Morpholinyl anthracycline derivatives

Abstract

The present invention relates to new morpholinyl anthracycline derivatives which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

Claims

1. A compound of formula (I) ##STR00089## wherein: R1 is halogen or NR4R5; R2 is an optionally substituted group selected from straight or branched C.sub.2-C.sub.6 alkyl, NR7R8-C.sub.2-C.sub.6 alkyl, R6O—C.sub.2-C.sub.6 alkyl and COR9; R3 is hydrogen or a straight or branched C.sub.1-C.sub.4alkoxy; R4 and R5 are independently hydrogen, a monosubstituted-benzyl, a disubstituted-benzyl, or an optionally substituted group selected from straight or branched C.sub.1-C.sub.6 alkyl, NR7R8-C.sub.1-C.sub.6 alkyl, R6O—C.sub.1-C.sub.6 alkyl, R7R8N—C.sub.1-C.sub.6 alkylcarbonyl, R6O—C.sub.1-C.sub.6 alkylcarbonyl, R7R8N—C.sub.1-C.sub.6 alkylaminocarbonyl, R6O—C.sub.1-C.sub.6 alkylaminocarbonyl, R7R8N—C.sub.1-C.sub.6 alkylsulphonyl, R6O—C.sub.1-C.sub.6 alkylsulphonyl, R7R8N—C.sub.1-C.sub.6alkoxycarbonyl and R6O—C.sub.1-C.sub.6 alkoxycarbonyl; or R4 and R5, taken together with the N atom to which they are bound, form a heterocyclyl substituted with R4; R6, R7 and R8 are independently hydrogen or an optionally substituted straight or branched C.sub.1-C.sub.6 alkyl; R9 is OR6, NR7R8 or an optionally substituted group selected from straight or branched C.sub.1-C.sub.4 alkyl, NR7R8-C.sub.1-C.sub.4 alkyl and R6O—C.sub.1-C.sub.4 alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia) or (Ib), according to claim 1, ##STR00090## wherein R1 is fluorine or NR4R5, wherein one of R4 or R5 is hydrogen and the other is hydrogen or an optionally substituted group selected from straight or branched C.sub.1-C.sub.6 alkyl, NR7R8-C.sub.1-C.sub.6 alkyl, R6O—C.sub.1-C.sub.6 alkyl, R7R8N—C.sub.1-C.sub.6 alkylcarbonyl, R6O—C.sub.1-C.sub.6 alkylcarbonyl, R7R8N—C.sub.1-C.sub.6 alkylaminocarbonyl, R6O—C.sub.1-C.sub.6 alkylaminocarbonyl, R7R8N—C.sub.1-C.sub.6 alkoxycarbonyl and R6O—C.sub.1-C.sub.6 alkoxycarbonyl.

3. The compound of formula (Ia), according to claim 2, wherein R2 is COR9.

4. The compound of formula (Ia), according to claim 2, which is selected from the group consisting of: (8S,10S)-8-acetyl-1-fluoro-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-1-fluoro-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-1-amino-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-8-acetyl-1-amino-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-8-acetyl-6,8,11-trihydroxy-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, (8S,10S)-8-acetyl-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, and (8S,10S)-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier or diluent.

6. A pharmaceutical composition according to claim 5, further comprising one or more chemotherapeutic agents.

7. A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

8. A method for treating cancer, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I), as defined in claim 1.

9. The method of claim 8, wherein the mammal in need thereof is a human.

10. The method of claim 8, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gall-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin carcinoma, squamous cell carcinoma, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma and mesothelioma.

11. A process for the preparation of a compound of formula (I) as defined in claim 1, which comprises: first, reacting the compound of formula (VII) ##STR00091## wherein R3 and R10 are as defined in claim 1 and R9 is OR6 or NR7R8, wherein R6, R7 and R8 are as defined in claim 1, or the compound of formula (VIII) ##STR00092## wherein R3 and R10 are as defined in claim 1, or the compound of formula (III) ##STR00093## wherein R3 and R10 are as defined in claim 1, or the compound of formula (IX) ##STR00094## wherein R3 and R10 are as defined in claim 1, and R12 is group selected from straight or branched C.sub.1-C.sub.4 alkyl, NR7R8-C.sub.1-C.sub.4 alkyl and R60-C.sub.1-C.sub.4 alkyl, or the compound of formula (X) ##STR00095## wherein R3, R10 and R12 are as defined in claim 1, or the compound of formula (XI) or (XIa) ##STR00096## wherein R3, R6, R7, R8 and R10 are as defined in claim 1, or the compound of formula (XII) or (XIIa) ##STR00097## wherein R3, R6, R7, R8 and R10 are as defined in claim 1, or the compound of formula (V) ##STR00098## wherein R3 and R10 are as defined in claim 1, or the compound of formula (XIII) ##STR00099## wherein R3 and R10 are as defined in claim 1, with DMDO; then, treating the resultant compound of formula (XX) ##STR00100## wherein R3, R10 and R2 are as defined in claim 1, with cyanuric chloride or with an iron (II) salt, and finally, if desired removing the protecting group/s to obtain a compound of formula (I) as defined in claim 1, optionally converting a first compound of formula (I) into a second compound of formula (I) by known chemical reactions; and/or, if desired, converting such a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into a free compound of formula (I).

