The present invention relates to new cardiotonic steroids and their use in the treatment of cancer. In particular, the present invention provides new hellebrin and hellebrigenin derivatives and their use as anticancer agent.

Background of the invention

Cardiotonic steroids (CSs) or cardiotonic glycosides represent a group of compounds that share the capacity to bind to the extra-cellular surface of the main ion transport protein in the cell, the membrane-inserted sodium pump (Na+/K+-ATPase) (Schatzmann HeIv. Physiol. Pharmacol. Acta 11 (1953) 346-354; Xie & Askari Eur J Biochem. 269 (2002) 2434-2439). These compounds have long been and continue to be used in the treatment of congestive heart failure as positive inotropic agents (Gheorghiade et al., Circulation 109 (2004) 2959- 2964). Retrospective epidemiological studies conducted during the late 20th century revealed intriguing results: very few patients maintained on CS treatment for heart problems died from cancer (Stenkvist Anti-Cancer Drugs 12 (2001 ) 635-636). CSs are the natural ligands and inhibitors of the Na+/K+-ATPase sodium pump and act by binding to the extracellular surface of said pump. This fact plus the altered expression of sodium pump subunits in different cancers (recently reviewed in Mijatovic et al., Expert Opin Ther Targets 12(1 1 ) (2008) 1403-1417) strongly suggest that targeting Na+/K+-ATPase could represent a novel means to combat a growing number of malignancies. The Na+/K+-ATPase sodium pump is a versatile signal transducer, and a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. For example, the α1 subunit of Na+/K+-ATPase was reported to be highly expressed in a majority of glioblastomas compared with normal brain tissues (Lefranc et al., Neurosurgery, 62(1 ) (2008) 21 1-222). It was also reported that, in human colorectal cancer, an up-regulation of Na+, K+- ATPase α3-isoform and down-regulation of the α1-isoform was observed (Sakai et al. FEBS Lett. 563(1 ) (2004)151-154, and Mijatovic et al AACR Annual Meeting, (abstract n° 1 195, 2008)) It was also reported that the α1 -subunit is up-regulated in renal clear cell carcinoma and thereby is a significant and independent predictor of disease specific death from renal clear cell carcinoma (Seligson et al., J Urol 179(1 ), (2008), 338-345°. The α1 subunit of the sodium pump was also reported to be up-regulated non-small cell lung cancers (Mijatovic et al., J Pathol 212(2) (2007)170 - 179). The α1 subunit of the sodium pump was also reported to be down-regulated bladder cancers (Espineda et al., Cancer 97(8) (2003) 1859-1868)

The foregoing evidence suggests that the sodium pump is a relevant molecular target for the prevention and treatment of proliferative diseases. However, the battery of substances useful to impinge on this molecule is presently somewhat restricted (recently reviewed in Mijatovic et al., BBA-Rev Cancer 1776(1 ) (2007) 32-57). Consequently, there exists a need for further reagents which target the sodium pump and, in particular, for such reagents having advantageous properties, such as, for example, reagents that are increasingly effective and/or decrease unwanted side-effects, and/or are more selective for cancerous cells, and/or are less erosive for healthy cells, and/or are comparably specific for particular cancer types, and/or are less toxic, etc.

Chemically, CSs are compounds presenting a steroid nucleus with a lactone moiety at position 17 (Figure 1 ). Glycosylated CSs contain a sugar moiety at position 3. The nature of the lactone ring at position 17 defines the class of CS: cardenolides (with an unsaturated butyrolactone ring) and the bufadienolides (with a α-pyrone ring).

Several plants (more particularly those belonging to Asclepiadacea, Apocynaceae, Ranunculaceae and Scrophulaήaceae families) are recognized to contain CSs. CSs are also extensively found in animal species and occur mainly in toads (species of the Bufo genera). Several independent investigators have also found that mammalian tissues and body fluids (including brain, adrenal glands, heart, blood plasma, cerebrospinal fluid and urine) contain digitalis-like compounds (reviewed in Mijatovic et al., BBA-Rev Cancer 1776(1 ) (2007) 32- 57).

The bufadienolide class of CSs remains largely unexplored despite their structural abundance and great natural profusion. Plants of the family Ranunculaceae (mainly Helleborus species) are known to contain several bufadienolides, such as hellebrin, hellebrigenin, helleborein, helleborin. The structure of hellebrin and hellebrigenin is shown in Figure 2.

Most chemotherapeutic agents currently used in the clinic for the treatment of cancer aim to take advantage of cell division itself and gain much of their selectivity from the fact that cancer cells divide more rapidly than their normal counterparts. In addition, the life duration of cancer cells is longer than that of normal cells in the tissue of which the cancer arose. A major problem with the currently used cytotoxic molecules reside in their lack of specificity: normal cells are themselves being injured. As a consequence, these drugs share in common an elevated toxicity.

There is still a need to develop new compounds having improved pharmacological and therapeutic activities for the treatment of cancer. It is accordingly one of the objects of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. In particular, it is an object of the present invention to provide novel hellebrin and hellebrigenin derivatives, which have a cytotoxic activity with reduced general toxicity and that might be orally bioavailable enabling thus the development or drugs for oral use which is more comfortable for the patients than intravenous injections.

Summary of the invention

The present invention provides compounds of the Formula I or II, stereoisomeric forms thereof, tautomers, racemates, prodrugs, metabolites, pharmaceutically acceptable salts, hydrates, or solvates thereof,

wherein L is Ci.i ₂ alkylene, -NH-, -NR ⁸ -Ci _-6 alkylene, -NR ⁸ -Ci _-6 alkylene-NR ⁹ -, -S-Ci _-6 alkylene; wherein R ⁸ and R ⁹ are each independently selected from hydrogen or a group comprising Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, and aminocarbonylCi _-6 alkyl;

X ¹ is selected from -CH=N-R ¹⁰ Or -CH ₂ -NR ¹¹ R ¹⁰ ; wherein R ¹⁰ and R ¹¹ are each independently selected from hydrogen, -OR ¹³ or -NR ¹⁴ R ¹⁵ ; wherein R ¹³ is hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , Het ² d _-6 alkyl, or aminocarbonylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or d _-6 alkyloxy; wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -i ₀ aryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , or Het ² d _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or d _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from azetidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy;

X ² is selected from O, S or NR ¹⁶ , wherein R ¹⁶ is hydrogen or a group selected from Ci- ₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , or Het ² d _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or Ci _-6 alkyloxy;

X ³ is selected from -CH ₂ -, -C(=O)-, -C(=S)-;

R ¹ is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, and aminocarbonylCi _-6 alkyl,

R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, Ce-ioarylCi-ealkylcarbonyloxy,

Ci _-6 alkyloxyCi.6alkyloxy, C _3- 6cycloalkyloxy, and Cs-βcycloalkyld-ealkyloxy; R ⁴ is selected from the group comprising hydroxyl, -X ² -X ³ -L-R ¹ , Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy; or

R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, 3-mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4- galactobiosyloxy, maltotriosyloxy, isomaltotriosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, trehalosaminyl-oxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1 -hydroxy-α-D-allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2- amino-2-deoxy-D-galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy- D-glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy-galactosyloxy, 2- amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-4-O- β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D-galactosyl-D-glucosyloxy, 6'-N- acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O-α-L-fucosyl-D-glucosyloxy, 6-0(2- acetamido^-deoxy-β-D-glucosyO-D-galactosyloxy, 2-acetamido-2-deoxy-3-O-β-D-galactosyl- D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D-glucosyl-D-galactosyloxy, 3-fucosyl-D- lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β-D-galactosyl-D-glucosyl oxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, acyl or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, and di-, tri-, oligo- and polysaccharide thereof; R ⁵ is selected from the group comprising formyl, hydroxyCi _-6 alkyl, C _2-6 alkyl; d-ealkylcarbonyloxyd-βalkyl, -X ¹ , di-ioarylcarbonyloxyd-ealkyl, and

Ce-ioarylCi-ealkylcarbonyloxyd-ealkyl;

R ⁶ is selected from the group comprising hydrogen, d _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , and Het ² d _-6 alkyl; and R ⁷ is selected from the group comprising hydrogen, d _-6 alkyl, C ₆ -ioaryl, C6-ioarylCi _-6 alkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , and Het ² d _-6 alkyl; with the proviso that when L is -NR ⁸ -d _-6 alkylene, -NR ⁸ -d _-6 alkylene-NR ⁹ -, then R ⁶ and R ⁷ are not hydrogen.

The invention further provides the use of the compounds of Formula I or Il as a medicament. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of Formula I or II.

The invention further provides the use of a compound according to the invention for the preparation of a medicament for the prevention and/or treatment of cancer, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith. In an embodiment, said cancer is selected from leukemia, non-small cell lung cancer, small cell lung cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, colon cancer, bladder cancer, sarcoma, pancreatic cancer, colorectal cancer, head and neck cancer, liver cancer, bone cancer, bone marrow cancer, stomach cancer, duodenum cancer, oesophageal cancer, thyroid cancer, hematological cancer, or lymphoma.

The invention also provides a method for treating cancer comprising administering at least one compound of Formula I or Il in an individual in need thereof.

The present invention further provides kits for use in treating cancer and related disorders in an individual in need thereof comprising a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of Formula I or II, optionally, in combination with a pharmaceutically acceptable carrier.

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Brief description of the drawings Figure 1 represents some examples Cardiotonic steroids' structure. Figure 2 represents the structure of hellebrin and hellebrigenin. Detailed description

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

The present invention provides new hellebrin and hellebrigenin derivatives of Formula I or II, or stereoisomer thereof, and their use as anticancer agent. The present invention also provides methods for the preparation of said compounds. The invention further provides a pharmaceutical composition comprising an effective amount of said compounds and the use of said compounds as a medicament and/or for the treatment of diseases associated with cell proliferation, and in particular in the treatment of cancer.

In an embodiment, the present invention provides compounds of Formula I or II, or stereoisomeric forms thereof, wherein L is Ci_i ₂ alkylene, -NH-, -NR ⁸ -Ci_6alkylene, -NR ⁸ -Ci _-6 alkylene-NR ⁹ -, or -S-Ci _-6 alkylene; wherein R ⁸ and R ⁹ are each independently selected from hydrogen or a group comprising Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, and aminocarbonylCi _-6 alkyl; preferably L is Ci_i ₂ alkylene, -NH-, -NR ⁸ -Ci _-6 alkylene, -NR ⁸ -Ci_ ₆ alkylene-NR ⁹ -, wherein R ⁸ and R ⁹ are each independently selected from the group comprising hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl; preferably L is Ci_i ₂ alkylene, or -NR ⁸ -Ci _-6 alkylene, wherein R ⁸ and R ⁹ are each independently selected from hydrogen, Ci- βalkyl, or C _6- i ₀ aryl; preferably L is -(CR ¹⁷ R ¹ V, -NH-, -NR ⁸ -(CR ¹⁷ R ¹⁸ ) _n -, -NR ⁸ -(CR ¹⁷ R ¹⁸ ) _n -NR ⁹ -, -S-(CR ¹⁷ R ¹ V; wherein n is an integer selected from 1 , 2, 3, 4, 5 or 6, and R ⁸ , R ⁹ , R ¹⁷ , and R ¹⁸ are each independently hydrogen or C^alkyl; preferably n is 1 , 2, 3 or 4 and R ⁸ , R ⁹ , R ¹⁷ and R ¹⁸ are each independently hydrogen or Ci _-2 alkyl; preferably L is Ci _-6 alkylene, -NH-Ci- ₆ alkylene, -NH-Ci _-6 alkylene-NH-, or -S-Ci _-6 alkylene, and R ⁸ , and R ⁹ , are each independently hydrogen or Ci _-4 alkyl preferably L is Ci _-5 alkylene or -NH-Ci _-5 alkylene, more preferably L is selected from the group comprising -CH ₂ , -NH-, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -CH(CH ₃ )-CH(CH ₃ )-, -(CHz) ₃ -, -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -(CHz) ₄ -. -(CHz) ₅ -, -CH(CHa)-CH ₂ -CH ₂ -; -CH ₂ -CH ₂ -CH(CH ₃ )-, -CH(CH3)-CH(CH ₃ )-CH ₂ -, or -CH ₂ -C(CH3) ₂ -(CH ₃ ) ₂ -, -NH-CH ₂ , -NH-CH ₂ -CH ₂ -, -NH-CH(CH ₃ )-, -NH-CH ₂ -CH(CH ₃ )-, -NH-CH(CH ₃ )-CH ₂ -; -NH- CH(CH ₃ )-CH(CH ₃ )-, -NH-(CHz) ₃ -, -NH-CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -NH-(CH ₂ ) ₄ -, -NH-(CH ₂ ) ₅ -, -S-CH ₂ , -S-CH ₂ -CH ₂ -, -S-CH(CH ₃ )-, -S-CH ₂ -CH(CH ₃ )-, -S-CH(CH ₃ )-CH ₂ -; _-S-(CH ₂ ) ₃ -, -S-CH ₂ - C(CHs) ₂ -CH ₂ -, and -S-(CH ₂ ) ₄ -; more preferably L is -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ - CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -CH(CH ₃ )-CH(CH ₃ )-, -(CH ₂ ) ₃ -, -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -NH-CH ₂ , -NH-CH ₂ -CH ₂ -, or -NH-CH(CH ₃ )-; more preferably L is -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -(CH ₂ ) ₃ -, -CH ₂ -C(CHs) ₂ -CH ₂ , Or -NH-CH ₂ -;

