet, 2H, J)

ArH), &lt; 15 &gt; C NMR spectra (75.44 MHz, CDCl3, [delta]): 19.6 (CHp, J 25.5 (CH2), 65.5 (OCH2), 67.0 (OCH), 125, 9, 128.7, 128.8, '

129.6 * and 150.2 (aryl CH), 127.9, 128.0, 128.2, 154.8, 141.1, J 142.5, 146.7, 147.6 (aryl C) , 170.5 (O = O ester), 182.8 ξ and 182.9 (O = O quinone). í ...... É: '..... _' · · á

Stage 7 · Cis p-Nitrobenzyl ester (1R, 5R) and (1S, 5S) (5,12-dioxo-7,10-dimethoxy-1-methyl-5,4,5,12-tetrahydro- droantraceno [2 5-c] pyran-5-yl) benzoic acid

The disgrace described above in Step 2 of Example 4? with the reaction of 95 mg (0.4 mmol) of the suitin of Example 1, step 4, 71 mg (0.2 mmol) of quinone from step 5 above, 42 mg (41% yield) of the title tetracycl, m.p. 154-156 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ): 1.68 (d, 5H, J = 7.6 Hz, CHβ, 2.75 (ddd, 1H, J = 5.6 Hz, 10.7 Hz) and

! 92 ΐζ ΐζ 92 92 92 92 92 92 92 92 92 92 - - 92 - 18.6 Hz, CHHa), 3.27 broad doublet of triplet, 1H, J = 2.8 Hza 18.6 Hz, HCHe), 4.00 (s, 3H, OCH 2), 4.01 (s, 3H, OCH 2), 4.28 (dd, 1H, J = 2.8 H and 10.7 Hz, OCH), 5.06 (m, 1H, OCHCH2) , 5.38 (broad singlet, 2H, OCH 3), 6.90 (s, 2H, ArH), 7.59 (d, 2H, J = 8.9 Hz, ArH), 8.26 (d, 2H, J = 8.9 Hz, ArH), 8.95 (s, 1H, Ar H), 8.98 (s, 1H, Ar H). IR spectrum (PT, CDCl3, .delta. (C = o-esters)> 1θ (C = O quinone) Mass spectrum (DCI, 240, NH4, m / e): 517 (100, M &lt; + >) , 382 (68, M &lt; + &gt; * - c7h5no2);

Step 8: Trans p-Nitrobenzyl ester (1E, 3H) and (1E, 3S) (5,12-dioxo-7,10-dimethoxy-1-methyl-3,4,5,12-tetrafluoro-dacanoacetate) clpyran-3-yl) acidic acid

In the same manner as described in step 2 of Example 4 above, 70 mg (0.3 mmol) of sultin from step 4 of Example 1 and 53 mg (0.15 mmol) of quinone from above were reacted. 4 gave 30 mg (44% yield) of the title tetra-cycle, mp 180-182 ° C. H NMR spectrum (200 MHz, CDCl3, T): 1.57 (d, 3H, J = 6.8 Hz, CH2), 2.84 (ddd, 1H, J = 2.1 Hz, 9, 1 Hz and 19.0 Hz, HCHa), 3.06 (ddd, 1H, J = 1.2 Hz, 4.6 Hz and 18.9 Hz, HCHe), 3.95 (s, 3H, 00 ^) 3.96 (s, 3H, OCH2), 4.63 (dd, 1H, J = 4.69 Hz, and 8.9 Hz, OCH3), 5.29 (m, 1H, OCH3), 5 , 30 (broad singlet, 2H, OCH 2), 6.86 (s, 2H, ArH), 7.50 (d, 2H, J = 8.8 Hz, Ar H), 8.16 (d, 1H, J = 8.8 Hz, ArH), 8.91 (s, 1H, ArH), 8.92 (s, 1H, ArH). 15 C NMR (75.44 MHz, CDCl 3, δ) 19.7 (CH 3), 25.4 (CH 2), 55.9 (twice OCH 2), 65.5 (OCH 2), 67.1 and 67.8 (OCH), 107.6, 123.4, 123.9, 128.7 (aryl CH), 127.4, 127.5, 128.6, 140.9, 142.3, 146.8 and 150.9 (aryl C), 170.4 (C = O ester), 182.8 and 182.2 (O = O quinone). IR spectrum (FT, ‘CDCl,, V τη -v-) * 1757 (O = O ester), 1664 (C = O quinone). ± Π.3Χ Example 6

Step-1: 5,8-Dimethoxyisochroman-3-carboxylic acid

A solution containing 133 mg (0.5 mmol) of ethylbenzyl isochroman from step 5 in Example 1 in 10 ml of tetrahydrofuran (R). Ť ί ^ ^ ^ ť ť ť ť ť ť ť 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75 75. EXAMPLE 5J Preparation of tetrahydroacetic acid 12,5-3-pyran. -5-7-derivatives methylated at the 1-position

OPNB

OCH, OCH 3 0¾

OPNB-94 - 10 mL of 1 M aqueous sodium hydroxide solution was added. The mixture is stirred for half an hour at room temperature. It is then concentrated to 5 ml and 25 ml of water are added. The aqueous layer was extracted three times with 10 mL portions of dichloromethane, acidified with concentrated aqueous! hydrochloric acid and reextracted four times with 50 ml of ethyl acetate. The combined ethyl acetate layers were washed twice with water, evaporated to give 125 mg (99%) of the title chromosuccinic acid, mp 217-118 ° C. NMR spectrum (200 MHz, DMSO-d6): 2.88 (broad ddt, 1H, J = 9.9 Hz, 17 Hz, HCHaCH), 5.15 (ddd, 1H, J = 1.4 Hz, 5.62 (s, 5H, OCH2), 5.95 (s, 5H, OCH3), 4.46 (dd, 1H, J = 4.5 Hz and 9); 9 Hz, OCHC = O), 4.75 (broad dt, 1H, J = 16.4 Hz, ar H, CH2 O) 5.05 (broad dd, 1H, J = 16.5H, ArHCHeO), 6.92 (dd, 2H, J = 11.2 Hz, Ar H). 15C NMS spectrum (75.44 MHz, CDCl 3): 26.7 (CH 2), 49.9 (OCH 2), 55.9 and 56.1 (irOGH 2), 65.5 (OCH), 108, 7 and 109.1 (aryl CH), 125.1, 124.5, 150.6 and 152.5 (aryl CH), 210.2 (COOH). Step 2: Methyl (5,8-dimethoxyisochroman-5-yl) ketone To a solution containing 150 mg (6.5 mmol) of isochromanilic acid (261) in 15 mL of anhydrous tetrahydrofuran is added dropwise over five hours. minutes at -78 ° C in an atmosphere of 0.94 ml of 1.4 M methyllithium in ether solution. The solution was stirred at -78 ° C for 10 minutes, then allowed to warm to room temperature and stirred for a further 2 hours. Then methanol (1 mL), water (25 mL) was added and the mixture was extracted three times with 50 mL. ml of dichloromethane. The combined organic layer was washed with 25 mL of water, 25 mL of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed by flash chromatography (eluting with 10% ethyl acetate in toluene). There was thus obtained 110 mg (74%) of the title isochroman ketone, m.p. 84-85 ° C. @ 1 H NMR spectrum (200 MHz, CHCl3, .delta.): 2.52 (br, 5H, COCH3), 2.59 (broad doublet of doublets, 1H, J = 11.5 and 17.00 Hz, HCHa), 5 , 04 (ddd, 1H, J = 1.5 Hz, 5.8 Hz and 17.1 H, HCHe), 5.78 (s, 5H, OCH2), 5.79 (s, 5H, OCH3). , '>',, K vb J7 '? 95- 4.08 (dd, 1H, J = 3.8 Hz and 11.4 Hz, O-CH), 4.66 (broad dub-flight, 1H, J = 15, 9 Hz, HcHa-O), 5.04 (broad doublet, 1H, J = 15.9 Hz, 1 HCHe) -O), 6.66 (dd, 2H, J = 9.0 Hz, ArH). 15 C NMR spectrum (75.44 MHz, CDCl 3, δ): 24.7 (CH 2), 25.9 (CH 2), 55.4 and 55.6 (ArOCH 2, 64.7 (00¾), 79.1 ( OCH), 107.2 and 107.7 (aryl CH), 122.2, 123.9, 149.2 and 151.0 (aryl C), 208.4 (C = O). ^, Xmax) with 1717 (0 = 0).

Stage 3! Methyl (5,8-dioxo-5,8-dihydroisochroman-3-yl) ketone · To a stirred solution containing 700 mg (3 mmol) of isochroman from step 2 in 20 mL of acetonitrile was added dropwise at room temperature over five minutes. a solution containing 2.0 g (3.6 mmol) of ammonium nitrate in 20 ml of water. Stirring is continued for five minutes. Dichloromethane (100 ml) was added. Subsequent washing of the aqueous layer was carried out with 50 mL of water and 50 mL of brine.

After drying over magnesium sulfate and evaporating the solvent, 560 mg (92% yield) of yellow isochromandione is obtained as a dark yellow oil. 1 H NMR spectrum (300 MHz, CDCl 3, δ): 2.54 (s, 3H, COCH 2, 2.48 (dddd, 1H, J = 2.8 Hz, 4.0 Hz, '10, 1) Hz and 19.2 Hz, HCHa), 2.8? (Dm, 1H, J = 19.2 Hz, HCHe), 4.06 (dd, 1H, J = 4.0 Hz and 10.1 Hz, OCH), 4.52 (dt, 1H, J = 3.3 Hz and 18.6 Hz, HCHa-O), 4.83 (ddd, 1H, J = 1.0 Hz, 2.7 Hz and 18.6 Hz, HCHe-O), 6.80 (dd, 2H, J = 10.2 Hz, HC = CH) 15C NME spectrum (75.44 MHz, CDCl 3, δ): 23.1 (CH 2), 25 , 8 (CH 2), 62.7 (OCH 2), 77.7 (OCH), 136.0 and 136.4 (CH), 183.3 and 139.6 (quaternary C), 185.17 and 185.24 ( C = 0 quinoline, 206.4 (COCH 3), IR spectrum (CDCl 3, γ) 1722 (COCH 3) and 1659 (O = O) quinoline.

Step 4: Methyl- (11-hydroxy-5,12-dioxo-3,4,5,12-tetrahydro-anthracene-2,3-c] pyran-3-yl) -ketoh and methyl- (5-hydroxy- 5,12-dioxo-3,4,5,12-tetrahydroanthracene-12,3 "c] pyran-3-yl) ketone, compound BCH-687

These compounds were obtained by the same procedure as described above in Stage 1 of Example 3, except that. methyl (5,8-dimethoxyisochroman-3-yl) ketone is used in this example. - 96 -

Flash chromatography of the residue yields a mixture of both regioisomers (64%) which need not be separated for the next step. However, both isomers can be separated by preparative HPLC. Less polar isomeric NMR spectrum (300 MHz, CDCl 3, δ): (s, 3H, CH 3), 2.62 (m, 1H, HCH 2 CHC = O), 3.08 (m, 1H) , HCHaCHC = O), 4.10 (dd, 1H, J = 10.0 and 3.7 Hz, HCHa-O), 5.02 (broad oak-flights 1H, HCHe-O), 7.75 (m, 2H, ArH), 7.97 (m, 1H, ArH), 8.12 (s, 1H, Ar H), 8.50 (m, 1H, Ar H), 13.86 (s, 1H, ArOH). The polar isomer had a @ 1 H @ 1 H NMR spectrum (30 MHz, CDCl3, .delta.): 2.35 (s, 3H, CH2), 2.59 (m, 1H, HCHeCHCO), 3.05 (broad doublet triplets, J = 19.0 Hz and 2.8 Hz, HCHaCHCO), 4.08 (dd, 1H, J = 10.0 Hz and 3.9 Hz, CH), 4.44 (triplet doublet, 1H) , J = 22.5 Hz and 6.7 Hz and 3.5 Hz, HCHaO), 5.03 (broad doublet, 1H, J = 18.7 Hz, HCHe-O), 7.71 (m, 2H, ArH), 7.95 (m, 1H, Ar H), 8.13 (s, 1H, Ar H), 8.46 (m, 1H, Ar H), 13.70 (s, 1H, ArOH).

The autoxidized product, methyl- (5,12-dihydroxy-6,11-dioxo-3,4,6,11-tetrahydro-anthraceno [2,3-c] pyran-3-yl) -ketone was also obtained in 8% yield. BCH-688, tt 210 ° C (dec). @ 1 H NMR Spectrum (300 MHz, CDCl3, .delta.): 2.40 (s, 3H, COCH3, 2.81 (m, 1H, CH2), 3.22 (ddd, 1H, J = 2.0 Hz, 4.0 Hz and 18.1 Hz, HCH), 4.15 (dd, 1H, J = 3.9 Hz and 10.6 Hz, OCH), 4.79 (doublet of triplets, 1H, J = .2, 2 Hz and 17.4 Hz, OHCH3), 5.20 (dd, 1H, J = 1.1 Hz and 17.4 Hz, HCH3), 7.84 (m, 2H, ArH), 8.36 (m , 2H, ArH), 13.18 (s, 1H, ArOH), 13.51 (s, 1H, ArOH).

Step 5: Methyl (6,11-diacetoxy-5,12-dioxo-3,4,5,12-tetrahydro-dendroeno [2,3-a] pyrah-3-yl) -ketone .......

In the same manner as described in Example 3, steps 7 and 8, the title compound was obtained in a yield of 45%. 1 H NMR Spectrum (300 MHz, CDCl 3, δ): 2.35 (s, 3H, COCH 3), 2.51 (s, 5H, OCOCH 2, 2.54 (s, 3H, OCOCH 2), 2 ' 72 (m, 1H, HCHa), 3.05 (m, 1H, HCHe), 4.08 (m, 1H, OCHC-O), 4.75 (broad doublet, OH, OH), 5, 08 (broad doublet, 1H, OHCH6), 7.65 (m, 2H, ArH), 8.15 (m, 2H, ArH).

A mixture of monoacetoxylated compounds could be isolated

- 97 - BCH-721., Methyl- (6-hydroxy-11-acetoxy- and 6-acetoxy-11-hydroxy-5,112-dioxo-3,4,5,12-tetrahydroanthracene-2,3,3-pyran) .Beta.-yl) -I / IVVT.fwdarw.-ketone in yield. 10%

Step 6: Methyl (11-acetoxy-1,6-dihydroxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl) ketone

Following the procedure of Step 9 of Example 3, the title compound was obtained in a yield of 24%. HMR spectrum (300 MHz, CDCl 3, δ): 2.38 (s, 3H, COCH 3), 2.52 (s, 3H, OCOCH 3), 3.04 (m, 2H, C 6 H), 4.55 (m, 1H, OCHC-O), 6.36 (broad singlet, 1H, OCHOH), 7.82 (m, 2H, ArH), 8.23 (m, 2H, ArH). | ..

Step 7: Methyl- (1'S, 1R, 3S) and (1'S, 1S, 3R) - (1- (2 ', 3', 6'-tri-deoxy-3'-trifluoroacetamido-L-4 ' -O) -L-lyxohexopyranoso) -6-hydroxy-11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydroanthracene-12,3-c pyran-3-yl] - | the desired pyranoantracycline glycoside may be added to the ketone. &amp; in a 37% yield if the usual glycosylation procedure (step 10, Example 1) is followed. NMR spectrum (300 MHz, CDCl 3) 1.21 (overlapped doublet, 3H, 6'-CH 3), 2.11 (m, 2H, 2 '- (3'), 2.38 (singlet, 3H, - 2.53 (singlet, < 3 &gt; H, -OCOCfip, -2.68 (multiplet, 1H, HCHa), [delta] 3.21 (m, 1H, HCHe), 4.39 (m, 1H, [delta] 5'-CH), 4.63 (m, 2H, 3'a | 4'-CH), 5.16 (dd, 1H, J = 4.1 Hz and 12.6 Hz, O-CH), 5 5.78 (broad, 1H, 1'-CH), 6.21 (s, 1H, O-CH-O), 7.81 (m, 2H, ArH), 8.25 ( overlapped multiplet, 6H, ArH), 13.69 j (s, 1H, arOH). <0 '· - 1 ·

Step 8i (1'S) Methyl-L1- (N-trifluoroacyl-alanosamine) -6-hydroxy-11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydro-1-ol. anthraceno [2,3-c] pyran-3-yl-ketone

The cooled solution (at - 5 ° C) containing 48.4 mg of (0.06 mmol) glycoside from the previous step in 5 mL of dichloromethane was treated with 5 mL of 0.2 M for 15 minutes? sodium hydroxide solution. The reaction stopped

AND

The reaction mixture was acidified to pH about 6. The reaction mixture was then extracted with dichloromethane (2 x 15 mL). The combined organic phase was washed with water (3 x 50 mL) and dried over sodium sulfate. Purification by HPLC (Sephrex CN5U, hexane-ethyl acetate 80-20%) afforded 5.5 mg (14.5% yield) of the desired compound, mp 255-256 ° C. NMR spectrum (500 MHz, CDCl 3, δ): 1.50 (d, "5H, J = 6.7 Hz, CH 3), 1.87 (m, 1H, 2'-HCHa), 2.12 (m, 1H, 2'-HCHe), 2.57 (s, 5H, -COCH 2, 2.55 (s, 5H, OCOCH 2, 2.62 (m, 1H, HCH a), 5.14 (m, 1H, HCHe), 5.65 (broad singlet, '1H, 4'-CH), 4.17 (broad quartet, 1H, J = 6.7 Hz, 5Z-OH), 4.59 (m, 1H, 5z-OH), 4.60 (dd, 1H, J = 5.6 Hz and 11.4 Hz, O-CH), 5.57 (broad gray, 1H, 1'-CH), 6.15 ( s, 1H, O-CH-O), 6.67 (broad oak, 1H, J = 8.4 Hz, NH), 7.79 (m, 2H, ArH), 8.21 (m, 1H) ,

ArH), 8.29 (m, 1H, ArH), 15.49 (singlet, 1H, ArOH).

Step 1: 5-Formyl-5,8-dimethoxyisochroman

(5,8-Dimethoxyisochroman-5-yl) formic acid ethyl ester (697 mg, 2.62 mmol) was dissolved in toluene (20 mL) and cooled to -78 ° C. The reaction mixture was slowly added to -78 ° CDIBAL (2.97 mL, 1.5 M, 4.45 mmol) slowly under cooling at -15 ° C. According to thin layer chromatography, which was performed immediately after the addition was complete, the reaction was complete. Chilled methanol (4 mL) was slowly added to the reaction mixture (evolution of hydrogen!). The mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases are combined, washed with brine and dried over magnesium sulfate. Flash chromatography of the crude product yielded the title product in 85% yield (485 mg). 1 H NMR spectrum (500 MHz, CDCl 3, δ 2.65 (dd, 1H, J = 16.8 Hz and 11.5 Hz, HCH 2 CHC = O), 2.99 (dd, 1H, J '= 17.0 Hz and 5.8 Hz, HCHeCHC-O), 5.76 (singlet, 5H, OCH2), 5.77 (s, 5H, OCH2), 4.09 (doublet of dublet, 1H, J = 10 , 7 Hz and 4.4 Hz, He = 0), 4.87 (doublet of oak-flight, 2H, J = 10.58 Hz and 15.9 Hz, HCHa, e-0), 6.66 (m, 2H, ArH).

HOO O HOO O HOO

Oco o derivatives with methylketone sub-strituent: 'Λ · ί'ώ / ·' + - 1.00 -

Step 2: 3- (1-Hydroxy-2-methoxymethoxy) ethyl-5,8-dimethoxy-isochroman

Goat Bu 2 SnCl 2 · OMOM (1.066 g, 2.92 mmol) in 12 mL of tetrahydrofuran was cooled to -78 ° C under argon. This solution was stirred while adding butyllithium (1.1 mL, 2.5 M, 2.75 mmol). After 30 minutes, 3-formyl-5,8-dimethoxyisochromene (483 mg, 2.18 mmol) was added. After 43 minutes, the cold reaction mixture was shaken between water and ether. The organic phase is dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude residue (hexane / ethyl acetate 1: 1) gave the title compound in 66% yield (431 mg). For the mixture of the two diastereoisomers, the following spectral data was obtained: 1 H NMR spectrum (300 MHz, CDCl 3, ppm, µl): from 2.49 to 3.10 (m, 3H, HCH a, e-CH-C-O and OH), 3.55 (s, 3H, CH 2 CH 3), from 3.55 to 3.92 (m, 6H, CH 2 -OMM, CH 2 CH = O 'and CH-OH), 3.69 (s, 3H, OCH 3) 3.71 (s, 3H, OCH2), 4.55 (r, 1H, HCHa-O), 4.64 (s, 2H, OCH2-OCH2, 4.90 (m, 1H, HCHe-O). 6.57 (m, 2H, ArH) IR spectra (Pure) 3464 (hydroxyl), 2940, 2830 and 1480 cm @ -1.

Step 3. 5,8-Dimethoxy-3- (methoxymethoxy) acetoisochroman To a stirred solution of oxalic acid chloride (3.37 mL, 36.67 mmol) in 80 mL of dichloromethane was added dimethyl sulfoxide (2.99 mL, 38.67 mmol) in vacuo. 10 ml of dichloromethane at -78 ° C under an argon atmosphere over a period of ten to ten minutes. Stirring was continued for 15 minutes before a solution of 3- (1-hydroxy-2-methoxy-methoxy) -ethyl-5,8-dimethoxy-isochroman (3.842 g, 12.89 mmol) in 20 mL of dichloromethane was added. added for 5 minutes.

Then the mixture was stirred at -78 ° C for 45 minutes, triethylamine (19.6 mL) was added and the reaction mixture was warmed to room temperature over one hour. The reaction was quenched with 100 mL of water. The aqueous layer was extracted with dichloromethane (3 x 100 mL), the combined organic phases were washed with water and brine and dried over magnesium sulfate. After filtration and concentration, a yellow residue is obtained, which is purified by flash chromatography (hexane-e-101-ethyl acetate = 7: 3) to give 5.295 g (86% yield) of the title compound. Nuclear Magnetic Resonance Spectrum (500 MHz, CDCl 3, δ): 2.65 (dd, 1H, J = 15.9 and 5.7 Hz, HCH 2 CHC = O), 5.07 (doublet of multiplet, 1H, HCHCHCHCO), 5, 39 (s, 3H, CH 2 OCH 2), 3.75 (s, 5H, OCH 3), 5.76 (s, 5H, OCH 2), 4.19 (dd, 1H, J = 11.4 Hz and 5.8 Hz, CH-O), 4.60 (s, 2H, C 1 H 2 OCH 2), 4.79 (dd, 2H, J 1 = 111.0 Hz and 15.9 Hz), 6.65 (m, 2H, Ar H). 15 C NMR spectrum (75.44 MHz, CDCl 3, δ): δ 25.57, 56.01, 56.18, 65.51, 70.21, 97.06, 107.84, 108.57 '. , 122.59, 124.53, 149.81, 151.62.206, 78.Ίδ spectrum (neat): 2960, 2910, 1755 (CO), 1620, 1580, 1540 and 1480 cm -1.

Step 4: 5- (Methoxymethoxy) aceto-5,8-dioxoisochroman 5,8-Dimethoxy-5- (ethoxymethoxy) acetoisochroman (5.155 g, 10.59 mmol) was dissolved in acetonitrile (55 mL) and the solution was cooled to Low: 1 ° C. While cooling and stirring, a solution of ammonium nitrate (GAN) (17.53 g in 55 ml) was added dropwise. The ice bath is then removed and stirring is continued for about 15 minutes. Water (50 mL) was added and the mixture was extracted with dichloromethane. The organic phases are washed with water and dried over magnesium sulfate. Filtration and concentration in vacuo gave a reddish oil which was found to be a pure title compound without the need for flash chromatography. Yield 85% (2.58 g). @ 1 H NMR spectrum (500 MHz, CDCl3, .delta., (.Delta.): 2.52 (m, 1H, HCH3 --CHC.dbd.O), 2.90 (m, 1H, CH2CHC.dbd.O), 5.39 (s, 3H, OGHgOGH4), 4.19 (dd, 1H, J '= 10.5 Hz and 5.8 Hz, HC-O), 4.44 (triplet of doublets, 1H, J = 18.7 Hz, 5.7 Hz, HCHa-O), 4.54 (b, 2H, OCH2OCH2), 4.70 (s, 5H, COOCH2M0M), 4.77 (dd, 1H, J = 18.6 Hz and 2.5 Hz, HCHe-O), 6.75 (m, 2H, ArH).

Step 5: 5- (2-Methoxymethoxy) aceto-6-hydroxy-1,2,5,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 5- (2-methoxy-methoxy) aceto-11 -Hydroxy-1,2,5,4-tetrahydro-2-oxa-naphthalene-5,12-dione To a solution of LDA (9.42 mmol) in 50 ml of tetrahydrofuran is added dropwise a solution of homophthalic anhydride (1.53 g,

'Siri' x $; · ι · - 102 - 9.43 mmol) in 3 ml of tetrahydrofuran in an argon atmosphere at -78 ° C. After five minutes, a solution of 3- (2-methoxymethoxy) aceto-5,8-dioxoisochroman (2.3589 g, 8.14 mmol) in 35 mL of tetrahydrofuran was added. Stirring was continued for 1 minute at -78 ° C, then for 30 minutes at room temperature. Thereafter, the reaction mixture was left in an ice bath overnight. The reaction was quenched by the addition of saturated ammonium chloride solution (40 mL). The mixture was partitioned between 1N hydrochloric acid (15 mL) and dichloromethane (150 mL). The organic layer is washed with brine, dried over sodium sulfate and concentrated by evaporation of the solvent. This gives a crude residue which is purified by flash chromatography. A mixture of two regioisomers (46%) is obtained. A mixture of both isomers yielded the following spectral data. 1 H NMR spectrum (3θ MHz, CDCl 3, δ): 2.58 (m, 2H, HCH 2 CHC = O), 3.04 (dd, 2H, J 1 = 19.2 Hz) 3.36 (s, 6H, OCH2); 4.22 (m, 2H, CH-O); 4.57 (s, 4H, OCH2 OCH5); (m, 2H, HCHa-O), 4.58 (s, 4H, COCH8 -OMOM), 4.87 (m, 2H, 'HCH2-O), 7.67 (m, 4H,' ArH), 7 69 (m, 2H, ArH), 7.86 (m, 2H, ArH), 8.38 (m, 2H, ArH). Xspectrum (pure sample): 2925, 2843, 1740 (CO), 1654, 1639, 1608, and 1568 c and "1".

Step 6: 6- and 11-Acetoxy-3- (2-methoxymethoxy) aceto-1,2,3,4-tetrahydro- (2-oxa) naphthalene-5,12-dione

A mixture of the compounds of Step 5 (above) (1.9θ2 g, 5.15 mmol) was dissolved in 13 mL of dichloromethane. Acetic anhydride (26.7 ml), pyridine (26.7 ml) and gDMAP (0.518 g) were added sequentially. Stirring of the reaction mixture was continued for an additional 3 minutes. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layers were combined, washed with hydrochloric acid (4%), water, dried over sodium sulfate and concentrated. The crude residue was chromatographed by flash chromatography, eluting with 1: 1 hexane: ethyl acetate. This gives a mixture of the desired title compounds in a yield of greater than 80%. The following spectral data were obtained for this mixture: 1 H NMR spectrum (300 MHz, CDCl 3): 2.54 (m, 2H, HCH 2 CHC = O), 3.10 (m, 2H, - 103 - CH 2 OCH 2, 4.23) (dd, 2H, J = 10.48 Hz and 3.84 Hz, OCHC = O), 4.58 (s, 2H, &quot; C04CHO0O), 4.58 (br, 2H, COCHgOMOM), 4.58 (m, 2H, HCHa-O), 4.72 (s, 4H, OOCH2 OCH3), 4.95 (m, 2H, " HCHe-O), 7.72 (m, 4H, ArH) ), 8.19 (m, 4H, ArH), 8.54 (s, 1H, ArH), 8.58 (s, 1H, ArH).