Description

EXAMPLES

(1) The synthetic preparation of some compounds of formula (I) of the invention is described in the following examples. The compounds of the present invention, as prepared according to the following examples, were also characterized by .sup.1H-NMR and/or by Exact mass data ESI(+).

(2) .sup.1H-NMR spectra were recorded at a constant temperature of 28° C. on a Varian INOVA 400 spectrometer operating at 400.50 MHz and equipped with a 5 mm z-axis PFG Indirect Detection Probe (.sup.1H{.sup.15N-.sup.31P}).

(3) Chemical shifts were referenced with respect to the residual solvent signals (DMSO-d.sub.6: 2.50 ppm for .sup.1H, where not otherwise specified). Data are reported as follows: chemical shift (δ), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br. s.=broad singlet, td=triplet of doublets, dd=doublet of doublets, ddd=doublet of doublets of doublets, m=multiplet, spt=septet), coupling constants (J, Hz), and number of protons.

(4) Exact mass data ESI(+) were obtained on a Waters Q-Tof Ultima mass spectrometer directly connected with a Agilent 1100 micro-HPLC system as previously described (M. Colombo, F. Riccardi-Sirtori, V. Rizzo, Rapid Commun. Mass Spectrom. 2004, 18, 511-517).

(5) The examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings.

(6) TABLE-US-00002 ABBREVIATIONS DCC N,N′-dicyclohexylcarbodiimide DCM dichloromethane DIPEA N,N-diisopropylethylamine DMDO dimethyldioxirane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDCI N-ethyl-N′,N′-diisopropylcarbodiimide hydrochloride EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et.sub.2O diethyl ether EtOAc ethyl acetate EtOH ethanol HCl hydrochloric acid HOBt 1H-benzotriazol-1-ol MeOH methanol Na.sub.2SO.sub.4 sodium sulfate NaHCO.sub.3 sodium hydrogen carbonate NaOH sodium hydroxide PPTS pyridinium p-toluenesulfonate TEA triethylamine TFA trifluoro acetic acid THF tetrahydrofurane

Example 1

Step A1, Step B3 (according to A6a and A6b)

(8S,10S)-8-acetyl-1-fluoro-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 1) [R1=F, R2=CH3CO—, R3=CH3O—]

(7) ##STR00052##

Step A1

(1S,3S)-3-acetyl-10-fluoro-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-lyxo-hexopyranoside [(III)]

(8) ##STR00053##

(9) (1S,3S)-3-acetyl-10-fluoro-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside (70.0 mg, 0.136 mmol) [prepared as reported in WO90/09392] was dissolved in dry DMF (3 mL); a solution of diiso-propylethylamine (106 mg, 0.82 mmol) in dry DMF (2 mL) and a solution of (1S)-2-iodo-1-(2-iodoethoxy)-1-methoxyethane (IIa) (965 mg, 2.71 mmol) in dry DMF (10 ml) were added. The reaction mixture was stirred at room temperature in the dark for 48 hours, until no starting material was detectable (HPLC analysis). The reaction mixture was then diluted with DCM and washed with water. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, the solvent was evaporated under vacuum and the residue was purified by flash chromatography (eluant: EtOH/DCM; 0.2/9.8) on silica gel (230-400 mesh) affording the desired product (35 mg, red wax).

(10) ESI MS: m/z 616 (MH.sup.+)

(11) .sup.1H NMR (500 MHz, CHCl.sub.3-d) δ ppm 1.39 (d, J=6.71 Hz, 3H) 1.78-1.85 (m, 2H) 2.09-2.14 (m, 1H) 2.46-2.56 (m, 3H) 2.61 (dd, J=11.41, 3.97 Hz, 1H) 3.03 (d, J=19.04 Hz, 1H) 3.27 (dd, J=19.10, 1.77 Hz, 1H) 3.40 (s, 3H) 3.57 (ddd, J=11.57, 5.34, 3.11 Hz, 1H) 3.70 (s, 1H) 3.92-3.99 (m, 1H) 4.04 (q, J=6.47 Hz, 1H) 4.48-4.52 (m, 1H) 4.67 (s, 1H) 5.28-5.30 (m, 1H) 5.56 (br. s., 1H) 7.54 (dd, J=10.44, 8.48 Hz, 1H) 7.83 (td, J=7.97, 4.58 Hz, 1H) 8.25 (d, J=7.69 Hz, 1H) 13.31 (s, 1H) 13.72 (s, 1H)

(12) By analogous procedure the following compound is prepared:

(1S,3S)-10-fluoro-3,5,12-trihydroxy-3-(hydroxyacetyl)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-lyxo-hexopyranoside [(III)]

(13) ##STR00054##

(14) ESI MS: m/z 632 (MH.sup.+)

Step B3 (A6a)

(1S,3S)-3-acetyl-10-fluoro-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl (3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranoside [(XX)]

(15) ##STR00055##

(16) (1S,3S)-3-acetyl-10-fluoro-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-Iyxo-hexopyranoside (28 mg, 0.045 mmol) [prepared as reported in step A1] was dissolved in DCM (3.0 mL). The solution was treated with a 0.1 M solution of DMDO in acetone (0.8 mL) at room temperature for 30 minutes, until no starting material was detectable (HPLC analysis). The reaction mixture was then concentrated to dryness under vacuum, affording the desired intermediate (red wax, 24.1 mg).

(17) ESI MS: m/z 632 (MH.sup.+)

(18) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.23 (d, J=6.7 Hz, 3H) 1.96-2.00 (m, 1H) 2.10 (m, 1H) 2.35 (s, 3H) 2.33-2.38 (m, 1H) 2.56-2.64 (m, 2H) 2.94-3.00 (m, 1H) 3.07-3.12 (m, 1H) 3.13-3.16 (m, 1H) 3.23-3.29 (m, 1H) 3.37 (s, 3H) 3.38-3.46 (m, 2H) 3.86-3.95 (m, 1H) 3.99 (q, J=6.7 Hz, 1H) 4.14 (s, 1H) 4.22-4.29 (m, 1H) 4.32 (br. s., 1H) 4.91 (dd, J=8.1, 2.3 Hz, 1H) 5.20 (dd, J=4.6, 1.9 Hz, 1H) 5.60 (d, J=3.9 Hz, 1H) 7.62 (dd, J.sub.HH=8.3, J.sub.HF=10.8 Hz, 1H) 7.91 (m, 1H) 8.20 (d, J.sub.HH=7.7 Hz, 1H) 13.26 (br. s., 1H) 13.69 (br. s., 1H)

(19) By analogous procedure the following compound is prepared:

(1S,3S)-10-fluoro-3,5,12-trihydroxy-3-(hydroxyacetyl)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl (3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranoside [(XX)]

(20) ##STR00056##

(21) ESI MS: m/z 648 (MH.sup.+)

Step B3 (A6b)

(22) The Title Compound (Compd. 1)

(23) To a solution of compound (1S,3S)-3-acetyl-10-fluoro-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl (3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranoside [(XX)] (20 mg, 0.032 mmol) in 5.0 ml of dry CH.sub.3CN, K.sub.2CO.sub.3 (13.2 mg, 0.096 mmol) and cyanuric chloride (11.8 mg, 0.064 mmol) were added. The reaction mixture was vigorously stirred in the dark at room temperature for 20 minutes, until no starting material was detectable. A solution of 3-amino-1,2-propanediol (17.5 mg, 0.192 mmol) in water (0.84 ml) was then added to the reaction mixture and the aqueous phase was extracted with DCM (4×10 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The crude was purified by flash column chromatography (AcOEt/toluene; 4/6) on silica gel (230-400 mesh), affording 7.0 mg of title compound as red solid.

(24) ESI MS: m/z 614 (MH.sup.+)

(25) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.29 (d, J=6.6 Hz, 3H) 1.68-1.73 (m, 1H) 1.86-1.91 (m, 1H) 2.05 (dd, J=14.8, 4.3 Hz, 1H) 2.34 (s, 3H) 2.42-2.47 (m, 1H) 2.67-2.81 (m, 2H) 2.93-2.98 (m, 1H) 3.05-3.11 (m, 1H) 3.37 (s, 3H) 3.42-3.47 (m, 1H) 3.52-3.58 (m, 1H) 3.71-3.76 (m, 1H) 4.03 (dd, J=7.1, 1.8 Hz, 1H) 4.06-4.12 (m, 1H) 4.26 (d, J=2.8 Hz, 1H) 4.53 (d, J=2.8 Hz, 1H) 4.54 (s, 1H) 5.20 (dd, J=4.3, 2.1 Hz, 1H) 5.35 (t, J=5.5 Hz, 1H) 7.60 (dd, J.sub.HH=8.3, J.sub.HF=11.6 Hz, 1H) 7.89 (m, 1H) 8.19 (dd, J.sub.HH=7.7, J.sub.HF=0.8 Hz, 1H) 13.25 (br. s., 1H) 13.61 (br. s., 1H)

(26) Analogously, by using the suitable starting material, the following compounds are prepared:

(8S,10S)-1-fluoro-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 2) [R1=F, R2=HOCH2CO—, R3=CH3O—]

(27) ##STR00057##

(28) ESI MS: m/z 630 (MH.sup.+)

(8S,10S)-8-acetyl-6,8,11-trihydroxy-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 5) [R1=HO(CH2)2NH—, R2=CH3CO—, R3=CH3O—]