X ¹ is selected from -CH=N-R ¹⁰ or -CH ₂ -NR ¹¹ R ¹⁰ , wherein R ¹⁰ and R ¹¹ are each independently selected from hydrogen, -OR ¹³ or -NR ¹⁴ R ¹⁵ ; wherein R ¹³ is hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonylCi-ealkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, or aminocarbonylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or Ci _-6 alkyloxy; wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , or Het ² Ci _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci- ₆ alkyl, or Ci _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from azetidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy; preferably X ¹ is -CH=N-R ¹⁰ or -CH ₂ - NH ₂ ; wherein R ¹⁰ is selected from hydrogen, -OR ¹³ , Or -NR ¹⁴ R ¹⁵ ; wherein R ¹³ is hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, Ci- ₆ alkoxycarbonylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, or aminocarbonylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , or Het ² Ci _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci- ₆ alkyl, or Ci _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from azetidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy; preferably X ¹ is -CH=N-R ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, -OR ¹³ or -NR ¹⁴ R ¹⁵ ; wherein each R ¹³ and R ¹⁴ is independently hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi- ₆ alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci-βalkyI, or d^alkyloxy; wherein R ¹⁵ is selected from hydrogen or a group selected from d _-6 alkyl, C _6- ioaryl, C6-ioaryld-6alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, d_ ₆ alkyl, or d _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, d-βalkyl, and d. ₆ alkyloxy; preferably X ¹ is -CH=N-O-R ¹³ or -CH=N-NR ¹⁴ R ¹⁵ , wherein each R ¹³ and R ¹⁴ is independently hydrogen or a group selected from d _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or d _-6 alkyloxy; wherein R ¹⁵ is selected from hydrogen or a group selected from d _-6 alkyl, C _6- ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci- ₆ alkyl, or d-βalkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy; preferably X ¹ is -CH=N-R ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, -OH, -0-Ci- ₆ alkyl, -O-C ₆ -i ₀ aryl, -O-d-ealkylCe-ioaryl, -O-Ci _-6 alkylCO ₂ H, -O-Ci _-6 alkylCθ ₂ Ci _-6 alkyl, -O-Het ¹ , -O-Het ² ; -NH ₂ , -NH-Ci _-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH-Cβ-ioaryl, -N(C _6- ioaryl) ₂ , -NH-d-ealkylCe-ioaryl, -N(Ci _-6 alkyl)(C6-ioaryl), - NH-Het ¹ , -NH-Het ² , -NR ¹⁴ R ¹⁵ , with each d _-6 alkyl, C ₆ -i ₀ aryl, Het ¹ , Het ² as a group or part of a group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or d _-6 alkyloxy, and R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy; preferably X ¹ is -CH=N-R ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, -OH, -O-d _-6 alkyl, -O-C ₆ -i ₀ aryl, -O-d-ealkylCe-ioaryl, -O-d _-6 alkylCO ₂ H, -O- Ci _-6 alkylCO ₂ Ci _-6 alkyl, -NH ₂ , -NH-Ci _-6 alkyl, -N(C _1-6 alkyl) ₂ , -NH-C _6-- i ₀ aryl, -N(C _6- i ₀ aryl) ₂ , -NH- d-ealkylCe-ioaryl, -N(Ci _-6 alkyl)(C6-ioaryl), -NH-d _-6 alkylCO ₂ H, - NR ¹⁴ R ¹⁵ , with each d _-6 alkyl, or C ₆ -ioaryl, as a group or part of a group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci- ₆ alkyl, or Ci _-6 alkyloxy, and R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; preferably X ¹ is -CH=N-R ¹⁰ ; wherein R ¹⁰ is selected from hydrogen, -OH, -O-Ci _-6 alkyl, -O-d-ealkylCe-ioaryl, -O-Ci _-6 alkylCO ₂ H, -O-Ci _-6 alkylCθ ₂ Ci _-6 alkyl, -NH ₂ , -NH-Ci- ₆ alkyl, -N(C _1-6 alkyl) ₂ , -NH-C ₆ -i ₀ aryl, -N(C ₆ -ioaryl) ₂ , -NH-d-βalkylCβ-ioaryl, -N(Ci _-6 alkyl)(C ₆ - i _O aryl), -NR ¹⁴ R ¹⁵ , with each Ci _-6 alkyl, or C ₆ -ioaryl, as a group or part of a group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or Ci _-6 alkyloxy, and R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; preferably X ¹ is selected from -CH ₂ -NH ₂ , -CH=N-O-H, -CH=N-O- Ci _-6 alkyl, -CH=N-O-C _6- i ₀ aryl, -CH=N-O-Ci _-6 alkylC _6- i ₀ aryl, -CH=N-O-Ci _-6 alkylCO ₂ H, -CH=N-O- Ci _-6 alkylCO ₂ Ci _-6 alkyl, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁴ R ¹⁵ , -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N- NR ¹⁵ Ci _-6 alkylC ₆ -ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkylCO ₂ H, -CH=N-NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ Ci- ₆ alkylCO ₂ Ci _-6 alkyl, wherein R ¹⁵ is selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C6-ioarylCi _-6 alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or Ci _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; X ² is selected from O, S or NR ¹⁶ , wherein R ¹⁶ is hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , or Het ² Ci _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, d-βalkyl, or preferably X ² is selected from O or NR ¹⁶ , wherein R ¹⁶ is selected from hydrogen, d _-6 alkyl, C ₆ -ioaryl, C6-ioarylCi _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci- ₆ alkyl, or d _-6 alkyloxy; preferably X ² is selected from O or NR ¹⁶ , wherein R ¹⁶ is selected from hydrogen, d _-6 alkyl, or C _6- ioaryl; preferably X ² is selected from O or -NH, more preferably X ² is O;

X ³ is selected from -CH ₂ -, -C(=0)- or -C(=S)-; preferably X ³ is -CH ₂ - or -C(=0)-, more preferably X ³ is -C(=O)-;

R ¹ is selected from the group comprising hydrogen, -NH ₂ , d _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ d _-6 alkyl, Het ² , Het ² d _-6 alkyl, and aminocarbonylCi _-6 alkyl ; preferably R ¹ is selected from the group comprising O NH

hydrogen, -NH ₂ , Ci _-6 alkyl, C ₆ -i ₀ aryl, C ₆ -ioarylCi _-6 alkyl, »d ° , "\ ^HX , ^R \ ^HX , and ; preferably R is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, C _6- o o _π 7 u o i _O aryl, ^u , ^M and ^R ; preferably R is selected from the group comprising o o

RV X _R6 A hydrogen, -NH ₂ , Ci _-6 alkyl, ^u , and ^R ; preferably R is selected from the group o

RV. comprising hydrogen, -NH ₂ , Ci _-6 alkyl, and ° ,Λ

R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-6 alkyloxy,

Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, Ce-ioaryld-ealkylcarbonyloxy,

Ci _-6 alkyloxyCi.6alkyloxy, C _3-6 cycloalkyloxy, and Cs-ecycloalkyld-ealkyloxy; preferably R ² and R ³ are each independently selected from the group comprising hydroxyl, d-βalkyloxy, Ci _-6 alkylcarbonyloxy, C ₆ -ioarylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxy ; preferably R ² and R ³ are each independently selected from the group comprising hydroxyl, d-βalkyloxy, Ci _-6 alkylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxy ; preferably R ² and R ³ are each independently hydroxyl, Ci _-6 alkyloxy, or Ci _-6 alkylcarbonyloxy; preferably R ² and R ³ are each independently hydroxyl or Ci _-6 alkyloxy; preferably R ² and R ³ are each independently hydroxyl or methoxy; more preferably R ² and R ³ are each independently hydroxyl;

R ⁴ is selected from the group comprising hydroxyl, d-βalkyloxy, -X ² -X ³ -L-R ¹ , Ci _-6 alkylcarbonyloxy, C ₆ -ioarylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxy; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -X ² -C(=O)-L-R ¹ , Ci _-6 alkylcarbonyloxy, C ₆ -ioarylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxy; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-C(=O)-L-R ¹ , Ci _-6 alkylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxy; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-CO-L-H, -0-CO-L-NH ₂ , -O-CO-L-d-ealkyl, -O-CO-L-Ce-ioaryl, -O-CO-L-CO-O-R ⁷ , -O-CO-L-CO-R ⁶ , and Ci _-6 alkylcarbonyloxy; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -0-CO-L-NH ₂ , -0-CO-L-C ₆ -ioaryl, -O-CO-L-d-ealkylCe-ioaryl, -O-CO-L-CO-O-R ⁷ , and -O-CO-L-CO-R ⁶ ; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-CO-L-H, -0-CO-L-NH ₂ , -O-CO-L-d-ealkyl, -O-CO-L-Cβ-ioaryl, -0-CO-L- d-ealkylCe-ioaryl, -O-CO-L-CO-O-R ⁷ , -O-CO-L-CO-R ⁶ , and d _-6 alkylcarbonyloxy; preferably R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -0-CO-L-NH ₂ , -0-CO-L-CO- O-R ⁷ , and -O-CO-L-CO-R ⁶ ; preferably R ⁴ is hydroxyl or Ci _-6 alkyloxy; preferably R ⁴ is hydroxyl, or methoxy; more preferably R ⁴ is hydroxyl; or

R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, 3-mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4- galactobiosyloxy, maltotriosyloxy, isomaltotriosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, trehalosaminyl-oxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1 -hydroxy-α-D-allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2- amino-2-deoxy-D-galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy- D-glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy-galactosyloxy, 2- amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-4-O- β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D-galactosyl-D-glucosyloxy, 6'-N- acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O-α-L-fucosyl-D-glucosyloxy, 6-0(2- acetamido^-deoxy-β-D-glucosyO-D-galactosyloxy, 2-acetamido-2-deoxy-3-O-β-D-galactosyl- D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D-glucosyl-D-galactosyloxy, 3-fucosyl-D- lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β-D-galactosyl-D-glucosyl oxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, acyl or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D- ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6- deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, maltotriosyloxy, isomaltotriosyloxy, N- acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyloxy, rhamnosaminyloxy, trehalosaminyloxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, acyl or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, and di- or tri-saccharide thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, maltotriosyloxy, isomaltotriosyloxy, N- acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyloxy, rhamnosaminyloxy, trehalosaminyloxy, L or D isomers thereof, α or β form thereof, acyl or benzoyl derivatives thereof, and di- or tri- saccharide thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L- rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6- deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, L or D isomers thereof, α or β form thereof, acyl or benzoyl derivatives thereof, and di- or tri-saccharide thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2- deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6- deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, lactosyloxy, cellobiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; preferably R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy or rhamnosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof;