Step 7i of 5- (2-Hydroxy-1-propylene-ketal) -acetoxy-6-acetoxy-1,2,3,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 3- (2-hydroxy-l- aceto-11-acetoxy-1, 2, 3, 4-tetrahydro-2-oxa-naphthalene-5,12-dione

The mixture of tetracyls from step 6 above (70 mg, 0.16 mmol) was dissolved in toluene (30 mL). Then 1,3-propanediol (1 ml) and PPTS (2 mg) were added. The reaction mixture was refluxed overnight with Dean Starker to remove water from the reaction mixture during the reaction. The reaction mixture was extracted with dichloromethane, the organic phases are combined, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude residue was chromatographed by flash chromatography eluting with ethyl acetate: dichloromethane (1: 1) to give the desired title products (66 mg) in 94% yield. The following spectral data were recorded as isomeric mixture. @ 1 H NMR spectrum (300 MHz, CDCl3, .delta.) 1.55 (m, 2H, O-CH2-CH-H-CH2-O), 1.85 (m, 2H, O-CH2-CH- H -CH 2 O, 2.05 (m, 2H, OH), 2.25. (m ", 2H, HCH 2 CHC), 2.58 (s, 3H, OCOCH 3), - 2.61 (s, 3H, OCOCH 2 ', 2.80 (m, 2H, HCSeCHCl 3), from 3.55 to - 4.15 (m, 14H, O-CH 2 -CH 2 O, CH 3 OH and HC-O), 4.52 (m, 2H, HCH 2 -O), 4.94 (m, 2H, HCHe-O), 7.69 (m, 4H, ArH), 8.07 (m, 4H, ArH), 8.52 (s, 1H, ArH), 8.57 (s, 1H, ArH). ): 5454.6, 2929.2, 2878.6, 1766.4 (CO), 1658.0, 1612.4 cm -1.

Step 8: 3- (2-Acetoxy-1-propylene-ketal) -aceto-6-acetoxy-1,2,3,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 3- (2-acetoxy-1-propylene-ketal) acetoxy-1,2,3,4-tetrahydro-2-oxa to phthalene-5,12-dione

A mixture of tetracyclic compounds from step 7 above (567 mg, 0.84 mmol) was dissolved in dichloromethane (20 mL). i · »λ.ϊ · r / si <t '* / -íý}, · žroM» s) á ^ fet fet «g ^ fá <AlÓA' • fA.íQ L tki <* Λ v \ t Acetic anhydride (1.0 mL), pyridine (1.0 mL) and LMAP (60.9 mg) were added sequentially to this solution. The reaction was completed within half an hour. The reaction mixture was extracted with dichloromethane. The organic phases are combined, washed with water and dried over magnesium sulfate. Concentration in vacuo gave a residue as a residue. This residue was chromatographed by flash chromatography tograph, eluting with hexane: ethyl acetate (7 mL). The desired product was obtained as a mixture of two substances (278 mg, 0.6 mmol, 69%). The following spectral data were obtained for this mixture. Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl 3, ppm, δ): 1.85 (m, 4H, OCH 2 CH 2 -OCH 2), 2.11 (b, 6H, CH 3 OCOCCH 3), 2.60 (s, 3H, OCOCH 3), 2.63 (s, 3H, OCOCH2), 2.86 (m, 4H, HCH3, CHCl3), 3.98 (m, 10H, OCH2 CH2-CH2-O and OCHC3), 4.29 ( d, 2H, J = 11.87 Hz, CH2-OCH2CH2), 4.5 (m, 2H, HCHa-O), 4.94 (dd, 2H, CH2CH2), 5.05 (d, 2H, CH2 -) 7.70 (m, 4H, ArH); 8.10 (m, 4H, ArH); 8.56 (s, 1H, ArH); 8.61 (s, 1H, H);

ArH). IR spectra (neat) 2922.3, 1774.8, 1745.6 (0 = 0), 1669.9 and 1617.5 (0 = O quinone), 1431.1 cm -1.

Step 9 * 3- (2-Acetoxy-1-propylene ketal) aceto-6-acetoxy-1-hydroxy-1,2,3,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 3 "- (2- acetoxy-1-propylene ketal) -aceto-11-acetoxy-1-hydroxy-1,2,3,4-tetrahydro-2-oxa-naphtene-5,12-dione

A mixture of tetracyclic compounds from Step 8 above (34 mg, 0.09 mmol) was dissolved in carbon tetrachloride (13. mL). NBS (32 mg, 0.18 mmol) and benzoyl piperoxide (2 mg) were added to this mixture. . The reaction mixture is refluxed under sunlight (under argon) for one hour. It is then concentrated by evaporation in vacuo, the residue is stirred with a mixture of tetrahydrofuran and water (6 ml, 1: 1) and then extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated in a vacuum. The crude residue thus obtained was flash chromatographed, eluting with ethyl acetate: dichloromethane (1: 1) to give the desired product as a mixture in 59% yield (26.5 mg, 0.05 mmol). This mixture provided

V - 105 - following spectral data. 1 H NMR Spectrum (500 MHz, CDCl 3, ppm, Z 1 -): 1.85 (m, 4E, OCH 2 -CH 2 -CH 2 -O), 2.12 (s, 6H, CH 2 OOCCH 3), 2.60 (s, 5H, OCOCH 3, 2.62 (b, 5H, OCOCH 3), 2.86 (m, 4H, HCH a, e CHCl 3), 4.08 (m, 8H, OCH 2 -CH 2 -CH 2 -O), 4.58 (d, 2H, CH 2 -OCOCH 3), 4.46 (dd, 2H, OCHCl 3), -4.89 (broad doublet, 2H, J = 12.05 H, CH 2 OCOCH 3), 6.14 (broad doublet, 2H, J = 12.64 Hz, CHOH), 7.71 (m, 4H, ArH), 8.05 (m, 4H, ArH), 8.56 (a, 1H, ArH), 8.59 (s, 1H, ar H) IR spectrum (neat): 5402.0 (OH), 2925.5, 1772.2, 1755.0, 1666.8, 1617.5, 1445.7 cm "* 1.

Step 10: 5- (2-Hydroxy) aceto-6-hydroxy-1,2,5,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 5- (2-hydroxy) aceto-11-hydroxy-1 2,5,4-tetrahydro-2-oxa-naphthalene-5,12-dione

The reaction mixture containing the two tetracyclic isomers of step 5 above (500 mg, 50%, 0.59 mmol) was dissolved in 20 mL of methanol. 10 ml of a 2.5 N hydrochloric acid solution are then added to the solution. The mixture was stirred at room temperature for half an hour, extracted with dichloromethane (150 ml), the organic layer was separated, washed with water and dried over magnesium sulfate. Filtration and evaporation gave a residue which was purified by flash chromatography. Obtained an indivisible mixture of the title compounds (20 mg, 15%). The following spectra were obtained for this mixture. 1 H NME spectrum (500 MHz, ODCl 3): 2.80 (m, 1H, HCH 2 CHC = O), 5.1 (m, 1H, HCH 2 CHC = O), 5.67 (s, 2H, CH 2 OH) 5.84 (s, 5H, OCH 2, 4.55 (m, 1H, CH-O), 4.68 (m, 1H, HCH 2 O), 5.05 (m, 1H, HCH 2 O), 7.71 (m, 2H, ArH), 7.94 (m, 1H, Ar H); 8.11 (m, 1H, Ar H); 8.48 (m, 1H, Ar H); exchangeable hydroxyl), 15.85 (s, 1H, exchangeable hydroxyl proton).

Step 11: 6,11-Diacetoxy-5- (2-methoxymethoxy) acetol, 2,5,4-tetrahydro-2-oxanaphthalene-5,12-dione

The mixture of tetracyclic compounds from above 5 (275 mg, 0.71 mmol) was treated with acetonitrile (570 mg, 5.1 mmol) in the dark in the presence of 10 ml. The mixture is concentrated in vacuo and the residue is partitioned between water and chloroform, the organic layer is washed with brine, dried over magnesium sulphate and concentrated by evaporation. The residue obtained is treated with acetic anhydride (4 ml), pyridine (4 ml) and DMAP (68 mg) and allowed to react for two days, 20 ml of water and 30 ml of dichloromethane are added. sodium chloride and dried over anhydrous magnesium sulfate, Flash Chromatography to give the title compound (47 mg, 17%). The following spectral data are data mixtures of isomeric compounds. &lt; 1 &gt; H NMR spectrum (300 MHz, CDCl3, [delta]) : 2.50. (s, 3H, OCOCH3, 2.51 (s, 3H, OCOCH2), 2.25 (m, 1H, HCH3 CH-C.dbd.O), 3.10 (m, 1H, CH2CHC.dbd.O), 3.40 (s, 3H, CH 2 OCH 5), 4.27 (m, 1H, CHO), 4.61 (s, 2H, CH 2 CH 3), 4.72 (s, 2Ξ, COCHgOMOM), 4.70 (m, 1H, HCHe-O), 5.05 (m, 1H, "HCHe-O), 7.75 (m, 2H, ArH), 8.16 (m, 2H, ArH). IR spectrum (pure): 2934, 1775, 1742 (CO), 1683 and 1598 cm -1.

Step 12: 3- (2-Hydroxy) aceto-6-acetoxy-1-hydroxy-1,2,3,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 3- (2-hydroxy-hydroxy) aceto-11-acetoxy-1-hydroxy-1,2,3, z-tetrahydro-2-oxa-naphthalene-5,12-dione

A mixture of tetracyclic compounds from above 11 (30 mg, 0.06 mmol) was dissolved in acetone and water (12 mL, 1: 1, 58.42). Concentrated hydrochloric acid (about 4 mL) was added dropwise to this solution.

The mixture was stirred at room temperature for several hours until starting materials were consumed. Subsequently, saturated sodium bicarbonate solution is added until the pH is 8. The mixture is then extracted with dichloromethane, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude residue thus obtained is chromatographed by flash chromatography eluting with ethyl acetate / dichloromethane. 1: 1 to give the title compound as a mixture (39%, 9.3 mg, 0.02 mmol). The following is obtained for this mixture: spectral data. 1 H NMR spectrum (3θ MHz, CDCl 3, δ); 2.62 (s, 6H, OGOCH2), 3.15 (m, 2H, 'HCH3CHC-O), 3.62 (m, 2H, JCHCHCHC-O), 4.62 (m, 4H, CH3 OH) , 4.88 (m, 2H, CH = O), 6.16 (m, 2H, J = 13.95 Hz, CHOH), 7.74 (m, 4H, ArH), 8.11 (m .delta. 4H, .delta.), 8.62 (m, 2H, ArH). IR spectrum (pure): 3367.6 (broad signal, OH), 2952.2, 2855.7, 1771.7;

1738.8 (0 = 0), 1664.9 and 1617.9 (CO quinone) cm -1. L i i í í

I-108 - Preparation of Tetrahedronate Anthracene-2,3-Cyanopyrrole-5-Al-Derivatives with a Hydroxythryl-ketone Substituent

Example. 8

Step 1: 3-Harbomethoxy-5,8-dimethoxy isothiocyanate 1,4-Dimethoxy-2,3-dibromomethylbenzene (10.0 g, 30.88 mmol) was dissolved in dichloromethane and methanol (750 mL, 6: 1 mixture). 4). To this solution was added 2-mercaptoacetic acid ethyl ester (4.02 mL, 37.06 mmol) under argon under stirring. The mixture was then cooled to 0 ° C. To this mixture sodium dodecemethoxide (4.37 M, 8.5 mL, 37.06 mmol) was added over two hours using an automatic injection pump. After five minutes, the solvent was evaporated. The crude residue was redissolved in tetrahydrofuran (400 mL) and cooled again (to 0 ° C). Sodium alcohol (2.10 g, 30.88 mmol) was then added. The ice bath was removed and the reaction mixture was stirred for another 2 hours. The reaction mixture is then quenched with saturated ammonium chloride and extracted with ether. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was then treated with NaOME in methanol and tetrahydrofuran for 2 hours at 0 ° C. The reaction mixture was extracted with ether (100 mL + 100 mL). The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography. The yield of the title compound is 45% yield. Rf spectrum (3θ MHz, CDCl 3, ppm, δ): 2.97 (ad, 1H, J = 16.51 Hz and 8.79 Hz, HCHaCHC = O) , 3.36 (dd, 1H, J = 16.7H and 5.1Hz, HC2CH2CHC = O), 3.73 (m, 2H, HCHa, e-O), 3.75 (s, 3H, OCH 3, 3.78 (s, 6H, twice OCH 2), 3.85 (m, 1H, HC-S), 6.69 (m, 2H, 4rH).

Step 2: 3-Carbomethoxy-5, 5-dioxoisothiochroman R stirred solution of isothiochroman from Step 1 above (253 mg, 0.94 mmol) in 3 mL of acetonitrile was added dropwise to a solution of ammonium nitrate (1.55 g, 283 mmol) in 3 mL. water. The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 10 minutes and then extracted with dichloromethane (3 x 10 mL). The combined organic layers are washed with sodium chloride solution and water, dried over magnesium sulfate and concentrated by evaporation. This gave a residue of 110 - (213 mg, 0.89 mmol) in 95% yield as a pure material (1H NMR spectrum). Spectrum (300 MHz, CDCl 3) δ 2.90 (m, 2H, HCHa, εCHC = O), 3.56 (m, 2H, HCHα, εS), 3.73 (s, 3H, OCH) 3.74 (s, 3H, OCH2), 3.75 (m, 1H, HC-S), 6.75 (m, 2H, ArH). HIBR spectrum (75.44 MHz, ODCl 3): 22.2, 26.0, 37.4, 52.8, 136.2, 137.0, 140.0, 140.5, 172.0 (CO ester), 185 , 8, 187.0 (CO quinones). IR spectrum (pure): 2956, 1736, 1658, 1607, 1442, 1409 cm @ -1.

Step 3: 3-Ethyl-bomethoxy-6-hydroxy-1,2,3,4-tetrahydro- (2-thienyl) -naphthalene-5,12-dione and 3-carbomethoxy-11-hydroxy-1,2,3 4-tetrahydro- (2-thia) naphthacene-5,12-dione A solution of homophthalic anhydride (160.2 mg, 0.99 mmol) was added dropwise to a stirred solution of LDA (0.98 mmol in 4 mL of tetrahydrofuran). ) in 4 ml of dry tetrahydrofuran at -78 ° C under argon. After stirring for 10 min, a solution of quinone from step 3 above (213.0 mg, 0.89 mmol) in 4 mL of tetrahydrofuran was added. Stirring was continued for 1 minute at -78 ° C and then for 2 hours at room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL). The reaction mixture was partitioned between 0.5 H hydrochloric acid (10 mL) and dichloromethane (50 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 7: 3 hexane: ethyl acetate. This gave a mixture of the title compounds (125 mg, 40%). This mixture gave the following spectral data. NMR Spectrum (300 MHz, CDCl 3, (f): 3.09 (doublet of multiplet, 1H, HCH 3 CHC = O), 3.21 (doublet of multiplet, 1H, HCH 2 CHC = O), 3.73 (m, 1H, CHS) , 3.76 (s, 3H, OCH2), 3.77 (s, 3H, OCH3), 3.82 (m, 2H, HCH3, e-O), 7.69 (m, 2H, ArH) , 7.71 (m, 1H, Ar H), 8.09 (s, 1H, Ar H), 8.44 (m, 1H, Ar H), 13.80 (s, 1H, hydroxyl-exchangeable proton), 13.89 (s, 1H, exchangeable proton hydroxyl group).

- 111 -

Step 4: 6-Acetoxy-3-carbomethoxy-1,2,3,4-tetrahydro-2-thia-naphthacene-5,12-dione, and 11-acetoxy-3-carbomethoxy-1,2,3,4- tetrahydro-2-thianaphthalene-5,12-dione

The tetracyl mixture of step 3 above (95 mg, 0.268 mmol) was treated with acetic anhydride (2 mL) in pyridine (2 mL) in the presence of a catalytic amount of DMAP (54 mg) in 10 mL of dichloromethane at room temperature. After stirring for half an hour, the mixture is poured into 25 ml of ice water and diluted with 25 ml of dichloromethane. The organic layer was washed twice with 0.5 N hydrochloric acid (2 x 20 mL) and dried over sodium sulfate. Filtration and subsequent concentration in a vacuum gave a yellow residue which was purified by flash chromatography. The title product (56 mg, 53%) was obtained. The following spectral data data were obtained for a mixture of both

1634, 1623 (CO quinone) cm. Example 9

Step 1: 2-Benzoyloxyacetoacetic acid tert-butyl ester To a stirred solution of acetoacetic acid tert-butyl ester (10 mL, 60 mmol) in benzene (120 mL) and tetrahydrofuran (60 mL) was added sodium hydride (1, 2 mL). 5 g, 61 mmol) in single portions after 15 minutes. Benzoyl peroxide (2.91 g, 12 mmol) dissolved in benzene (30 mL) was added. After one hour, the reaction mixture is washed with 50 ml of saturated aqueous ammonium chloride solution, twice with 50 ml of saturated aqueous sodium hypophosphite solution and 50 ml of saturated aqueous sodium hydroxide solution. The organic layer was then dried over magnesium sulfate and the solvent removed in vacuo. The excess B-butyl acetoacetate was removed by distillation under reduced pressure. The residue (light yellow oil) (2.4 g, 72%) was characterized as tert-butyl 2-benzyloxyacetacetic acid

EXAMPLE 8 Preparation of Tetrahedronoantraceno [2,3-c] thiophen-4-yl-dehydrogenate.

i -►

4

OCH, BCH 696

OCH, OAc

O

The acids are represented by 1 H NMR spectrum, 1 H NMR spectrum, 1 H NMR spectrum, 1 H NMR spectrum. (300 MHz, CDCl 3): 1.52 (s, 9H, -C ((3 H 5) 5), 2.42 (s, 3H, -CH 3), 5.63 (s, 1H, -CH-O) ), 7.47 (dt, J = 0.7 Hz and 7.4 Hz, 2H, ArH), 7.61 (doublet of triplet, J = 0.7 Hz and 7.4 Hz, 1H, ArH) , 8.13 (dd, J = 1.4 and 7.1 Hz, 2H, ArH).

Step 2: 3,6-Dimethoxy-2-bromoethylene-1- (3-tert-butylcarbonyloxy-3-benzyloxy-2-butanone-4-yl) benzene To a stirred solution containing 500 mg (1, 55 mmol) of 3,6-dimethoxy-1,2-dibromomethylene-benzene and 684 mg (2.46 mmol) of 2-benzoyloxy-acetic acid tert-butyl ester in 11 ml of acetonitrile and 6.5 ml of tetrahydrofuran are added 1 cesium carbonate. After 45 minutes, the reaction mixture was filtered through silica gel. The solvent is then removed in vacuo. 948 mg of crude 3,6-dimethoxy-2-bromo-thylene-1- (3-tert-butylcarboxyloxy-3-benzoyloxy-2-butanone-4-yl) -benzene was obtained. @ 1 H NMR spectrum. (300 MHz, CDCl 3): 1.45 (s, 9H, -C (CH 3) 2), 2.41 (s, 3H, -COCH 3), 5.53 (s, 3H, -OCH 3), 3 82 (s, 3H, -OCH2), 3, θ3 (two doublets, J = 14.8 Hz, 2H, ArHCH2 -), 4.79 (s, 2H, --Cl2Br), 6.72 (two doublets, J = 9.0 Hz, 2H, ArH), 7.38 (m, 2H, ArHCO-), 7.54 (m, 1H, ArHCO-), 7.81 (m, 2H, ArHCO- ) ',

Step 3: 3,6-Dimethoxy-2-bromomethylene-1- (3-benzoyloxy-2-butanone-4-yl) -benzene To a stirred solution containing 948 mg of crude β-ketone ester in 12 mL of acetone, slowly 6 ml of 48% hydrobromic acid are added. The reaction mixture was heated to 50 ° C for 105 minutes, then poured into 50 mL of water and 50 mL of ether and 100 mL of saturated aqueous sodium bicarbonate solution was added slowly. The aqueous layer was extracted with 50 mL of ether. The organic layers were washed with 50 mL of saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent gave 828 mg of a pale yellow oil which was characterized as 3,6-dimethoxy-2-bromo-thylene-1- (3-benzoyloxy-2-butanone-4-yl) -benzene. 1 H NMR spectrum (300 MHz, CDCl 3, δ) δ 2.29 (S, 3H, -COCH 3), 3.24 (dd, J = 9.0 Hz and 14.3 Hz, 1H, CH 3 -) CH-O-), 3.45 (dd, J = 4.6 and 14.3 Hz, 1H, --C2 --CH2 O), 3.81 (s, 3H, --OCH5), 3.83 (s, 3H, -OCH2), 4.80-114 - (two doublets, J = 9.7 Hz, 2H, -CH2-Br), 5.51 (dd, J = 4.6Hz and 9.0) Hz, 1H, -CH-O-, 6.77 (two doublets, J = 9, Hz, 2H, ArH), 7.43 (m, 2H, ArHCO-), 7.55 (m, 1H) , ArHCO-), 7.95 (m, 2H, ArHCO-)

Step 4: 5,6-Dimethoxy-2- (5-benzoyloxy-2-butanone-4-yl) -benzaldehyde To a stirred solution containing 828 mg of crude benzyl bromide in 10 mL of dimethyl sulfoxide was added 590 mg (4). 65 mmol) of sodium bicarbonate. The reaction mixture is heated at 90 ° C for 25 minutes, then poured into 150 ml of water and extracted with 5 x 50 ml of ethyl ether. The organic layers were washed with 50 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was evaporated. The chromatograph was flash chromatographed, eluting with 5: 1 hexanes: ethyl acetate. The title compound was obtained in 60% yield (519 mg). 1 H NMR Spectrum (500MHz, CDCl 3, δ): 2.54 (ε, 5H, -COCH 3), 5.65 (m, 2H, ArH-CH 2 -), 5.81 (s, 5H, -CH 3) ), 5.84 (s, 5H, -OCH3), 5.42 (dd, J = 5.1 Hz on 9.1 Hz, 1H, -CH-O), 6.85 (d, J = 9, 2 Hz, 1H, ArH), 7.04 (d, J = 9.2 Hz, 1H, ArH), 7.41 (m, 2H, ArHCOO-), 7.54 (m, 1H, ArHCOO-), 8.00 (m, 2H, ArHCO-), 10.62 (s, 1H, --CHO).

Step 5: 5,6-Dimethoxy-2- (5-hydroxy-2-butanone-4-yl) dimethyl acetal to a stirred solution of 519 mg (0.95 mmol) ketoaldehyde in 10 mL methanol and 2 mL of orthoformate, 50 mg of p-toluenesulfonic acid are added. After 5.5 hours, 600 mg of potassium hydroxide and 5 ml of water are added. The reaction mixture was refluxed for 4 hours. The solution was then cooled, the methanol was evaporated and 25 ml of water and 25 ml of ethyl ether were added. The aqueous layer was extracted with 2 x 25 mL of ethyl ether. The organic layers were washed with 25 mL of saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave 280 mg of crude dimethyl acetyl 5,6-dimethoxy-2- (5-hydroxy-2-butanone-4-yl) benzaldehyde oil. @ 1 H NMR Spectrum (500 MHz, CDCl3, .delta.): 1.55 (s, 1H, --CH2), J1 'at position: J1'. * - 115 - i

5.05. (dd, J = 2.9 Hz and 13.9 Hz, 1H, -CH8-CH-O-), 3.26 (s, 13H, -OCH3), 3.27 (m, 1H, -CH3); CH-O-), 3.50 (s, 3H, -OCH3, 3.51 (s, 3H, -OCH3), 3.55 (s, 5H-OCH3), 3.75 (s, 3H, 3.76 (s, 3H, -OCH3), 4.07 (m, 1H, -CH-O-), 4.17 (d, J = 6.6Hz, 1H, -OH) , 5.86 (br, 1H, ArHCH-O), 6.75 (two doublets, J = 9.0 Hz, ArH).

Step 6: Dimethyl acetal methyl 1- (1,5,8-trimethoxysulfon-5-yl) ketone. To a stirred solution containing 280 mg of crude product of the above-mentioned step (5) in 4 ml of methanol, 30 mg of pyridinium-p-toluenesuflonate are added. Thirty minutes later | 100 µl of triethylamine was added and methanol was evaporated. Odparek se? dissolved in methylene chloride and filtered through silica gel. The solvent is evaporated and the residue is purified (not necessary because the crude residue is pure according to NMR spectrum) by flash chromatography, eluting with hexanes: ethyl acetate (5: 1). The isochroman analog is obtained in a higher yield. than 80% (for two steps) (225 ng). @ 1 H-NMR spectrum (300 MHz, CDCl3, .delta.) 1.40 (s, 3H, --CH3), 2.47 (dd, J = 11.8 Hz and {17.6 Hz, 1H, --CH2 - CH-, 2.79 (dd, J = 3.8 Hz and 17.6 Hz, 1H, δ -CH 2 -OH-), 3.29 (s, 3H, -OCH 2), 3.52 (s, 5H, -OCH3), 3.62 J (s, 3H, -OCH3), 3.78 (s, 3H, -OCH3), 3.81 (s, 3H, -OCH3); 4.55 (dd, J = 3.8 Hz and 11.8 Hz, 1H, -CH 2 -CH-O), 5.63 (s, 1H, 4

ArH-CH-O), 6.73 (two doublets, J = 8.9 Hz, 2H, ArH). . ;

Step 7 * Methyl- (1-methoxy-5,8-dioxo-5,8-dihydroisochroipan-5-yl) -ketone | To a stirred solution of the compound of Step 6 (7 mg, 0.023 mmol) in acetonitrile (0.5 mL) at 0 ° C slowly? Ammonium nitrate (CAN) (44 mg, 0.069 mmol) in water (0.5 mL) was added. After thirty minutes, water (10 ml) was added and the mixture was extracted with dichloromethane. The organic phases are washed. sodium chloride and dried over magnesium sulfate. Zfriltrová-; and concentrated in vacuo to give a yellow oil of the title compound which no longer needed any further purification. @ 1 H NMR spectrum (300 MHz, CDCl3, .delta.): 2.34 (s, 3H, --CO - CH2), 2.39 (dd, - 116 - J = 11.3 Hz and 19.8 Hz, 1H, -CH 3 -CH), 2.85 (dd, J = 4.1 Hz and 19.3 Hz, 1H, -CH 2 -CH-), 3.61 (s, 3H, -Oi), 4.48 (dd, J = 4.1 Hz and 11.5 Hz, 1H, OHg-CH-O), 5.52 (s, 1H, AHH-CH-O), 6.78 (two doublets, J = 10) , 2 Hz, 2H, Ar H) -.