(29) ##STR00058##

(30) ESI MS: m/z 655 (MH.sup.+)

(8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 6) [R1=HO(CH2)2NH—, R2=HOCH2CO—, R3=CH3O—]

(31) ##STR00059##

(32) ESI MS: m/z 671 (MH.sup.+)

(8S,10S)-8-acetyl-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 7) [R1=H2N(CH2)2NH—, R2=CH3CO—, R3=CH3O—]

(33) ##STR00060##

(34) ESI MS: m/z 654 (MH.sup.+)

(8S,10S)-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 8) [R1=H2N(CH2)2NH—, R2=HOCH2CO—, R3=CH3O—]

(35) ##STR00061##

(36) ESI MS: m/z 670 (MH.sup.+)

Example 2

Step A1, Step B3 (According to A6a and A6b)

(8S,10S)-8-acetyl-1-amino-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [(I)] (compd. 4) [R1=NH2—, R2=CH3CO—, R3=CH3O—]

(37) ##STR00062##

Step A1

(1S,3S)-3-acetyl-10-amino-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-Iyxo-hexopyranoside [(III)]

(38) ##STR00063##

(39) (1S,3S)-3-acetyl-10-amino-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside (165.0 mg, 0.322 mmol) [prepared as reported below in Example 3] was dissolved in dry DMF (3.0 mL); a solution of diiso-propylethylamine (221 mg, 1.71 mmol) in dry DMF (3 mL) and a solution of (1S)-2-iodo-1-(2-iodoethoxy)-1-methoxyethane (IIa) (2.0 g, 5.64 mmol) in dry DMF (10 mL) were added. The reaction mixture was stirred at room temperature in the dark for 48 hours, until no starting material was detectable (HPLC analysis). The reaction mixture was then diluted with DCM and washed with water. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, the solvent was evaporated under vacuum and the residue was purified by flash chromatography (eluant: EtOH/DCM; 0.2/9.8) on silica gel (230-400 mesh) affording the desired product (105.0 mg, red solid).

(40) ESI MS: m/z 613 (MH.sup.+)

(41) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.22-1.28 (m, 3H) 1.65-1.83 (m, 2H) 2.30-2.36 (m, 4H) 2.40 (dd, J=11.22, 4.94 Hz, 3H) 2.46-2.54 (m, 2H) 2.87-2.96 (m, 1H) 3.04-3.11 (m, 1H) 3.32 (s, 3H) 3.50 (ddd, J=11.34, 6.51, 2.83 Hz, 1H) 3.65 (br. s., 1H) 3.77-3.89 (m, 1H) 4.04 (d, J=6.51 Hz, 1H) 4.44 (dd, J=4.63, 2.41 Hz, 1H) 5.16 (d, J=1.99 Hz, 1H) 5.43-5.47 (m, 1H) 7.12-7.16 (m, 1H) 7.24 (br. s., 1H) 7.50-7.55 (m, 1H) 7.58-7.61 (m, 1H)

(42) By analogous procedure the following compounds are prepared:

(1S,3S)-10-amino-3,5,12-trihydroxy-3-(hydroxyacetyl)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-lyxo-hexopyranoside

(43) ##STR00064##

(44) ESI MS: m/z 629 (MH.sup.+)

(45) Analogously, by using the suitable starting material, the following compounds are prepared:

(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-[(2-hydroxyethyl)amino]-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranoside

(46) ##STR00065##

(47) ESI MS: m/z 557 (MH.sup.+)

(1S,3S)-3-acetyl-10-[(2-aminoethyl)amino]-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranoside

(48) ##STR00066##

(49) ESI MS: m/z 556 (MH.sup.+)

(50) Protection

N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]- -L-lyxo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide

(51) ##STR00067##

(52) (1S,3S)-3-acetyl-10-amino-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-lyxo-hexopyranoside [(III)] (80.0 mg, 0.130 mmol) was dissolved in dry DCM (11 mL) and trifluoroacetic anhydride (273.0 mg, 1.3 mmol) was added. The reaction mixture was stirred at room temperature in the dark for 30 minutes, until no starting material was detectable (HPLC analysis). The reaction mixture was then diluted with DCM and washed with saturated NaHCO.sub.3 aqueous solution (3×10 mL), and then with water (1×10 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, the solvent was evaporated under vacuum and the residue thus obtained was treated with MeOH (10 mL) at room temperature for 15 minutes, and then evaporated under vacuum affording the desired product (77.0 mg, red wax).