R ⁵ is selected from the group comprising C _2-6 alkyl; formyl, hydroxyCi _-6 alkyl, -X ¹ , d-ealkylcarbonyloxyd-ealkyl, Ce-ioarylcarbonyloxyd-ealkyl, and

Ce-ioarylCi-ealkylcarbonyloxyd-ealkyl; preferably R ⁵ is selected from the group comprising d- ₆ alkyl; formyl, hydroxyd _-6 alkyl, -CH=N-R ¹⁰ and -CH ₂ -NR ¹¹ R ¹² ; preferably R ⁵ is selected from the group comprising C ₂ -6alkyl; formyl, hydroxyd-βalkyl, -CH ₂ -NH ₂ , -CH=N-O-H, -CH=N-O- Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC6-ioaryl, -CH=N-O-d _-6 alkylCO ₂ H, -CH=N-O- Ci _-6 alkylCO ₂ Ci _-6 alkyl, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ C _6- i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkylC _6- ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkylCO ₂ H, -CH=N-NR ¹⁵ d _-6 alkyl, -CH=N-NR ¹⁵ Ci _-6 alkylC0 ₂ d _-6 alkyl, d-ealkylcarbonyloxyd-ealkyl, C ₆ -ioarylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxyd-ealkyl; preferably R ⁵ is selected from the group comprising formyl, hydroxyd-βalkyl, -CH=N-O-H, - CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC6-ioaryl, -CH=N-O-d _-6 alkylCO ₂ H, - CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkylC6-ioaryl, and d-ealkylcarbonyloxyd-ealkyl; preferably R ⁵ is selected from the group comprising C _2-6 alkyl; formyl, hydroxyd _-6 alkyl, -CH=N-O-H, -CH=N-O-d _-6 alkyl, -CH=N-0-Ci _-6 alkylC6-ioaryl, - CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkylC6-ioaryl, and -CH=N-O-Ci_ ₆ alkylCO ₂ H; preferably R ⁵ is selected from the group comprising formyl, hydroxyd. ₆ alkyl, -CH=N-O-H, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ d _-6 alkyl, -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, and -CH=N-O-Ci _-6 alkyl; preferably R ⁵ is formyl, hydroxyd _-6 alkyl, or -CH=N-O-H; preferably R ⁵ is formyl or -CH=N-O-H; preferably R ⁵ is formyl; R ⁶ is selected from the group comprising hydrogen, d _-6 alkyl, C ₆ -ioaryl, C6-ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , and Het ² d _-6 alkyl, preferably R ⁶ is selected from the group comprising hydrogen, d _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl; preferably R ⁶ is selected from hydrogen, d _-6 alkyl, or C ₆ -ioaryl, preferably R ⁶ is selected from d _-6 alkyl, or C ₆ -ioaryl, and

R ⁷ is selected from the group comprising hydrogen, d _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , and Het ² d _-6 alkyl; preferably R ⁷ is selected from the group comprising hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl; preferably R ⁷ is selected from hydrogen, Ci _-6 alkyl, or C _6- ioaryl; preferably R ⁷ is hydrogen or Ci _-6 alkyl; with the proviso that when L is -NR ⁸ -Ci _-6 alkylene, -NR ⁸ -Ci _-6 alkylene-NR ⁹ -, then R ⁶ and R ⁷ are not hydrogen. In an embodiment, Het ¹ is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or morpholinyl, preferably Het ¹ is selected from pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and Het ² is selected from the group comprising pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, and pyrazinyl; preferably Het ² is selected from the group comprising pyrrolyl, furanyl, imidazolyl, pyrazolyl, pyridinyl, and pyrazinyl.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. The term "C _1-6 alkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula C _n H _2n +i wherein n is a number ranging from 1 to 6. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, Ci _-6 alkyl includes all linear, or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, /-propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n-butyl, /-butyl and tert- butyl); pentyl and its isomers, hexyl and its isomers, and the like. The term "C ₃ -6cycloalkyl", as a group or part of a group, refers to a saturated or partially saturated cyclic alkyl radical containing from about 3 to about 6 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term as a group or part of a group, refers to groups that are divalent, i.e., with two single bonds for attachment to two other groups. The term "Ci _-6 alkylene", as a group or part of a group, refers to Ci _-6 alkyl groups that are divalent. Non- limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, propylene, ethylethylene, 1-methylethylene and 1 ,2-dimethylethylene.

The term "C _1-6 alkyloxy" or "C _1-6 alkoxy", as a group or part of a group, refers to a radical having the Formula -OR ^a wherein R ^a is as defined herein. Non-limiting examples of suitable alkyloxy include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, te/f-butyloxy, pentyloxy and hexyloxy.

The term "C _3-6 cycloalkyloxy", as a group or part of a group, refers to a radical having the Formula -OR ^a wherein R ^d is Cs-βcycloalkyl as defined herein.

The term "Cs-βcycloalkyld-ealkyloxy", as a group or part of a group, refers to a radical having the Formula -OR ^e wherein R ^e is d-βalkoxy as defined herein

The term "carbonyl", as a group or part of a group, refers to a C=O moiety.

The term "C ₆ -ioaryl", as a group or part of a group, is phenyl, naphthyl, indanyl, or 1 ,2,3,4- tetrahydro-naphthyl.

The term "C ₆ -ioarylCi. ₆ alkyl", as a group or part of a group, means a Ci _-6 alkyl as defined herein, wherein a hydrogen atom is replaced by a Cβ-ioaryl as defined herein. Examples of aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2- naphthyl)-butyl, and the like.

As used herein, the term "oxo" or "=O" forms a carbonyl moiety with the carbon atom to which it is attached. The term "formyl" or "-CHO", as a group or part of a group, is an aldehyde moiety whereby the C atom binds to the carbon atom to which it is attached.

The term "hydroxyCi _-6 alkyl", as a group or part of a group, represents a group of Formula -R ^a -OH, wherein R ^a is Ci _-6 alkylene as defined herein.

The term "hydroxycarbonyld-ealkyl", as a group or part of a group, represents a group of Formula -R ^a -COOH, wherein R ^a is as defined herein.

The term "d-ealkoxycarbonyld-ealkyl", as a group or part of a group, represents a group of Formula -R ^a -C00R ^b , wherein R ^a is Ci _-6 alkylene as defined herein and R ^b is Ci _-6 alkyl as defined herein.

The term "aminocarbonyl", as a group or part of a group, refers to the -CO-NH ₂ group. The term "aminocarbonyld-ealkyl", as a group or part of a group, represents a group of Formula -R ^a -CONH ₂ , wherein R ^a is as defined herein.

The term "d _-6 alkylcarbonyloxy", as a group or part of a group, represents a group of Formula -0-C0R ^b , wherein R ^b is as defined herein. The term "C ₆ -ioarylcarbonyloxy", as a group or part of a group, represents a group of Formula -0-C0R ^f , wherein R ^f is Cβ-ioaryl as defined herein.

The term "C ₆ -ioarylCi. ₆ alkylcarbonyloxy", as a group or part of a group, represents a group of Formula -O-COR ^C , wherein R ^c is C ₆ -ioarylCi _-6 alkyl as defined herein. The term "Ce-ioarylCi-ealkylcarbonyloxyd-ealkyl", as a group or part of a group, represents a group of Formula -R ^a -O-COR ^C , wherein R ^a is Ci _-6 alkylene as defined herein and R ^c is C ₆ -ioarylCi _-6 alkyl as defined herein.

The term "C _1-6 alkyloxyCi-6alkyloxy", as a group or part of a group, represents a group of Formula -0-R ^a -0R ^b , wherein R ^a is as defined herein and R ^b is as defined herein.

The terms "Het ¹ " or "heterocyclyl", as a group or part of a group, is defined as a saturated or partially unsaturated monocyclic, or bicyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur. Non limiting exemplary Het ¹ groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, pyrrolidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4- ylsulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl., preferably Het ¹ is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or morpholinyl.

The term Ηet ¹ Ci _-6 alkyl", as a group or part of a group, represents a group of Formula -R ^a -Het ¹ , wherein R ^a is Ci _-6 alkylene as defined herein and Het ¹ has the same meaning as that defined above.

The terms "Het ² " or "heteroaryl", as a group or part of a group, is defined as an aromatic monocyclic, or bicyclic heterocycle having preferably 3 to 12 ring members, more preferably

5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur. Non-limiting examples of a Het ² include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1- b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3- benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2- benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl. Preferably Het ² is selected from the group comprising pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, and pyrazinyl.

The term Ηet ² Ci _-6 alkyl", as a group or part of a group, represents a group of Formula -R ^a -Het ² , wherein R ^a is Ci _-6 alkylene as defined herein and Het ² has the same meaning as that defined above.

The glycosyl terms such as "glucosyl" (also named "glucopyranosyl") "rhamnosyl" etc refer to the residue formed by detaching the anomeric hydroxy group from a saccharide. For instance, the term "rhamnosyl" refers to the residue formed by detaching the anomeric hydroxyl group from rhamnose. The term "glycosyloxy" includes the oxygen of the glycosidic bond.

As used herein before, the term "one or more" covers the possibility of all the available C-atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable, e.g. halogen or alkyl, occurs more than one time in any constituent, each definition is independent. As used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

Whenever used hereinafter, the term "compounds of the invention" or "derivatives" or "analogues" or a similar term is meant to include the compounds of general Formula I or II, i.e. the hellebrin and hellebrigenin derivatives and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 and their N-oxides, salts, stereoisomeric forms, racemic mixtures, pro-drugs, esters and metabolites, as well as their quaternized nitrogen derivatives. The N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. The terms described above and others used in the specification are well understood to those in the art.

The compounds according to the invention contain one or more asymmetric carbon atoms that serve as chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). The invention comprises all such optical forms in all possible configurations, as well as mixtures thereof.

More generally, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers, and mixtures thereof are included within the scope of the invention.

The term stereochemical^ isomeric forms of the compounds according to the invention, as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound herein encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the invention either in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

Preferred features of the compounds of this invention are now set forth. One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L, X ¹ , X ² , X ³ , R ² , R ³ , R ⁴ , R ⁵ have the same meaning as that defined herein and wherein Het ¹ is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or morpholinyl, preferably Het ¹ is selected from pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and Het ² is selected from the group comprising pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, or pyrazinyl; preferably Het ² is selected from the group comprising pyrrolyl, furanyl, imidazolyl, pyrazolyl, pyridinyl, and pyrazinyl.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is Ci _-6 alkylene; -NH-, -NR ⁸ -Ci _-6 alkylene, -NR ⁸ -Ci _-6 alkylene-NR ⁹ -, wherein R ⁸ and R ⁹ are each independently selected from hydrogen or a group comprising Ci _-6 alkyl, C ₆ -ioaryl, and C ₆ -ioarylCi _-6 alkyl;

X ¹ is -CH=N-R ¹⁰ or -CH ₂ -NH ₂ ; wherein R ¹⁰ is selected from hydrogen, -OR ¹³ or -NR ¹⁴ R ¹⁵ ; wherein R ¹³ is hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, or aminocarbonylCi-βalkyl, each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci _-6 alkyl, or Ci _-6 alkyloxy; wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , or Het ² Ci _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from azetidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy;

X ² is selected from O or NR ¹⁶ , wherein R ¹⁶ is selected from hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, C6-ioarylCi _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or Ci _-6 alkyloxy;

X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, C ₆ -ioaryl,

O NH o O

C ₆ -ioarylCi _-6 alkyl, ° , ^« S . ^μ AA , ^« "SS ^H AA and ^R

R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy ;

R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -X ² -C(=O)-L-R ¹ , Ci _-6 alkylcarbonyloxy, C _6- ioarylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy; or