Step 8: Methyl (1-methoxy-6- and 11-hydroxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl) -ketone To a stirred mixture of sodium hydride (8.7 mg, 0.36 mmol) in tetrahydrofuran (2 mL) at 0 ° C was added homophthalic anhydride (57 mg, 0.35 mmol) and after ten minutes, the compound of Step 7 (79 mg, 0, 0) was added. The reaction mixture was warmed to room temperature and, after one hour, 1N hydrochloric acid (10 ml) was added and the mixture was extracted with dichloromethane, the organic phase was washed with brine, dried over sulphate. The residue was purified by flash chromatography, eluting with toluene: acetone (95: 5) to give the title compound in 10% yield (13 mg). , (Δ): 2.36 (s, 3H, -CO-CH 3), 2.55 (dd, J = 11.8 Hz and 19.7 Hz, 1H, -CH 2 -CH-O-), 3.07 (dd, J = 4.1 Hz and 19.7 Hz, 1H, CH2-CH-O), 3.68 (s, 3H, -OCH2), 4.56 (dd, J = 4.1 Hz and 11.8 Hz, 1H, -CH-CO), 5.71 (s, 1H, -O-CH-O), 7.7 (m, 2E, ArH), 7.95 (dd, J = 1.6 Hz and 7.1 Hz, 1H, ar H), 8.09 (s, 1H, ArH), 8.46 (dd, J = 1.6 Hz and 8.7 Hz, 1H, ArH). ''

Step 9: Methyl (5,8-dimethoxy-1-hydroxyisochroman-3-yl) ketone E stirred solution of crude product as above 5 (1.89 g, 5.49 mmol) in acetone (80 mL) and water (25 mL) was added p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 mL, 1.43 mmol) was added and the mixture stirred for an additional 5 minutes. The mixture is then evaporated to a volume of about 10 ml. Acetone (80 mL) and water (15 mL) were added. Subsequently, p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) is added. After 3.5 hours, triethylamine (3 mL, 2.15 mmol) was added. - 117 -

The reaction mixture was concentrated to low volume and extracted with ether (3 x 100 mL). The extract is washed with a chloride solution

Sodium chloride (5 ml), dried over magnesium sulfate and evaporated. This gave completely pure 1-hydroxyisochroman (1.3 6, 94% yield), m.p. Mp 136-138 ° C. XH HMR spectrum (CDCl 3, 300 MHz, δ): 2.32 (3H, s, CH 2 O), 2.51 (1H, dd, J = 12.4 Hz and 17.5 Hz, H-4 ), 2.97 (1H, d, J = 3.5 Hz, -OH), 3.06 (1H, dd, J = 4.1 Hz for 17.5 Hz, H-4), 3.77 and 3 , 82 (3H, each singlet, ArOCH 3), 4.70 (1H, dd, J = 4.1 Hz and 12.4 Hz, H-3), 6.22 (1H, d, J = 3, 4 Hz, 1H), 6.71 and 6.76 (1H, both doublets, J = 9.0 Hz, ArH).

Step 10: Methyl- (1-hydroxy-5,8-dioxo-5,8-dihydroisochroman-3-yl) -ketone. To a stirred solution of the above compound 9 (123 mg, 0.488 mmol) in acetonitrile (10 mL) at 0 ° C was added ammonium nitrate (802 mg, 1.46 mmol; CAN) in water (6 mL). After thirty minutes, water (40 ml) was added and the mixture was extracted with dichloromethane. The organic phases are washed with brine and dried over magnesium sulfate. Filtration and evaporation in vacuo gave a yellow oil of the title compound which did not require further purification (106 mg, 98%). 1 H NMR Spectrum (300 MHz, CDCl 3, δ T): 2.31 (br, 3H, -CO-CH 3), 2.39 (dd, J = 11.5 Hz and 19.6 Hz, 1H, - CHa-CH), 2.88 (dd, J = 4.2'Hz and 19.6 Hz, 1H, -CH 2 -CH), 3.90 (broad singlet, 1H, -OH), 4.65 ( dd, J = 4.2 Hz and 11.5 Hz, 1H, CH 2 -CH-O), 6.04 (s, 1H ', ArH-CH-O), 6.80 (two doublets, J = 10, 2 Hz, 2H, Ar H).

Step 11: Methyl (1-hydroxy-6- and 11-hydroxy-5,12-dioxo-3,4-5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl) ketone To the stirred solution homophthalic anhydride (87 mg, 0.536 mmol) in tetrahydrofuran (6 mL) at 0 ° C was added sodium bis (trimethylsilyl) amide (0.536 mmol, 536 µL) in tetrahydrofuran. After five minutes, the reaction mixture was cooled to -78 ° C. A solution (obtained from hydroxy-quinone (119 mg, 0.536 mmol), methoxypropene (300 µL) of the catalytic amount of pyridinium p-toluenesulfonate) in dichloromethane (2 mL) was added. After one hour at -78 ° C, the reaction mixture was stirred at room temperature for 1 hour

Ate fiate ^ ŠŠŠifisiisiisiisiisiisióóóófiáááá; The mixture is warmed to room temperature over two hours, then 1N hydrochloric acid (5 ml) is added and after five minutes the mixture is extracted with dichloromethane. The organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with toluene: acetone (90:10) to give 12 mg (7% yield) of the title compound. Nuclear Magnetic Resonance Spectrum (300 MHz, BMSO, δ): 2.26 (s, 3H, -CO-CH 3), 2.49 (dd, J = 11.5 Hz and 19.4 Hz, 1H, -CH 2 -) CH-O), 2.85 (dd, J 1 = 4.2 Hz and 19.4 Hz, 1H, -CH 2 -CH-O), 4.64 (dd, J = 4.2'Hz and 11, 5 Hz, 1H, -CH-CO), 5.95 (d, J = 6.2 Hz, 1H, -O-CH-O), 6.26 (d, J = 6.2 Hz, 1H, -OH) ), 7.81 (m, 2H, Ar H), 8.13 (s, 1H, Ar H), 8.22 (d, J = 7.7 Hz, 1H, Ar H), 8.36 (d, J = 8.0Ήζ, 1H, ArH), 15.71 (s, 1H, ArOH). Example 10

Step L N, N-Diethyl (2,5-dimethoxy) benzamide To a stirred solution of 2,5-dimethoxybenzoic acid (6.61 g, 36.3 mmol) in 50 mL of dichloromethane is added a solution of (GOCl) 2 in dichloromethane (2). 0.5M, 20 mL, 40.0 mmol) at 0 ° C under an argon atmosphere. Gas addition of pyridine (0.2 ml) was observed. The reaction was warmed to room temperature and stirred for three hours. The volatiles were removed. The residue was dissolved in 300 ml of diethyl ether. Ethylamine (5.26 mL, 50.8 mmol) was added dropwise at 0 ° C under argon. The resulting mixture was stirred at room temperature for an additional three hours, then quenched by the addition of saturated potassium carbonate solution. The organic layer was washed with 2N sodium hydroxide and water, dried over magnesium sulfate and evaporated. Flash chromatography of the residue, eluting with dichloromethane: ethyl acetate (1: 1), afforded the title compound (8.34 g, 35.1 mmol) in 97% yield (8.34 g, 55.1 mmol) as a white solid. NMR Spectrum (CDCl 3): 1.05 (3H, triplet, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 3.16 (2H, quartet, J = 7) 1 Hz), 3.56 (2H, m, 5.77 (5H, s), 5.78 (5H, s), 6.77 (1H, m), 6.84 (2H, m). EXAMPLE 9 5 Brief Synthesis of Anthracene-1,2,3-cypyrrolidin-3-yl-acyl with methrylketone side chain

OH O

I λ.ϊ'Δ ~ Lm. ·>,,>> M m m m m m m m m m m m 2 2 2. knows'. í '-k., "- 120 -

Step 2: N, N-Diethyl (2,5-dimethoxy-6-methyl) benzamide in a stirred solution of TMEDA (2.23 mL, 14.8 mmol) in 25 mL of tetrahydrofuran is added sec.butyllithium. 11.35 mL, 14.8 mmol) in an argon atmosphere at -78 ° C. After 20 minutes, a solution of N, N-diethyl (2,5-dimethoxy) benzamide (1.4 g, 5.9 mmol) in 5 ml of tetrahedronate was added dropwise at -78 ° C. The reaction mixture was stirred at the same temperature for one hour. Methyl iodide (1.4o ml, 22.5 mmol) was then added. The resulting mixture was stirred for one hour at -78 ° C and 20 mL of saturated ammonium chloride solution was added. The reaction mixture is extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography, eluting with dichloromethane: ethyl acetate (1: 1), gave the pure title compound (1.42 g, 5 → 66 mmol) in 96% yield. 1 H NMR Spectrum (CDCl 3, δ): 1.02 (3H, triplet, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 2.11 (3H, š), 3.12 (2H, q, J = 7.2 Hz), 3.45 (2H, m), 3.75 (5H, s), 3.79 (5H, s), 6.68 (1H, d, J = 8.9 Hz), 6.76 (1H, doublet, J = 8.9 Hz).

Step 3: 3,4-Dihydro-5,8-dimethoxy-3-vinylisocoumarin To a stirred solution of the benzamide from Step 2 above (3.51 g, 14.0 mmol) in 140 mL of tetrahydrofuran at -78 ° C under an argon atmosphere butyllithium (2.5 M, 9.0 mL, 22.5 mmol) was added. The addition is performed dropwise. The solution turns red during the addition. After stirring for 3 minutes, acrolein (2.25 mL, 35.6 mmol) was added. Stirring was continued for one hour at -78 ° C. The reaction is then stopped by adding 100 ml of saturated ammonium chloride solution. The mixture was extracted with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated. Without further purification, this residue was dissolved in 180 mL of benzene, the solution was heated to reflux and refluxed for 5 days in the presence of camphorsulfonic acid (2.95 g, 12.6 mmol). After cooling to room temperature, 200 mL of sodium bicarbonate (5 ° C) and 200 mL of dichloromethane were added. The organic layer is separated, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the residue, eluting with a mixture of dichloromethane with hexane and ethyl acetate (2: 4: 1) gave the title isocoumarin (1.28 g, 5.47 mmol) in a total yield of 59%. @ 1 H NMR Spectrum (CDCl3, .delta.): 2.76 (1H, dd, J = 16.9 Hz and 10.9 Hz), 5.22 (1H, dd, J = 16.9 Hz and 5.3 Hz) ), 5.85 (3H, s), 5.91 (5H, s), 4.85 (1H, m), 5.29 (1H, dd, J = 10.6 Hz and 1.1 Hz) , 5.44 (1H, dd, J = 17.5 Hz and 1.1 Hz), 6.0 (1H, m), 6.88 (1H, d, J = 9.1 Hz), 7.06 (1H, d, J = 9.1 Hz).

Step 4: 5,4-Dihydro-1,5,8-trimethoxy-5-vinylisocoumarin To a stirred solution of isocoumarin from step 5 (above) (9.4 mg, 0.4 mmol) in 8 mL of toluene is added. DIBAL-H solution (1M, 0.50 mL, 0.50 mmol) at -78 ° C in an argon atmosphere. The resulting mixture was stirred at -78 ° C for 1.5 hours. Sodium sulfate decahydrate (100 mg, 0.51 mmol) was added. The reaction mixture was allowed to warm to room temperature, the solids were removed by filtration and washed with acetone. The filtrate was evaporated. An oily residue is obtained which contains the corresponding lactol. Without further purification, the residue was left to react for 10 minutes at room temperature with 5 ml of methanol, 1 ml of trimethoxymethane and PTSA (50 mg, 0.16 mmol). The solvents were removed on a rotary evaporator. The residue was chromatographed by flash chromatography, eluting with hexane: ethyl acetate (7: 3). The title isoquicarin (65 mg, 0.26 mmol) was obtained in 65% yield (total). @ 1 H HMR spectrum (CDCl3, .delta.): 2.47 (1H, dd, J = 17.2 Hz and 12.0 Hz), 2.85 (1H, dd, J = 17.2 Hz and 5, 6 Hz), 5.56 OH, s), 5.78 (5H, s), 3.82 (5H, s),. 4.65 (1H, m), 5.24 (1H, triplet doublet, J = 10.6 Hz, and 1.4 Hz), 5.45 (1H, doublet of triplet, J = 17.3 Hz and 1 4 Hz), 5.65 (1H, s), 6.05 (1H, m), 6.70 (1H, d, J = 8.9 Hz), 6.76 (1H, d, J '= 8.9 Hz).

Step 5J 1-Methoxy-5-vinylisochroman-5,8-dione Add a solution of isocoumarin from step 4 above (50 mg, 0.12 mmol) in two ml of acetonitrile to a stirred solution of the solution (1 mL of water in one mL of water). at 0 [deg.] C. For five minutes the reaction mixture was allowed to warm to room temperature and stirred for an additional thirty minutes.

AND

S έ ξ i ·· δ?

It is measured with - 122 - dichloromethane and 10 ml water. The organic layer was washed with water. dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with hexane-ethyl acetate (7: 3) to give a pure product (15 mg, 0.07 mmol) in 57% yield along with the by-product. (10 mg, 0.05 mmol, 40% yield). The by-product can be converted to the desired product in 92% yield by reaction with strimethoxymethane in methanol with PTSA at room temperature. NMR spectrum (CDCl 3, δ) 2.29 (1H, dd, J = 19.4 Hz and 11.4 Hz), 2.65 (1H, dd, J = 19.4 Hz and 5.6 Hz) ), 5.55 (3H, s), 4.52 (1H, m), 5.27 (1H, dd, J = 10.5 Hz and 1.4 Hz), 5.41 (1H, dd, J). 5.45 (1 H, s), 5.98 (1 H, m), 6.74 (1 H, d, J = 10.2 Hz), 6.78 ( 1H, d, J = 10.2 Hz).

Step 6: 6-Hydroxy-1-methoxy-1,2,5-4-tetrahydro-5-vinyl-2-oxa-naphthalene-5,12-dione To a stirred solution of diisopropylamine (0.254 mL, 1.8 mmol) in 6 mL of tetrahydrofuran was added a solution of butyl lithium (2.5 M, 0.725 mL, 1.8 mmol) at 0 ° C under an argon atmosphere.

The mixture was stirred for 20 minutes. The freshly prepared LD.A solution was cooled to -78 ° C and stirred for an additional five minutes. Add dropwise the homophthalic anhydride (294 mg, 1.8 µl) solution in 4 mL of tetrahydrofuran. The solution turns yellow, green and yellowish. After the addition, the mixture was stirred for a further five minutes while quinone from step 5 above (332 mg, 1.5 mmol) in 4 mL of tetrahydrofuran was rapidly added via syringe. The resulting mixture was stirred for 20 minutes at -78 ° C, two hours of room temperature and then left in the refrigerator overnight. The mixture is diluted with 10 ml of saturated ammonium chloride solution to stop the reaction, and partitioned between 1N hydrochloric acid and dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation of the solvent. The residue was then purified by flash chromatography, eluting with 2: 2: 1 hexane: dichloromethane and ethyl acetate to give the title compound in 55% yield (276 mg, 0.82 mmol) as a single regioisomer. Melting point of product: 150 ° C (decomposition). 1 H NMR spectrum (CDCl 3, δ): 2.46 (1H, doublet of doublets, J = 19.2 Hz, α <11.4 Hz), 2.89 (1H, doublet of doublets, J = 19, 4 Hz and 3.7 Hz), {3.61 (3H, s), 4.60 (1H, m), 5.30 (1H, doublet of doublets, J = | = 10.6 Hz and 1.3 Hz ), 5.45 (1H, doublet of doublets, J = 17.3 Hz | and 1.4 Hz), 5.63 (1H, s), 6.04 (1H, m), 7.70 (2H, m 7.95 (1H, d, J = 7.4 Hz), 8.11 (1H, s), 8.48 (1H, d, J = 7.3 Hz), J 13.83 ( 1H, s). 150 nme spectrum (CDCl 3 δ) δ 27.80, 56.85, 66.90, 94.11, 117.51, 122.41, 125.43, 128.64, 129.68, , 131.11, 131.87, "156.63, 137.49, 142.12, 144.99, ξ 163.21, 181.95 and 188.66. J

Step 7 6-Acetoxy-1-methoxy-1,2,3,4-tetrahydro-3-vinyl-2-oxa-naphthalene-5,12-dione To a stirred solution of tetracyclic quinone from step 6 (230 mg, 0.68) pyridine (7 ml), acetic anhydride (7 ml) and DMAP (123 mg, 1.00 mmol) were added at room temperature in 35 ml of dichloromethane. The reaction mixture was stirred for two hours. The mixture was then poured into a mixture of concentrated water (20 ml) and dichloromethane (20 ml). The organic layer was washed with water, 0.1 N hydrochloric acid, dried over magnesium sulfate, filtered and concentrated. This gave a crude residue which was purified by flash chromatography. Yield 69% of the title compound (178 mg, 0.47 mmol), mp 228-229 ° C · C spectra (pure): 1208, 1611, 1643, 1667 , 1763, 2912 cm -1): 2.41 (1H, dd, J = 19.0 Hz 2.82 (1H, dd, J = 19.0 Hz and 3.5 (1H, m), 5.29 (1H) , dd, J = 11.0 dd, J = 17.0 Hz and 1.5 Hz), 5.64 (2H, m), 8.06 (1H, m), 8.14 (1H spectral (GDCl2), : 21.14, 27123.77, 127.00, 128.61, 130.01, 136.93, 139.80, 145.38, 168.90, 11.1 H NMR spectrum (CDCl 3, and 11.0 Hzi) 2.61 (s, 3H),

Hz), 3.61 (3H, s), 4.58Hz and 1.5 Hz), 5.44 (1H, (1H, s), 6.01 (1H, m), 7.72m), 8 , 59 (1H, s). 15 C NMR δ 78, 56.22 / 93.43, 116.62, 130.16, 130.24, 130.31, 135.52, 181.70, and 182.50. i (5

L 1 ’í

AND

I! $ 1 th

Step 8: 6-Acetoxy-1-hydroxy-1,2,3,4-tetrahydro-3-vinyl-2-oxa-naphthacene-5,12-dione To a stirred solution of tetracycline from above

Example 10: Preparation of Tetrahydroanthraceno [2,3-c] piperan-5-ylphoderivative with vinyl side chain

BCH716 -125-7 (16 mg, 42 mmol) in 5 mL of dichloromethane was added a solution of B-bromo-9-BBN in dichloromethane (1M, 0.105 mL, 105 mmol) at 0 ° C under argon. The reaction mixture was stirred for one hour at 0 ° C. 5 µl of ice water are then added. · The reaction mixture is extracted with dichloromethane, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (hexane: dichloromethane / ethyl acetate = 2: 2: 1). The title compound was obtained in a yield of 26% (4 mg, 11 mmol). δδ spectrum (pure): 1191, 1610, 1640, 1770, 2919, 3440 cm -1, or NMR spectrum (CDCl 3, 2.45 (13, dd, J = 19.0 Hz and 11, 0 Hz), 2.60 (5H, s), 2.86 (1H, dd, J = 19.0 Hz and 5.3 Hz), 4.61 (1H, m), 5.28 (1H, dd) , J = 11.0 Hz and 1.5 Hz), 5.42 (1H, dd, J = 17.0 Hz and 1.5 Hz), 5.62 (1H, broad singlet), 5.81 (1H , s), 6.00 (1H, m), 7.73 (2H, m), 8.67 (1H, m), 8.14 (1H, m), 8.65 (13, s). 11

Step 1: 2-Methoxyisopropyloxyacetic acid methyl ester to a stirred solution of methyl glycolate (5 mL, 64.8 mmol) and 2-methoxypropene (12.5 mL, 130.5 mmol) in dry dichloromethane (15 mL) at 0 ° G is added catalytic amount of pyridinium p-toluenesulfonate (100 mg). This mixture was stirred at 0 ° C for 2 hours. Saturated sodium bicarbonate solution was added, the methylene chloride layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The product was preset together with anhydrous potassium carbonate under reduced pressure (2666 Pa) at 62-84 ° C (yield 9.9% → 94%). @ 1 H NMR spectrum. (300 MHz, α-tone-d6): 1.28 (6H, singlet), 5.15 (3H, s), 5.67 (3H, s), 4.01 (2H, s).

Step 2: 5- (2z-Bromomethyl-5 *, 6'-dimethoxy) -phenyl-2-methoxysopropyloxy-propionic acid methyl ester. at 0 ° C, - 126 - 2.5 M butyllithium in hexanes (3.95 mL, 9.8 mmol) was added. The mixture is stirred for 10 minutes at 0 ° C, then cooled to -78 ° C. Protected methyl glycolate from Step 1 above (1.59 g, 9.7 mmol) in tetrahydrofuran was added. (6. ml). The mixture was stirred at -78 ° C for 15 minutes. 1,2-Dibromomethyl-3,6-dimethoxybenzene (1.5 S, 5.1 mmol) was then added in dry tetrahydrofuran (16 mL) and HMPA (2 mL) over 10 minutes. The mixture was stirred for one hour at -78 ° C. The temperature is increased to -4-0 ° C over the next fifty minutes. Saturated ammonium chloride solution (20 mL) was added. Tetrahydrofuran.se. removed at 25 ° C. The residue was extracted with ether. The ether extract was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated and the residue chromatographed on silica gel, eluting with 5% triethylamine in hexane: ethyl acetate (4: 1). Yield: 1.37 g (66 title compound. 1 H HMP spectrum (300 MHz, acetone-dg) ((δ): 1.05 (5H, s, CH 3 +), 1.15 (3H, s, CHp, 2.78 (3H, s, OMe), 3.01 (1H, doublet of doublets, J '= 8.9 Hza @ 13.5 Hz, H-3), 3.66 (3H, s, COOMe), 3.83 (6H, s, ArOCH2), 4.43 (1H, dd, J = 5.0 Hz and 8.8 Hz, H-2), 4.81 (2H, s,

ArCH 3 Br), 3.21 (1H, doublet of doublets, J = 5.1 Hz and 13.5 Hz, H-3), 6.88 and 6.95 (1H, d, each J = 9 Hz, ArH).

Step 3J 3- (2-Bromomethyl-3- (6-dimethoxy) -phenyl-2-hydroxy-propionic acid methyl ester). To a solution of 3- (2Z-bromomethyl-3Z, 6Z-dimethoxy) -phenyl-2-methoxy-isopropyl-pyloxypropionic acid methyl ester (29 g, 71 mmol) in diethyl ether (40 mL) was added 1N hydrochloric acid (20 mL). The mixture was stirred at room temperature for three hours. The ether layer was separated, washed successively with sodium chloride solution, dried over magnesium sulfate and evaporated. A tactile product is obtained as an oil in quantitative yield. 1 H NMR spectrum (300 MHz, CDCl 3, δ): 3.10 (1H, dd, J = 8.7 Hz and 13.9 Hz, H-3), 3.29 (1H, dd, J = 13, 8 Hz and 4.3 Hz, H-3), 3.77 (3H, s, COOMe), 3.79 (3H, s, ArOMe), 3.83 (3H, s, ArOMe), 4.47 ( 1H, dd, J = 8.7 Hz and 4.5 Hz, H-2), 4.72 (2H, s, ArCHg), 6.74 (1H, J = 9.0 Hz, ArH), 6, 80 (1H, d, J = 9.0 Hz, ArH)

Step 4: 5,8-Dimethoxy-isochroman-2-yl-formic acid To a solution of methyl ester 2- (2-bromomethyl-2-yl, 6-dimethoxy) -phenyl-2-hydroxy-propionic acid (20 mg) 0.09 mmol) in dry tetrahydrofuran (2 mL) was added sodium hydride (60% disodium in oil, 25 mg, 0.6 mmol). The mixture was stirred at 50 ° C for 2.5 hours. A small amount of ice was carefully added and the mixture was extracted with dichloromethane. The aqueous portion was acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with brine, dried, and the solvent was distilled off. 1 H NMR spectrum (200 MHz, CDCl 3, δ): 2.74 (1H, doublet of doublets, J = 11.2 Hz and 17.1 Hz, H-2 and H-4), 2.19 (1H, doublet doublet of doublets (ddd), J = 1.2 Hz, 2.8 Hz and 17.1 Hz, "H-4), 2.74 and 2.77 (2H, s, each of these bands, OMe), 4 , 26 (1H, dd, J = 2.9 Hz and 11.2 Hz, H-2), 4.7 (1H, d, J = 15.9 Hz, H1),; 5.06 (1H, doublet , J = 15.9 Hz, H1), 6.62 (1H, doublet, J = 12.2 Hz) and 6.67 (1H, doublet, J = 12.2 Hz) (both signals are aromatic protons) ).

Step 5: 2- (2z-Formyl-2z, 6z-dimethoxy) phenyl-2-methoxyisopropyloxypropionic acid methyl ester

2- (2z-Bromomethyl-2H, 6-dimethoxy) -phenyl-2-methoxy-isopropyloxy-propionic acid methyl ester (1.2 g, 2.9 mmol) was redissolved in dry dimethylsulfoxide (25 mL). Sodium bicarbonate (622 mg, 7.4 mmol) was added to the solution.

This mixture was stirred at 95 ° C for 45 minutes. It was then cooled, quenched with water (125 mL) and extracted with ether (2 x 200 mL). The extracts were then washed with brine (25 mL) and dried over magnesium sulfate. The solvent is evaporated. Yield 9 g of the title compound (90% yield). NMR data (200 MHz, acetone-d 6): 1.16 (2H, s, CH 3), 1.18 (2H, s, CH 3, 2.99 (5H, s, OCH 2), 2, 53'OH, s, GOOMe), 2.82 (2H, s, ArOH), 2.88 (2H, s, ArOJ), 7.04 (1H, d, J = 10.0 Hz, ArH) , 7.21 (1H, d, J = 10.0 Hz, ArH), 10.50 (1H, s, CHO).

Step 6: 5,8-Dimethoxy-1-hydroxyisochroman-3-yl-formic acid methyl ester To a solution of 3- (2'-formyl-3-yl, 6'-dimethoxy) -phenyl-2-methoxy-isopropyloxy-propionic acid methyl ester (4.2 g, 12.4 mmol) in tetrahydrofuran (75 mL) containing water (4 mL) was added pyridinium p-toluenesulfonate (230 mg). The mixture was stirred at room temperature for 1.75 hours. Triethylamine (3 mL) and saturated ammonium chloride solution (60 mL) were added. Tetrahydrofuran is removed at 25 ° C. The mixture was extracted with ether (3 x 150 mL). The ether extract was washed with sodium chloride solution, dried and evaporated. 3.9 g of 1-hydroxyisochroman (95% yield) were obtained (onaprosto pure compound according to the NMS spectrum). Melting point 127-129 ° C. MSB spectrum (300 MHz, CDCl 3, δ) 2.69 (1H, dd, J = 12.3Hz and 17.6 Hz, H-4), 3.07 (1H, broad hydroxyl 6 signal) 3.13 (1H, doublet of doublets, J = 17.5 Hz and 3.8 Hz, H-4), 3.78 (3H, s, COOMe), 3.82 (3H, s, ArOMe) 3.83 (3H, s, ArOMe), 4.91 (1H, dd, J = 12.3 Hz and 3.8 Hz, H-3), 6.24 (1H, broad singlet, H1), 6 , 71 (1H, d, J = 8.9 Hz, ArH), 6.77 (1H, doublet, J = 8.9 Hz, ArH).

Step 7,1-Hydroxy-3-carbomethoxy-5,8-dioxoisochroman To a stirred solution of isochroman from Step 6 above (232 mg, 0.865 mmol) in 10 mL of acetonitrile was added a solution of diammonium nitrate (1.422 g, 2 mL). , 59 mmol) in 7 ml of water at 0 ° C. the reaction mixture was slowly allowed to warm to room temperature, stirred for five minutes, then quenched by the addition of water (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed, dried over magnesium sulfate, concentrated and used for the next reaction without further purification (201 mg, 0.8 * 14 mmol, 98%). 1 H NME spectrum (CDCl 3, (f): 2.55 (1H, m), 2.95 (1H, dd, J = 19.5 H 2 and H, H, 3.15 (1H, broad); 3.84 (3H, s), 4.86 (1H, m), 6.04 (1H, s), 6.79 (2H, m).