(53) ESI MS: m/z 709 (MH.sup.+)

(54) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.25 (d, J=6.59 Hz, 3H) 1.76 (dd, J=8.68, 2.61 Hz, 2H) 2.27-2.45 (m, 8H) 2.52 (t, J=10.99 Hz, 2H) 2.96-3.03 (m, 1H) 3.08-3.15 (m, 1H) 3.30-3.33 (m, 3H) 3.50 (ddd, J=11.27, 6.57, 2.61 Hz, 1H) 3.66 (br. s., 1H) 3.79-3.87 (m, 1H) 4.05 (q, J=6.62 Hz, 1H) 4.44 (dd, J=4.70, 2.35 Hz, 1H) 5.17 (d, J=2.27 Hz, 1H) 5.45 (s, 1H) 7.97 (t, J=8.15 Hz, 1H) 8.24 (d, J=7.50 Hz, 1H) 8.99 (d, J=8.18 Hz, 1H)

Step B3 (A6a)

N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({(3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide [(XX)]

(55) ##STR00068##

(56) N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({2,3,6-trideoxy-3-[(2S)-2-methoxymorpholin-4-yl]-α-L-lyxo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide (72.0 mg, 0.102 mmol) was dissolved in DCM (6.4 mL). The solution was treated with a 0.1 M solution of DMDO in acetone (1.7 mL) at room temperature for 30 minutes, until no starting material was detectable (HPLC analysis). The reaction mixture was then concentrated to dryness under vacuum, affording the desired intermediate (red wax, 73.0 mg).

(57) ESI MS: m/z 725 (MH.sup.+)

(58) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.23 (d, J=6.51 Hz, 3H) 2.32-2.39 (m, 4H) 2.57 (d, J=4.54 Hz, 1H) 2.74 (d, J=11.65 Hz, 1H) 2.96-3.02 (m, 1H) 3.08-3.15 (m, 1H) 3.25-3.45 (m, 7H) 3.57 (br. s., 1H) 3.92 (d, J=12.79 Hz, 1H) 4.04 (d, J=6.88 Hz, 1H) 4.18 (s, 1H) 4.21-4.28 (m, 1H) 4.92 (dd, J=8.21, 2.08 Hz, 1H) 5.19 (d, J=2.19 Hz, 1H) 5.61 (d, J=3.71 Hz, 1H) 7.97 (t, J=8.10 Hz, 1H) 8.23 (d, J=7.64 Hz, 1H) 8.98 (d, J=8.32 Hz, 1H)

(59) By analogous procedure the following compound can be prepared:

(1S,3S)-10-amino-3,5,12-trihydroxy-3-(hydroxyacetyl)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl (3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranoside [(XX)]

(60) ##STR00069##

(61) ESI MS: m/z 645 (MH.sup.+)

Step B3 (A6b)

N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide [(I)]

(62) ##STR00070##

(63) To a solution of compound N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({(3ξ)-2,3,6-trideoxy-3-[(2S)-2-methoxy-4-oxidomorpholin-4-yl]-α-L-threo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide [(XX)] (60.0 mg, 0.083 mmol) in 13 mL of dry CH.sub.3CN, K.sub.2CO.sub.3 (34.4 mg, 0.249 mmol) and cyanuric chloride (30.6 mg, 0.166 mmol) were added. The reaction mixture was vigorously stirred in the dark at room temperature for 15 minutes, until no starting material was detectable. A solution of 3-amino-1,2-propanediol (45.3 mg, 0.5 mmol) in water (0.22 mL) was then added to the reaction mixture and the aqueous phase was extracted with DCM (4×10 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The crude was purified by flash column chromatography (AcOEt/toluene; 4/6) on silica gel (230-400 mesh), affording 12.0 mg of title compound as red solid.

(64) ESI MS: m/z 707 (MH.sup.+)

(65) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.29 (d, J=6.58 Hz, 4H) 1.70 (d, J=15.21 Hz, 1H) 1.90 (d, J=15.59 Hz, 2H) 2.04-2.08 (m, 2H) 2.45 (d, J=14.98 Hz, 1H) 2.69-2.76 (m, 1H) 2.77-2.83 (m, 1H) 2.97 (s, 1H) 3.08-3.14 (m, 2H) 3.38 (s, 4H) 3.45 (d, J=6.88 Hz, 2H) 3.56 (d, J=5.22 Hz, 2H) 3.74 (s, 1H) 4.04 (d, J=1.89 Hz, 2H) 4.09 (d, J=6.88 Hz, 1H) 4.26 (d, J=2.72 Hz, 1H) 4.52-4.54 (m, 2H) 5.22 (br. s., 1H) 5.36 (t, J=5.60 Hz, 1H) 7.98 (t, J=8.06 Hz, 1H) 8.26 (d, J=7.87 Hz, 1H) 9.00 (d, J=8.10 Hz, 1H)

(66) Deprotection

(67) The Title Compound (Compd.4)

(68) ##STR00071##

(69) The N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide intermediate (4.8 mg, 0.00679 mmol) was cooled at 0° C. and 0.1 N NaOH aqueous solution (0.5 mL) was added. The reaction mixture was stirred in the dark 0° C. for 15 minutes, until no starting material was detectable. The reaction mixture was then diluted with H.sub.2O and extracted with DCM (4×5 mL). The combined organic phases were washed with saturated aqueous NaCl solution (1×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under vacuum, affording 4.0 mg of title compound as red solid.