R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, 3-mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4- galactobiosyloxy, maltotriosyloxy, isomaltotriosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, trehalosaminyl-oxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy-α-D-allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2- amino-2-deoxy-D-galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy- D-glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy-galactosyloxy, 2- amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-4-O- β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D-galactosyl-D-glucosyloxy, 6'-N- acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O-α-L-fucosyl-D-glucosyloxy, 6-0(2- acetamido^-deoxy-β-D-glucosyO-D-galactosyloxy, 2-acetamido-2-deoxy-3-O-β-D-galactosyl- D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D-glucosyl-D-galactosyloxy, 3-fucosyl-D- lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β-D-galactosyl-D-glucosyl oxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, acyl or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof;

R ⁶ is selected from the group comprising hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl; and

R ⁷ is selected from the group comprising hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein

L is Ci_i ₂ alkylene or -NR ⁸ -Ci_6alkylene, wherein R ⁸ and R ⁹ are each independently selected from hydrogen, C _1-6 alkyl, or C ₆ -i ₀ aryl;X ¹ is -CH=N-R ¹⁰ or -CH ₂ -NH ₂ ; wherein R ¹⁰ is selected from hydrogen, -OR ¹³ , or -NR ¹⁴ R ¹⁵ ; wherein R ¹³ is hydrogen or a group selected from Ci-

₆ alkyl, C ₆ -ioaryl, C ₆ -ioarylCi _-6 alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ ,

Het ¹ Ci _-6 alkyl, Het ² , Het ² Ci _-6 alkyl, or aminocarbonylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, Ci- εalkyl, or wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen or a group selected from Ci _-6 alkyl, C ₆ -ioaryl, C ₆ -ioarylCi- ₆ alkyl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ² , or Het ² Ci _-6 alkyl; each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, d-βalkyl, or d-βalkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from azetidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, or thiomorpholinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, Ci _-6 alkyl, and Ci _-6 alkyloxy;

X ² is O; X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, C ₆ -ioaryl, o o

C ₆ -ioarylCi _-6 alkyl, ° , and ^κ ;

R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-6 alkylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy;

R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-C(=O)-L-R ¹ , Ci _-6 alkylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy; or

R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, maltotriosyloxy, isomaltotriosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyloxy, rhamnosaminyloxy, trehalosaminyloxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, acyl or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, and di- or tri- saccharide thereof;

R ⁵ is selected from the group comprising C _2- 6alkyl; formyl, hydroxyCi _-6 alkyl, -CH ₂ -NH ₂ , -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC ₆ -ioaryl, -CH=N-O-Ci _-6 alkylCO ₂ H, -CH=N-O-Ci _-6 alkylCO ₂ Ci _-6 alkyl, -CH=N-NHR ¹⁵ ,

-CH=N-NR ¹⁵ C ₆ -ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkylC ₆ -ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkylCO ₂ H, -CH=N-NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ Ci _-6 alkylCθ ₂ Ci _-6 alkyl, d-ealkylcarbonyloxyd-ealkyl, C _6- ioarylcarbonyloxy, and Ce-ioaryld-ealkylcarbonyloxyd-ealkyl;

R ⁶ is selected from hydrogen, Ci _-6 alkyl, or C _6- ioaryl; and

R ⁷ is selected from the group comprising hydrogen, Ci _-6 alkyl, C ₆ -ioaryl, and C6-ioarylCi _-6 alkyl. One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ¹ is selected from the group o o comprising hydrogen, -NH ₂ , C _1-6 alkyl, C ₆ -i ₀ aryl, ^ ⁰ , and ^R ; and X ¹ , X ² , X ³ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and L have the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-C(=O)-L-R ¹ , and Ci _-6 alkylcarbonyloxy; and X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁵ and L have the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ⁵ is selected from the group comprising formyl, hydroxyCi _-6 alkyl, -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC ₆ -ioaryl, -CH=N-O-Ci _-6 alkylCO ₂ H, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ Ci _-6 alkyl, - CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkylC6-ioaryl, and d-ealkylcarbonyloxyd-ealkyl; and X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ , and L have the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -O-CO-L-H, -0-CO-L-NH ₂ , -O-CO-L-Ci _-6 alkyl, -0-CO-L-C _{6- l} oaryl, -O-CO-L-d-ealkylCe-ioaryl, -O-CO-L-CO-O-R ⁷ , -O-CO-L-CO-R ⁶ , and Ci _-6 alkylcarbonyloxy; wherein R ⁶ is selected from hydrogen, d _-6 alkyl, or C _6- ioaryl and R ⁷ is selected from the group comprising hydrogen, d _-6 alkyl, C _6- ioaryl, and C ₆ -ioarylCi _-6 alkyl; or R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, θ-deoxy-S-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, maltotriosyloxy, isomaltotriosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyloxy, rhamnosaminyloxy, trehalosaminyloxy, L or D isomers thereof, α or β form thereof, acyl or benzoyl derivatives thereof, and di- or tri-saccharide thereof; and X, R ¹ , R ² , R ³ , R ⁵ , R ⁶ and L have the same meaning as defined herein.

Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula Ia or Na,

Ia Na wherein X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and L have the same meaning as that defined herein.

Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula Ib or lib,

Ib Nb wherein X ¹ , X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and L have the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein X ¹ is -CH=N-O-R ¹³ and R ¹³ has the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein X ¹ is -CH=N-NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ have the same meaning as that defined herein.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is selected from the group comprising -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -CH(CH ₃ )-CH(CH ₃ )- , -(CH ₂ ) ₃ -, -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, -CH(CH ₃ )-CH ₂ -CH ₂ -; -CH ₂ -CH ₂ -CH(CH ₃ )-, - CH(CH ₃ )-CH(CH ₃ )-CH ₂ -, and -CH ₂ -C(CH ₃ ) ₂ -(CH ₃ ) ₂ -; X ¹ is -CH=N-O-R ¹³ or -CH=N-NR ¹⁴ R ¹⁵ , wherein each R ¹³ and R ¹⁴ is independently hydrogen or a group selected from d-βalkyl, Ce- i _O aryl, C ₆ -ioarylCi- ₆ alkyl, hydroxycarbonylCi _-6 alkyl, d-ealkoxycarbonyld-ealkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, nitro, halo, d-βalkyl, or d^alkyloxy; wherein R ¹⁵ is selected from hydrogen or a group selected from d-βalkyl, C ₆ -ioaryl, C6-ioaryld-6alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, d _-6 alkyl, or d _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl, said heterocyclyl group being optionally substituted with one or two substituents independently selected from the group comprising hydroxyl, halo, d-βalkyl, and d _-6 alkyloxy;

X ² is O and X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, -NH ₂ , d _-6 alkyl, o o

C ₆ -ioaryl, ^υ , and ^κ ; R and R are each independently selected from the group comprising hydroxyl, d _-6 alkyloxy, d _-6 alkylcarbonyloxy, and di-ioaryld-ealkylcarbonyloxy; R ⁴ is selected from the group comprising hydroxyl, d _-6 alkyloxy, -O-CO-L-H, -0-CO-L-NH ₂ , -O- CO-L-d _-6 alkyl, -O-CO-L-Cβ-ioaryl, -O-CO-L-CO-O-R ⁷ , -O-CO-L- CO-R ⁶ , and Ci _-6 alkylcarbonyloxy; or R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, θ-deoxy-S-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, threosyloxy, sorbosyloxy, tagatosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, maltotriosyloxy, isomaltotriosyloxy, N- acetylgalactosaminyloxy, mannotriosyloxy, chitobiosyloxy, chitobiosemannosyloxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyloxy, rhamnosaminyloxy, trehalosaminyloxy, L or D isomers thereof, α or β form thereof, acyl or benzoyl derivatives thereof, and di- or tri- saccharide thereof; R ⁵ is selected from the group comprising formyl, hydroxyd-βalkyl, -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC6-ioaryl, -CH=N-O- Ci _-6 alkylCO ₂ H, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ d _-6 alkyl, -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N- NR ¹⁵ d-6alkylC6-ioaryl, and d-ealkylcarbonyloxyd-ealkyl; R ⁶ is selected from d _-6 alkyl or C _6- i _O aryl; and R ⁷ is selected from hydrogen, d _-6 alkyl, or C _6- ioaryl.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is selected from the group comprising CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -CH(CH ₃ )-CH(CH ₃ )-, -(CHz) ₃ -, -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -, -NH-CH ₂ , -NH-CH ₂ -CH ₂ -, and -NH-CH(CH ₃ )-;

X ¹ is selected from -CH ₂ -NH ₂ , -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-

0-Ci _-6 alkylC _6- ioaryl, -CH=N-O-Ci _-6 alkylCO ₂ H, -CH=N-O-Ci _-6 alkylCO ₂ Ci _-6 alkyl, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁴ R ¹⁵ , -CH=N-NR ¹⁵ C ₆ -ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkylC ₆ -ioaryl,

-CH=N-NR ¹⁵ Ci _-6 alkylCO ₂ H, -CH=N-NR ¹⁵ Ci _-6 alkyl, or -CH=N-NR ¹⁵ Ci _-6 alkylCO ₂ Ci _-6 alkyl, wherein R ¹⁵ is selected from hydrogen or a group selected from Ci _-6 alkyl, C _6- ioaryl,

C ₆ -ioarylCi _-6 alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or Ci _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; X ² is O, and

X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, C ₆ -ioaryl, ; R and R are each independently selected from the group comprising hydroxyl, Ci _-6 alkyloxy, Ci _-6 alkylcarbonyloxy, and Ce-ioarylCi-ealkylcarbonyloxy; R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -0-CO-L-NH ₂ , -0-CO-L-C6-ioaryl, -0-CO-L- Ci _-6 alkylC6-ioaryl, -O-CO-L-CO-O-R ⁷ , and -O-CO-L-CO-R ⁶ ; or R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D- ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6- deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, L or D isomers thereof, α or β form thereof, acyl or benzoyl derivatives thereof, and di- or tri-saccharide thereof; R ⁵ is selected from the group comprising C _2-6 alkyl;formyl, hydroxyCi _-6 alkyl, -CH=N-O-H, -CH=N-O- Ci _-6 alkyl, -CH=N-O-Ci _-6 alkylC _6- i ₀ aryl, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ C _{6- l} oaryl, -CH=N-NR ¹⁵ Ci _-6 alkylC6-ioaryl, and -CH=N-O-Ci _-6 alkylCO ₂ H; R ⁶ is selected from Ci- ₆ alkyl, or C _6- ioaryl; and R ⁷ is hydrogen or Ci _-6 alkyl.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is selected from the group comprising -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -, -CH(CH ₃ )-CH(CH ₃ )- , -(CH ₂ ) ₃ -, and -CH ₂ -C(CH ₃ ) ₂ -CH ₂ -;

X ¹ is selected from -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C ₆ -i ₀ aryl, -CH=N-0-Ci _-6 alkylC _6- ioaryl, -CH=N-O-Ci _-6 alkylCO ₂ H, -CH=N-O-Ci _-6 alkylCO ₂ Ci _-6 alkyl, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁴ R ¹⁵ , -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkylC ₆ -ioaryl, -CH=N-NR ¹⁵ Ci- ₆ alkyl, wherein R ¹⁵ is selected from hydrogen or a group selected from Ci _-6 alkyl, C _6- ioaryl, C6-ioarylCi _-6 alkyl, Het ¹ , or Het ² , each group being optionally substituted with one or two substituents independently selected from hydroxyl, halo, nitro, Ci _-6 alkyl, or C-i-βalkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; X ² is O and X ³ is -C(=O)-; o o

R is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, ^υ , and ^κ ; R and R ³ are each independently selected from the group comprising hydroxyl, C-i-βalkyloxy, Ci _-6 alkylcarbonyloxy, and benzylcarbonyloxy ; R ⁴ is selected from the group comprising hydroxyl, Ci _-6 alkyloxy, -0-CO-L-NH ₂ , -O-CO-L-CO-O-R ⁷ , and -O-CO-L-CO-R ⁶ ; or R ⁴ is selected from the group comprising glucopyranosyl-α-L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy-α-D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, 6-deoxy-3-O-methylgalactosyloxy, rhamnosylglucosyloxy, rhamnosylrhamnosyloxy, fructosyloxy, sucrosyloxy, ribulosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; R ⁵ is selected from the group comprising formyl, hydroxyCi _-6 alkyl, -CH=N-O-H, -CH=N-NHR ¹⁵ , -CH=N- NR ¹⁵ Ci _-6 alkyl, -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, and -CH=N-O-Ci _-6 alkyl; R ⁶ is C _1-6 alkyl or C ₆ -i ₀ aryl, and R ⁷ is hydrogen or Ci _-6 alkyl.

An embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein R ² and R ³ are each independently hydroxyl or and X ¹ , X ² , X ³ , R ¹ , R ³ , R ⁴ , R ⁵ , and L have the same meaning as that defined above; preferably R ² and R ³ are each independently hydroxyl or methoxy; preferably R ² and R ³ are each independently hydroxyl.

An embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is selected from the group comprising -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -(CH ₂ ) ₃ -, and -CH ₂ - C(CH ₃ ) ₂ -CH ₂ -; X ¹ is selected from -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-O-C _6- i ₀ aryl, -CH=N-0-Ci _-6 alkylC ₆ -ioaryl, -CH=N-0-Ci _-6 alkylC0 ₂ H, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁴ R ¹⁵ , -CH=N-NR ¹⁵ C ₆ -ioaryl, -CH=N-NR ¹⁵ Ci _-6 alkyl, wherein R ¹⁵ is selected from hydrogen or a group selected from Ci _-6 alkyl, C _6- ioaryl, C ₆ -ioarylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from halo, nitro, Ci _-6 alkyl, or C-i-βalkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, or piperazinyl; X ² is O and X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, - o

NH ₂ , Ci _-6 alkyl, and ^υ ; R and R are each independently hydroxyl, or Ci _-6 alkyloxy; R is hydroxyl, or Ci _-6 alkyloxy; or R ⁴ is selected from the group comprising glucopyranosyl-α-L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, θ-deoxy-3-O-methylgalactosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; R ⁵ is formyl, or hydroxyC-i-βalkyl; and R ⁷ is hydrogen or Ci _-6 alkyl.

One embodiment of the present invention concerns compounds of Formula I or II, any subgroup thereof, or stereoisomeric forms thereof, wherein L is selected from the group comprising -CH ₂ , -CH ₂ -CH ₂ -, -CH(CH ₃ )-, CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ -; -(CHz) ₃ -, and -CH ₂ - C(CH ₃ ) ₂ -CH ₂ -;

X ¹ is selected from -CH=N-O-H, -CH=N-O-Ci _-6 alkyl, -CH=N-0-Ci _-6 alkylC ₆ -ioaryl, -CH=N-O- Ci _-6 alkylCO ₂ H, -CH=N-NHR ¹⁵ , -CH=N-NR ¹⁴ R ¹⁵ , -CH=N-NR ¹⁵ C ₆ -i ₀ aryl, -CH=N-NR ¹⁵ Ci _-6 alkyl, wherein R ¹⁵ is selected from hydrogen or a group selected from Ci _-6 alkyl, C _6- ioaryl, C6-ioarylCi _-6 alkyl, each group being optionally substituted with one or two substituents independently selected from halo, nitro, Ci _-6 alkyl, or Ci _-6 alkyloxy; or R ¹⁴ and R ¹⁵ together with the N atom to which they are attached form a heterocyclyl group selected from morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl;

X ² is O and X ³ is -C(=O)-; R ¹ is selected from the group comprising hydrogen, -NH ₂ , Ci _-6 alkyl, o and ^υ ; R and R are each independently hydroxyl, or d-βalkyloxy; R is hydroxyl, or methoxy; or R ⁴ is selected from the group comprising glucopyranosyl-α-L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, lactosyloxy, cellobiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, L or D isomers thereof, α or β form thereof, and acyl or benzoyl derivatives thereof; R ⁵ is formyl or hydroxyC-i-βalkyl, and R ⁷ is hydrogen or d-ealkyl.

Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula Id , Ic2, Nd or Ilc2,

Nd Ilc2 wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ and L have the same meaning as that defined herein, preferably R ¹ is hydrogen, C _6- ioaryl, or Ci _-6 alkyl.

Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula Id1 , Id2, Ild1 or Nd2,

Hd-I Nd2 wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ and L have the same meaning as that defined herein, preferably R ¹ is hydrogen, C _6- ioaryl, or Ci _-6 alkyl. Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula Ie1 , Ie2, Ile1 or Ne2,

Ile1 Ne2 wherein R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ and L have the same meaning as that defined herein; preferably R ¹ is hydrogen, C _6- ioaryl, or Ci _-6 alkyl.

Particular subgroups of compounds of Formula I or Il are those represented by the following structural Formula If 1 , If2, NfI or Nf2,

NfI 1112 wherein R ¹ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁸ and L have the same meaning as that defined herein; preferably R ¹ is hydrogen, C _6- ioaryl, or Ci _-6 alkyl. In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I or Il or any subgroup thereof.

The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I or II, and any subgroup thereof, for which general reference is made to the prior art cited hereinbelow. The term "pro-drug" as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bioavailability and are readily metabolized into the active inhibitors in vivo. The term "pre-drug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated.

For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form of a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, and the like. Such salts, hydrates, solvates, etc., and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US- A-6,372,778, US-A-6,369,086, US-A-6,369,087, and US-A-6,372,733.

For therapeutic use, the salts of the compounds according to the invention are those wherein the counterion is pharmaceutically or physiologically acceptable.

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen- containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

The pharmaceutically acceptable esters of the compounds according to the invention refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred. However, other esters such as phenyl-alkyl may be employed if desired. The compounds of the invention are particularly useful as medicament. The compounds according to the invention show cytotoxic activities, which implies that they may be used in various medical applications. As is demonstrated in the examples given below, the compounds according to the invention have in vitro anti-tumor activity. The compounds according to the invention bind to the alpha-1 subunit and/or to the alpha-3 subunit of Na ⁺ ,K ⁺ -ATPase.

The term "binding" as used herein generally refers to a physical association, preferably herein a non-covalent physical association, between molecular entities, e.g., between a "ligand" (generally referring to any agent, e.g., a substance or molecule) and a "receptor" (generally referring to any molecule). Preferably, a "receptor" may be a polypeptide or protein, such as, e.g., the alpha-1 subunit or the alpha-3 subunit of NKA, or variants or fragments thereof, or a nucleic acid encoding such, etc. Preferably, a "ligand" may be, e.g., a polypeptide or protein, an antibody, a peptide, a peptidomimetic, an aptamer, a chemical substance (preferably an organic molecule, more preferably a small organic molecule), a lipid, a carbohydrate, a nucleic acid, etc.

Furthermore, the compounds according to the invention exhibit a low toxicity level. "Toxicity" is related to the detrimental effect a compound may exhibit on healthy cells, tissues or organs. The toxicity level of the compounds according to the invention is surprisingly low. The compounds according to the invention combine the essential features of a good anti- tumor activity and a low level of toxicity. Consequently the compounds according to the invention may be used in pharmaceutical compositions for the treatment of various diseases. In addition, because they have a relatively low level of toxicity the compounds according to the invention may be used during longer periods of treatments.

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic effective amount of at least one compound according to the invention.

The term "therapeutically effective amount" as used herein means that amount of compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

The pharmaceutical composition can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one compound according to the invention having Formula I or Il or any subgroup or derivative thereof, one or more solid or liquid pharmaceutical excipients and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine.

Particular forms of the pharmaceutical composition may be, for example, solutions, suspensions, emulsions, creams, tablets, pills, capsules, nasal sprays, liposomes or micro- reservoirs, especially compositions in orally ingestible or sterile injectable form, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration. The solid carrier may comprise one or more excipients, e.g. lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, fillers, disintegrating agents, binders, e.g. cellulose, carboxymethylcellulose or starch or anti-stick agents, e.g. magnesium stearate, to prevent tablets from adhering to tabletting equipment, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Tablets, pills and boluses may be formed so as to disintegrate rapidly or to provide slow release of the active ingredient. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying, and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained, or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ o, β- or v- cyclodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention are obviously more suitable due to their increased water solubility.

Appropriate cyclodextrins are o, β- or γ-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl, particularly acetyl; alkyloxycarbonylalkyl or carboxyalkyloxyalkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6- dimethyl- β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2- carboxymethoxy)propyl- β-CD, and in particular 2-hydroxypropyl- β-CD (2-HP- β-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. An interesting way of formulating the compounds according to the invention in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds according to the invention. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors.

More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.

The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.

The water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20 ⁰ C solution. Preferred water- soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. The compounds according to the invention as defined hereinabove can be prepared by first preparing a solid dispersion of the compounds according to the invention, and then optionally grinding or milling that dispersion. Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt- extrusion being preferred.

It may further be convenient to formulate the compounds according to the invention in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an a nti retroviral agent and (c) a seal-coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to US-A- 6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule, or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300, or 400 mg per unit dosage. Another important feature attributed to the compounds according to the invention is their broad application possibility. The compounds according to the invention are highly active against several types of cancers. As will be shown in the examples described below, the compounds according to the invention exert significant anti-tumor effects on several tumor models tested, including glioma, colon, lung (non small cell lung cancer NSCLC), prostate, breast and pancreatic cancer (see examples). Importantly, the compounds according to the invention exhibit anti-tumor activity on a broad panel of histological tumor types. In addition, the compounds according to the invention bind to the alpha-1 subunit and/or to the alpha-3 subunit of Na ⁺ ,K ⁺ -ATPase and they exhibit a relatively low toxicity level. Therefore, due to their favorable pharmacological properties the compounds according to the present invention are particularly suitable for use as medicaments in the treatment of individuals suffering from diseases associated with cell proliferation. In another embodiment, the compounds according to the present invention are used as a medicament, in particular for the prevention and/or treatment of cancer, and/or for preventing, treating, and/or alleviating complications, and/or symptoms, and/or inflammatory responses associated therewith. In yet another embodiment, the compounds according to the present invention are used in the preparation of a medicament for treating diseases associated with cell proliferation. In particular the compounds according to the present invention are used in the preparation of a medicament for treating cancer. The term "treating" as used herein includes treating any one or more of the conditions underlying or characteristic of cancer. Treatment of cancer means administration of a medicament with the result that cancer is reduced or the patient is cured.

The term "individual," as used herein refers to an animal, preferably a mammal such a human or an animal, and most preferably a human, who has been the object of treatment, observation or experiment.

The term "diseases associated with cell proliferation"' as used herein refers to, but is not limited to, any type of cancer or condition involving cell proliferation.

The compounds of the invention may be especially used in (the preparation of a medicament for) the treatment of cancers such as, but not limited to, leukemia, non-small cell lung cancer, small cell lung cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, glioma, colon cancer, bladder cancer, head and neck cancer, pancreas cancer, sarcoma, pancreatic cancer, colorectal cancer, skin cancer, liver cancer, bone cancer, bone marrow cancer, stomach cancer, duodenum cancer, oesophageal cancer, thyroid cancer, hematological cancer, and lymphoma. Accordingly, the present invention provides a method for the treatment and/or prevention of cancer comprising administering to an individual an effective amount of at least one compound of Formula I or II, or any subgroup thereof as defined above. By way of example, in an embodiment of the invention, cancer is treated in a subject in need of treatment by administering to the subject a therapeutically effective amount of at least one compound of Formula I or II, or any subgroup thereof, effective to treat the cancer. The subject is preferably a mammal (e.g., humans, domestic animals, and commercial animals, including cows, dogs, monkeys, mice, pigs, and rats), and is most preferably a human.

In addition, the compounds according to the invention may also be very suitable in the treatment of scar tissue and wounds. It is believed that most, if not all, of the compounds of the present invention can act as active ingredients in treating scar tissue and in promoting wound healing and tissue regeneration.

In another embodiment, the invention relates to a method of treatment of diseases associated with cell proliferation comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. In particular, the invention relates to a method of treating cancer comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention.