Step 8: 3-Carbmethoxy-1,1-dihydroxy-1,2,3,4-tetrahydro-2-oxa-naphthalene-5,12-dione and 3-carbomethoxy-1,6-dihydroxy-129-! 1, 2,5,4-tetrahydro-2-oxanaphthalene-5,12-dione To a freshly prepared LDA solution (1.7 mmol) in 5 ml of te trahydrofuran, a solution of i. of homophthalic anhydride (189.7 g, 1.17 mmol) in 4 mL of tetrahydrofuran under argon. After stirring for 5 min at -78 ° C, a solution of quinone (1.15 mmol) in 4 mL of tetrahydrofuran is added via a syringe needle. stirring is continued for one hour at -78 DEG C. and then for 2 hours at room temperature. The mixture is left to stand overnight in a refrigerator, then poured into 25 ml of 1K hydrochloric acid solution, extracted with dichloromethane (three times 20 ml). The combined organic phases. The mixture was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue is purified by flash chromatography. This gave a mixture of the title compounds (1: 1, 15: 0, 52%). The following spectral data were obtained for this mixture. IR spectrum (neat): 146, 1501, 1612, 1658,; 1742, 2952, 5428 cm -1. NMR spectrum (CDCl 3, δ): 2.71 (2H, 5 m), 5.18 (2H, m), 5.18 (2H, m), 5.87 (5H, s), 5.88 (5H, s), J 4.92 (2H, m), 6.25 (1H, s), 6.27 (1H, s), 7.71 (4H, m). 7.95 [mu] (2H, d, J = 7.7 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.46 (2H, J, J = 7, &lt; tb > 6 Hz), 15.75 (1H, s), 15.77 (1H, s)

Stage 9! Methyl (1,5,8-trimethoxyisochroman-5-yl) formate acid

The compound of Step 6 above is reacted at room temperature with an excess of trimethyl ester. Thiourea in methanol for 12 hours. Is the quantitative? yield of the title compound. Nuclear Magnetic Resonance Spectrum (500 MHz, CDCl 3, δ T) δ 2.71 (dd, 1H, J = 12.4 Hz and 17.5 Hz, HCH a), 5.10 (dd, 1H, J = 4.0 ') 5.59 (s, 5H, OCH3); 5.81 (s, 5H, OCH3); 5.85 (s, 5H, OCH3); s, 5H, OCH 3, 4.80 (doublet of doublets, 1H, J = 4.0 Hz and 12.4 H, O-CH), 5.71 (s, 1H, t)

O-CH-O), 6.74 (two doublets, 2H, HC = H). J b

Step 10: (1-Methoxy-5,8-dioxo-5,8-dihydro-iso-isochroman-5-yl) formic acid methyl ester

This compound was obtained in 90% yield by the procedure of Step 7 in Example 9. 1 H NMR Spectrum (500 MHz, CDCl 3): - 130 -:: <{: / 'A' 1: <.... - · ~. Example 11: Brief synthesis of anthracenol 2,3-cypran-3-yl derivatives with ester side chains.

OCH

Ae-O. ^ OCH, CH, CH,

*About me

3H

- 131 - 2.54 (doublet of doublet of doublets, 1H, J = 1.2 Hz, 11.7 Hz and 19.5 Hz, HCHa), 2.88 (dd, 1H, J = 4.1 Hz and 19.5 Hz 5.55 (s, 5H, COOCH3), 3.57 (s, 3H, OCH3), 4.10 (dd, 1H, J = 4.1 Hz and 11.7 Hz, OCHO) , 5.49 (s, 1H, O-CH-O), 6.75 (twenty, 2H, HC = CH). J '‘' Example 12

Step 2,5-Dimethoxy-6-hydroxymethyl-benzaldehyde trimethyleneacetal To a solution of trimethyleneacetal 2,5-dimethoxybenzaldehyde (10.5 g, 46.9 mmol) in dry ether (200 mL) at -10 ° C add 2.5 M butyllithium (30 mL, 75 mmol). This mixture was stirred at -7 ° C for 5.5 hours. Dry paraformaldehyde (2.6 g) was added rapidly and the mixture was stirred at 0 ° C for a further 2 hours. It was then stirred overnight at room temperature, poured into saturated ammonium chloride solution and diluted with ether. The ether layer was separated, washed with brine (50 mL), dried over magnesium sulfate and the solvent was distilled off. The crude product was chromatographed on silica gel, eluting with dichloromethane: ethyl acetate (7: 1) to give pure product (5.5 g, 46% yield) as an oil. @ 1 H NMR spectrum (300 MHz, CDCl3, .delta.); 2.30 (2, m, CEL, acetal), 3.23 (1H, 'triplet, J = 6.8 Hz, CH3 OH), 3 , 78 (3H, s, -OMe), 3.80 (3H, s, -OMe), 3.98 (2H, m, CH 2 CH 2), 4.26 (2H, dd, J = 4.6 and 11) , 3.03 (2H, d, J = 6.8 Hz, CH2 OH), 6.21 (1H, s, H1), 6.77 (1H, d, J = 10 Hz, ArH), 6.86 (1H, d, J = 10 Hz, ar H).

Step 2: 2,5-Dimethoxy-6-mesyloxymethyl-benzaldehyde trimethyleneacetal To a 2,5-dimethoxy-6-hydroxymethyl-benzaldehyde trimethyleneacetal solution (19.8 g, 78 mmol) in dry dichloromethane (225 mL) at 0 ° Add triethylamine (22 mL, 156 mmol) and methanesulfonyl chloride (9 mL). Stir the mixture at 0 ° C for two hours. Saturated ammonium chloride solution (50 mL) was added slowly. The dichloromethane layer was separated, washed with water (132 ml, 25 ml) and brine (25 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 25 g of product (96%). Melting point: 87-90 ° C. 1 H NMR, spectrum (300 MHz, CD CDCl 3, δ): 3.22 (3H, s, -SO 2 Me), 3.77 (3H, s, 0Me), 3.80 (3H, s, OMe), 3.95 (2H, m, CH 2 CH 2), 4.24 (2H, dd, J = 4.6 Hz and 11.3 Hz, CH 2 CH 2), 5.77 (2H, s / CH 3 -OMS 6.18 (1H, s, methine proton H1), 6.88 (2H, aromatic protons), 2.35 (2H, multiplet, GH2 acetal).

Step 3s 2- (2'-3'-, 6'-Dimethoxybenzyloxy) acetic acid methyl ester

A mixture of methyl glycol ester (3.2 mL, 41 mmol) and sodium methoxide in methanol (4.37 M solution, 7.5 mL, 52 mmol) was heated at 50 ° C for 4.5 h under a nitrogen atmosphere. Methanol was removed and dry dimethylsulfoxide (5 mL) was added. The mixture was cooled to 10 ° C. Mesylate is added slowly. from step 2 above (4.9 g, 14.9 mmol) in dimethylsulfoxide (5 mL). The mixture was stirred overnight at room temperature. Ice (about 50 g) was added and the mixture was extracted with ether (three times 200 ml), washed with water (30 ml), dried and evaporated.

| The residue was dissolved in ether (100 mL) and 50 mL of 1N HCl was added. The mixture was stirred at room temperature for 1.5 hours room. The ether layer was separated, washed with brine sodium chloride (20 ml), dried and evaporated. The crude product was chromatographed on silica gel (hexanes / ethyl acetate = 2: 1 as eluent) to give 1.89 g of pure product. (45%), m.p. 177-179 ° C. 1 H NMR spectrum (300 MHz, CDCl 3, δ): 3.73, 3.81 and 3.84 (3H, s, 3 × OMe), 4.16 (2H, s, CH 2 -COOCH 3), 4, 97 (2H, s, benzyl CH2 group), 6.94 (1H, d, J = 9.2 Hz, aromatic proton), 7.08 (1H, d, J = 9.2'Hz, I aromatic proton) , 10.58 (1H, s, -CHO). Ί v | Step 4: 3,4-dihydro-5,8-dimethoxy-isochroman-3-yl-formate? acid

A mixture of sodium (280 mg, 12.2 mmol) and dry toluene? (15 ml) was heated to reflux.

I1 2- (2'-Formyl-3, 6'-dimethoxy-benzyloxy) -acetic acid methyl ester is added; (1.26 g, 4.7 mmol) in toluene (15 mL). The mixture was refluxed for five hours, cooled and slowly taken up in methanol (10 mL). Methanol is distilled off. Tetrahydrofuran (25 mL) and 2N Hydroxide Sodium (25 mL) were added. The mixture was stirred at room temperature for 1.5 hours. Ψ, remove the etrahydrofuran, extract with dichloromethane (50 mL), acidify the aqueous layer with dilute hydrochloric acid, extract with ethyl acetate (150 mL twice), wash with brine (25 mL), dry and distill off solvent. . The crude product was dissolved in dichloromethane and the solution was reacted overnight at 5 ° C with p-toluenesulfonyl chloride (5θ mg) in pyridine (1 mL). The product obtained after usual treatment is heated with pyridine at a temperature of 120 ° C and held at that temperature for three hours. The mixture was then cooled by dilution with water, neutralized with 5N hydrochloric acid, extracted with ethyl acetate (50 ml x 3), the solvent was removed and the product was dissolved in dichloromethane (50 ml). Extract with 10% sodium bicarbonate (2 x 25 mL). The aqueous extract was acidified with dilute hydrochloric acid, extracted with ethyl acetate (2 x 75 mL), washed with brine, dried and evaporated. This gave a substantially pure solid (500 mg, 27%). "4M MB spectrum (500 MHz, GDC 13, δ): 5.77" (5H, s, OMe), 5.79 (5H, s, OMe), 5.26 (2H, s, benzylic CIL,) ' 6.71 (1H, d, J = 9.1 Hz, aromatic proton), 6.77 (1H, d, J = 9.1 Hz, aromatic proton), 7.52 (1H, s, olefinic) proton).

Step 5i (5,8-Pimethoxy-isochroman-5-yl) -formic acid To a solution of isochroman (5 mg, 0.02 mmol) in dry methanol (5 mL) is added magnesium chloride shavings over 10 hours. small pieces (one piece at a time). The mixture was stirred overnight. Then the reaction mixture is acidified with dilute hydrochloric acid. The methanol was removed and extracted with ether. The ether extract was washed with brine, dried and evaporated. The residue (1 mg) showed a spectrum identical to the 1 H NMR spectrum of 5,8-dimethoxy-isochroman-5-yl-formic acid;

Step 6: (1-Formyl-trimethyleneacetal-3,6-dimethoxy) -benzylthioacetic acid ethyl ester To a stirred solution of trimethyleneacetal 2-bromomethyl-3,6-dimethoxy-benzaldehyde (650 mg, 2.05 mmol) was added a solution of 2- mercaptoacetic acid (0.25 mL, 2.28 mmol) in 1 mL of methanol and a solution of sodium methoxide (4.37 M in methanol, 0.47 mL, 2.05 mmol) at 0 ° C in an argon atmosphere. The resulting mixture was slowly warmed to room temperature. The temperature was stirred for six hours. 20 ml of water and 100 ml of diethyl ether are added. The aqueous layer was extracted with ether (3 x 20 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated to an almost pure title product which was used without further purification for the next reaction.

Step 7 (1-Formyl-3,6-dimethoxy) -benzylthioacetic acid methyl ester

The reaction residue from step 6 above is dissolved in 20 ml of ether and 15 ml of 1N hydrochloric acid.

After stirring at room temperature for 2 hours, the organic layer is separated, washed with 5% sodium bicarbonate solution, dried, filtered and concentrated. Flash chromatography evaporation of hexane with ethyl acetate (7: 3 ratio) afforded the title product (474 mg, 1.67 mmol) in a total yield of 81% (yield grade). HMR spectrum (CDCl 3) δ 3.32 (s, 2H), 3.72 (s, 3H), 3.82 (s, 3H), 3.87 (b, 3H), 4.29 (s, 3H), 3.92 (s, 3H) 2H), 6.89 (1H, d, J = 9.0 Hz), 7.08 (1H, d, J = 9.0 Hz), 10.60 (1H, s). 15 C NMR (CDCl 3, δ): 26.45, 34.47, 52.57, 56.5, 56.70, 111.46, 117.70, 123.71, 130.34, 152.11, 157 , 96, 171, 74a, 193.12.

Step 8: 3,4-Dihydro-3-carbomethoxy-5,8-dimethoxyisothio-chroman To a stirred solution of the aldehyde from above. 7 (400 mg, 1.4 mmol) in 30 mL of benzene was added sodium methoxide powder (152 mg, 2.8 mmol). The resulting mixture was heated to reflux for hours. The solid is removed by rinsing and filtering and washing with benzene. The filtrate was evaporated. The evaporation was purified by flash chromatography. There was thus obtained the title compound (166.1 g, 0.65 mmol) in 45% yield together with the recovered starting material (85 mg, yield 20%). W spectrum (CDCl 3, δ): 5.82 (s, 5H), 5.85 (s, 3H), 5.87 (s, 5H), 5.94 (s, 2H), 6.75 (1H , d, J = 9.0 Hz), δ 6.91 (1H, d, J = 9.0 Hz), 8.14 (1H, s). C C HMR spectrum (CDCl 3, f): 25.81 , 52.74, 56.50, 56.47, 109.96, 114.15, J 119.58, 125.56, 128.50, 128.97, 149.68, 151.45 and 166.17.

Step 9i 5-2a-Methoxy-5,8-dimethoxyisothiochroman t To a stirred solution of isothiochroman from above? of step 8 (129 mg, 0.48 mmol) in 20 mL of methanol was added 50 of about 50 mg of magnesium pieces. The reaction mixture starts to bubble after a 20-minute induction period at room temperature in a water bath. Small pieces of magnesium are added until all starting material is consumed. Saturated 10 ml was then added. ? ammonium chloride solution, 10 ml water and 50 ml diethyl ether.

The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation. It is obtained. a crude product which is purified by flash chromatography. The title compound was obtained in 82% yield (105 mg, 0.59 mmol). It was found that the spectral data of thi-1 the compound compounds are identical to the spectral data of the compound which was obtained from Step 1 in Example 8 above. b

Other Example 15 -

Stage 1: trimethyleneacetal 2,5-dimethoxy-6-hydroxyethylbenzaldehyde | To a cooled (at -40 ° C) solution containing 1.68 g 2,5-dimethoxybenzaldehyde (7.4 mmol) of trimethyleneacetal in 50 ml of anhydrous diethyl ether was added with stirring, and 4.8 ml of 2.5M butyllithium in hexanes were added under stirring in an argon atmosphere. The mixture was stirred for 5 hours at -5 ° C. Then, 557 mg (6.0 mmol) of cyanide cyanide (GuCN) was added and stirring was continued for one hour. 1.0 g of ethylene oxide is added to the mixture. • asis- 156 -

Alternative Preparation of Isochroman Aisothiochroman Derivatives Example 12:

OMe OMe - 137 -

The mixture was stirred at 4 ° C overnight, then washed with 20 mL of water, 20 mL of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give a residue which was flash chromatographed to give a flash residue. 54-7 mg (27% yield) of trimethyleneacetal 2,5-dimethoxy-6-hydroxyethylbenzaldehyde as a white solid. Melting point 155-156 ° C. Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl 3, δ): 1.48 (broad doublet, 1H, J = 15.6 Hz, HCHe), 2.52 (m, 1H, f HCHa), 5.48 (doublet of triplet, 2H, J = 4.76 Hz and 12.0 Hz, 'arCHp, 5> 79 (s, 6H, twice 00¾), 5.86 to 4.08' (overlap multiplet, 4H, twice OCHHe and CH20H ), 4.29 (m, 2H, two-OHCHa), 6.28 (s, 1H, O-CH-O), 6.79 (doublet ,ublet, 2H, J = 9.0 Hz, C NMR spectrum (75.44 MHz, CDCl 3, δ): - 25.9 and 29.5 (CH 2), 55.7 and 56.5 (OCH 2), 62.5 (CH 2 OH) , 67.9; (twice OCH 2), 97.6 (O-CH-O), 109.5 and 111.8 (aryl CH), 126.5, 129.2, 15θ, 8 and 152.8 (aryl); C) IR spectrum (PT, CDCl 3,% ax) J 5350, 3550 (broad signal, OH), 1257 and 1089 t (C-O). Calcd: δ 268.1511, found: 268, 1516. j

Step 2: 5,8-Dimethoxy-1-hydroxyisochroman ϊ

A solution containing 150 mg (0.56 mmol) of 2,5-dimethoxy-6-hydroxyethylbenzaldehyde trimethylene acetal in 5 ml of THF. with tetrahydrofuran, was stirred at room temperature for one hour with 5 ml of 0.2M aqueous hydrochloric acid. The mixture was then diluted with> 25 mL of dichloromethane, washed sequentially with 25 mL portions of aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was flash chromatographed to give 97 mg (82% yield) of the title 1-hydroxyisochroman. Melting point: 217-219 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ T): 2.73 (m, 2H, 5 CH 2), δ, θ9 (broad singlet, 1H, interchangeable proton hydroxy group), 3.84 (s, 5H) 5.88 (s, 5H, OCH2), 4.05 (m, 1H, OHCH), 4.27 (m, 1H, OHCH), 6.12 (broad singlet, 1H, OCH) , 6.77 (doublet of doublets, 2H, J = 7.2 Hz, ArH) &lt; 15 C NMR spectrum (75.44 MHz, CDCl3, [delta]): 22.2 (0¾), 55.5 and 55.7 (00%). ), 56.8 (00¾), 87.4 (OCH), 107.9 and 109.4 (ar-CH), 124.2, 124.8, 150.4 and 150.6 (aryl C) . IR 138138 spectrum (FT, CDCl3, δ): 3650 (C-O). Mass spectrum (HB) for i (broad signal, OH), 1260 cm @ -1;

Step 3: 1-Hydroxy-5,8-dioxo-5,8-dihydroisochroman To a stirred solution containing 75 mg (0.36 mmol) of 5,8-dimethoxy-1-hydroxyisochroman from Step 2 above in 2 mL of tetrahydrofuran, The solution containing 546 mg (1.0 mmol) of nitric diammonium nitrate was added dropwise over four minutes to two ml of water. The mixture was stirred for 5 minutes, diluted with 10 ml of dichloromethane, the organic phase was separated, washed with 5 ml of water, 5 ml of brine and dried over magnesium sulfate. Evaporation of the solvent gave a yellow oil which was found to contain pure isochromandione (62 mg, 96% yield). 1 H NMB spectrum (200 MHz, CDCl 3, δ): 2.54 (m, 2H, CH) 3.51 (d, 1H, J = 4.4 ' Hz, exchangeable hydroxyl proton), 4.09 (m, 2H, OCH), 5.88 (d, 1H, J = 4, 4 Hz, O-CH-O), 6.79 (doublet of doublets, 2H, J = 10.1 Hz, HC = CH) -1 H NMR spectrum (75.44 MHz, CDCl 3, δ "): 21, 5 (CH 2), 56.4 (OCH 2), 85.3 (OCH), 136.3 and 136.4 (aryl CH), 138.4 and 141.3 (CH), 185.3 and 186.4 ( 0 = 0 quinone).

Step 4: 2,5-Dimethoxy-6- (2-hydroxypropyl) -benzaldehyde trimethyleneacetal

Using the procedure described in step 1 of this example, 238 mg (32% yield) of the desired trimethylenation of the benzaldehyde was obtained by reaction of 739 mg (3.3 mmol) of 2,5-dimethoxybenzaldehyde trimethylene acetal with propylene oxide reagent and the following purification by flash chromatography, eluting with ethyl acetate: toluene (5: 95); mp 160-161 ° C. @ 1 H NMR Spectrum (300 MHz, CDCl3, .delta.): 1.33 (d, 3H, J = 6.1 Hz, CH2 -), 1.49 (broad doublet, 1H, J = 13.7 Hz, " HCHe), 2.30 (m, 1H, HCHa), 3.10 (doublet of doublets, 1H, J = 2.4 Hz and 14.1 Hz, HCH), 3.47 (doublet of doublets, 1H, J = 9 , 5 Hz and 13.9 Hz, HCH), 3.78 (s, 6H, OCH 2), 4.02 (overlapped multiplet, 3H 2 HO-CH and 2 HCHe-O), 4.30 (m, 2H, twice CH $ -O), 6.27 (s, 1H, O-CH-O), 6.78 (dd, 2H, J = 9.0 Hz, ar H). 159.1 (CH3), 25.8 and 55.7 (0¾), 55.6 and 56.5 (OCH3), 67.5 (CHOH), 67.6 and 67.5 (CH3), , 7 (00¾), 97.4 (O-CH-O), 109.4, .EL, 7 (aryl CH), 125.9, 129.5, 150.7 and 152.7 (aryl C). Mass spectrum: m / z 22: 5 calc .: 282.1467 (M +), found: 282.1449, IR: (FT, CDCl 3, m / z): 5500-5550 (broad signal, OH), 1257 and 1094 (C-O).

Step 5: 5,8-Dimethoxy-1-hydroxy-5-methylisochroman

Applying the procedure described in step 2 of this example yields 215 mg (86% yield) of isochroman substituted at the 5-position by reaction of 250 mg of trimethyleneacetal 2,5-dimethoxy-6- (2-hydroxypropyl) - benzaldehyde after flash chromatography (eluted with 20% ethyl acetate in hexanes). Melting point: 240-241 ° C. 1 H NMR Spectrum (200 MHz, CDCl 3, δ): 1.41 (d, - 5H, J = 6.2 Hz, CHβ, 2.54 (doublet of doublets, 1H, J = 11.4 Hza 17.4) Hz, HCHa), 2.81 (dd, 1H, J = 5.25 Hz and 17.5 Hz, HCHe), 5.02 (d, 1H, exchangeable hydroxyl proton, J = 5.4 Hz), 5, 81 (s, 5H, OCH3), 5.85 (s, 5H, OCH3), 4.57 (m, 1H, OCH), 6.12 (d, 1H, J = 5.5 Hz, O-CH); -O), 6.74 (dd, 2H, J = 8.9 Hz, ArH). 13 C NMR spectrum (75.44 MHz, CDCl 3, δ): 21.5 (0¾), 29.8 (CH 2) ), 55.7 and 55.8 (OCH 2, 62.6 (O-GH), 88.6 (O-CH-O), 107.9 and 109.5 (aryl CH), 124.6, 150, 47, 150.55 (aryl C 1 H) spectrum (FT, CDCl 3, V-QV): 5650 (broad signal, OH), 1260 (C-0). M + * 224.1049, found: 224.1056.

Step 6: 1-Hydroxy-5,8-dioxo-5-methyl-5,8-dihydroisochroman. Oxidative demethylation of 556 mg (1.5 mmol) of 5,8-dimethoxy-1-hydroxy-5-methylisochroman with 2.94 g (5 mmol) of di-ammonium nitrate as described in Step 5 of this Example affording 262 mg (90% yield) of isochromandione as a yellow oil. 1 H NMR Spectrum (200 MHz, CPCl 3, δ): 1.58 (d, 5H, J = 6.5 Hz, CH 3), 2.15 (doublet of doublet of doublets, 1H, J = 1, 2 Hz, 11.0 Hz | and 19.5 Hz, HCHa), 2.62 (dd, 1H, J = 5.5 Hz and 19.5 Hz, HCHe), | 5.16 (d, 1H, J = 4.5 Hz, exchangeable hydroxyl group proton), 4.51 (m, 1H, O-CH 2, 5.91 (d, 1H, J = 4.5 Hz) , O-CH-O), 6.78 (doublet of doublets, 2H, J = 10.2 Hz, ArH). Ν <Λ'ϊ; · "'- :: <ί · <-λζ? / ,; Λ r r r r r r r r r r r r r r r r r r r r r

Step 7: 1,2-Oxoobutan-3-one trimethylene ketal In a three-necked round bottom flask, 1,2-oxidobutan-3-one (29.776 g, 0.35 mmol), prepared as described in Hou-se (Organic Synthesis) , III, page 552.), mixed with 1,3-propanediol (118 mL, 1.59 mmol) and benzene (35 mL). Pyridinium tosylate (8.49 g, 0.035 mmol) was added to the mixture. The mixture was heated to reflux, whereby the water was separated on a Dean-Stark trap until all of the ketone was consumed. The solution is then washed twice with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and the organic phase is dried over sodium sulfate and most of the solvent is distilled off. The remaining mixture was pre-distilled under reduced pressure. A protected epoxy ketone is obtained in a yield of 22%, boiling point 75 ° C at 2667 Pa. 1 H NMR spectrum (300 MHz, CDCl 3, ppm): 1.28 (s, 3H, CH 3), 1.60 (m, 2H, epoxy ring), 2.61 (dd, 1H, HCH-O-CH) ), 2.66 (dd, 1H, HCH-O-CH), 3.00 (t, 1H, HCH-O-CH), 3.91 (multiplet, 4H, trimethyleneacetal). 1 H NMR spectrum (75.44 MHz, CDCl 3, ppm): 19.80 (CH 2, R 2 C-CH 2), 25.42 (CH 2, -O-CH 2 -CH 2 -CH 2 -O-), 43.27 (CH 2, CH 2 -O-CH-), 56.46 (CH 2 -O-CH), 60.84 (CH 2, -O-CH 2 -CH 2 -CH 2 -O-), 61.15 (CH 2) , -O-CH 2 -CH 2 -CH 2 -O-), 96.65 (quaternary C, CH 3 C (O (CH 2) 5 O) IR: (FT, CDCl 3, cm -1): 1494 (multiples, CH 2 -) 0, epoxide ring, mass spectrum (HR): for O &lt; + &gt; H &lt; 20 &gt;, calculated: 144.0786, &lt; + &gt; J, found: 144.0746.

Step 8: 2,5-Dimethoxy-6- (2-hydroxy-3-butanone-trimethylene-ketal) -benzaldehyde trimethylene ketal

A solution of 2.5M butyllithium (4.01 mmol) was added in an argon atmosphere at -15 ° C to a stirred solution of 2.5-dimethoxybenzaldehyde 0.5 g trimethylene acetal (2.23 mmol) in 20 mL anhydrous ether. The mixture was stirred for 5 hours at -7 ° C. At this point, 1.48 ml of boron etherfluoride (12.04 mmol) was added to 0.868 g (6.02 mmol) of 1,2-oxidobutan-3-one trimethylether ketal with stirring at -78 ° C. The lithium salt just formed is added to this new mixture. The reaction was allowed to stir overnight at -78 ° C. The reaction is then quenched by the addition of 20 mL of saturated ammonium chloride.

? Ether is added and the phases are separated. The organic layer is washed twice with 75 mL of water, once with saturated sodium chloride, and dried over magnesium sulfate. The residue is purified by flash chromatography. This gives the desired isochroman in a yield of 13.5. NMR Spectrum (300 MHz, CDCl 3, ppm): 1.54 (s, 3H, GH 2), 1.58 (mulletlet, 1H, -O-CH 2 -HCE-GH 2 -O-), 1, 88 (multiplet, 1H, -O-CH2-HCHe-CH2-O-), 2.71 (dd, 1H, HCH-CH (OH)), 2.78 (dd, 1H, HCH-CH-O), 3.76 (broad singlet, 6H, twice OCH 2), 3.95 (multiplet, 4H, -O-CH 2 -CH 2 -CH 2 -O-), 5.75 (s, 1H, H1), 6.70 ( doublet of doublets, 2H, ArH). 1 C NMR spectrum (75.44 MHz, CDCl 3, ppm); 21.55 (-C-CH2), 25.55 (O-CH2-CH2-GH2-O-), 55.66 and 56.10 (O-CH2-CH2-CH2-O-), 59.99 (CH 3 -CH-O), 63.43 and 68.21 (O-CH 2), 76.56 (CH 2 -CH-O), 94.16 (CH-OH), 99.11 (quaternary G to -total cycle), 108.60 and 109.86 (CH aromatic). 18 Spectrum - (FT, GDG1 =, cm -1): 3670 (OH).

Step 9 1-Hydroxy-3- (ethan-1-on-trimethylene ketal) -5,8-oxo-5,8-dihydroisochroman-4

A solution of 63.59 g of di-citric acid nitrate (1.16.10 mmol) in one ml of water is added dropwise to a stirred solution of 12 mg of 2,5 "dimethoxy-6- (2-hydroxy-3-butanone-tri-methylene ketal) -benzaldehyde trimethylene ketal (3). 87.10 µM in 1 mL acetonitrile at room temperature. After eight minutes, the mixture was diluted with 10 mL of dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were washed twice with water, once with saturated sodium chloride and dried over magnesium sulfate. The residue obtained by evaporation of the solvent affords a mixture of the compounds containing the desired chione. 18 spectrum (FT, CDCl 3, cm -1): 3600-3700 (broad band hydroxyl), 1664 (C = O, strong band, quinone).