(70) ESI MS: m/z 611 (MH.sup.+)

(71) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.70 (dt, J=15.06, 5.82 Hz, 2H) 1.87 (dt, J=15.17, 5.54 Hz, 1H) 2.34 (s, 3H) 2.43 (d, J=14.41 Hz, 1H) 2.68-2.81 (m, 2H) 2.91-2.96 (m, 1H) 3.07 (d, J=18.66 Hz, 1H) 3.37 (s, 3H) 3.44 (q, J=5.87 Hz, 1H) 3.51-3.61 (m, 2H) 3.74 (ddd, J=11.63, 8.25, 2.96 Hz, 1H) 4.01-4.04 (m, 1H) 4.06-4.13 (m, 1H) 4.26 (d, J=2.66 Hz, 1H) 4.54 (d, J=2.58 Hz, 1H) 5.21 (br. s., 1H) 5.37 (t, J=5.61 Hz, 1H) 7.16 (d, J=8.57 Hz, 1H) 7.54 (t, J=7.89 Hz, 1H) 7.62 (d, J=7.06 Hz, 1H)

(72) Analogously, by using the suitable starting material, the following compound is prepared:

(8S,10S)-1-amino-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione (compd. 3) [R1=NH2—, R2=HOCH2CO—, R3=CH3O— ]

(73) ##STR00072##

(74) ESI MS: m/z 627 (MH.sup.+)

Example 3

Preparation of the Intermediates of Formula (II)

(75) ##STR00073##

Step G2, Deprotection, Protection, Step G3, Deprotection

Synthesis of (1S,3S)-3-acetyl-10-amino-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranoside

(76) ##STR00074## ##STR00075##

Step G2

Synthesis of the intermediate (8S,10S)-1-[(3,4-dimethoxybenzyl)amino]-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydrotetracene-5,12-dione (XIV)

(77) ##STR00076##

(78) To a solution of (8S,10S)-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl 4-fluorobenzenesulfonate (400 mg, 0.682 mmol) [prepared as reported in GB2215332] in THF (10 mL), 3-4 dimethoxybenzylamine (0.532 mg, 3.1 mmol) was added. The solution was heated at 60° C. and stirred for 24 hours in the dark. Then, the solvent was partially removed under vacuum, the dark violet precipitate collected by filtration, washed with THF (3 mL) and then with Et.sub.2O (10 mL). The solid was finally dried in the oven under vacuum at 30° C. to yield the title intermediate (188 mg, y=48%).

(79) Analogously, by using the suitable amines, the following compounds are prepared:

(8S,10S)-6,8,10,11-tetrahydroxy-1-[(2-hydroxyethyl)amino]-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydrotetracene-5,12-dione

(80) ##STR00077##

(81) ESI MS: m/z 472 (MH.sup.+)

(82) .sup.1H NMR (499.75 MHz, DMSO-d.sub.6) δ ppm 1.33 (s, 3H), 1.82 (dd, J=14.3, 4.3 Hz, 1H), 2.20 (d, J=14.3 Hz, 1H), 2.67 (d, J=18.7 Hz, 1H), 3.10 (d, J=18.7 Hz, 1H), 3.45-3.49 (m, 2H), 3.68-3.72 (m, 2H), 3.92-4.01 (m, 4H), 5.00 (t, J=5.1 Hz, 1H), 5.05-5.11 (m, 1H), 5.35 (d, J=7.6 Hz, 1H), 5.44 (s, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.56 (d, J=6.8 Hz, 1H), 7.70 (dd, J=8.7, 6.8 Hz, 1H), 9.61 (t, J=5.1 Hz, 1H), 13.52 (br. s., 1H), 13.74 (br. s., 1H)

(8S,10S)-1-[(2-aminoethyl)amino]-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydrotetracene-5,12-dione

(83) ##STR00078##

(84) ESI MS: m/z 471 (MH.sup.+)

(85) Deprotection

Synthesis of the intermediate (8S,10S)-8-acetyl-1-amino-6,8,10,11-tetrahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione (XIV)

(86) ##STR00079##

(87) To cold trifluoroacetic acid (2 mL), (8S,10S)-1-[(3,4-dimethoxybenzyl)amino]-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydrotetracene-5,12-dione (133 mg, 0.230 mmol) and 2 drops of anisole were added. The solution was stirred at 5° C. for 20 min and then at room temperature for 2 hours until no starting material was detectable. The reaction was diluted with water (5 mL), neutralized with NaHCO.sub.3 solution then, the aqueous phase extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered, the solvent evaporated under vacuum and the crude treated with Et.sub.2O (10 mL). The dark violet precipitate was collected by filtration and dried in the oven under vacuum at 30° C. to yield the desired intermediate (82 mg, y=93%).