For these purposes, the compounds or the pharmaceutical composition of the present invention may be administered orally, parenterally, i.e. including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques, by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the Formula I or Il that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.001 to 1000 mg per kilogram body weight, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087, and US-A-6,372,733, and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

Essentially, the primary modes of treatment of solid tumor cancers comprise surgery, radiation therapy and chemotherapy, separately and in combination. The compounds according to the invention are suitable for use in combination with these medicinal techniques. The compounds of the invention may be useful in increasing the sensitivity of tumor cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumors by chemotherapeutic agents. The compounds and their pharmaceutically acceptable salts and/or solvates may also be useful for sensitizing multidrug-resistant tumor cells. The compounds according to the invention are useful therapeutic compounds for administration in conjunction with DNA-damaging cytotoxic drugs or radiation used in radiotherapy to potentiate their effect.

In another embodiment of the method of the invention, the administration may be performed with food, e.g., a high-fat meal. The term "with food" means the consumption of a meal either during or no more than about one hour before or after administration of a pharmaceutical composition according to the invention. Some of the compounds can additionally orally bioavailable enabling thus the development or drugs for oral use which is more comfortable for the patients than intravenous injections.

For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. The oral administration of a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt or ester or solvate thereof, is suitably accomplished by uniformly and intimately blending together a suitable amount of said compound in the form of a powder, optionally also including a finely divided solid carrier, and encapsulating the blend in, for example, a hard gelatin capsule. The solid carrier can include one or more substances, which act as binders, lubricants, disintegrating agents, coloring agents, and the like. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Oral administration of a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt or ester and/or solvate thereof can also be accomplished by preparing capsules or tablets containing the desired amount of said compound, optionally blended with a solid carrier as described above. Compressed tablets containing the pharmaceutical composition of the invention can be prepared by uniformly and intimately mixing the active ingredient with a solid carrier such as described above to provide a mixture having the necessary compression properties, and then compacting the mixture in a suitable machine to the shape and size desired. Molded tablets maybe made by molding in a suitable machine, a mixture of powdered compound according to the invention moistened with an inert liquid diluent. When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous or intravenous administration, the compounds of the invention, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3- butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. The pharmaceutical compositions of this invention can be administered to humans in dosage ranges specific for each compound comprised in said compositions. The compounds comprised in said composition can be administered together or separately.

It will be understood, however, that specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound of the invention employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The compounds according to the invention may be prepared by a method of chemical synthesis, starting from Hellebrin or other compounds. The methods of synthesis of the compounds according to the invention involve chemical modifications of Hellebrin or derivatives thereof. Hellebrin can be obtained by any convenient method, for example by chemical synthesis. Alternatively, it may also be obtained from extraction and purification from e.g. plants of the Ranunculaceae family, which produce Hellebrin naturally, e.g. Helleborus foetidus, Helleborus orientalis or Helleborus niger.

It will also be clear that when the desired compounds of the invention, and/or the starting materials, precursors, and/or intermediates used in the preparation thereof, contain functional groups that are sensitive to the reaction conditions used in the preparation of the compounds of the invention (i.e. that would undergo undesired reactions under those conditions if they were not suitably protected) can be protected during said reaction with one or more suitable protective group, which protective group can then be suitably removed after either completion of said reaction and/or as a later or final step in the preparation of the compounds of the invention. Protected forms of the inventive compounds are included within the scope of the present invention. Suitable protective groups, as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention.

The following examples are meant to illustrate the present invention. These examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention. Examples

Example 1 : Compounds according to the invention:

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic organic chemistry, biological testing, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. The compounds according to the invention are prepared by a method of chemical synthesis, starting from Hellebrin or other compounds. Hellebrin can be obtained by any convenient method, for example by chemical synthesis or from extraction and purification from e.g. plants of the Ranunculaceae family, for e.g. Helleborus foetidus, Helleborus orientalis, Helleborus niger, Helleborus purpurascens, Helleborus atrorubens, Helleborus dumetorum or Helleborus multifidus. Hellebrigenin can be obtained in good yield by treatment of Hellebrin with a glycolytic enzyme (Cellulase, naringinase).

In particular compounds of Formula 11 and Nb encompassed in the present invention can be prepared according to the general procedure shown hereunder in scheme 1 and scheme 2, respectively, wherein R ¹² is hydrogen or D-glucopyranosyl-a-L-rhamnosyl, R ²⁰ has the same meaning as R ¹ or is a protected form of R ¹ , X ⁴ is a suitable leaving group or an activated form thereof, or R ²⁰ together with -X ³ -X ⁴ form a -0-CO-O- group and X ² , X ³ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹¹ , and L have the same meaning as that defined herein.

Scheme 1 Preparation of Compound 1 (UNBS5463):

In a dry round-bottom flask, under N ₂ , hellebrin (50 mg, 6.9 10 ^"5 M) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OH-HCI (24 mg, 3.5 10 ^"4 M) was then added and the mixture was stirred at room temperature for 48h. The mixture was then concentrated in vacuo. Chromatography on normal silica was performed with CHC^/MeOH 4/1 as eluent and the solvent was removed under vacuo. The solid was dissolved into H ₂ O/MeOH (1/1 , 25 ml). The solution was concentrated at 30 ⁰ C under vacuo then lyophilized overnight, then stocked at - 20 ⁰ C. 48 mg of compound 1 were obtained (yield = 95%).

Compound 1 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 10.51 (1 H, s), 7.94 (1 H, dd, J = 2.7 and 9.6); 7.66 (1 H, s), 7.55 (1 H, d, J = 1.5); 6.31 (1 H, d, J = 9.6); 5.45 (1 H, d, J = 3.6); 5.03 (4H, m); 4.74 (1 H, s); 4.41 (2H, m); 4.26 (1 H, bs); 4.01 (1 H, bs); 3.87 (1 H, s); 3.65-1.10 (34H) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 740.4 (M+H); 722.4; 578.4; 432.3; 414.3; 396.3. Preparation of Compound 2 (UNBS5466):

In a dry round-bottom flask, under N ₂ , hellebrin (60 mg, 8.3 10 ^"5 M) was suspended in EtOH (12 ml) and pyridine (1.2 ml). NH ₂ OBn. HCI (68 mg, 4.3 10 ^"4 M) was then added and the mixture was stirred at room temperature for 48h. The mixture was then concentrated in vacuo. Chromatography on normal silica was performed with CHC^/MeOH 6/1 as eluent then the solid was dissolved into H ₂ O/MeOH (1/1 , 25 ml). The solution was concentrated at 30 ⁰ C under vacuo then lyophilized overnight, then stocked at -20 ⁰ C. 65 mg of compound 2 were obtained (yield = 95%).

Compound 2 was characterized by: - ¹ H NMR (300 MHz, DMSO) as follows : 7.93 (1 H, dd, J = 2.1 and 9.9); 7.79 (1 H, s), 7.54 (1 H, d, J = 1.5); 7.35-7.28 (5H); 6.31 (1 H, d, J = 10.2); 5.46 (1 H, d, J = 3.9); 5.08- 4.99 (5H, m); 4.92 (1 H, d, J = 5.4); 4.74 (1 H, s); 4.41 (2H, m); 4.23 (1 H, bs); 3.99 (1 H, bs); 3.94 (1 H, s); 3.67 (3H, m); 3.50 (2H, m); 3.15 (4H, m); 2.14-1.10 (25H) and 0.50 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 830.4 (M+H); 668.4; 522.3; 504.3; 486.3.

Preparation of Compound 3 (UNBS5467):

In a dry round-bottom flask, under N ₂ , hellebrin (50 mg, 6.9 10 ^"5 M) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OMe. HCI (29 mg, 3.5 10 ^"4 M) was then added and the mixture was stirred at room temperature for 48h. The reaction process was followed by TLC (normal SiO ₂ , CHC^/MeOH = 4/1 ). Chromatography on normal silica was performed with CHCI ₃ /MeOH 4/1 as eluent. The solvents were removed under vacuo then the solid was dissolved into H ₂ O/MeOH (1/1 , 40 ml). The solution was concentrated at 30 ⁰ C under vacuo then lyophilized overnight. This last operation was repeated, then stocked at -20 ⁰ C. 32 mg of compound 3 were obtained (yield = 62%).

Compound 3 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.93 (1 H, dd, J = 2.4 and 9.6); 7.71 (1 H, s), 7.54 (1 H, d, J = 1.5); 7.35 (1 H, m); 6.31 (1 H, d, J = 9.9); 5.45 (1 H, d, J = 3.6); 5.07-4.93

(4H, m); 4.75 (1 H, s); 4.41 (2H, m); 4.26 (1 H, bs); 4.00 (1 H, bs); 3.93 (1 H, s); 3.80- 3.65 (6H, m); 3.50 (2H, m); 3.12 (4H, m); 2.14-1.14 (24H) and 0.57 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 754.3 (M+H); 592.3; 446.2; 428.2; 410.2. Preparation of Compound 4 (UNBS5471):

In a dry round-bottom flask, under N ₂ , hellebrin (50 mg, 6.9 10 ^"5 M) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OCH ₂ CO ₂ H-HCI (109 mg, 3.5 10 ^"4 M) was then added and the mixture was stirred at room temperature for 48h. The reaction process was followed by TLC (normal SiO ₂ , CHCI ₃ /MeOH = 2/1 ). Chromatography on normal silica, CHCI ₃ /MeOH 2/1 was performed. The solvents were removed under vacuo then second chromatography on normal silica, CHC^/MeOH 4/1 then 2/1 then pure MeOH. The solvents were removed under vacuo then the solid was dissolved into H ₂ O/MeOH (1/1 , 20 ml). The solution was concentrated at 30 ⁰ C under vacuo then lyophilized overnight, then stocked at -20 ⁰ C. 29 mg of compound 4 were obtained (yield = 55%). Compound 4 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.95 (1 H, dd, J = 2.7 and 9.3); 7.72 (1 H, s), 7.55 (1 H, d, J = 1.5); 7.35 (1 H, m); 6.31 (1 H, d, J = 9.6); 5.18-5.05 (3H, m); 4.74 (1 H, s); 4.40 (2H, m); 4.28 (1 H, bs); 4.10 (1 H, bs); 3.99 (1 H, s); 3.91 (1 H, s); 3.71-3.66 (4H, m); 3.50 (2H, m); 3.12 (2H, m); 2.14-1.10 (25H) and 0.59 (3H, s). - mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 799.4 (M+H); 490.2; 472.2; 454.3; 436.2; 363.2.

Preparation of Compound 5 (UNBS5468):

In a dry round-bottom flask, under N ₂ , hellebrigenin (65 mg, 1.6 10 ^"4 M) was dissolved in EtOH (10 ml) and pyridine (1 ml). NH ₂ OH-HCI (54 mg, 7.8 10 ^"4 M) was then added and the mixture was stirred at room temperature for 24h. The reaction process was followed by TLC

(normal SiO ₂ , DCM/MeOH = 9/1 ). The mixture was then concentrated in vacuo and chromatography on normal silica, DCM/MeOH 9/1 was performed. The solvents were removed under vacuo then the solid was dissolved into H ₂ O/MeOH (1/1 , 40 ml). The solution was concentrated at 30°C under vacuo then lyophilized overnight, then stocked at -20 ⁰ C. 65 mg of compound 5 were obtained (yield = 94%).

Compound 5 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 10.45 (1 H, s), 7.93 (1 H, dd, J = 2.7 and 9.9); 7.65 (1 H, s), 7.54 (1 H, d, J = 1.5); 6.31 (1 H, d, J = 9.3); 5.25 (1 H, d, J = 3.6); 4.99 (1 H, s); 4.23 (1 H, s); 4.03 (1 H, bs); 2.15-1.96 (5H); 1.71-1.10 (15H) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 863.4 (2M+H); 432.2; 414.2; 396.2; 378.3; 368.2.