Step 10: 2,5-Dimethoxy-6- (1-hydroxy-2,3-isopropylidenepropane) benzaldehyde trimethyleneacetal A solution of 2.5M butyllithium (4.014 mmol) is added to a stirred solution of 0 in an atmosphere of argon at -15 ° C. 5 g of 2,5-dimethoxybenzaldehyde triethylene acetal (2.23 mmol) in 20 ml of anhydrous ether. The mixture was stirred at -7 ° C for 5 hours. 1 - 142 - 0.78 g of isopropylidene-D-glyceraldehyde (6.02 mmol) was added to this mixture at -78 ° C. The isopropylidene derivative is prepared in advance by the method of David Y. Json (Syntheicic Communications 18 (4), 337 (1988)). This mixture was warmed to room temperature and allowed to react overnight. Add the ether. The solution was washed twice with water, once with saturated sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was flash chromatographed to give the desired product. Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl 3, ppm): 1.35 (multiplet, 1H, -O-CH 2 -HCH-CH 2 -O-), 1.42 (broad singlet, 3H, CH 2), 1.50 ( broad singlet, 3H, CH 2), 2.25 (multiplet, 1H, O-CH 2 -CH 2 -CH 2 -O-), 3.76 and 3.79 (2s, 6H, O-CH 3), 3.90 ( multiplet, 4H, -O-CH 2 -CH 2 -CH 2 -O-), 4.24 (two doublets of doublets, 2H, CH 2 isopropylidene group), 4.85 (quartet, 1H, CH isopropylidene group), 5.78 (t, 1H, -CH (OH)), 6.21 (s, 1H, trimethyleneacetal group), 6.81 (dd, 2H, aromatic protons). IR spectrum (PT, pure material, cm @ -1): 3400 (broad band, hydroxyl) Mass spectrum (HR) θ for θ ]ο ^ ^77777777: 35 35 35 35 354.1678 µM + nalezeno, found: 354.1670.

Step 11: 1,4-Dihydroxy-3-hydroxymethyl-5,8-dimethoxy-isochroman

Reaction of trimethyleneacetal 2,5-dimethoxy-6- (1-hydroxy-2,3-isopropylidenepropane) benzaldehyde with silica gel gave the desired isochroman in a yield of 23%. 1 H NMR Spectrum (300 MHz, CDCl 3, ppm): 3.48 (dd, 1H, CH (OH) -CH-HC-OH), 3.81 (s, 3H, OCH 3, 3.86 (s, s); 3H, OCH 2, 4.03 (triplet, 1H, -CH (OH) -CH-HCH-OH), 4.51 (broad doublet, 1H, -CH- (OH) -CH-CH 2 OH), 4.89 ( dd, 1H, (OH) CH-CH-CH 2 OH, 6.50 (s, 1H, -CH-O-CH-CH 2 OH), 6.81 (dd, 2H, aromatic protons). , 44 MHz, CDCl 3, ppm: 56.11 (-CH 3 OH), 56.39 ((OH) CH (O) -CH-CH 2 OH), 63.64 and 66.07 (twice -O-CH 2). , 76.92 ((OH) CH-CH-CH 2 OH), 95.13 ((OH) CH-O-CH-CH 2 OH), 111.40 and 111.75 (OH, aromatic carbon), 122.02 and 125. , 36 (aromatic C attached to the pyranyl ring), 149.80 and 152.36 (aromatic C atoms not "methoxy") IC spectrum (FT, pure substance, cm "): 3520 (OH, not too intense due to hydrogen bridge) ii, íaíííiii £;

Mass spectrum (HR) calculated for C- pHH--O O: 238.0841lM + ‘H‘OJ, found: 238.0871.

Step 12: 1,4-Dihydroxy-3-hydroxymethyl-5,8-dioxo-3,4,5,8-tetrahydro-benzo [2,3-c] pyran To a stirred solution of 12 mg of 1,4-dihydroxy-3-hydroxymethyl-3,8 -dimethoxyisochroman in 2 ml of acetonitrile at room temperature

- / i A solution of di-nitric nitrate (1.40.10 mmol) in 1 ml of water is added dropwise. The reaction is monitored by chromatography on a thin layer (TLC). However, the product moves with the same R 6 as the starting material, but is much more active in the UF region than the starting material and can thus be identified in this way. After stirring for 10 minutes, the reaction is complete. Dichloromethane (10 mL) was added and the layers were separated. Extracted the aqueous layer twice with water, dried over magnesium sulfate once with saturated sodium chloride. The residue obtained by distilling off the solvents yielded the desired isochroman in 62% yield. Melting point: 138-140 ° C. Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl 3, ppm): 3.44 (doublet of doublets, 1H, J = 8.43 Hz, 2.08 Hz, CH (OH) -CH-CH (OH)), 4.04 ( dd, 1H, J = 8.38 Hz and 6.70 Hz, CH (OH) -O-CH-HCH (OH) -, 4.32 (broad singlet, 1H, -CH (OH) -CH- CH2 (OH)), 4.87 (doublet of doublet of doublets, 1H, J = = 6.35 Hz, 2.16 Hz and 1.21 Hz, ((OH) CH-CH-CH2 (OH)), 6, 20 (broad singlet, 1H, (OH) -CH-O-CH-CH2 (OH)), 6.80 (doublet of oak-flight, 2H, aromatic protons), spectrum (FT, CDCl3, cm2): 3600 to 3630 (OH, middle band), 1670.7 (0 = 0 quinone). 'Ύ · ώιΧ ;; 3Μ £ ύ? <Ί / Κί; ι ;;. Ί <\ t Example 13 Preparation of other key isochromandions for the preparation of other heteroanthracyclinones.

OH o - 145 - Example 14

Step 1: 5,12-Dimethoxy-5-carbomethoxy-1,2,5-dimethyl-tetrahydrofuran. 2-Thianaphthalene-6,11-dione 1,4-Dimethoxy-2,5-dibromomethylanthraquinone (5.5 g, 7.76 mmol) was dissolved in a mixture of dichloromethane with methanol (500 mL, 6: 4). 2-mercaptoacetic acid ethyl ester (1.02 ml, 9.51 mmol) was added to this solution with stirring under argon atmosphere. The mixture was then cooled to 0 ° C. Sodium methoxide (4.57M, 2.15 mL, 9.51 mmol) was added dropwise. The reaction mixture was stirred for an additional hour and then concentrated in vacuo. The dry residue was redissolved in tetrahydrofuran and cooled to 0 ° C. Sodium ethoxide (0.65 g, 9.51 mmol) was added.

The ice bath was removed and the reaction was stirred until the room temperature was warmed. The reaction was then quenched by the addition of ammonium chloride and extracted with dichloromethane. The organic layers are combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. This gave a residue which was flash chromatographed on hexane-ethyl acetate-dichloromethane (5: 1: 6) to give the desired products (679 mg) in 22% yield. NMR spectrum (500 MHz, CDCl 3, δ) 1.28 (triplet, 5H, J = 7.0 Hz), 5.17 (dd, 1H, J = 16.62 and 7.85 Hz, HCHa-C = O), 5 ^ (doublet of doublets, 1H, J = 16.7 Hz and 5.5 Hz, HCHeCHC = O), 5.76 and 5.77 (m, 2H, OCHC = O or HCHa) 5.78 (m, 1H, HCHe-S), 4.20 (quartet, 2H, J = 7.0 Hz), 7.74 (multiplet); , 2H, ArH), 8.17 (multiplet, 2H, ArH).

Step 2: 5-Carbethoxy-5,12-dihydroxy-1,2,5,4-tetrahydro-2-thiophenyl-6,11-dione stirred solution of the compound of Step 1 (20 mg, 0.05 mmol) in 5 mL of dichloromethane at -78 ° C was added boron tribromide (2.04 mL) under an argon atmosphere. The reaction mixture is stirred at -78 ° C for 1.5 hours. The reaction was then quenched with 5 mL of water and 10 mL of dichloromethane. The organic layer was separated, washed with water and dried over magnesium sulfate.

After filtration, the solvent is distilled off. A residue was obtained which was virtually pure title compound - 146 - (19 mg, 0.05 mmol, 100%). 1 H NMR Spectrum (CDCl 3, T): 1.29 (3H, triplet, J = 7.0 Hz), 3.28 (2H, m), 3.90 (3H, m), 4.22 (2H) , quartet, J = 7.1 Hz), 7.80 (2H, m), 8.31 (2H, m), 13.49 '(1H, s), 13.50 (1H, s). @ 1 H NMR Spectrum (.delta., O - 0.90 (3H, triplet, J = 7.1 Hz), 3.08 (1H, m), 3.33 (1H, m), 3.42 (1H, m) 3.88 (4H, m), 7.85 (2H, m), 8.14 (2H, m), 13.78 (1H, s), 13.86 (1H, s). @ 1 H NMR spectrum (OD) .delta. 14.13, 22.74, 26.11, 39.32, 61.74, 126.93, 133.48, 134.36, 155.10, 156.30, 168.01 and 186.64.

Step 3: 1,4-Diacetyl-2,3-dimethyl-anthraquinone To an stirred suspension of 2,3-dimethyl-quinazin (5.10 g, 18.637 mmol) in dry dichloromethane (250 mL) is added anhydric acid (40 mL). pyridine (40 mL) and dimethylaminopyridine (DMAP, 1.7 g) · The mixture was allowed to stand at room temperature under argon for two hours, then poured into ethyl acetate / ice (1: 1, 800 mL) and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate. Flash chromatography with toluene and ethyl acetate (95.5%) gave 2.517 g (38% yield) of pure compound, m.p. Mp 222-224 ° C. 1 H NMR Spectrum (CDCl 3, δ): 2.27 (s, 6H, CH 3), 2.53 (s, 6H, COCH 2, 7.72 (m, 2H, ArH), 8.15 (multiplet, 2H, ArH).

Step 4: 1,4-Diacetyl-2,3-bis (bromomethyl) anthraquinone

A mixture of diacetized quinizarin from step 1 above (2.221 g, 8.801 mmol), NBS (3.956 g, 22.002 mmol) and benzoyl peroxide (178 mg) in tetrachloromethane (350 mL) was refluxed under argon for 100 minutes. five hours. Additional NBS (0.5 mmol) of benzoyl peroxide (0.2 mmol) was added. The reflux is continued for a further three hours. The solution is then cooled. Evaporation of the solvent in vacuo followed by flash chromatography (97.5% with 2.5% toluene / ethyl acetate) afforded 3.095 g of the title compound in 88% yield. Temperature: 225-227 °. NMR Spectrum (CDCl 3, δ): 2.56 (singlet, 6H, OCOCH 3), 4.59 (broad singlet, 4H, CHBr), 7.75 (multiplet, 2H, ArH), 8.14 (multiplet, 2H, ArH). &amp;>>::;; í í í í «« i i i i i i i ^ ^

- y Λ. 147 -

Example 14: Preparation of pyrano- and thioprone-substituted antraoyclinone groups from 2,5-dimethyl-quinazines.

. IN? ,,, '' X, '. ·' '<' ·,.

Anti-tumor efficacy

In vitro cytotoxicity of BCH-242 was investigated. Cytotoxicity was evaluated on 57 tumor cell line lines to determine the potential of this compound as an antitumor drug. These tests were conducted in the Therapeutic Therapy Development Program of the Cancer Treatment Department of the National Cancer Institute, Bethesda, Maryland. This method consists of incubating different concentrations of drug with cell inoculation for two days. At the end of this assay, viable cells are evaluated by sulforhodamine B staining. This procedure is described by M. R. Boydy, " Status of the NCIP Clinical Antitumor Drug Discovery Screne ", Principlesand Practices of Oncology 1-12, 1989. These 57 cell lines include two mouse leukemia lines (P588 parental and adriamycin resistant lines) and 56 human cell lines. from

Three parameters were calculated: GI ^ Q (logarithm of molar concentration of drug // compound required for 50% inhibition of cell growth, TGI (logarithm of molar concentration of compound required to completely block cell growth) and LC ^ q (logarithm of molar concentration of compound required for it is noted that the first two para-meters (GI ^ q and TGI) are related to antiproliferative effects, while the third parameter (LC ^ q) indicates true cytotoxicity. The BCH-242 analogue is capable of inhibiting the growth of the cell lines of both mouse leukemias (parental P588 and adriamycin-resistant lineages) in the BCH-242 efficacy profile. the same range (-5.78 and -5.65) BCH-242 shows a similar cytotoxic effect to the MCP-7i parental lines on the lines adriamycin-resistant (-5,27 and -5,15) · The ability to show efficacy on cell lines that are known to be drug-resistant presupposes that the compound can exert an advantageous mechanism and that the compound may be clinically useful The various human and mouse leukemia lines, although sensitive to the antiproliferative effect of BCH-242, exhibit some resistance to the cytotoxic effect of the compound. However, most cell tumors of solid tumors ultimately exhibit cytotoxicity to the thromo / drug. Since the potency of the respective compound for leukemia is usually predictive of clinical toxicity, it is believed that BCH-242 may be clinically effective for certain solid tumors, with minimal myelotoxic effect.

Antiproliferative and cytotoxic effects of BCH-242 on tumor cell lines panel / cell line log1QGI50 log1QTGI log10EC50 leukemia CCRP-CEM -5.83 -5.35> -4.00 HL-60TB -5.70 -5.30> -4.00 K562 -5,72 -5,35> t-4,00 MOLT-4 -5,89 -5,49 -5,09 RPMI-8226 -5,77 -5,35 -4,47 Lung cancer NS- 549 -5.51 -5.00 -4.42 EKVX -5.75 -5.47 -5.20 HOP-18 -5.72 -5.31 -4.78 HOP-62 -5.25 -4 , 75 -4.37 HOP-92 -5.70 -5.43 -5.17 NCI-8226 -5.56 -5.18 -4.59 NCI-H23 -5.74 -5.49 -5, 23 NCI-H322 -4.90 -4.55 —4.16 NCI-H460 -5.71 -5.40 -5.09 NCI-H522 -6.04 -5.68 -5.34-150 -

Anbiproliferative and cytotoxic effects of BCH-242 on tumor cell lines (continued) panel / cell line. l ° g10GI50 log ^ gTGI log1 () LC50? SC lung cancer DMS-114 -5,80 -5,52 -5,24 DMS-273 -5,68 -5,35 -5,01 gastric cancer COLO-205 -5,95 -5,65 -5,31 DLD-1 -5,80 -5,49 -5,17 HCC-2998 -5,65 -5,24 -4,72 HCT-15 -5,78 -5,45 -5,12 HT-29 -5 , 81 -5,45 -5,09 KM-12 -5,49 -4,97 -4,49 KM-20L2 -5,66 -5,27 -4,75 SW-620 -5,88 -5, 54 -5,19 CNS cancer SF — 268 -5,31 -4,59 -4,40 SF-295 -5,62 -5,15 -4,59 SF-539 -5,69 -5,36 -5 , 05 SNB-19 -5.42 -4.88. -4.44 SNB-75 -5.53 -5.06 -4.52 SNB-78 -4.82> —4.00> -4.00 U-251 -5.60 -5.14 -4, 59 XF-498 L -5.79 -5.50 -5.22. melanoma LOX-IMVI -5,73 -5,49 -5,24 MALME-3M -5,75 -5,49 -5,24 Ml9 — MEL -5,81 -5,51 -5,21 SK-MEL- 2. -5.77 -5.51 -5.24 SKUffiL-28 -5.62 -5.37 -5.11 SK-MEL — 5 -5.85 -5.55 -5.26 UMCC-257 -5, 70 -5,44 -5,18 UMCC-62 -5,76 -5,50 -5,25 ovary cancer IGROV-1 -5,75 -5,42 -5,10 OVCAR-3 -5,82 -5 , 52 -5.25

- 151 -

Antiproliferative and Cytotoxic Effects of BCH-242 on Tumor Cell Lines (Completion) Panel ^ Los10GI ^ 0 lo ^ jPGI log10LC50 OVCAR-4 -5,74- -5,48 -5,22 OVCAR-5 -5,70. -5,46 -5,23 OVCAR-8 -5,49 -5,49 -5,19 SK-OV-3 -5,27 -4,77 -4,38 Renal cancer A498 -4,86 -4, 57 -4.28 CAEL-1 -5.52 -5.12 -4.59 RXP-395 1 «-5.89 -5.58 -5.27 SN-12C -5.79 -5.52 -5 , 26 SN12EL -5,48 -5,12 —4,60 UO-31 -5,62 -5,25 -4,77 other MCF-7 -5,81 -5,54 -5,27 MCF-7 / ADR -5,76 -5,46 -5,15 P388 -5,76> -4,00 P3888 / ABR -5,63 -4,99 -4,16 Wednesday '-5,65 -5,28 -4 , 84 Example 16

In Vitro Heteroantracycline Assays In an NCI in Bethesda, Maryland, anthracycline analogue series were evaluated. The same protocol (protocol) as described in Example 15 was used for BCH-242. In Table I and II, the mean GI ^O and LC ^Q values obtained for cell line groups by cancer type are summarized. various derivatives are disclosed in Tables III to XI. Table I shows that heteroantracycline derivatives exhibit weaker antiproliferative activity than daunomycin (DNM) - 152 - or adriamycin (ADR) for various cancers. It is clear from Table II that heteroantracycline agents are able to kill solid tumor cells. The range of cytotoxic mean potency is from -4.09 for BCH-674 to -5 -532 for BCH-242 for solids. More noteworthy is the fact that the average cytotoxicity in leukemia is usually much lower than with DNM or ADR. This is a desirable property and may indicate lower toxicity of the bone marrow than the clinical agents of DNM and ADR. Since myelotoxicity limits the individual dose that can be administered to the patient, it follows from these results that higher and more therapeutically useful single doses of heteroantracyclines of the present invention can be used in chemotherapy of solid tumors.

Table of the Average LOG ^ qGI OT Cell Lines No. NO NSC of Lung SC Lung DNM -7.25 + 0.10ADR -7.51 + 0.52242 -6.50 + 0.14 670 -5.78 + 0, 10,671 -5.74 + 0.05 672 -5.89 + 0.09 673 -5.97 + 0.06 674 -5.06 + 0.14 675 -5.53 + 0.11 681 -5, 69 + 0.05 685 -5.74 + 0.056589 -4.81 + 0.04 -7.04 + 0.25 -7.33 + 0.76 -6.01 + 0.54 -5.51 +0.32 -5.34 + 0.58 -5.45 + 0.29 -5.76 + 0.56 -5.05 + 0.58 (IR) -5.05 + 0.33 -5, 54 + 0.28 -5.52 + 0.23 -4.87 + 0.13 -7.14 + 0.01-7.27 + 0.12-6.45 + 0.26-5.48 + 0.23-5.60 + 0.06-5.69 + 0.14-5.74 + 0.00 - 4.88 + 0.14 -6.82 + 0.31 -6.61 + 0, 35 -6.50 + 0.32 -5.69 + 0.17 -5.72 + 0.05 -5.78 + 0.18 -6.10 + 0.32 -4.87 + 0.29 - 5.14 + 0.22 -5.06 + 0.24 -5.77 + 0.04 -5.73 + 0.01 -4.94 + 0.02 -5.85 + 0.21 -5, 89 + 0.24 -4.95 + 0.05

CNS -7.04 + 0.15 -7.07 + 0.26 -5.81 + 0.23 -5.44 + 0.30 -5.37 + 0.19 -5.33 + 0.25 - 5.65 + 0.06 -4.86 + 0.7 (1R) + -4.97 + 0.19 (IR) -5.54 + 0.15 -5.47 + 0.17 -4.89 +0.10 155

Table I (continued) BCH No Ovarian Melanoma Renal Moderate Potency in DNM Vessels -6.95 + 0.21 -6.86 + 0.18 -6.79 + 0.47 -6.95 + 0, 22 í ADR -6.92 + 0.26 -6.55 + 0.19 -6.74 + 0.41 -6.93 + 0.29 242 -6.36 + 0.41 -6.13 + 0 , 41 -6.02 + 0.22 -6418 + 0.24 670 -5.75 + 0.12 -5.42 + 0.40 -5.36 + 0.35 -5.52 + 0.13 671 -5.68 + 0.09 -5.44 + 0.35 -5.55 + 0.14 -5.53 + 0.14 672 -5.81 + 0.14 -5.50 + 0.35 - 5.38 + 0.26 -5.56 + 0.18 673 -5.83 + 0.05 -5.81 + 0.26; -5,80 + 0,09 -5,81 + 0,13 674 -4,88 + 0,12 -4,80 + 0,09 -5,05 + 0,27 -4,91 + 0,09 675 -5.23 + 0.23 -5.07 + 0.28 -5.04 + 0.30 -5.08 + 0.08 681 -5.95 + 0.29 -5.57 + 0.12 - 5.52 + 0.27 -5.68 + 0.16 683 -5.95 + 0.25 -5.68 + 0.12 -5.50 + 0.29 -5.68 + 0.18 684 - 4.90 + 0.05 -4.94 + 0.05 -4.95 + 0.04 -4.92 + 0.03 + Means the number of cell lines that resist the cytotoxicity of the compound (LOG ^ qGI ^ q is less than -4.00).

Table II

Average LQG1QLG ^ 0 BCH c cell lines. NSC lung leukemia SC lung stomach CHS DNM -4,30 + 0,36 -5,07 + 0,37 t-5,58 + 0,09 -4,83 + 0,37 -5.08 + 0.42 ADR -4.76 + 0.10 -5.01 + 0.26 -5.39 + 0.18 -4.86 + 0.27 -5.03 + 0.35 242 -4.00 -5.21 + 0.38 -5.58 + 0.27 -5.59 + 0.36 — 4.86 + 0.24 670 -4.00 -4.62 + 0.27 - 4.41 -4.60 + 0.29 -4.58 + 0.15 Ue + (1H) (2R) 671 -4.00 -4.52 + 0.41 -4.26 + 0.20 UR ) -4.80 + 0.50 -4.37 + 0.24 672 -4.37 + 0.15 -4.56 + 0.08 -4.40 + 0.20 -4.55 + 0.18 —4.50 + 0.16 673 -4.00 — 4.66 + 0.43 -4.44 + 0.04 -4.46 + 0.45 -4.57- + 0.22 674 -4, 00 —4.16 + 0.10 -3.92 + 0.14 -4.01 + 0.27 —4.20 + 0.06 675 -4.00 -4.25 + 0.23 —4.21 +0.04 -4.07 + 0.22 -4.21 + 0.11

154 - 681 -4.00 -4.64 + 0.41 -5.18 -5.14 + 0.27 -4.65 + 0.24 (1) 683 -4.00 -4.55 + 0, 42 -5.08 -4.98 + 0.38 (1? -, 4.50 + 0.21O) 689 -4.00 -4.38 + 0.06 (3R) -4.37 + 0, 05 -4.41 + 0.03 -4.59 + 0.05. (2R)

Table II (continued) BCH KZ c. Ovarian melanoma renal mean potency in DNM solid tumors -5.64 + 0.17 -4.78 + 0.20 -4.78 + 0.46 -5.11 + 0.34 ADR -5.56 + 0.29 -4.74 + 0.05 - 4.87 + 0.38 -5.07 + 0.28 242 -5.41 + 0.07 -5.35 + 0.19 - 5.22 + 0.21 -5.32 + 0.20 670 -4.69 + 0.29 (IR) '4.40 + 0.13 -4.53 + 0.16 -4.57 + 0, 09 671 —4.67 + 0.57 -4.47 + 0.35 -4.63 + 0.24 -4.53 + 0.17 672 — 4.67 + 0.18 -4.59 + 0, 13 —4.62 + 0.08 -4.56 + 0.08 673 -4.87 + 0.50 — 4.66 + 0.50 -4.96 + 0.32 -4.66 + 0.18 674 -4.05 + 0.17 -4.08 + 0.17 -4.24 + 0.14 -4.09 + 0.11 675 -4.10 + 0.23 -4.20 + 0.16 -4.25 + 0.10 - 4.18 + 0.07 681 -5.30 + 0.12 -4.78 + 0.18 -4.66 + 0.40 (1) -4.91 + 0 , 27,683 -5.15 + 0.22 -4.80 + 0.33 -4.58 + 0.36 -4.81 + 0.25 689 -4.38 + 0.04 -4.37 + 0 , 07-4,43 + P, 01 (2R) -4,39 + 0,02 + means the number of cell lines that resist the cytotoxicity of the compound (LOG ^ qLC ^ q is less than -4,00). All the following Tables III to XII were compiled in the National Cancer Institute as part of the Therapeutic Development Program. Molar units were used in all tables. Tests were conducted from 7.11.1989 to 18.I2.I99O. The results were evaluated from 16.7.1990 to 1.3.1991.

Tests in each table refer to one compound. The designation of the compound is given in brackets after the table number.

Table III (Compound BCH-242)

Table IV (Compound BCH-47O). 1 i: i:: 1 1 i i::::. . 1 l · e 7 ♦ i •: I in lilies 2 2 2 2 2 i i i i Λ Λ Λ Λ Λ 0; 000 A 1 'O A 1 0 A i OOO A A 1 TT | - «? 55? 5? 5 A Ί ^ ·» <· ® x 3 -jíllllí 0000 ’? 2 5 .11.11 JL L. fj 1-lil I-. . 1 1 | - ----- t 1 »4 1 1 1 1 1 I» -r | 1 1 • 1 »11 - O ♦ 8 í 003 m 2 2 2 P ε s-i ·? i? ·? A 0 0 OOO OOOOOOOOOOO Π Il il. . I. * I i li. .1. I. - i 1 1 li | -? 1 1 1 1 1 1 1 1 1 II 300 ^ μ Π Γ e s 5 e M 300 30 &amp; O OOO oooo, OOO: \ t

Table V (Compound BCH-6?)

Table VI (Compound BCH-673)

Table VII (Compound BCH-674)? Α Α A 'S3 15 1 A A 1 A τι <τ * τ- A A A mim? A w - - —I mmm A A mm A * SSSSgSSSS 1 1 1 ll .1 II »« 1 ”" -r ^ "- i · r 1 | 1 1 - w z; ??? ; ·; · Mim? in????;??? ?????? 2 2S ·; 3 A - - © n II 1 ... 1. - II O 1 -J | · ““;;;;;;;;; · · · · · · · · Mm mm mm mm cu cu cu cu cu cu cu 'uou 1/1' Qt £ Οι N (--· · · · · · cz cz cz cz cz cz (((((((((((((((((((((((((((((((((((((((X X X X X X X) O III 1-I I <(i <<<ij ij ij ij ij ij ij (1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 · · · · · Itt 1 1 1 ift «: ·· * w *> kb U. d. - ~ · · - * - · UH IQ U - JQU * - í- Π ί H -Η 1 t |, ϊι ŮJ Οι fJ 0 x J 7 O 1 1 | JL 1 ic 1 li 1 1 1 i 1 ai> 1 * 0> Z Σ> ojuuu> Tr3> ti- Ll UZ “* Σ 1 b. * l S S. S S í c i i i i i i IZ IZ IZ IZ IZ IZ IZ IZ IZ IZ IZ IZ IZ IZ cu cu cu cu cu cu cu cu w «« i- z 2 *> w O. 3 4 k 4 k 4 4 a> € 4 k c. Cl dl oX ύ i £

- 162 -

Table I2 (Compound 681)

Table X (Compound .BCH-685) &lt; tb &gt;

Table XI (compound BGH-689)

Table XII (compound

166 Example 17

Tests of Heterantracyclinones by Cloning, In Vitro Tables XIII and XIV summarize the mean values of a50 and LG50 obtained by β 1 i as well as the application of different heteroantracyclinones to cell line groups by cancer type. Original results for these compounds obtained in NCI (Bethesda, Maryland) , USA) are shown in Tables XV to XXII. In this example, the same procedure as BCH-242 in Example 15 was used.

Most noteworthy is that some of the heteroantacyclinones (BCH-651, BCH-657, BCH-660) listed in Tables XIII and XIV exhibit potent antiproliferative (GI ^ q) and potential cytotoxic (LC ^ q) potencies. In the case of BCH-657 and BCH-660, the mean potency of LC ^ q in solid tumors is similar to that observed for DAY and ADR. The same trend observed for the heteroantracyclines of Example 16, when the anti-leukemic activity is suppressed, is repeated for heteroantracyclinones from this example. This aspect may be beneficial in the clinical use of heteroantracyclinones in the chemotherapy of solid formers.