(88) ESI MS: m/z 384 (MH.sup.+)

(89) .sup.1H NMR (400.5 MHz, DMSO-d.sub.6) δ ppm 1.99 (dd, J=14.4, 4.6 Hz, 1H), 2.13-2.19 (m, 1H), 2.30 (s, 3H), 2.88-2.95 (m, 1H), 2.98-3.05 (m, 1H), 5.07 (m, 1H), 5.29 (br. s., 1H), 6.07 (s, 1H), 7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.51 (dd, J=7.3, 1.1 Hz, 1H), 7.55-7.60 (m, 1H), 8.05 (br. s., 2H), 13.49 (br. s., 1H), 13.85 (br. s., 1H)

(90) Analogously, by using the suitable starting material, the following compounds can be prepared:

(8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-1-[(2-hydroxyethyl)amino]-7,8,9,10-tetrahydrotetracene-5,12-dione

(91) ##STR00080##

(92) ESI MS: m/z 428 (MH.sup.+)

(93) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.98 (dd, J=14.2, 4.6 Hz, 1H), 2.16 (d, J=14.2 Hz, 1H), 2.31 (s, 3H), 2.88-2.94 (m, 1H), 2.98-3.04 (m, 1H), 3.46-3.49 (m, 2H), 3.68-3.72 (m, 2H), 5.01 (t, J=5.1 Hz, 1H), 5.05-5.10 (m, 1H), 5.30 (d, J=6.7 Hz, 1H), 6.10 (s, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.70 (dd, J=8.7, 7.1 Hz, 1H), 9.62 (t, J=5.1 Hz, 1H), 13.47 (br. s., 1H), 13.76 (br. s., 1H)

(8S,10S)-8-acetyl-1-[(2-aminoethyl)amino]-6,8,10,11-tetrahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione

(94) ##STR00081##

(95) ESI MS: m/z 427 (MH.sup.+)

(96) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ ppm 1.97 (dd, J=14.2, 4.6 Hz, 1H), 2.14 (d, J=14.2 Hz, 1H), 2.31 (s, 3H), 2.88-2.94 (m, 1H), 2.98-3.04 (m, 1H), 3.05-3.22 (m, 4H), 5.05-5.10 (m, 1H), 5.30 (d, J=6.7 Hz, 1H), 6.10 (s, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.54 (d, J=7.1 Hz, 1H), 7.70 (dd, J=8.7, 7.1 Hz, 1H), 9.60 (t, J=5.1 Hz, 1H), 13.46 (br. s., 1H), 13.76 (br. s., 1H)

(97) Protection

Synthesis of the intermediate N-[(8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide

(98) ##STR00082##

(99) The intermediate (8S,10S)-8-acetyl-1-amino-6,8,10,11-tetrahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione (600.0 mg, 1.56 mmol) was dissolved in dry DCM (120 mL) and trifluoroacetic anhydride (1.2 mL) was added. The reaction mixture was stirred at room temperature in the dark for 5 minutes, until no starting material was detectable (HPLC analysis). The reaction mixture was then diluted with DCM (100 mL) and washed with saturated NaHCO.sub.3 aqueous solution (3×100 mL), and then with water (1×100 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, and the solvent was removed under vacuum. The residue thus obtained was purified by flash chromatography (eluant: CH.sub.3COCH.sub.3/DCM; 0.3/9.7) on silica gel (230-400 mesh) affording the desired product (494.1 mg, red solid).

(100) ESI MS: m/z 480 (MH.sup.+)

(101) .sup.1H NMR (500 MHz, CHCl.sub.3-d) δ ppm 2.22 (dd, J=14.5, 4.9 Hz, 1H), 2.36-2.41 (m, 1H), 2.45 (s, 3H), 3.01 (d, J=18.7 Hz, 1H), 3.23 (dd, J=18.7, 2.2 Hz, 1H), 3.81 (d, J=5.2 Hz, 1H), 4.54 (s, 1H), 5.35 (m, 1H), 7.93 (dd, J=8.4, 7.7 Hz, 1H), 8.29 (dd, J=7.7, 1.1 Hz, 1H), 9.12 (dd, J=8.4, 1.1 Hz, 1H), 13.29 (br.s., 1H), 13.29 (s, 1H), 13.46 (s, 1H).