Preparation of Compound 6 (UNBS5544):

In a dry round-bottom flask, under N ₂ , hellebrigenin (60 mg, 0.144 mmole) was dissolved at 0 ⁰ C in dry CH ₂ CI ₂ (5 ml). Dimethylaminopyridine (176 mg, 10eq) was then added and the mixture was stirred at room temperature for 10 min. Succinic anhydride (144 mg, 10eq) was then added and the mixture was stirred at 40 ⁰ C overnight. Water (5 ml) was then added and the mixture was then extracted with ethyl acetate. This organic phase was then washed with a 5% hydrochloric acid solution and a saturated NaCI solution. The organic phase was then dried over Na ₂ SO ₄ filtrated and concentrated in vacuo. Chromatography on normal silica, CHCIs/MeOH 100/2.5 was performed. The solvents were removed under vacuo to obtain the compound 6 (41 mg, yield = 55%).

Compound 6 was characterized by: - ¹ H NMR (300 MHz, DMSO) as follows : 12.19 (1 H, bs), 10.37 (1 H, s), 7.91 (1 H, dd, J = 2.7 and 9.9); 7.52 (1 H, d, J = 1.5); 6.29 (1 H, d, J = 9.9); 4.93 (1 H, s); 4.31 (1 H, s); 4.22 (1 H, bs); 2.55-0.80 (25H) and 0.55 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 517.3 (M+H); 381.3; 363.3; 335.3. Preparation of Compound 7 (UNBS5545):

In a dry round-bottom flask, under N ₂ , hellebrigenin (66 mg, 0.158 mmole) was dissolved at

0 ⁰ C in dry CH ₂ CI ₂ (5 ml). Dimethylaminopyridine (195 mg, 10eq) was then added and the mixture was stirred at room temperature for 10 min. Glutaric anhydride (144 mg, 10eq) was then added and the mixture was stirred at 40 ⁰ C overnight. Water (5 ml) was then added and the mixture was then extracted with ethyl acetate. This organic phase was then washed with a 5% hydrochloric acid solution and a saturated NaCI solution. The organic phase was then dried over Na ₂ SC> ₄ filtrated and concentrated in vacuo. Chromatography on normal silica, CHCIs/MeOH 100/2.5 was performed. The solvents were removed under vacuo to obtain the compound 7 (42 mg, yield = 50%).

Compound 7 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 12.1 1 (1 H, bs), 10.03 (1 H, s), 7.92 (1 H, dd, J = 2.7 and 9.9); 7.52 (1 H, d, J = 1.5); 6.29 (1 H, d, J = 9.9); 4.93 (1 H, bs); 4.32 (1 H, s); 4.23 (1 H, bs); 2.60-0.80 (27H) and 0.54 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 531.4 (M+H); 381.3; 363.3; 335.3.

Preparation of Compound 8 (UNBS5556):

In a dry round-bottom flask, under N ₂ , hellebrigenin (60 mg, 0.144 mmole) was dissolved at 0 ⁰ C in dry CH ₂ CI ₂ (5 ml). Dimethylaminopyridine (176 mg, 10eq) was then added and the mixture was stirred at room temperature for 10 min. 3,3-Dimethylglutaric anhydride (409 mg, 20eq) was then added and the mixture was stirred at 40 ⁰ C for 3 days. Water (5 ml) was then added and the mixture was then extracted with ethyl acetate. This organic phase was then washed with a 5% hydrochloric acid solution and a saturated NaCI solution. The organic phase was then dried over Na ₂ SO ₄ filtrated and concentrated in vacuo. Chromatography on normal silica, CHCI ₃ /MeOH 100/2.5 was performed. The solvents were removed under vacuo to obtain the compound 8 (21 mg, yield = 26%).

Compound 8 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 12.05 (1 H, bs), 10.03 (1 H, s), 7.91 (1 H, dd, J = 2.4 and 9.6); 7.52 (1 H, d, J = 1.5); 6.29 (1 H, d, J = 9.6); 4.96 (1 H, bs); 4.31 (1 H, s); 4.17 (1 H, bs); 2.50-0.80 (31 H) and 0.54 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 559.3 (M+H); 541.3; 523.3; 495.2; 417.2; 381.2; 363.2; 335.2. Preparation of Compound 9 (UNBS5575):

In a dry round-bottom flask, under N ₂ , hellebrigenin (60 mg, 0.144 mM) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OCH ₂ CO ₂ H-HCI (79 mg, 0.721 mM) was then added and the mixture was stirred at room temperature for 2Oh. 0.5 ml of distilled water was added and the reaction mixture was evaporated to dryness. Chromatography on normal silica, CHCI ₃ /MeOH 100/3 was performed. The solvents were removed under vacuo then the solid was dissolved into H ₂ O/MeOH (1/1 , 20 ml). The solution was concentrated and compound 9 was obtained as a solid m = 48 mg (yield = 68%).

Compound 9 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.7 and 9.7); 7.75 (1 H, s), 7.52 (1 H, d, J = 1.5); 6.29 (1 H, d, J = 9.6); 5.03 (1 H, brs); 4.43 (3H, m); 4.02 (1 H, bs); 2.45 (1 H, m); 2.10-1.10 (22H) and 0.57 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 490.23 (M+H); 472.23; 454.21.

Preparation of Compound 10 (UNBS5557):

In a dry round-bottom flask, under N ₂ , hellebrigenin (50 mg, 0.120 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OBn. HCI (60 mg, 5 eq) was then added and the mixture was stirred at room temperature for 2Oh. The mixture was then concentrated in vacuo then a chromatography (CHCIs/EtOH 100/2.5) was performed. 49 mg of compound 10 were recovered (yield = 78%).

Compound 10 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.91 (1 H, dd, J = 2.4 and 10.2); 7.76 (1 H, s), 7.52 (1 H, d, J = 1.5); 7.32-7.10 (6H); 6.29 (1 H, d, J = 9.6); 5.46 (1 H, d, J = 3.9); 5.26 (1 H, d, J = 3.6); 5.02-4.99 (4H, m); 4.19 (1 H, bs); 4.01 (1 H, bs); 2.45 (1 H, m); 2.12- 1.00 (17H) and 0.49 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 522.2 (M+H); 504.2.

Preparation of Compound 11 (UNBS5558):

In a dry round-bottom flask, under N ₂ , hellebrigenin (50 mg, 0.120 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ OMe. HCI (50 mg, 5 eq) was then added and the mixture was stirred at room temperature for 2Oh. The mixture was then concentrated in vacuo then a chromatography (CHCI ₃ /EtOH 100/2.5) was performed. 46 mg of compound 1 1 were recovered (yield = 86%).

Compound 1 1 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.7 and 9.3); 7.67 (1 H, s), 7.52 (1 H, d, J = 1.5); 6.29 (1 H, d, J = 9.6); 5.2 (1 H, m); 4.26 (1 H, bs); 4.00 (1 H, bs); 3.72 (3H, s); 2.43 (1 H, m); 2.07 (2H, m); 1.62-1.10 (19H) and 0.55 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 446.2 (M+H); 428.2; 410.3.

Preparation of Compound 12 (UNBS5576):

In a dry round-bottom flask, under N ₂ , hellebrigenin (60 mg, 0.144 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ (HCI) (104 mg, 5 eq) was then added and the mixture was stirred at room temperature for 24h. 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (CHC^/MeOH 100/2) was performed. 56 mg of compound 12 were recovered (yield = 77%). Compound 12 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 9.64 (1 H, s); 7.94 (1 H, dd, J = 2.7 and 10.2); 7.58 (1 H, s), 7.53 (1 H, d, J = 1.5); 7.15 (2H, m); 6.89 (2H, m); 6.65 (1 H, dd, J = 7.2 and 7.5); 6.31 (1 H, d, J = 9.9); 5.26 (1 H, m); 5.01 (1 H, s); 4.30 (1 H, s); 2.48 (1 H, m); 2.07 (2H, m); 1.62-1.20 (19H) and 0.59 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 507.3 (M+H).

Preparation of Compound 13 (UNBS5577):

In a dry round-bottom flask, under N ₂ , hellebrin (80 mg, 0.1 10 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ (HCI) (80 mg, 5 eq) was then added and the mixture was stirred at room temperature for 24h. 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH/H ₂ O 90/10/8) was performed. 63 mg of compound 13 were recovered (yield = 71%). Compound 13 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 9.64 (1 H, s); 7.94 (1 H, dd, J = 2.7 and 10.2);

7.56 (1 H, s), 7.51 (1 H, d, J = 1.5); 7.13 (2H, m); 6.87 (2H, m); 6.63 (1 H, dd, J = 7.2 and

7.5); 6.29 (1 H, d, J = 9.3); 5.42 (1 H, m); 5.02 (4H, m); 4.73 (1 H, s); 4.38-4.30 (3 H, m);

4.02 (1 H, brs); 3.86 (1 H, s); 3.62-2.96 (m); 2.49 (1 H, m); 2.03-1.20 (21 H) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 815.3 (M+H). Preparation of Compound 14 (UNBS5578):

In a dry round-bottom flask, under N ₂ , hellebrigenin (60 mg, 0.144 mmole) was suspended in EtOH (7 ml) and pyridine (0.7 ml). NH ₂ N(CHs) ₂ (0.055 ml, 5 eq) was then added and the mixture was stirred at 0 ⁰ C for 4h then returned to room temperature for 4 days. 3 ml of methanol was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (CHCI ₃ /MeOH 95/5) was performed. 15 mg of compound 14 were recovered (yield = 22%).

Compound 14 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.7 and 10.2); 7.51 (1 H, d, J = 1.5); 6.91 (1 H, s); 6.27 (1 H, d, J = 9.9); 5.26 (1 H, m); 5.11 (1 H, d, J = 4.5); 4.96 (1 H, s); 4.20 (1 H, s); 3.98 (1 H, brs); 2.63 (6H, s); 2.20-1.20 (19H) and 0.54 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 459.3 (M+H).

Preparation of Compound 15 (UNBS5579):

In a dry round-bottom flask, under N ₂ , hellebrigenin (81 mg, 0.195 mmole) was suspended in EtOH (2 ml) and pyridine (0.2 ml). 4-aminomorpholine (0.095 ml, 5 eq) was then added and the mixture was stirred at 55°C for 48h. The mixture was then concentrated in vacuo. A chromatography (CHCI ₃ /MeOH 100/2) was performed. 61 mg of compound 15 were recovered (yield = 62%).

Compound 15 was characterized by: ¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.1 and 9.9); 7.51 (1 H, d, J = 1.5); 7.43 (1 H, s); 6.29 (1 H, d, J = 9.6); 3.99 (1 H, brs); 3.72 (4H, m); 2.90 (4H, m); 2.45 (1 H, m); 2.10-1.20 (18H) and 0.55 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 501.3 (M+H).

Preparation of Compound 16 (UNBS5594):

In a dry round-bottom flask, under N ₂ , hellebrin (60 mg, 0.083 mmole) was suspended in extra dry toluene (10 ml), 4-aminomorpholine (0.04 ml, 5 eq) was then added and the mixture was stirred at reflux for 4h. 5 ml of methanol was added and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH 95/5 to 85/15) was performed. 49 mg of compound 16 were recovered (yield = 74%).

Compound 16 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.4 and 9.6); 7.52 (1 H, brs); 7.25 (1 H, s); 6.28 (1 H, d, J = 9.3); 5.42 (1 H, m); 5.47 (1 H, m), 5.02 (4H, m); 4.72 (1 H, s); 4.38-4.22 (4H, m); 3.98 (1 H, brs); 3.78-2.79 (m); 2.45 (1 H, m); 2.12-1.20 (18H) and 0.54 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 809.1 (M+H). Preparation of Compound 17 (UNBS5611):

In a dry round-bottom flask, under N ₂ , hellebrin (100 mg, 0.138 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ -P-OCH ₃ (HCI) (120 mg, 5 eq) was then added and the mixture was stirred at room temperature for 24h. 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH/H ₂ O 90/10/8) was performed. 36 mg of compound 17 were recovered (yield = 32%).

Compound 17 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 9.35 (1 H, s); 7.92 (1 H, dd, J = 2.4 and 9.6); 7.51 (1 H, s), 6.79 (4H, m); 6.28 (1 H, d, J = 9.9); 5.41 (1 H, m); 5.02-4.89 (4H, m); 4.73 (1 H, s); 4.39-4.29 (3H, m); 4.02 (1 H, brs); 3.84 (1 H, s); 3.70-2.96 (m); 2.49 (1 H, m);

2.09-1.23 (24H) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 845.1 (M+H).

Preparation of Compound 18 (UNBS5612):

In a dry round-bottom flask, under N ₂ , hellebrin (100 mg, 0.138 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ -P-CH ₃ (HCI) (109 mg, 5 eq) was then added and the mixture was stirred at room temperature for 24h. 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH/H ₂ O 90/10/8) was performed. 34 mg of compound 18 were recovered (yield = 30%).

Compound 18 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 9.48 (1 H, s); 7.93 (1 H, dd, J = 2.7 and 9.9); 7.52 (1 H, s), 6.94 (2H, m); 6.77 (2H, m); 6.29 (1 H, d, J = 9.9); 5.43 (1 H, m); 5.02-4.82 (4H, m); 4.73 (1 H, s); 4.39-4.29 (3H, m); 4.02 (1 H, brs); 3.85 (1 H, s); 3.69-2.96 (m);

2.17 (3H, s); 2.15-1.23 (m) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 829.1 (M+H). Preparation of Compound 19 (UNBS5613):

In a dry round-bottom flask, under N ₂ , hellebrin (100 mg, 0.138 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ -P-F (HCI) (112 mg, 5 eq) was then added and the mixture was stirred at room temperature for 72h. 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH/H ₂ O 90/10/8) was performed. 82.3 mg of compound 19 were recovered (yield = 71.7%).

Compound 19 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 9.61 (1 H, s); 7.92 (1 H, dd, J = 2.0 and 7.2); 7.53 (1 H,dd, J = 2.0 and 9.6), 6.99 (2H, m); 6.91 (2H, m); 6.29 (1 H, d, J = 9.9); 5.41 (1 H, m); 5.02-4.89 (4H, m); 4.73 (1 H, s); 4.39-4.29 (3H, m); 4.37 (2H, m) ; 4.30 (1 H, s); 4.02 (1 H, brs); 3.85 (1 H, s); 3.69-2.96 (m); 2.15-1.20 (m); 1.23 (3H, d, J = 6.0) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 833.1 (M+H).

Preparation of Compound 20 (UNBS5614):

In a dry round-bottom flask, under N ₂ , hellebrin (100 mg, 0.138 mmole) was suspended in EtOH (10 ml) and pyridine (1 ml). NH ₂ NHC ₆ H ₅ -P-NO ₂ (HCI) (317.2 mg, 5 eq) was then added and the mixture was stirred at room temperature for 48h followed by 4 h at reflux 0.5 ml of water was added to the mixture and the mixture was then concentrated in vacuo. A chromatography (AcOEt/MeOH/H ₂ O 90/10/8) was performed. 112.7 mg of compound 20 were recovered (yield = 95.1%).

Compound 20 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 10.84 (1 H, brs); 8.07 (2H, d, J = 9.6); 7.94 (1 H,dd, J = 2.4 and 9.6); 7.78 (1 H,s); 7.52 (1 H,bs), 6.97 (2H, bd, J = 8.7); 6.28 (1 H, d, J = 9.3); 5.43 (1 H, m); 5.03-4.74 (3H, m); 4.74 (1 H, s); 4.39-4.33 (3H, m); 4.37 (2H, m) ; 4.02 (1 H, brs); 3.94 (1 H, s); 3.63-2.90 (9H, m); 2.15-1.20 (m); 1.24 (3H, d, J = 6.0) and 0.56 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 860.19 (M+H); 698.1 ; 552.1.

Preparation of Compound 21 (UNBS5610):

In a dry round-bottom flask, under N ₂ , hellebrigenin (100 mg, 0.240 mmole) was dissolved at 0 ⁰ C in dry CH ₂ CI ₂ (I O ml). Dimethylaminopyridine (292.8 mg, 10eq) was then added and the mixture was stirred at room temperature for 10 min. Boc-glycine N-hydroxysuccinimide ester (Boc-Gly-OSu) (653.4 mg, 10eq) was then added and the mixture was stirred at room temperature overnight. Water (5 ml) was then added and the mixture was then extracted with ethyl acetate (three times). This organic phase was then washed with a 5% hydrochloric acid solution and a saturated NaCI solution. The organic phase was then dried over Na ₂ SO ₄ filtrated and concentrated in vacuo. Chromatography on normal silica, CHC^/MeOH 100/2.5 was performed. The solvents were removed under vacuo to obtain the compound 21 protected on its Boc form (136 mg, yield = 98.9%).

The trifluoroacetic salts of the free amine was then obtained as follow :

In a dry round-bottom flask, under N ₂ , the protected compound of 21 (100 mg, 0.174 mmole) was dissolved at 0 ⁰ C in 4ml_ of a mixture 1/1 of CH ₂ CI ₂ and trifluoroacetic acid. The mixture was stirred at 0 ⁰ C for 10 min then for 1 h at room temperature. The solvents were removed under vacuo and the residue was chromatographied on normal silica, CHC^/MeOH 100/3 to obtain the expected compound 21 (71.3 mg, yield = 69.8%).

Compound 21 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 10.06 (1 H,s); 8.06 (3H, m); 7.91 (1 H, dd, J = 2.4 and 9.6); 7.51 (1 H, d, J = 2.4), 6.29 (1 H, dd, J = 0.8 and 9.6); 5.05 (1 H, bs); 4.37- 4.34 (2H, m); 3.80-3.66 (2H, m); 2.5-1.0 (m); 1.0-0.90 (1 H, m) and 0.55 (3H, s). mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 474.1 (M+H).

In Table 1 which is set forth below, compounds of the invention are set out in tabulated form. In Tablei , an arbitrarily assigned compound number and structural information are set out.

Table 1

The present invention encompasses the compounds of Formula I or II, any subgroup thereof, compounds listed in Table 1 , as well as stereoisomers, tautomers, racemates, prodrugs, metabolites thereof, or pharmaceutically acceptable salts and/or solvates thereof.

Example 2: In vitro characterization of the biological effects of the compounds according to the invention - Effect on overall cell growth

MTT tests were performed in order to rapidly, i.e. within 5 days, measure the effect of compounds of this invention on the overall cell growth. The test measured the number of metabolically active living cells that were able to transform the yellow product 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (herein referred as MTT) into the blue product formazan dye by mitochondrial reduction. The amount of formazan obtained at the end of the experiment, measured by means of a spectrophotometer, is directly proportional to the number of living cells. Optical density determination thus enabled a quantitative measurement of the effect of the investigated compounds as compared to the control condition (untreated cells) and/or to other reference compounds such as Hellebrin. Six human cancer cell lines described in table 2 were used in the following MTT tests. These cancer cell lines cover six histological cancer types, being prostate, glioma, pancreas, colon, lung, and breast cancers. Additionally, two normal fibroblast cell lines (skin WS1 and lung ccd-25Lu) were used in order to investigate potential compound selectivity towards cancer over normal cell models.

To perform the assay, cells were allowed to grow in 96-well micro-wells with a flat bottom with an amount of 100 μl of cell suspension per well with 1 ,000 to 4,000 cells/well depending on the cell type used. Each cell line was seeded in a well known MEM 10 % serum culture medium.

Table 2

The detailed experimental procedure was the following: after a 24-hour period of incubation at 37°C, the culture medium was replaced by 100 μl of fresh medium in which the tested compound was previously dissolved, at the following molar concentrations: 10 ^"9 M, 5.10 ^"9 M, 10 ^"8 M, 5.10 ^"8 M, 10 ^"7 M, 5.10 ^"7 M, 10 ^"6 M, 5.10 ^"6 M, and 10 ^"5 M. Each experimental condition was repeated 6 times.

After 72 hours of incubation at 37°C with (experimental conditions) or without (control condition) the compounds to be tested, the medium was replaced by 100 μl MTT dissolved in RPMI (1640 without phenol red) at a concentration of 1 mg/ml. The micro-wells were subsequently incubated during 3 hours at 37° C and centrifuged at 400 g during 10 minutes. MTT was removed and formazan crystals formed were dissolved in 100 μl DMSO. The micro-wells were shaken for 5 minutes and read on a spectrophotometer at wavelengths of 570 nm (maximum formazan absorbance) and 630 nm (background noise).

For each experimental condition, the mean optical density was calculated, allowing the determination of the percentage of remaining living cells in comparison to the control. Table 3 shows the IC ₅₀ measured for human cancer cell lines for each cell line and median value for the six tested cell lines. Table 4 provides the IC ₅ O measured for 2 normal human fibroblast cell lines, for hellebrin and hellebrigenin and some generated derivatives according to the present invention. The IC ₅ O represents the range of nanomolar concentrations of the compound tested that resulted in a 50% inhibition of overall cells growth.

Table 3

ND: not yet determined.

A number of compounds of the present invention displayed very potent in vitro anti-tumor activity (nanomolar range) and there is a remarkable difference in cytotoxic activity towards cancer versus normal cell lines: none of the tested compounds reached the IC ₅ O value for normal WS1 fibroblast cell line, while 2 compounds displayed IC ₅₀ value in micromolar range in ccd-25Lu lung fibroblasts showing that compounds of the present invention display in vitro marked selectivity toward cancer cells.

Example 3 In vitro characterization of the biological effects of the compounds according to the invention - Inhibitory Action on the Na+/K+-ATPase The effects of the tested compounds on Na7K ⁺ -ATPase activity was evaluated by a colorimetric assay, based on the increase of color intensity resulting from the formation of a complex between orthophosphate and Biomolgreen. The color intensity is proportional to the amount of orthophosphate released and thereby to the activity of the sodium pump.

The assay was performed on 96 well microplates and in quadruplicates. The enzyme and the potential inhibitors were incubated together for 20 min to allow the eventual interactions and bindings. ATP was then added. The reaction was allowed to proceed for 15 min, and was stopped afterward by biomolgreen. The optical density (OD) was read (at wavelengths of

655nm) with a microplate reader. The mean of the quadruplicats [T] was calculated and the mean of the values obtained with 1 mM ouabain [Ct+] was taken as the 100 % inhibition while the first testing point (0.5nM) was used as Ct- (0% inhibition).

The percentage of Na7K ⁺ -ATPase activity was calculated as: 100 ^* (T - Ct ₊ ) / (Ct- - Ct ₊ )

The most important parameter was the concentration at which 50 % of the Na7K ⁺ -ATPase activity was inhibited. Table 5 shows the IC ₅ O of the Na7K ⁺ -ATPase activity inhibition for compounds according to the invention, and for reference compounds hellebrin and hellebrigenin. The IC ₅₀ represents the range of nanomolar concentrations of the compound tested that resulted in a 50% inhibition of the Na7K ⁺ -ATPase activity.

Table 5

This example showed that majority of compounds with high cytotoxic activity were also characterized by high inhibitory activity of the sodium pump. Also, hellebrigenin derivatives according to the invention exhibited greater inhibitory activity when compared to the hellebrin derivatives. Example 4: In vivo characterization of the anti-tumor effects of the compounds according to the invention - Determination of the acute toxicity in female mice (B6D2F1):

Preliminary investigations by the inventors suggested a good oral bioavailability of this type of compounds indicating that they could be developed as agent for oral administration that is more convenient for cancer patients and also allow frequently repeated metronomic administration (instead of cyclic high dose intravenous administration). In line with this, some of the compounds of the present invention were tested for the maximum tolerated dose when administered as single oral dose. The assay was carried out on hellebrin, hellebrigenin and compounds 1 (UNBS5463) and 5 (UNBS5468). Even when administered at 80mg/kg, the highest tested dose, none of the above cited compounds provoked the lethality and consequently, no precise MTD could be determined, meaning that all four compounds were very well tolerated. However, when the animals' behavior was monitored just after drug administration, compound 5 (UNBS5468) did not affect at all the tested animals while hellebrigenin at 80 mg/kg seriously altered the movements of the mice during the first hour post-injection. Thus the present compound offers better safety margin than hellebrigenin. All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention encompassed by the claims.