BCH-687, which has no benzylic substituents, has significant antiproliferative (GI-q) and cytotoxic (LC ^ 0) activity on solid tumors. This is unexpected, since the known anthracyclinones lacking benzyl substituents do not normally exhibit anticancer activity. - 167 -

Table XIII $ ·

Mean LOG ^ qGi ^ q BCH cell lines NSC NSC lung SC lung gastric CNS 1 DNM -7.25 + 0.10 -7.04 + 0.25 -7.14 + 0.01 -6.82 + 0 , 51 -7.04 + 0.15 1 ADR -7.51 + 0.52 -7.33 + 9.76 -7.27 + 0.12 -6.61 + 0.55 -7.07 + 0 , 26 L 650 -4.21 + 0.16> -4.00> -4.00> -4.00 -4.34 + 0.15 c · i;} (3R) (1R) + ΐ 651 - 5.48 + 0.06 -5.11 + 0.53 -5.56 + 0.09 -5.47 + 0.12 -5.00 + 0.25 653 -4.80 + 0.40 -4 , 55 + 0.20 -4.54 + 0.06 -4.45 + 0.12 -4.50 + 0.17 (5R) (IR) (IR) ξ 657 -6.56 + 0.06 - 5.95 + 0.56 -5.90 + 0.26 -6.10 + 0.50 -5.73 ± p, 14,658> -4.00> -4.00> -4.00 -4, 21 + 0.10 -4.33 + 0.16 £ («0 W 660 -6.50 + 0.08 -6.01 + 0.55 · -6.00 + 0.28 -6.21 + 0 , 25 -6.02 + 0.24 in (IR) 5,687 -4.91 + 0.12 -4.81 + 0.55 -5.09 + 0.25 -4.95 + 0.28 —4 , 59 + 0.16 j-688 —4.44 + 0.21> -4.00> -4.00> -4.00 -4.27 + 0.14 E2E1

Table XIII (continued) moderate potency x ovarian melanoma renal in DNM solid tumors -6.95 + 0.21 -6.86 + 0.18 -6.79 + 0.47 -6.95 + 0.22 ADR -6 , 92 + 0.26 -6.55 + 0.19 -6.74 + 0.41 -6.95 + 0.29 650> -4.00> -4.00 -4.28 + 0.20 ( 4R) —4.28 + 0.05 651 -5.56 + 0.15 -5.25 + 0.12 -5.00 + 0.27 -5.28 + 0.25 653 -4.48 + 0 , 16 -4.42 + 0.25 -4.24 + 0.22 (3R) -4.40 + 0.10 657 -5.87 + 0.22 -5.77 + 0.22 -5.88 +0.25 -5.89 + 0.11 658> -4.00> -4.00 -4.53 + 0.17 (4R) -4.29 + 0.06 660 -6.02 + 0 28 -6.02 + 0.24 -6.04 + 0.54 -6.05 + 0.57 687 -5.05 + 0.27 -4.94 + 0.57 -4.69 + 0.25 - 4.87 + 0.17 688> -4.00 -4.12 + 0.01 (2R)> -4.00 -4.28 + 0.15

<* ..S - 168 - means the number of cell lines that resist cytotoxic compounds (LOG ^ qGI ^ q is greater than -4.00)

Table XIV

Average LOG ^ qLC ^ q BCH # leukemia and NSG cell lines of SC lung gastric CNS DNM -4,50 + 0,56 -5,07 + 0,57 -5,58 + 0,09 -4,85 + 0 , 57 -5.08 + 0.42 ADR -4.76 + 0.10 -5.01 + 0.26 -5.59 + 0.18 -4.86 + 0.27 -5.05 + 0, 55 650> -4.00> -4.00> -4.00> -4.00> -4.00 651> -4.00 —4.5O + 0.56 (3R) + -4.21+ 0.01 -4.38 + 0.11 (2E) -4.19 + 0.10 655> -4.00> -4.00} —4.00> -4.00> —4.00 657> -4.00 -4.94 + 0.51 (4R)> -4.00 -4.87 + 0.43 (6E) -4.88 + 0.56 (2R) 658> -4.00> - 4.00> -4.00> -4.00> -4.00 660> -4.00 -4.71 + 0.45 (2R) 5 —4.00> -4.00 -4.80+ 0.45 687> -4.00? -4.25 + 0.07> -4.18 -4.25 + 0.09> -4.15 688+> -4.00> -4.00> —4.00> -4.00> - 4.00

Table XIV (continued) BCH median in melanoma c. Ovarian renal solid tumors DNM -5.64 + 0.17 — 4.7 8 + 0.20 -4.78 + 0.46 -5.11 +0.54 ADR -5.56 + 0.29 -4.14 + 0.05 -4.87 + 0.58 -5.07 + 0.28 650> -4.00> -4.00> - 4.00 »-4.00 651 -4.46 + 0.25 -4.55 + 0.04 (IR) -4.26 + 0.10 -4.50 + 0.09 655> -4.00 > -4,00> -4,00 657 -4,88 + 0,29 (4R) -4,76 + 0,59 (IR) -4,92 + 0,49 — 4,88 +0.66 658> -4.00> -4.00> -4.00> -4.00 660 -4.98 + 0.42 (5R) -5.18 + 0.08 (IR) -5 , 10 + 0.40 -4.95 + 0.18 - 169 - 'í í í í í-f' '' '' ',,,::::::::::: - - -

Table XVI (continued) BCH No Ovarian Melanoma Renal Middle Potency in Solid Tumors 68? —4.28 + 0.09 -4.15 + 0.11> -4.21 -4.21 + 0.05 (IR) (2R) 688> -4.00> -4.00> -4, 00 -4.00 + means the number of cell lines, compounds (LOG ^ qLC ^ q is less that resistant to cytotoxicity than -4.00) All the following Tables XV to XXII were compiled in the National Cancer Institute within the Therapy Development Program. The molar units were used in all of these tables. Tests in Tables XV to XXII were carried out from 22. The results were evaluated between 26 November 1992 and 1 March 1991. The table numbers are given by the results of the results in the table, for example the results in Table XV refer to compound number BCH-650.

Table XV (Compound BCH-650) 1 "'‘ t ·' - 170 -

Table XVI (Compound BCH-651)

Tatoilka XVII (Compound BCH-653)

- 173 -

Table XVlli (Compound BCH-6? 8)? 1? 9? 11 1 5,.-11 .. il 1 ni II r-1 CM -J 1 1 * 1 1 II 1 1 "1 2 1 1 Tin 1 I1 Ο ♦ o V» a 8 8 8 T Í 31 31 31? 11131 3 A ΑΛΑ 13 AA 13 311111 AA Λ AAA 11313131 AA 333131 11 33 Λ 33 33 33 33 33 33 33 33 33 33 31 <7 • ib • 1 '| 11 1 1 1 ~ ο J 3 J 3 333 333 1333333 S2 23 333132 33333333 333331 ?? 333333 33133333 §52 ♦ ci c Λ * 1 1 1 lil I ι. ι. 1 · “|| CM CM O 1 I ηρ ^ ι · ι” I | 1 '"ϊ |" ι 1 β S 3 M 3 *? 'Ϊ ’?’? 333 3333333 ι l 33 33 333331 33333333 333333 33 333313 33333331 522 ♦ Cl ♦ Ql I I - U 3 G «- T>>? 2r. ss 5?,? i i Λ Π ď ď;; "? ó τ" τ r K u with 3? 5Sg? □ -í · * «c 3u> ihu> §vjfió *« JEtreS »33 o ~ o o fa 3> i '1: ί -? 2ΐ? Ϊ́Κ2ί? IS ě š έ έ ss h: gss

i '·.' · »ΐ '

B

and; t - 176 -

Table XXII (compound «BCH-688]

Γΐ, .Λ-ς / v ;; Example 18

In vitro efficacy of heteroantracyclinones on cell lines that exhibit multiple drug resistance (MDR)

The anti-cancer activity of the heteroantracyclinones and hetroantracyclines of the present invention was confirmed by a second independent assay. This biological study was conducted at the Department of Obstetrics at McGill University in Montreal, Canada. This study included the use of adriamycin-sensitive cell lines and multi-drug-resistant cell lines. Next, the methodology used for anti-cancer testing is described. Biological results are presented after this protocol.

Search Test

For in vitro testing, we chose a cloning assay for the tumors to measure the ability of tumor cells to form colonies (multicellular growth units) as a result of cell division in semi-solid agar IVan Hoff D. D., ClarkG. M., Stogdill B.J., Sarodosy. F., O'Brien Μ. T., Casper. T., Mattox, D.E., P.P., Crux, A.B, Standbach, J.F.: Prospective clinical trial of human tumor cloning system, Cancer Res. 4, 1926-1931 (1983), Corbett T.H., Vale- riote A, F. Rodent Models in Experimental Chemotherapy, in "Roden Models in Experimental Cancer Therapy", Red. F. Kališ, Pergamon Press, 1987. A more laborious version of the baseline test (colony formation by soft agar colony formation disc diffusion assay) was used. This test defines the relative efficacy of the respective tumor cell line. The effect of the test substance on tumor cells can be measured by inhibiting colony formation upon delivery of the compound at various concentrations to a filter disc [LoRussoP., Wozniak AJ, Polin L., Capp D., Leopold WR, Werbel LM, Biernat L., Dan Μ . Ξ .: "Antituomor efficiacy of PD115934 (NSC 366140) against tumors of mice", Cancer Res., 49: 49 494905 (199O).

- 179 -

Colony Form Assay A modified technique of this assay was used to investigate the antiproliferative efficacy of the compounds tested. Tumor cells from solid tumors and ascitic lines were seeded with an overlayed agar matrix. The cell lines to be tested are suspended in the top layer of 0.4% Noble Agar (Difco # 0.00142-01) in RPMI-1066 (Difco # 3201875) in an amount between 10 and 2.Kr of cells per 60mm Petri bowl. A sowing efficiency is provided for each line in order to achieve optimal platelet count. Prior to administration of the compound, the sowing was checked to confirm uniform dispersion of the individual cells. The lower layer contained 0.8% Noble agar, 0.8% medium (Tryptic Soy Broth Difco No. 37-1) in CMR-1066 / Fische. The lower layers were used between the second and ninth days of the transformation. The plated dishes (agar bottom layer, topsheet layer and applied compound) were incubated in a humidified 5% carbon dioxide atmosphere at 37 ° C, incubation for 10-20 days depending on the time needed for observation. corresponding colonies (defined as cell aggregates consisting of more than 50 cells), both control and inhibited by the compound. The compounds were administered on a paper filter disc (Whatman No. 1) with a diameter of 6.5 mm placed on the upper layer at a distance of 1/3 from the edge of the dish. The anti-clonogenic activity of the compounds was measured as the zone of inhibition from the edge of the disc closer to it, by colony. This zone of inhibition was controlled by an inverted microscope (40x) and measured with a micrometer mounted on an ocular microscope. The eyepiece microscope was calibrated for the appropriate combination of eyepiece and objective lens.

To obtain comparable values, our calibration values are converted to values that are used in other laboratories. 200 units of activity are equivalent to 6.5 mm from the edge of the disc to the first colonies of ICorbett TH, Valeriote FA, Baker LH: " Is the P388 murine tumor nolonger adequate as a drug discovery model &quot; to 20, Martinus Nijhoff Publishers, Boston 1987.1.

• -v, i ·· ’

- 180

Each concentration was repeated three times. The scattering of these types of biological tests was surprisingly small. The original method was modified so that the solid tumor and leukemia were not concurrently drawn to the same Petri dish. Anticlonogenic tests with leukemia cells helped to discover most of the commonly used cytostatic compounds. Our assays for lineage tumors (animal or human) could help to define active compounds with specificity for solid tumors. This specific activity would be indicated by a higher level of cloning inhibition in solid tumors than leukemia. M., jr., Ski.pper. E., Trader M.W., Laster W.R., Jr., Griswold, D.P., Jr., Corbett, T.H.:Extention of Cross-Resistance Profiles for Agents., Cancer Treat. Rep. 57 »905-922 (1933) .3.

The following materials were used in this testing. Five cell lines, 2 rat tumor lines and 5 human tumor lines were used as cell lines (Table I). Animal Tumors: Two Transplantable Solid Tumors, One Reticular Cell Sarcoma, One Tumor Leukemia and ADR Resistant Tumor were passaged in vivo. P388a P388 / ADR Iart I.R., Talmadje, J.E., Eidler, I.J., " Metastatic Behavior of a Murine Reticulum Cell Sarcoma.x-Hibiting Organ Specific Growth. &Quot;, Cancer Res. 41, 1281-1287 (1981) .3, routinely passaged in DSA / 2, M5762Courte-nay V. D .: &quot; A soft agar colony assay for Lewis lung tumor &quot; J. Cancer 34, 39-45 (1976) .3, B16 melanoma. H. D., Vazquez J., Long A., Albert S. and Brennan M .; "A human cellline from a pleural effusion derived from a beast of the carcino", J. Natl. Cancer Inst. 51 »1409-1416 (1973) .3 aLewis. lung carcinoma [Soule HD, Vazquez J., Long A., Albert S. and Brennan 11: "A human cell line from pleuraleffusion derived from breast carcinoma", J. Natl. CancerInst., 51, 1409-1416 (1973) .3, routinely routed in C57B1 / 6, NCI, DCT Tumor Repository, NCI-FCRF, Erederick, People were supplied. MATB WT Rat Breast Cancer and MATB / ADR-181 - obtained from the Mon-Treal General Hospital Cancer Department ( Oncology Department, Montreal General Hospital, in vitro, murine tumors were stored in vivo to reduce the selection of subpopulations of cells normally present in a heterogeneous in vivo tumor. or from ascitic fluid storage in RPMI-1066.

C57BI / 6 and g DBA / 2 g mice (20 + 2 g), obtained from Charles River Labor, Que, were used as mice. These mice were used as tumor recipients. * <

Cells were prepared according to the procedure described by Corbet Schabel F. M., jr, Skipper. E., Trader M.W., LasterW. R., Jr., Griswold, D. P., Jr., Corbett T.H .: " Establishment Cross-resistance Profiles for New Agents "

Rap. §7, 905-922 (I983).]. Tumors were aseptically removed from the host and cut into 200-300 mg fragments in HBSS (Gibco # 3104020). Fragmented tumors were passed through a 0.250 mm mesh screen. The screen was washed twice with cold HBSS. The cell suspension was slightly centrifuged (100-150 x G) for five minutes, resuspended in HBSS and g agglomerated once more. Finally, the cell pellets are suspended in µg in the appropriate volume of medium. Tumors were disrupted by digestion of g with the agent (0.25%) Trypsin-EDTA (Gibco # 6105305) · The viability of all cell lines before the start of the experiments g was greater than 90% with the exception of the LL line and P399 / -ADR, which g showed variable degree of viability between 40 and 60%. §

Human MCF7 tumors (Cohen J.S.) Lyon R.C., Chen C.,

Faustino P.J., Batist G., Shoemaker M., Rubalcaba E., Gowan K.H., &Quot; Differences in phosphate metabolite levels in drug- -sensitive and resistant human breast cancer cell line determined by magnetic resonance spectroscopy &quot;, Cancer

Res. 46, 4087-4090 (1986)], MCF7 / ADRFogh J, Trempe G.i " New human tumor cell line " 5 in "Human Mism. 182 - tumor cells in vitro", pages 115-159, Plenum PublishingCorp., New York 1975. 3 and HT29Tom BH, Rutzky LP, Jakstys R., Oyasu C., Kahan B. D ,: "Human colonic adenocar-cinoma cells. 1. Establishment and description of a new line", In Vitro 12, 180-191, 197θ3 were obtained from NCI, DCT Tu-mor Respirators, NCI-FCRE, Frederick, Md. Tumors L8180Goldin A., Schépartz SA, Venditti JM, DeVita VT, jr .: "Historical Development and Curent Strategists of the National Cancer Institute Drug Development Program", Chapter 5, in "Methods in Cancer Research", Part XVI., Academie - ^ ress1979.3 and BE-1 lAlberts DS, 'Chen HSG:' Tab Summa-ry of pharmacokinetic parameters relevant to IN VITRO drugassay 'in' Cloning of human tumor stem cells *, pages 551 to 559, The Salmon, Progress in Clinical and BilogicalResearch 48, 1980.J were obtained from the Cancer Institute of the All-General Hospital in Montreal. was inoculated in RPMI-1640 supplemented with 10% fetal bovine bovine and 100 units of penicillin with streptornycin (Gibco No. 600 5140). Cell lines were routinely passaged twice weekly by trypsinization and stored in 25 or 75 cm 2 Falcon plastic flasks at 57 ° C in a humidified 5% carbon dioxide atmosphere. The following compounds were used in the assay: Doxorubicin hydrochloride available from a commercial source was used as an internal control. In some lines, the DOX control was used in newly synthesized agents. Our values for DOX as an internal control were consistent with those obtained from references in the literature [Goodman G.: ·: "Modulation of in vitro activity of Adriamycin and Vinblastin by Verapamil" in "Human tumor cloning", red . S. Ξ. Salmon and J.M. Trent, &quot; Proceedings of the Fourth Conference on Human Tumor Cloning, pages 589-3 &quot;

Both compounds were dissolved in dimethylsulfoxide (1 mg in 100 µL). The volume was adjusted to 250 µl with deionized sterile water (Millipor). Milliwater was used for further dilution - 183 - water. 25 µl of freshly prepared solution was applied to the filter disk and allowed to dry. At the same time, a second vehicle control (DMSO / Milliwater) is run. Vehicle control discs were found to provide no inhibition zone. In determining the potency of the compound, these compounds were tested in serial ten-fold dilutions. The results were expressed as units of Zone Units produced by the same mass concentration as LOX. Individual dilutions of both compounds and DOX were stored in sterile Cryovials (Gibco # 566656) at -20 ° C for no more than three days. The results obtained in the tumor cloning assay in which the semi-solid agar was used as the carrier confirm the antitumor activity of the heteroantracyclinones and heteroantracyclines described herein (Tables XXIII and XXIV). In human breast carcinoma line, MCF7 and 'MCF7 / ADR, similar levels of activity were found for both cell lines in BCH-687, BCH-692, BCH-699, BCH-700, BCH-701 and BCH-706, suggesting cross-resistance to adriamycin (Table XXIII).

More remarkably, BCH-684 and BCH-712 were more potent on the adriamycin-resistant cell line, MCF7 / ADR, than on the adriamycin-sensitive line. Similar results were obtained for KATB / WT and MATB / ADR breast cancer cell lines. In this case, BCH-677 »BCH-681, BCK-684, BCH-700, BCH-705 and BCH-702 did not show any cross-adriamycin resistance in MATB. BCH-704, BCH-710, and BCH-711 showed greater cytotoxicity in the resistant breast tumor cell line, MATB / ADR, than in the sensitive line. The results obtained with breast tumor lines indicate that the heteroantracyclinones and heteroantracyclines of this invention exert an advantageous cytotoxic mechanism. A considerable range of efficacy was observed for the compounds described in this example. The most effective were BCH-684, BCH-687, BCH-691, BCH-692, BCH-700, BCH-704, 3CH-706, and BCH-710. BCH-710 shows specificity for MATB / ADR, ADR-resistant rat mammary carcinoma and reticular cell carotid sarcoma. Breast cancer specificity has been demonstrated in .beta.-ΛΛ {- 184 - for BCH-7OO and BCH-7O4 compounds. A well broad spectrum of activity was observed with BCH-684, BCH-691 and BCH-692, with the exception of P588 and P588 / ADP leukemic cell lines, confirming the specificity of these compounds for solid tumors.Human gastric adenocarcinoma HT-29, LS180 and BE1 responded well to BCH-687, i.e., to an analog having no benzyl substituent. This is remarkable because analogous compounds from the anthracycline region are usually not significantly cytotoxic to tumor cells.

The data presented in this example support the results given in Examples 15, 16 and 17. Hetero-anthracyclinones and heteroantracyclines with a heteroatom in the ring, although described above, exhibit a wide range of antitumor activity with specificity for solid tumors . In some cases, cross-resistance with doxorubicin or daunorubicin has not been observed. The fact that cytotoxicity in haematologic malignant tumors is lower than in solid tumors indicates that myelotoxicity should be reduced. This repeating property indicates that the therapeutic index of the compounds of the invention is increased. Thus, the compounds of the present invention could be clinically useful because they have reduced bone marrow toxicity and because they demonstrate efficacy of some resistant tumor cell lines.

185 - Λ ·

Table Σλί-ί.χ

Concentration: 10 / Ug / Art

~ Ι • • • • ~ ~ ~ • • • • • • • • • • • • • Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ Ρ H H H H H H C C 0 f f f f f f f f f f f f f f f f f Η Η Η f f f f f f f φ ks ks ks ks »» »0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Ο Ο ** ο ο ο ο ο ο ο J J J J ί ί ί G G G G G G G ί ί ί ί ί ί W W W W W ) - 186 -

Table XXIV

100 yug / disk xX »o CU» CO CO 4 ø CM xX CO CM A • • «CM - J 44 I 44 O 44 44« 44 44 l 4 «4 1 44 44 44 44 44« «1,, 1 * 1 1 4 1 »b. <« 0 »IA * * x O x * * IA • • • • • • • • • • • • • • • 9 9 9 9 9 9 · 4 4 ▼ 4 4 4 · · · · · · · M M M M M M M M M M M M M M M M tA tA tA tA tA tA tA tA tA • l 1 4 t 4 · 4 4 · 1 ca T— «0 • Ό 9 • fA« 0 Τ Τ 1 1 CM 4 ^ -4 * r 0 0 Τ 4 X “4 Ό CM« CO tA • tA tA CM 1 4 CM 4 Ά 4 CM <44 • O 44 O 44 1 44 O «• 4 4 4 4« 44 44 44 44 • «« * t | 44 4 44 4 44 «44 4 O 44 4 44 4 CO Tn X» xJT * O 1 1 • OO x x O • O 4 o * o x o 4 o 4 • · 1 • «« • b. <M 4 4 o-co r 4 r r r Ά b b b b b b b b b b b 3 3 3 3 3 3 3 CM CM CM CM - í 1 t CM CM * “1 4 4 • · + + ♦“ 4 ”'+ ♦ + + ♦ * 4 · tA • <0A O t CM« • tA «0 OO CM I • t <« <O 4 CM ♦ Ό x x T CM CM CM CM CM CM CM CM CM CM CM CM CM o o o o o o o o o o o o o o o o o CM CM X ** 4 * 4 * 4 * 4 * 4 * - 1 * 1 * 1 CM 4 CM 4AA 4 CM 4 o 44 «44 O 44 44 1 1 44 4 1 1 4 44 44 44 44 44 1 1 I 9 44 4 44 4 44 44 4 44 ♦ 4 4 44 1 ia A X X X X 1 X co co co co co O O £ £ £ £ £ £ 4 R * CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CO x x tA tA tA 4 4 4 4 4 4 TA IA r • tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA »• O 4 O 4 w- O 4 CM 4 o 4 •« <«0« what O «0 • what CM« «OA O 4" CM <O • O · o 4 Ό 4 CM IA 4 4 ø in * tA CM 4- «4 IA · 4« 4 co 44 «44 O 44 44 * 44 44 4 1« 1 44 44 44 44 44 1 · t »(t 44 4 41 1 44 41 4 OO 4 44 4 OJ tn • COA O • O IA 1 • Ό O tA A O O 4 O O O tA tA O O O 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 | O O 1 1 X 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 tA tA tA tA tA ř ř ř ř ř ř ř A 4 x Ό 4 «0 4 • • *“ T ”1 • t -« •! • · + + + + + - ~ + + ““ “♦ MM 4 · + (• CM OO • coA 1 1 O o Ό co 1 4 O 4 CM · tA 4 CM O 4 CM 4 • χΧ o «CO O 9 to O xf> tA 4 O 4 - - • x ř o - - 4 o o • AA« t CO A «« «1 2 3 4 5« «1« 44 44 44 44 «I« «1 1 44 4 44 4 44 44 4 * 4 44 4 +4 4 * OOO tA * tA tA tA tA tA tA tA tA OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO OOO ((((((((((((x x x TA 1 · tA tA b b b b b b b b b b b b b b b b b b 1 1 1 1 1 1 CM CM CM CM CM CM CM CM CM CM CM CM CM CM T—, * • »CM • * - Τ Τ T T + + + + tA + + + - - - - - - - - - - - - O O O O O 4 CM 4 CM 4 • 44 I 44 ♦A <xX l O <CM 4 4 Ό 4 4- —4—4CO '* —4 · A'A 4A4O4COA1 1 «--Ο CO CO CO CO CO CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM 44 O 44 1 O · 44 44 44 44 4 • ΌAA4« CM ÍM tn «» « CD I, 4 ►- Ό CM «« bx WHAT CM CMI <AAI iiAA x bx 1 £ • '4 4 4 IAAxT bxØA 1 • «• 1 <- <· * · (f CM tbt 4 T - CM CM I, 4 4 ♦ 4 44 44 • O · 44 44 1 tu b - ca • • «<« «Ό I« «O b tA ·« CM CM · · · · · bx <what «CM Ό« • · 4 4 4 4 tA tA '' '' '' '' '' - - - - - - - - - - - - - - - what CM i CM 'tA 4 4 44 44 44 l 44 i 44 4 «44 4 CA CM IA A» bx t O x X -j 1 «1 4 Ό A CO« x «O b- CO 4 b tA A IA» mS · b- X xX 1 1 + + 4 4 Í O 4 O O 4 4 4 4 4 4 4 4 CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM O O O | x O 4 4 4 4 4 4 4 4 £ £ £ £ £ £ £ £ £ tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA CM 9 4 o Χ xX 4 A. x xf 1 4 Å • * x. • O «1 b. 44 44« 4 1 4 44 44 44 44 • u. Ie O 1 1 CO O • X »- A 4 4 O o ΜΪ O« A on A «4 o A CM CM 4 «1A IA 4 Ό IA * * * Ό • • • • • • • • • • • • • • • • • • • • • • CM 4 CM 4 4 4 44 44 44 44 44 44 TA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA tA IA IA IA IA IA IA IA «O bx bx <0« O NQ Ό 4 X5 4 Ό Ό O Ό * XXX 4 X «XXXX 4J O • O« ooo o 1 co co to, to · co co CD «44 I 44« 44 «» cm tm tm b ι ι ι ι ι Λ Λ 1 1 1 T T T T T T T T T T T T T T T T << - i 4 i 44 »44 i 44 i <M <bx 4 xX ι l · o · O * <- · i« CM »xX« CM <.- + - + - + - » · a · i »i« 4 · «« 44 4 41 t 44 t "CO« l st CO * K | 4 »« · 9 »4 · i» n i Ό i n · • b- - · -

• * »* O cm« κι «i cj

V- »'xX

44 * 44 I O (a) Zone units; 200 units of activity represents a 6.5mm clear zone from the edge of the disc b) The above dashes indicate that the compounds have not been tested on these cell lines

Claims (101)