(102) Analogously, by using the suitable starting material, the following compound is prepared:

N-(2-{[(8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl]amino}ethyl)-2,2,2-trifluoroacetamide

(103) ##STR00083##

(104) ESI MS: m/z 523 (MH.sup.+)

Step G3

Synthesis of N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-L-lyxo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide

(105) ##STR00084##

(106) In a dry three-necked round-bottomed flask under argon atmosphere, the intermediate N-[(8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-5,12-dioxo-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide (480.0 mg, 1.0 mmol) was dissolved in dry DCM (110 mL), and powdered molecular sieves (4 Å, 20.0 mg) were added. The reaction mixture was cooled at 10° C.; the solution of silver trifluoromethanesulfonate (334.0 mg, 1.3 mmol) in dry Et.sub.2O (15 mL) and the solution of 2,3,6-trideoxy-4-O-(trifluoroacetyl)-3-[(trifluoroacetyl)amino]-δ-L-lyxo-hexopyranosyl chloride (511.4 mg, 1.43 mmol) in dry DCM (15 mL) were simultaneously added. The reaction mixture was stirred at 10° C. in the dark for 45 minutes, until no starting material was detectable (HPLC analysis). Saturated NaHCO.sub.3 aqueous solution (50 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes, and then filtered through a celite pad. The organic phase was separated, washed with water and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed under vacuum, and the residue thus obtained was cooled at 0° C. and treated with MeOH (20 mL) and solid NaHCO.sub.3 for 15 minutes. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (eluant: CH.sub.3COCH.sub.3/DCM; 0.5/9.5) on silica gel (230-400 mesh) affording the desired product (320.0 mg, red solid).

(107) ESI MS: m/z 705 (MH.sup.+)

(108) .sup.1H NMR (500 MHz, CH.sub.3CN-d.sub.3) δ ppm 1.22 (d, J=6.47 Hz, 3H) 1.77 (dd, J=13.18, 4.64 Hz, 1H) 2.00 (td, J=13.15, 3.97 Hz, 1H) 2.10 (d, J=10.13 Hz, 1H) 2.33-2.35 (m, 1H) 2.87-3.00 (m, 1H) 3.01-3.13 (m, 1H) 3.22 (br. s., 1H) 3.61 (br. s., 1H) 4.09-4.16 (m, 1H) 4.22 (q, J=6.47 Hz, 1H) 4.29 (s, 1H) 5.10 (br. s., 1H) 5.40 (d, J=3.54 Hz, 1H) 7.32 (d, J=7.81 Hz, 1H) 7.89 (t, J=7.63 Hz, 1H) 8.11 (d, J=7.08 Hz, 1H) 8.89 (d, J=8.30 Hz, 1H) 13.08 (br. s., 2H)

(109) Analogously, by using the suitable starting material, the following compounds are prepared:

N-(2-{[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-L-lyxo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]amino}ethyl)-2,2,2-trifluoroacetamide

(110) ##STR00085##

(111) ESI MS: m/z 748 (MH.sup.+)

(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-[(2-hydroxyethyl)amino]-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-L-lyxo-hexopyranoside

(112) ##STR00086##

(113) ESI MS: m/z 653 (MH.sup.+)

(114) Deprotection

(115) The Title Compound (II)

(116) The intermediate N-[(8S,10S)-8-acetyl-6,8,11-trihydroxy-5,12-dioxo-10-({2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-L-lyxo-hexopyranosyl}oxy)-5,7,8,9,10,12-hexahydrotetracen-1-yl]-2,2,2-trifluoroacetamide (340.2 mg, 0.432 mmol) was cooled at 0° C. under argon and treated with a 0.1 N NaOH aqueous solution (12 mL). The reaction mixture was stirred in the dark at 0° C. for 1 hour, until no starting material was detectable (HPLC analysis). The reaction mixture was then diluted with DCM (50 mL), washed with saturated NaHCO.sub.3 aqueous solution (3×30 mL), then with water (1×30 mL) and finally with saturated NaCl solution (1×30 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4, the solvent was removed under vacuum affording the desired product (180.0 mg, red solid).

(117) ESI MS: m/z 513 (MH.sup.+)

(118) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ pm 1.14 (d, J=6.52 Hz, 2H) 1.47 (dd, J=12.61, 4.33 Hz, 1H) 1.60 (d, J=3.30 Hz, 1H) 2.06-2.21 (m, 2H) 2.24-2.27 (m, 3H) 2.86 (d, J=12.58 Hz, 1H) 2.88-3.01 (m, 2H) 3.28 (br. s., 1H) 4.09 (d, J=6.29 Hz, 1H) 4.45 (br. s., 1H) 4.94 (t, J=4.22 Hz, 1H) 5.19 (d, J=3.53 Hz, 1H) 5.44 (s, 1H) 7.24 (d, J=8.28 Hz, 1H) 7.50 (d, J=7.13 Hz, 1H) 7.51-7.52 (m, 0H) 7.55-7.59 (m, 1H) 8.06 (br. s., 2H)

(119) Analogously, by using the suitable starting material, the following compounds are prepared:

(1S,3S)-3-acetyl-10-[(2-aminoethyl)amino]-3,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranoside

(120) ##STR00087##

(121) ESI MS: m/z 556 (MH.sup.+)

(1S,3S)-3-acetyl-3,5,12-trihydroxy-10-[(2-hydroxyethyl)amino]-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2, 3,6-trideoxy-L-lyxo-hexopyranoside

(122) ##STR00088##

(123) ESI MS: m/z 557 (MH.sup.+)