- 187 - Τ Λ Τ. J) υ υ É Ν R R R Υ A compound of the eyebrow pattern wherein X 1 and X 2 are independently selected from the group consisting of oxygen, sulfur, C = N (R), wherein R is selected from the group consisting of hydrogen, alkyl of one to sixteen carbon atoms, one to sixteen carbon alkyl groups, and one to sixteen carbon alkylamino groups, X 1 is oxygen, sulfur, SO, SO 2, HO, or NR, wherein R is one to sixteen amino groups carbon atoms, alkyl groups of from one to sixteen carbon atoms, aryl groups of from one to sixteen carbon atoms, a haloyl group of from one to sixteen carbon atoms, or a hydrogen atom, Rp, R2, R6, R6, R6 and Rq represent a group which is snugly selected from the group consisting of hydrogen, hydroxyl, alkyl of one to sixteen carbon, alkoxy of one and sixteen carbon atoms, cycloalkyl groups having three to eight carbon atoms, tosyl groups, triflate groups, trifluoroacetate groups, halogen atoms, nitro groups, cyano groups, acyl groups of one to sixteen carbon atoms, arylacyl groups of one to sixteen carbon atoms, aminoalkylaminoalkoyl groups of the general formula JNH (CH 2) n NH (CH 2) m OH, wherein at m independently represent from 1 to 4, amino-alkylaminoalkyl halogens of the general formula NH (CH 2) n ·, NH (CH n) X, v which each independently represent an integer from 1 to 4, and X is a halogen atom, an amino group, - 188 - which may be unsubstituted or may carry one or two substituents which may be an alkyl group of one to eight carbon atoms, a cycloalkyl group of three to eight atoms carbon, arylalkyl, trifluorooyl, ar-alkyl or aryl; carbon atoms or one to eight carbon atoms alkynyl, haloalkylnitrosoureide of general formula NH (C0) N (NO) (CH2) nCH2X, wherein n is zero to four and X is halogen, thiol and the group of formula -OO (R) s = O, wherein R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, an alkoxyalkyl group, an aralkyl group, an araloxyalkyl group, an aryloxyalkyl group or an aryl group, R 8 is a hydrogen atom, a C1-C16 alkyl group, a three-carbon cycloalkyl group, an acyl group of the formula -C (R) s, or its dioxolane or dioxane ketal, wherein R is hydrogen, an alkyl group of one to sixteen carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an araloxyalkyl group, and a cyloxyalkyl group, an amino group which is either unsubstituted or is mono- or di-substituted by an alkyl group of one to eight carbon atoms, a cycloalkyl group of three to eight carbon atoms, an acyl group, a trifluoroacyl group, an aralkyl or an aryl group, a naturally occurring an amino acid such as alanine, arginine, cysteine, glycine, leuoine, lysine, methionine and the like, or a synthetic amine acid, R 8 can also be a group of the formula -G (R) (O-C 1 -C 5 alkyl) 2, wherein R is as defined above, -C (OR) = O, wherein R is hydrogen, alkyl of one to sixteen carbon atoms, cycloalkyl of three to eight carbon, hydroxyalkyl, alkoxyalkyl,. an aryloxyalkyl group, an araloxyalkyl group, an aryl group and an aralkyl group, a group of the general formula - 189 - CHGCCOR11 wherein R represents a hydrogen atom, a C1 -C16 alkyl group, a cycloalkyl group having three to eight carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an aryloxyalkyl group, an araloxyalkyl group, an aryl group, an aralkyl group, an amino group which is not substituted or is mono- or di-substituted by an alkyl group having one to eight carbon atoms, an cycloalkyl group having three to eight carbon atoms, an aloyl group R 4 is hydrogen, alkyl of one to sixteen carbon atoms, halogen, amine, hydroxyl, alkoxy of one to sixteen carbon atoms, thiol, aralkyl or aryl; a cyano group, a sulfide group, an acyl group the formula -C (R) = O, in which R represents a hydrogen atom, a C1 -C16 alkyl group, a three to eight carbon cycloalkyl group, a hydroxyalkyl group, an araloxyalkyl group, an alkoxyalkyl group, an aoyloxyalkyl group, an amino group which is not substituted or is mono- or di-substituted with an alkyl group of one to eight carbon atoms, a cycloalkyl group with three to eight carbon atoms, an acyl group, a trifluoroyl group, an aralkyl group or an aryl group, a naturally occurring amino acid, for example alanine, arginine, cysteine, glycine, leuoine, lysine, methionine and the like, or a synthetic amino acid group of the formula -G (OR) = O, wherein R is hydrogen, alkyl of one to sixteen, and carbon atoms, a cycloalkyl group having three to eight carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an aryloxyalkyl group, an araloxyalkyl group n, aryl, aralkyl and alkenyl of one to sixteen carbon atoms, Y and Ry are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy of one to sixteen, and carbon atoms, C 1 -C 16 alkyl groups, C 2 -C 16 acetylenyl groups, C 3 -C 8 cycloalkyl groups, C 2 -C 6 alkenyl groups, cyano groups, -OC (R) = O groups wherein R is an alkyl group of one to sixteen carbon atoms, a hydrogen atom, a cycloalkyl group having three to eight carbon atoms, an alkoxyalkyl group, and an aryl group, an alkyl group having the formula - C (R) = O, wherein R is a hydrogen atom thiol, thioalkyl of one to sixteen carbon atoms, an alkyl group of one to six-n carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a hydroxyalkyl group, an alkoxyalkyl group, an araloxyalkyl group, an acyloxyalkyl group, an amino group which is either unsubstituted or substituted by one or two substituents; the above or a synthetic amino acid, a group of the formula -O (OR) = O, wherein R represents a hydrogen atom, a C1-C16 alkyl group and a cycloalkyl group having three to eight carbon atoms, mono or oligosoharides usually present in other anthracyclines, e.g. one or two sugars selected from the group consisting of rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose-A, amicetose, aculose, redness, rhodinose and 2-deoxyfucose, asaccharide of formula 12R10. wherein - 191 - R 8 and R 10q independently represent a group selected from the group consisting of an atom for hydrogen, halogen, hydroxyl, ethoxy, alkoxy with one to sixth carbon atoms, alkyl groups with one to sixteen carbon atoms, cycloalkyl groups with three to five carbon atoms and thiol groups, R1, 1 represents an amino group which is not a substitution or is mono- or di-substituted with an alkyl group of from one to eight carbon atoms, an cycloalkyl group of from three to eight carbon atoms, an aryl group, a trifluoroacyl group, an aralkyl group, or an aryl group, a natural amino acid such as alanine, arginine, cysteine, glycine, leuoine, lysine, methionine and the like, a synthetic amino acid, a mono or dibenzylated amine group, an acylated amino group, a trifluoroylated amine group, a morpholino group, a cyano substituted morpholino group, a mono-, di-, tri- or tetra-methoxy * substituted morpholino a moiety, a mono-, di-, tri-, or terra-ethoxy group of subst morpholino group, hydroxyl group, hydrogen atom, halogen atom, ethoxy group, one to sixteen carbon alkoxy group, three to eight carbon cycloalkyl group, thiol group, sulfide group, NHCCH8 group of general formula CHCO10g in which R is an alkyl group of one to sixteen carbon atoms, an acyl group of one to sixteen carbon atoms, or an aroyl group having seven to sixteen carbon atoms, and n is a number from zero to five or chloroalkylnitrosoureide of the general formula N 1 CO 2 CNOXCHg 2 CHCl 3 wherein n is a number from zero to four, Rj2 is a hydrogen atom, a hydroxyl group or its, tetrahydropyranyl ether ζ-OTHP), a halogen atom, mono- or di-saccharides usually present in other antraoyclines, such as those listed above for the R,, amino group a pin, a mono- or di-alkylamino group, wherein each alkyl group is a group one to sixteen carbon atoms, a alkoxy group of one to sixteen carbon atoms, a cycloalkyl group of three to eight carbon atoms, a benzoate which is either unsubstituted or substituted by a nitro group, for example p-nitrobenzoate, the ethoxy group, the trifluoroacetoxy group and the chloroalkyl nitrosoureido group mentioned above for R j, including their isomers and mixtures including diastereoisomeric mixtures and racemic mixtures, tautomeric forms, pharmaceutically acceptable salts and chelated metal complexes. 2. A compound according to claim 1, wherein X1 and X2 are each independently selected from the group consisting of oxygen, sulfur, and NH, X1 is O, S, SO, X2. -NO 2, NH 4 and NO, R 1, R 8, R 8, R 8, R 8, R 8 and R 8 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy with one the four carbon atoms, the tosyl groups, the triflate groups, the fluorine atom, the chlorine atom, the aminoalkylaminoalcohol group of the formula NH (CH 2) n NH (CH 2) m OH, where n is one to three independently of one another, aminoalkylaminoalkyl chloride groups of the formula NH (CH 2) n NH (OH 2) m i wherein each independently represents numbers from one to three, the amino group, the chloroalkylnitrosoureide group of the general formula NH (CO) N (NO) (CH 2) n CH201, wherein n is the number from n to four and group of the formula -OG (R) = O, wherein R is hydrogen, alkyl of one to six carbon atoms and aryl, Rg is alkyl of one to four carbon atoms, hydrogen, acyl of-C (R) = O, wherein R is hydrogen, alkyl of one to eight carbon atoms, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl and amine, which is either unsubstituted or mono- or di-substituted by an alkyl group of one to eight atoms R 195 further represents a group of the formula -G (OR) = O, in which R is an atom of the formula C, 195 uhlíku,,,,,,,,, is an alkyl group having one to eight carbon atoms, an aryl group, an aralkyl group, or a group of the general formula -GH 2 G (OR) = O, wherein R is a group selected from the group consisting of from a hydrogen atom, a straight or branched chain alkyl group having one to eight U-atom atoms and an amino group which is either unsubstituted or is mono- or di-substituted with an alkyl group having from one to five carbon atoms, a cycloalkyl group having three to eight atoms carbon, aroyl, trifluoroacyl, aralkyl or aryl, R8 represents a hydrogen atom, a fluorine atom, an amino group, an alkoxy group having one to four carbon atoms, a sulfide group, an acyl group having the formula -C (R) = O, wherein R represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, a hydroxyalkyl group, an acyloxy alkyl group, an amino group or a cyano group, a group of the general formula -C (OR) = O, wherein R is a hydrogen atom, an alkyl group of one to eight carbon atoms, an aryl group, an alkenyl group of one to eight carbon atoms, ΐ and Ry independently represent a group such as It is selected from the group consisting of a halogen atom, a hydrogen atom, a hydroxyl group, an alkoxy group of one to eight carbon atoms, an alkylene group of two to eight carbon atoms, an alkenyl group of two to eight. carbon atoms, cyano groups of the formula -OC (R) = O, wherein R is hydrogen or alkyl of one to five carbon atoms, acyl groups of the formula -C (R) = O, wherein R is hydrogen, a thiol group, a C 1 -C 8 alkyl group, a hydroxyalkyl group or an amino group, a group of the formula -G (OR) = O, wherein R is hydrogen, alkyl of one to eight carbon atoms, or a carbohydrate of formula -K 1W 1. t-U-i S- * - 194 wherein R g and R jq independently represent a group selected from the group consisting of hydrogen, fluoro, chloro and hydroxyl, R 6 represents an amino group which is either unsubstituted or mono- or di-substituted an alkyl group of from one to eight carbon atoms, a cycloalkyl group of from three to eight carbon atoms, an aloyl group, a trifluoroyl group, an aralkyl group or an aryl group, a morpholino group, a cyano substituted roorolinium group, a mono-, di-, tri- or a tetra-methoxy-substituted morpholino, hydroxyl, mono- or di-alkylated amine group having from 1 to 16 carbon atoms, an alkoxy group having from one to eight carbon atoms, a group represented by the general formula NIKCHg = C 1 -COR 4 wherein R is an alkyl group with one up to eight carbon atoms, an acyl group of one to eight carbon atoms or an aroyl group of seven to twelve atoms at and n is an integer of one to five, a fluorosoureido moiety of the formula: wherein NH is a number from zero to four, or a fluorine atom, and R ^ 2 is a hydroxyl group or a tetrahydropyranyl ether thereof, a halogen atom, a mono- or oligosaoharide customary in other anthracyclines, for example one or more sugars such as rhodosamine, cinerulose-B, L-cinnamose, D-cinerulose, oinerulose A, amicetose, aoulose, rednose, rhodinose, 2-deoxyfucose, daunosarain and trifluoroethyldaunosine, amine, mono- or dimethylamine, one to eight carbon alkoxy, benzoate, p-nitrobobenzoate, acetoxy and trifluoroacetoxy, - 195 - and racemic including isomers and mixtures thereof including diastereoisomeric mixtures , tautomeric forms and pharmaceutically acceptable metal chelate complexes. 5. A compound according to claim 1, wherein X1 and X8 are independently selected from the group consisting of oxygen and NH, X1 is O, S, SO, NH, or NO; R 5 and R 8 not referring to 3 ° βθ are a group selected from the group consisting of hydrogen, hydroxyl, methoxy, aminoethylaminoethanol, aminoethylaminoethylene chloride, chloroalkylnitrosoureido of the formula NH (CO) N (NO). • (CH 2) n CH 2 Cl, wherein n is a number from zero to two, amino and fluoro, βθ is a one to four carbon atom, an acyl group of -O (R) = O wherein R. represents a methyl group, a hydroxymethyl group, an acyl * -oxymethyl group and an amine group, a group of the general formula -O (OR) t = O, wherein R represents a hydrogen atom, a methyl group or an ethyl group, a group of the formula -CHgCOR4O, wherein R represents a hydrogen atom, a methyl group or an ethyl group, R * represents a hydrogen atom, a fluorine atom, an amino group, a methoxy group, an acyl group of the formula - C (R) = O, in which R represents a hydrogen atom, an alkyl group of one to five carbon atoms, hydroxyalkyl, amine or cyano, -GCOR) = O, wherein R is hydrogen, alkyl of one to five carbon atoms, aryl, or alkenyl of one to one; four carbon atoms, Ϊ and R? independently represent a group selected from the group consisting of hydrogen, halo, hydroxyl, methoxy, cyano, acetate, and ethyl and saccharide of the formula - 196 - O in which 10 R. 9 12 selected from the group consisting of hydrogen and fluoro R @ 4 represents an amino group, a dimethylamino group, a trifluoroacetamide group, a morpholino group, a cyano substituted morpholino group, a mono-, di-, tri-, or methoxy methoxy substituted morpholino group; the formula NHCCH8) CHCOR6 wherein R is a C1 -C4 alkyl group, a C1 -C4 alkyl group or a seven or eight carbon atom group and a number of from two to five, a chloroalkyl nitrosoureido group. where n is a zero number to four, and a hydroxyl group and R 2 is a hydroxyl group or a tetrahydropyran ether, benzoate, p-nitrobenzoate, amine or fluorine atom thereof, including isomers and mixtures thereof, including diastereomeric mixtures and racemic mixtures, tautomeric forms, and pharmaceuticals acceptable salts and chelate complexes with metals. 4. The compound of clause 1, wherein the NH or NO, R 4, R 2, R 2, R 4, R 4, R 4 and R 8 independently of one another are selected from the group consisting of hydrogen, hydroxyl, amine and aminoethylaminoethanol Rg is methyl, ethyl, acyl, -C (R) = O, or trimethylene-197-ketal, wherein R is methyl, hydroxymethyl, acetoxymethyl, or amine; (OR) = O, wherein R is a hydrogen atom or a methyl group, or a group of the formula -CH 2 C (OR) = O, wherein R is hydrogen or methyl, R 8 is hydrogen, fluoro, amine, cyano or -C (OR) = O, wherein R is one to four carbon, Y and Br are independently selected from the group consisting of hydrogen, hydroxy group, bromine, chlorine, cyano, the acetate, acetyl and a saccharide of the formula 7 x is fluorine, R 1 is amino, dimethylamino, trifluoroacetamide, morpholino, cyano substituted morpholino, mono-, di-, tri- or tetra-methoxy substituted morpholino, NH (CH 2) CH (OR) 2 in which R represents a methyl group, an acyl group or a benzoyl group and n represents a number from three to five, or a chloroalkylnitrosoureido group of the general formula NH (CO) N (NO) (CH 2) n · 0Η201 where n is a number from zero to four, and R ^ 2 is hydroxyl, benzoate or p-nitrobenzoate, including isomers and mixtures thereof, including diastereomeric mixtures and racemic mixtures, tautomeric forms and pharmaceutically acceptable salts and chelate compounds. metal complexes. - 198 - 5. The compound of clause 1 which is (1ZS, 1R, 3S) or (1ZS, 1S, 3R) methyl ester [11-hydroxy-1- (2z, 3z, 6z-trideoxy-3z-trifluoroacetamido-L-lyxohexopyranoso) -5,12-dioxo-3,4, 12% tetrahydroanthraceno [2,3-c] pyran-3-yl] formic acid. 6. The compound of item 1 which is ethyl ester of 11-acetoxy-5.12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-formic acid. 7. The compound of item 1 which is (1S, 3S) ethyl ester or (1R, 3R) 11-ac ethoxy-1-hydroxy-5,12-dioxo-3,4,5,12-tetrahydro-anthracene [2, 3-C3-pyran-3-yl-formic acid. 8. The compound of item 1 which is ethyl ester (1SS, 1R, 3S) or (1ZS, 1S, 3R) [11-acetoxy-1- (2 ', 3 *, 6' - trideoxy-3z-tri-fluoracetamido) -4-O-O-p-nitrobenzoyl-L-lyxohexopyranoso) -5,12-dioxo-3,4,5,12-tetrahydroanthracene (2,3-c pyran-3-yl-13-formic acid. 9> Compound according to item 1, which is the methyl ester (L'S, 1R, 3S) or (1ZS, 1S, 3R) 16-acetoxy-1- (2 ', 3 ", 6z-trideoxy-3Z-trifluoro-acamide) Β-p-nitrobenzoyl-L-lyxohexopyranosole-5,12-dioxo-3,4,5,12-tetrahydro-dacanetraceno [2,3-c] pyran-3-yl-13-formic acid. 10. The compound of item 1, which is [6-hydroxy-5.12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-13-formic acid methyl ester. 11. The compound of item 1, which is N-hydroxy-5.12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl-3-formic acid methyl ester. 12. The compound of item 1 which is 6-acetoxy-5.12-dioxo-3,4,5,12-te trahydroanthracene-2,3-c 3 pyran-3-yl-13-formic acid methyl ester. - 199 - i ;; 13. The compound of item 1 which is methyl ester of 11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-formic acid. 14. The compound according to item 1, which is (1S, 3S) or (1R, 3R) 16-acetoxy-1-hydroxy-5,12-dioxo-3,4,5,12-tetrahydro-dicrazole methyl ester [2,3 -3-pyran-3-yl-formic acid. 15 · The compound of item 1 which is ethyl-1,1-hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthracene (2,3-c of 3-ranan-3-yl-formate). 16. The compound according to claim 1, which is H-hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl] formic acid ethyl ester. 17. The compound of claim 1 which is 16-acetoxy-5,12-dioxo-3, 4,5,12-tetrahydroanthracene-12,3-c pyran-3-yl-formic acid ethyl ester. 18. The compound of item 1 which is (1S, 3S) or (1R, 3R) 16-acetoxy-1-hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-cpyran] ethyl ester -3-yl-formic acid. 19. The compound of claim 1 which is (5,12-dihydroxy-6,11-dioxo-3,4,6,11-tetrahydroanthraceno [2,3-c-pyran-3-yl] formate ethyl ester). 20. The compound of item 1 which is ethyl ester (1S, 1R, 3S) or (1'S, 1S, 3R) 16-acetoxy-1- (2z, 3z, 6z-trideoxy-3z-tri-fluoroacetamido-4 '). -Op-nitrobenzoyl-L-lyxohexopyranoso) -5,12-dioxo-3, 4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl formic acid. 21. The compound of claim 1 which is 6-acetoxy-11-hydroxy-5,12-dioxo-3,4,5,12-tetrahydroanthracene-1,2,3-cpyran-3-yl formic acid ethyl ester. t? t! h • 200 - 22. The compound of item 1 which is (6-hydroxy-11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c3-pyran-3-yl] formic acid ethyl ester. according to claim 1, which is [6,11-Diacethoxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] 3-pyran-3-yl-formic acid ethyl ester. 24. The compound according to item 1, which is (1S, 3S) or (1R, 3R) -l-acetoxy-1,6-dihydroxy-5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-d] ethyl ester, tert -butylamino-formic acid. 25. The compound of item 1 which is ethyl ester (1SS, 1S, 3R) or (1ZS, 1B, 3S) [11-acetoxy-6-hydroxy-1- (2z, 3z, 6z-tri-deoxy-3z-trifluoroacetamido) -4'-O-p-Nitrobenzyl-L-lyxohexopyranoso) -5,12-dioxo-3,4,5,12-tetrahydroanthanoic acid-2,3,3-pyran-3-ylformamide. 26. The compound of item 1 which is ethyl ester (1'S, 1R, 3S) or (1ZS, 1S, 3R) 11-hydroxy-1- (2z, 3z-6z-trideoxy-3-tri-fluoro acetamido-L-lyxohexopyranoso) ) -5,12-Dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl-formic acid. 27. The compound of item 1 which is ethyl ester (1S, 1R, 3S) or (1Z, 1S, 3R) 6-methoxy-11-hydroxy-1- (2Z, 3Z, 6Z-tri-oxy-3). trifluoroacetamido-L-lyxohexopyranoso) -5,12-di-oxo-3 &lt; 4,5 &gt; 28. The compound of item 1 which is ethyl ester (1SS, 1R, 3S) or (1'S, 1S, 3R) [11-methoxy-6-hydroxy-1- (2z, 3z-6z-tri-deoxy-3z-trifluoroacetamido) -L-lyxohexopyranosyl-5,12-di-oxo-3, 4,5,12-tetrafluorophthalic acid-2,3-c] pyran-3-yl 13-formamide. 29. The compound of item 1 which is ethyl ester (1S, 1R, 3S) or (1S, 1S, 3R) 16-hydroxy-1- (2z, 3z-6z-trideoxy-3z-tri-201-fluoracetamido) -L-lyxohexopyranoso) -5? -Dioxo-3? 4? 5,12-tetrahydroanthracene-2,3-c] pyran-3-yl] formic acid. 3θ · The compound of item 1, which is methyl ester (1ZS, 1R, 5S) or (1 * S, 1S, 3R) 16-hydroxy-1- (2 *, 3Z, 6Z-trideoxy-3 * -tri-fluoroacetamido) -L-lyxohexopyranoso) -5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl] formic acid. 31. The compound of item 1 which is 5112-dioxo-3,4,5,12-tetrahydro-naphthalene-2,3,3-pyran-3-yl formic acid p-nitrobenzyl ester. 32. The compound of item 1, which is the (1S, 3S) p-nitrobenzyl ester or (1R, 3R) 11-hydroxy-5,12-dioxo-3,4,5,12-tehydrohydroanthracene-2,3-cpyran-3 -yl formic acid. 33. The compound of item 1 which is p-nitrobenzyl ester (1ZS, 1R, 3S) or (1ZS, 1S, 3R) &amp;-( 2 ', 3 ', 6 ' -trideoxy-3 ' -trifluoroacetamido-4 &apos; - O-p-nitrobenzoyl-1,1-lyxohexopyranosulfo-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl] formic acid. 34. The compound of item 1 which is the methyl ester (1ZS, 1R, 3S) or (1ZS, 1S, 3R) 11- (2 ', 3 *, 6'-trideoxy-3'-trifluoroaceta-mido-L-lyxohexopyranoso) -5,12-dioxo-3,4,5,12-tetrahydro-anthraceno [2,3-c] pyran-3-yl formic acid. 35 · The compound of item 1, which is the methyl ester (1S, 1S, 3S) or (1ZS, 1R, 3R) tl- (2z, 3 *, θ, "- f-oxyxy-3'-trifluoroacetam-do-L-ly) xohexopy ranoso) -5,12-dioxo-3,4,5,12-tetrahydro-traceno [2,3-c] pyran-3-yl] formic acid. 36. The compound of item 1 which is cis p-nitrobenzyl ester t (1R, 3R) or <1S, 3S) (5,12-dioxo-1-methyl-3,4,5,12-tetrahydroanthracene [2, 3-c] pyran-3-yl formic acid 3. The compound of item 1, which is used to convert the p-nitrobenzyl ester (1S, 3R) or (1R, 3S) -202- (5112-dioxo-1-methyl-5, 4,5,12-tetrahydroanthracene-2,5-c 3-pyran-5-yl-formic acid. 58. The compound of item 1 which is the cis p-nitrobenzyl ester (1R, 5R) or (1S, 5S) (5,12-dioxo-7,10-dimethoxy-1-methyl-5H-4, 5,12- tetrafluoride of the 2,5-cpyridin-3-yl 3 formic acid. 59. The compound of item 1 which is trans p-nitrobenzyl ester (1S, 5R) or (1R, 5S) (5,12-dioxo-7,10-dimethoxy-1-methyl-5,4,5 12-tetrahydroanthracene-2,5-cpyran-5-yl) formic acid. 40. The compound of item 1 which is methyl (11-hydroxy-5.12-dioxo-5,4,5,12-tetrahydroanthracene-12,5-cpyran-5-yl) -ketone. 41. The compound of (1) which is methyl (6-hydroxy-5.12-dioxo-5,4,5,12-tetrahydro-naphthalene-2,5,5-pyran-5-yl) -ketone. 42. The compound of item 1 which is methyl 16,11-diacethoxy-5,12-dioxo-5,4,5,12-tetrahydro-anthraceno [2,5-c] pyran-5-yl] ketone. 45. The compound of item 1 which is methyl (6-hydroxy-11-ac ethoxy-5,12-di oxo-5,4,5,12-tetrahydroanthecene-2,5-c-3-pyran-5-yl) ) -ketone. 44. The compound of item 1, which is methyl- (11-hydroxy-6-acetyloxy-5,12-dioxo-5,4,5,12-tert-butoxide-2,5-3-pyrazole). -5 ~ y 3) -ke to n. 45. The compound of item 1 which is (1S, 5S) or (1R, 5R) methyl-E1-acetoxy-1,6-dihydro-5,12-di oxo-5,4,5,12-tetrahydroanthracene 12,5-pyran-5-yl-3-ketone. - 203 - 46. The compound of clause 1, which is (1ZS, 1S, 3R) or (1ZS, 1R, 3S) methyl-1 H -acetoxy-6-hydroxy-1- (2z, 3z, 6z-trideoxy-3z-trifluoroacetamido). 4z-O-p-nitrobenzyl-L-xohexopyranoso) -5,12-di oxo-3,4,5,12-tert-butadiene-2-ene-2,3-pyran-3-yl-3- ketone. 47. The compound of clause 1 which is (1ZS, 1S, 3R) or (1ZS, IR, 3S) methyl-1-acethoxy-6-hydroxy-1- (2 of 3, 6Z-trideoxy-3z) -L-trifluoroacetamido-L-lyxohexopyranose) - 5112-dioxo-3, 4,5,12-tetrahydroanthreno [2,3-c] pyran-3-yl-3-ketone. 48. The compound of item 1 which is 3- (2-methoxymethoxy) -aceto-6-hydroxy-1,2,3,7-tetrahydro-d-2-oxa-naphthacene-5,12-dione. 49. The compound of item 1 which is 3- (2-methoxymethoxy) aceto-11-hydroxy-1,2,3,4-tetrahydro- (2-oxa) naphthacene-5,12-dione. 50. The compound of clause 1 which is 3- (2-methoxymethoxy) -aceto-6-acetoxy-1,2,3,4-tetrahydro- (2-oxa-naphthacene-5,12-dione). 3- (3- (2-Methoxymethoxy) aceto-11-acetoxy-1,2,3,4-tetrahydro- (2-oxa) naphthacene-5,12-dione, compound according to claim 1). 52. 3- (2-Hydroxy-1-propylene-ketal) and ethoxy-6-acetoxy-1,2,3,44-tetrahydro- (2-oxa) naphtha-5,12; -dion. 3- (3- (2-Hydroxy-1-propylene-ketal) -aceto-11-acetoxy-1,2,3,4-tetrahydro- (2-oxa) -naphthalene-5,12; -dion. 54. The compound of clause 1 which is 3- (2-acetoxy-1-propyloxy) 7. PZ111: </ r: - 204-lenketal) aceto-6-acetoxy-1,2,3 4-tetrahydro- (2-oxa) naphthalene-5-12-diene. 3- (3- (2-Acetoxy-1-propylene-ketal) -aceto-11-acetoxy-1,2,3,4-tetrahydro- (2-oxa) -naphthalene-5); 12-dion. 56. The compound of (1) which is (1R, 3R) or (1S, 3S) -3- (2-acetoxy-1-propylene ketal) aceto-6-acetoxy-1-hydroxy-1,2,3,4- et al. (2-oxa) naphthalene-5,12-dione. 57 · The compound of item 1, which is (1R, 3R) or (1S, 3S) -3- (2-acetoxy-1-propylene ketal) aceto-11-acetoxy-1-hydroxy-1,2,3,4- tetrahydro- (2-oxa) naphthacen-5,12-dione. 3- (3- (2-Hydroxy) aceto-6-hydroxy-1,2,3,4-tetrahydro- (2-oxa) naphthacene-5,12-dione, 58. The compound of claim 1. 3- (3- (2-Hydroxy) aceto-11-hydroxy-1,2,3,4-tetrahydro- (2-oxa) naphthacene-5,12-dione, 59. The compound of claim 1. 60. The compound of clause 1, which is 6,11-diacetoxy-3- (2-methoxythio) acetyl, 2,3,4-tetrahydro- (2-oxa) -phenol. , 12-dion. 61. The compound of (1) which is (1R, 3R) or (1S, 3S) -3- (2-hydroxy) aceto-6-acetoxy-1-hydroxy-1,2,3, tert-tetrahydro (2- oxa) to phenylene-5,12-dione. 62. The compound of clause 1 which is (1R, 3R) or (1S, 3S) -3- (2-hydroxy) acetyl-11-acetoxy-1-hydroxy-1,2,3,4-te tra-dro- (2-oxa) naphthacen-5,12-dione · 63. The compound of item 1 which is 3-carbomethoxy-6-hydroxy-1,2,3,4-tetrahydro- (2-thia) -tacacen-5,12-dione. 64. The compound of claim 1 which is 3-carbomethoxy-11-hydroxy-1,2,3,4-tetrahydro- (2-thia) naphthacene-5,12-dione. - 205 - 65. The compound of claim 1, which is 5-carbomethoxy-6-acylpyridine-1,2,5,4-tetrahydro- (2-thia) naphthalene-5,12-dione. 66. The compound of claim 1, which is 5-cyanomethoxy-11-acetoxy-1,2,5,4-tetrahydro- (2-tartaryl) -propion-5-dione. 67. The compound of clause 1 which is (1S, 5S) or (1R, 5R) -methyl- (1-methoxy-6-1-hydroxy-5,12-dioxo-5,4,5β-tetrahydro-danoanate) [2,5-C3-pyran-5-yl] -ketone. 68. The compound of clause 1 which is (1S, 5S) or (1R, 5R) -methyl- (1-methoxy-7-11-hydroxy-5,12-dioxo-5,4,5,12-tetra-halo). droantraceno 1,2,5-pyran-5-yl) ketone. 69. The compound of clause 1 which is (1S, 5S) or (1R, 5R) -me thy- (1,6-dihydroxy-5,12-dioxo-5,4,5,12-tetrahedrone) oa ntraceno [2,5-c] pyran-5-yl) ketone. 70. The compound of item 1 which is (1S, 5S) or (1R, 5R) -methyl- (1,11-dih ydroxy-5,12-dioxo-5,4,5,12-tetra; ydroane) -tra-ene-2,5-c pyran-5-yl) ketone · 1 / 71. The compound of (1S, 5S) or (1R, 5E) -6-hydroxy-1-methoxy-1,2,5,4-tetrahydro-5-vinyl- (2-oxa) ) -naphthalene-5,12-dioh. 72. The compound according to item 1, which is (1S, 5S) or (1R, 5R) - 6-acetyl-1-methoxy-1,2,5,4-tetrahydro-5-vinyl (2-oxa) ) -naphthalene-5,12-dione. 75 · The compound according to 1, which is (1S, 5S) or (1R, 5R) -6-acetoxy-1-hydroxy-1,2,5,4-tetrahydro-5-ynyl- (2-oxa) -naphthalene-5,12-dione. 74. The compound according to item 1, which is (1S, 5S) or (1R, 5R) -methyl, 1,11-dihydroxy-5,12-dioxo-5,4,5,12-tetrahydro-anthracene [2,5- pyran-5-yl-formic acid. - 75 - 75 (1S, 3S) or (1R, 3R), 1,6-dihydroxy-5,12-dioxo-3,4,5,12-tetrahydroantra, 12,3- pyran-3-yl formic acids. 76. The compound of item 1, which is 5,12-dimethoxy-3-carboxylic acid-1,2,3,4-tetrahydro- (2-thia) naphthacene-6,11-dione. 77. The compound of claim 1 which is 5,12-dihydroxy-3-carboxylic thoxy-1,2,3,4-tetrahydro- (2-thia) naphthalene-6,11-dione. 78. (7-Chloro-5,8-dioxo-3,8-dihydroisochroman-3-yl) formic acid ethyl ester. 79. (5,8-Dioxo-5,8-dihydroisochroman-3-yl) formic acid methyl ester. 80. (5,8-dioxo-5,8-dihydroisochroman-3-yl) formic acid p-nitrobenzyl ester, (5,8-dioxo-1-methyl-5,8-dihydroiso-chroman- cis) cis p-nitrobenzyl ester 3-yl) formic acid. 82. (5,8-Dioxo-1-methyl-5, 5-dihydro-isochroman-3-yl) formic acid trans p-nitrobenzyl ester. 83. Methyl (5,8-dioxo-5,8-dihydroisochroman-3-yl) formic acid. 84. 5,8-Dimethoxy-34-methoxymethoxy) acetoisochroman. 85 · 3- (Methoxymethoxy) aeto-5,8-dioxoisochroman. 86. 3-Carbmethoxy-5,8-dimethoxyisothiochroman. 87 3-Carbmethoxy-5,8-dioxoisothiochroman. 88. Methyl (1,5,8-trimethoxyisochroman-3-yl) ketone dimethyl ketal. - 207 - 89. Methyl (1-methoxy-5,8-dioxo-5,8-dihydroisochroman "3" 5'l) - ketone. ?: f. · v £ íj. 90. Methyl (5,8-dimethoxy-1-hydroxyisochroman-3-yl) ketone. v • 4 91. Methyl 1-hydroxy-5,8-dioxo-5,8-dihydroisochroman-3-3'-ketone. 92. 1-Methoxy-3 'Vinyl-isochroman-5,8-dione. S 93 «Methyl ester of (5,8-dimethoxy-1-hydroxyisochroman-3-yl) nitric acid. . g eats 94. (1,5,8-Trimethoxyisochroman-3-yl) methyl ester and the like. £ seliny. § 95 (1-Methoxy-5,8-dioxo-5,8-dihydroisochroman-3-yl) formic acid methyl ester. J 96. 1-Hydroxy-5,8-dioxo-3-methyl-5,8-dihydroisochroman. and 97. 1,4-Dihydroxy-3-hydroxymethyl-5,8-dioxo-5,8-dihydroisochromate. : £ 98. (1-Hydroxy-5,8-dioxo-5,8-dihydroisochroman-3-7) formic acid methyl ester. 99. 5,8-Dimethoxyisochroman-3-3'-1-formic acid. 101. 1-Hydroxy-3- (ethan-1-one (trimethylenebecyl) -5,8-dioxo-5,8-dihydroisochroman). 102. A compound of formula - 208 - R @ 1, R @ 2, (xii), R @ 1, R @ 2, O in which R @ 1 to R @ 8 are as defined in 1, 10,. (XII) wherein R 1 to R 8 are as defined in item 1, 104 ·. Compound of Formula XXIV (XXIV) wherein R 1 to R 6 and R 8 to R 8 are as defined in IO5. The compound of formula XXVR, R? point 1 (XXV), R 4, R 5, wherein R 1 to R Q are as defined in point 1. 106. A compound of formula XXVIIRi ° H ° r, (XXVII), R <Rj o £ - 209 - í k ”where R ^ to R? means as set forth in point 1. 107 'Compound of formula XLIII 108 (XLIII) wherein R 1 to R 6, R 8 is a compound of the general formula and R 8; are as defined in formula XLIV 1. wherein R 1 to R 6, R 8 and R 8; as indicated in point 1. IO9. Compound of Formula XLIV ✓ks. S'Rf R 0, 0 * 7, p-R, OOH (XLIV), wherein R 1 and R 2, R 6, R 6 and R 6 are R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6 and R 6. as indicated in point 1 above. 110. A compound of Formula XLV 210-111. Compound of Formula XLVI (XLVI), 112, wherein R5 to R6, R8 and R6 are as defined in 1. The compound of formula XLVII 6 (XLVII), 113, wherein R 1 to R 6, R 8 and R 8; are as defined in point 1, a compound of formula XLVIII Re (XLVIII), 114 wherein R 1 to R 6, R 8 and R 8; are as defined in point 1. Compound of formula IL (IL), wherein R 1 to R 4, R 1, R 2 ', R 2', R 2 ', R 2', R 2 ', R 2', R 2 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ', R 5', R 5 ''. and R5 to R6 g are as defined in point 1. 115. Compound of Formula (Ii) - 211 - wherein R 1 to R 6, R 8, R 8; and R5 to R6 are as defined in point 1, or a teutomer thereof. referred to in point 1, or a tautomer thereof. 117. A compound of formula XXXIX 118. A compound of Formula XL 119. Compound of formula LIV - 212 - (UV) wherein R 1 to R 6, R 8, R 8 and R 8; as indicated in point 1, or a tautomer thereof. wherein R 1 to R 6, R 8 to R 8 and Y are as defined in point 1 (LX), wherein R 1 to R 8 and Y are as defined in item 1, 122, Compound of Formula LXVII (X), (LXVII) wherein R 1 to R 6, R 8 to R 8 and X 11 are as defined in point 1. 12J. Compound of Formula LXVIII - 215-124. (LXVTII), wherein up to R 8 and X 6 are as defined in point 1. Compound of formula XII (XII), 125, wherein R 1 to R 8 and X 1 are as defined in point 1. Compound of formula X 126. Compound of Formula LXXII (X) in point 1, or a tautomer thereof. 127. Compound of formula XI - 214 - in point 1, or a tautomer thereof. means as shown (128), 128. A compound of formula XCI wherein R 1 to R 4, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6; and X1 represents both the aforementioned point 1, Pg represents a protecting group and L represents a leaving group. 129. A compound of formula XCII R 4 O OP 8 wherein R 4 to R 6, R 8, R 8; and X1 is as defined in 1, Pg is a protecting group and L is a leaving group. Compound of Formula XCIII 130 in which R 1, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 6 and X1 is as defined in 1 and Pg is a protecting group. - 215 - 151. Compound of Formula XCIV 132 wherein R 1 in R 1, R 1, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8; Pg represents a protecting group. and refer to the compound of formula XCV in point 1 and Pg represents a protecting group. Compound of Formula XCVI wherein R 1 to R 4, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6, R 6; and X1 represents both 1 and Pg represents a protecting group. I34. Compound of Formula XVII (XVII) wherein R 7 is as defined in point 1. •• tf / Α ·. -Ί · .Ί · Ά-. 'χ> <·> Al - 216 - (XVIII), 1. 135 · Compound of formula XVIII in which R? means as stated in point 136. A compound of Formula XX OCH in which Εθ and R? 137 · Compound of general formula XXI (XX), point 1. Re in which Rg and R? mean as stated \ t 138. A compound of formula XXII R 6 (xxi), item 1. in which Rg and R? are as m 139 · Compound of general formula XXVI 0 «7 (XXII), point 1. .0 (XXVI), o - 217-140 in which Rg and R? are as defined in 1. The compound of formula XXIX (XXIX), 141. wherein R8 and R8 are as defined in 1 and R5 is a protecting group. Formula XXX (XXX), 142 wherein Rg, Rg and R? is as defined in 1 and R5 is a protecting group. Compound of formula XXXII (XXXII), 143 in which Rg, Rg and R? are as defined in 1. The compound of formula XXXIII (XXXIII), in which Rg, θ R means as stated in point 1. - 218 - 144. A compound of Formula LVIII (LVIII) in which Εθ, Βθ and B? means as specified in point 1, 145. A compound of formula XXXIV (XXXIV) 146. A compound of formula XXXV (XXXV) in which Εθ, Εθ and R? is as defined in (1) and (E) is a protecting group. 147. A compound of Formula LIX (LIX) in which Εθ, Εθ, R? and Y is as defined in section 1, 148. Compound of formula XXXVI SS8BSS ΗβΗΗΒΒΒΗΒ 149. 150. 151. 152. - 219 - Compound of formula XXXVII (XXXVII), in which Βθ, Βθ and B? are as defined in point 1. Compound of formula XLI (XLI) wherein B 1 to B 4 are as defined in point 1. A compound of formula XXXVIII Rsor Rg (XXXVIII) wherein B 1 to B 4 and B 1 or Bg are as defined in point 1. The compound of formula LXIV (LXIV), - 220-153 in which Rg, R? and X1 are as defined in 1. The compound of formula LXV (LXV), 154. wherein Rg, Rg, R? and X 1 are as defined in 1. The compound of formula LXVI (LXVI), 155 where Rg, Rg, R? and X 1 are as defined in 1. The compound of formula LXIX (LXIX), 156. wherein R8, R8, R and X1 are as defined in item 1, a compound of formula LXX MeO OMe (LXX) wherein Rg, Rg, R? and X ^ is as defined in item 1, 157. A compound of formula LXXVII - 221 - och3 OH O A / I OEt LA (iraii), och3 wherein R 1 and X 1 are as defined in section 1. 158. A compound of Formula LXXVIII Compound of Formula LXXIX and X 3 is as defined in 1. wherein R g 160. A compound of Formula LXXXEII (LXXXIII) in which Rg, Rg, R? and X1 represents as shown in v1 and Pg represents a protecting group. point 161. Compound of Formula LXXXIV 222 - (Lxxnv) in which R &amp;, βθ, R? and X ^ is as defined in item 1, (LXXXV) in which βθ, βθ, R? and X 1 are as defined in 1, 16, and the compound of formula LXXXVI (LXXXVI) wherein Ηθ, βθ, R,, X ^ and X are as defined in 1, 164. The compound of formula LXXXVII 165. A pharmaceutical composition having antitumor and anti-cancer activity comprising an effective amount of at least one compound according to item 1 and a pharmaceutically acceptable carrier. - 223 - 166. A pharmaceutical composition having antitumor or anti-cancer activity comprising an effective amount of at least one compound of item 2 and a pharmaceutically acceptable carrier 167. A pharmaceutical composition having antitumor or anti-cancer activity comprising an effective amount of at least one compound of item 3 and a pharmaceutically acceptable carrier 168. A pharmaceutical composition having an antitumor or anti-cancer activity comprising an effective amount of at least one compound according to clause 4 and a pharmaceutically acceptable carrier 169. The pharmaceutical composition of any one of items 165 to 168, wherein the composition comprises an effective amount of at least one therapeutic agent. 17. The pharmaceutical composition of any one of items 165 to 168, wherein said compound is coupled to an agent that facilitates targeting of said compound to tumor or cancer cells. 171. The pharmaceutical composition of item 169, wherein said agent is selected from the group consisting of monoclonal antibodies, polyclonal antibodies, proteins and liposomes. 172. A pharmaceutical composition having anti-tumor or anti-cancer activity comprising an effective amount of at least one compound according to any one of items 102 to 164 and a pharmaceutically acceptable carrier. 173. The pharmaceutical composition of item 172 further comprising an effective amount of at least one therapeutic agent. 174, The pharmaceutical composition of item 172, wherein said compound is coupled to an agent that facilitates targeting of said compound to tumor or cancer cells. 175. The pharmaceutical composition of item 172, wherein said agent is selected from the group consisting of monoclonal antibodies, polyclonal antibodies, proteins and liposomes. 176. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of at least one compound of item 1 to a mammal in need thereof. 177. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of at least one compound of item 2 to a mammal in need thereof. 178. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of at least one compound of item 3 to a mammal in need thereof. 179. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of at least one compound of item 4 to a mammal in need thereof. 180. A method of treating cancer or a tumor, characterized in that the method comprises the step of providing a therapeutically effective amount of a composition comprising an effective amount of at least one compound according to 1 and a pharmaceutically acceptable carrier to a mammal in need thereof. 181. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of a composition comprising an effective amount of at least one compound of item 2 and a pharmaceutically acceptable carrier in need thereof. 182. A method of treating cancer or a tumor comprising administering a therapeutically effective amount of a composition comprising an effective amount of at least one compound according to clause 5 and a pharmaceutically acceptable carrier therefor. healing needs. 183. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of a composition comprising an effective amount of at least one compound of clause 4 and a pharmaceutically acceptable carrier in need thereof. 184. A method of treating cancer or a tumor comprising the step of administering a therapeutically effective amount of a compound of any one of items 102 to 164 to a mammal in need thereof. O 1; '• 4! . · < 185. A method of treating a bacterial, fungal, or viral condition in a patient in need of such treatment comprising the step of administering to said patient an effective amount of at least one compound of item 1. - 226 - 186. A method of treating a bacterial, fungal, or viral host in a patient in need of such treatment comprising the step of administering to said patient an effective amount of the composition of item 165, 187. A method of treating a bacterial, fungal, or viral host in a patient in need thereof, said method comprising the step of administering to said patient an effective amount of at least one compound of any one of items 102 to 164. 188. A method of treating a bacterial, fungal, or viral host in a patient in need thereof, said method comprising the step of administering to said patient an effective amount of a composition comprising a compound of any one of items 102 to 164. wherein R @ 1 to R @ 10, X @ 2, X @ 2 and X @ 1 are as defined in 1 above, and X is a saccharide as set forth in claim 1, characterized in that it comprises the step of reacting a compound of formula XII (XII), ΒβΒΒ - 22? wherein R 1 to X, X 1, X 2 and X 2 are as defined above, with a compound of formula XIII: (XIII) wherein R 1 to R 6 are as defined above and L is a substitutable atom or a substitutable group. ISO. Process for preparing a compound of formula (XII) íí h ·! wherein R 1 to R 8 are as defined in 1 and X 1, X 2 and X 2 are oxygen atoms, characterized in that the process comprises the following steps: reacting a lithium salt of an acetal of formula XV (XV) with an epoxide of formula XXXIO VRe (XXXI) optionally in the presence of a Lewis acid to form OCH, (XXXII) i cyclization of compound 3 of general formula XXXIIza to form compound of formula XXXIII - 228 - (XXXIII), by oxidizing a compound of formula XXXIII to form a compound of formula XXXIV converting a compound of formula XXXIV into compounds of formula XXXIX and XL by reaction with a compound of formula XXIII (XXIII) and converting compounds of formula XXXIX and XL into a compound of formula XII. 191. A process according to claim 190 wherein said compound of formula (XXXII) is obtained by reacting a compound of formula (XV) above with a compound of formula (XXVIIIo) R 1 O (XXVIII) wherein R 6 is a protecting group and R 8 and R 8 are each as set forth in point 1, the compound of general formula XXIX is formed the compound of formula XXIX is reacted with a compound of formula R 1 CH 2 X wherein X is a halogen atom and R 1 is as defined in section 1 to give a compound of formula XXX 3 v 3 in * (XXX), followed by deprotection of the compound of formula XXX to give said compound of formula XXXII. 192. The method of claim 190, wherein a compound of formula (XXIII) is used in place of the compound of formula (XXIII) 193. The process of claim 19 wherein the compound of formula (XXXIII) is oxidized to a compound of formula (XXXIV) to form a compound of formula (XXXVI). it is then reacted to a compound of formula XXXVII and this compound of formula (XXXVII) is reacted with a compound of formula (XXXVIII - 2 $ 0) (XXXVIII) to compounds of the general formulas. XXXIX and XL. (XHEV) in which R5 to R6, E8, Sg and Rr are as defined in claim 1, characterized in that they contain a reaction of a compound of formula XXXIV as indicated in I90 with o-quinodimethane obtained by a thermolous compound of formula XLI 195. Method (XLI). of formula XI wherein R 1 to R 6, R 8, R 8 and R 8; as defined in claim 1, characterized in that it comprises the following steps: reacting a compound of general formula - 231 - of formula XXXIV (XXXIV), referred to in point 190, with a compound of formula III (III) in which R5 to R6 are as defined in 1, with UF irradiation to give a mixture of tautomeric compounds of the general formulas Lili and UVR7 196. OH (HII) OH (UV) and glycosidation of said mixture of tautomeric compounds of the general formulas L11 and UV to form a compound of formula XI. A process for preparing a compound of formula (X) wherein R 1 to R 2, X 2 and Y are as defined in claim 1, comprising the following steps: reacting an intermediate of formula LXI (LXI), OCH, L - 2 ^ 2 - in which L is an identifiable group, a substitutable atom or a substituent of the formula LXIIH OEl (EXII) in the presence of base to adduct of formula LXIII OEl (LXIII), cyclization of a compound of formula (LXIII) in the presence of a base to form an intermediate of formula (LXIV) Η3R, O0Et yc V (LXIV), OCH, converting a compound of formula (LXIV); (LXV), oxidizing a compound of Formula LXV to a compound of Formula LXVI converting a compound of formula LXVI into a compound of formula LXVII by reaction with a compound of formula XXIII (XXIII) Converting a compound of formula LXVII into a compound of formula LXVIII (LXVIII), µ; oxidizing a compound of formula LXVIII to a compound of formula XII (XII) and converting a compound of formula (XII) to a compound of formula (X). dul, featuring! in that it comprises the following steps: - electrochemical reduction of the compound of general formula LXV (LXV) in the presence of the base of the compound of formula LXIX MeO OMe-234 - partial hydrolysis of the compound of formula LXIX under acidic conditions to the compound of formula LXX (LXX), the converseinin of general formula LXXI of a compound of formula LXX to form a compound of formula LXEI by reaction with a compound of general formula i wherein Z is an acceptor group, and converting a compound of formula LXXII to a compound of formula XI. 198. Method (LXV), formula LXV f, wherein θθ, Εθ and E ε denoting the degrees: lithium reaction are as defined in 1 above, comprising the following salts of acetal of formula XV (XV) with formaldehyde, adduct of formula LXXIII - 235 - conversion of the compound of general formula LXXIV of formula LXXIII to (LXXIV) wherein L is a substitutable atom or a substitutable group by reacting a compound of formula LXXIV with a compound of formula LXII (LXII) in the presence of a base of formula LXXV EtO X 3 H to form an adduct hydrolyzing the compound of formula LXXV under gentle conditions to a benzaldehyde of formula LXXVL O OEt (LXXVI) Cyclizing a compound of formula LXXVI under basic conditions to a compound of formula LXXVII (LXXVII) 199. and converting a compound of formula (LXXVTI) to a compound of formula (LXV): A process for the preparation of a compound of formula (LXV) according to claim 198, comprising the steps of: reacting a compound of formula (LXI) wherein L is a substitutable atom or group, in the presence of a base with a compound of formula LXXX (LXXX), X 3 Pg wherein Εθ and / or Εθ is preferably an electron withdrawing moiety and Pg is a protecting group to form an α-product of formula LXXXI of Formula LXXXI to give a compound of Formula LXXXII (LXXXII) and cyclization of a compound of formula LXXXII by Zabazic conditions to a compound of formula LXV. - 257 - 200. A process for preparing a compound of Formula X characterized in that the method comprises the steps of: oxidizing a compound of formula LXXXI (LXXXI), 17% in which Pg represents a protecting group of formula LXXXIII a compound of the general formula deprotecting the compound of general formula LXXXIII and cyclizing it under basic conditions of the product of general formula LXXXIV (LXXXIV), oxidizing a compound of formula (LXXXIV) to a compound of formula (LXXXV); I - 238 - (LXXXV), converting a compound of formula LXXXV to a compound of formula XII by reaction with a compound of formula XXIII (XXIII) and converting a compound of formula XII to a compound of formula X. 201. The method of Claim 200 wherein said compound of Formula X is obtained by converting a compound of Formula LXXXIV to a compound of Formula LXXXVI (LXXXVI), by oxidation of a compound of formula LXXVI to obtain a compound of formula LXXXVII (LXXXVII) and a compound of formula LXXXVII is reacted with a compound of formula XXIII (XXIII). - 239 - 202. A method for preparing a compound of Formula XI wherein Y is as defined in claim 1, wherein the process comprises the following steps as well as protecting a compound of formula (LXXXVIII) (LXXXVIII) to give a compound of Formula LXXXIX wherein Pg represents a protecting group, converting a compound of formula LXXXIX to a compound of formula XC 1 'o OP8 I7 Γ Ti LX (xc), O OPa L wherein L is a substitutable atom or a substitutable group, reacting a compound of formula XG is a compound of formula LXII (LXII) 240 - under basic conditions to a compound of formula XCII cyclizing a compound of formula XCII to a compound of formula XCIII (XCIII), converting a compound of formula XCIII to a compound of formula XCIV oxidizing a compound of formula XCIV to a compound of formula XCV 1 'O OPg R7 Rs R- * 3 xA (XCV) O OPg OH and converting a compound of formula XCV to a compound of formula XI. 203. The process of claim 202 wherein said compound of formula (XI) is obtained by reacting a compound of formula (XC) with a compound of formula (LXXX * 3PS (LXXX), Rf A '- 241 - wherein Rg and / or Rg is an electron withdrawing agent. to form an adduct of formula XCI which is cyclized to a compound of formula XCIII and then converted to a compound of formula XI. 204. The process of claim 203, wherein said compound of formula (XI) is obtained by oxidizing said compound of formula (XCI) to a compound of formula (XCVI) .beta. the protecting group is removed and the compound of formula XCVI is cyclized to the compound of formula XCV to convert the compound of formula XI. 205. Method wherein R5 to R6, R8, R8 to R8 and Y are as defined in claim 1, comprising the steps of: reacting 2,5-dimethoxybenzoic acid with oxalic acid chloride in the presence of a base and then diethyl-242-2. amine to give the benzamide of formula LVa reacting the compound of formula LVa with a strong base in a solvent to give the lithium salt, which is then reacted with an electrophilic reagent of the formula L-CH 2 R 2 in which R 6 is reacted with a base. means as set forth in point 191 and L represents a substitutable atom or group to form a benzoderivative of formula LVb reacting the benzoderivative of formula (LVb) with an electrophile of formula (LVI) LVI (LVI) wherein R 8 and R 8 are as defined above, in the presence of a soluble base in a solvent to form the general formula LVU adduct (LVII) in which Rg, Rg and R? as used hereinbefore, cyclize the adduct of formula LXVII in the presence of an acid to the isochromanone of formula LVIII-243 wherein R8, R8 and R are as defined above, reducing a compound of formula LVIII with a hydride to a hydroxyisochroman of formula XXXIII wherein Βθ, Eg, and as above, oxidative demethylation of a compound of formula XXXIII with ammonium nitrate to isochromandione wherein θθ, R &amp; and R? are as defined above, or condensation of a compound of formula XXXIV with a homophthalic anhydride of formula XXIII wherein R 1 to R 6 are as hereinbefore defined, in the presence of a strong base in the solvent for the tetracyclic of general formula XL 244 - (XL) wherein R 1 to R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 6 and R 8 are as defined above converting a compound of formula XL to a tetra-cyclic intermediate of formula XII wherein R 1 to R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8, R 8; and R 8 are as defined above, and the conversion of the intermediate of formula XII to the compound of formula X (X) wherein R 1 to R 8, R 8, R 8, R 8 and Y are as defined above, by means of the interconversion of the hydroxyl group of the formula XII to the Y group, which is as defined above. 14. The method of claim 205, wherein the compound of formula XXXIV OH 206-245 - in which Εθ, Εθ and E? are as above converted to isochromandione of formula LIX (LIX) in which Εθ, Εθ, E? and Y is as defined above, by transforming the hydroxyl group of the compound of formula XXXIV into one of the groups Y as described above, the compound of formula LIX is reacted with a homophthalic anhydride of formula XXIII (XXIII), wherein E 4 to E 4 and E 4 are as indicated, in the presence of a stable base, to obtain the tetracyclic derivative of the general formula LX (LX), wherein E ^ to E, E, E, E to Eg and Y are as indicated, and the compound of formula LX is converted to a compound of formula X by known methods. Represents: