WO2010102673A1 - Hellébrine et dérivés d'hellébrigénine - Google Patents

Hellébrine et dérivés d'hellébrigénine Download PDF

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WO2010102673A1
WO2010102673A1 PCT/EP2009/052985 EP2009052985W WO2010102673A1 WO 2010102673 A1 WO2010102673 A1 WO 2010102673A1 EP 2009052985 W EP2009052985 W EP 2009052985W WO 2010102673 A1 WO2010102673 A1 WO 2010102673A1
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Prior art keywords
alkyl
group
het
deoxy
cancer
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PCT/EP2009/052985
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English (en)
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Janique Dewelle
Mohamed El Yazidi
Eric Van Quaquebeke
Nancy De Neve
Tatjana Mijatovic
Laurent Ingrassia
Robert Kiss
Frank Van Vynckt
Nicolas Heureux
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Unibioscreen S.A.
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Priority to PCT/EP2009/052985 priority Critical patent/WO2010102673A1/fr
Publication of WO2010102673A1 publication Critical patent/WO2010102673A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
    • C07J19/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • the present invention relates to new cardiotonic steroids and their use in the treatment of cancer.
  • the present invention provides new hellebrin and hellebrigenin derivatives and their use as anticancer agent.
  • Cardiotonic steroids 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).
  • Na+/K+-ATPase the membrane-inserted sodium pump
  • 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).
  • 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.
  • the ⁇ 1 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 ⁇ 3-isoform and down-regulation of the ⁇ 1-isoform was observed (Sakai et al. FEBS Lett.
  • the sodium pump is a relevant molecular target for the prevention and treatment of proliferative diseases.
  • 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.
  • 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 ⁇ -pyrone ring).
  • CSs are also extensively found in animal species and occur mainly in toads (species of the Bufo genera).
  • mammalian tissues and body fluids including brain, adrenal glands, heart, blood plasma, cerebrospinal fluid and urine
  • digitalis-like compounds include 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
  • Ranunculaceae are known to contain several bufadienolides, such as hellebrin, hellebrigenin, helleborein, helleborin.
  • the structure of hellebrin and hellebrigenin is shown in Figure 2.
  • 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.
  • 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.
  • 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,
  • 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 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;
  • 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,
  • 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- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -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
  • 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.
  • 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.
  • 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.
  • Figure 1 represents some examples Cardiotonic steroids' structure.
  • Figure 2 represents the structure of hellebrin and hellebrigenin. Detailed description
  • 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.
  • 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-
  • 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
  • R is selected from the group comprising 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 ⁇ 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 ° , ⁇
  • R 2 and R 3 are each independently selected from the group comprising hydroxyl, Ci -6 alkyloxy,
  • R 4 is selected from the group comprising glucopyranosyl- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -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
  • 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
  • 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.
  • 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 pyrazin
  • 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.
  • 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.
  • 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.
  • C 3 -6cycloalkyl 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.
  • Ci -6 alkylene 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.
  • 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.
  • suitable alkyloxy include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, te/f-butyloxy, pentyloxy and hexyloxy.
  • C 3-6 cycloalkyloxy refers to a radical having the Formula -OR a wherein R d is Cs- ⁇ cycloalkyl as defined herein.
  • Cs- ⁇ cycloalkyld-ealkyloxy refers to a radical having the Formula -OR e wherein R e is d- ⁇ alkoxy as defined herein
  • C 6 -ioaryl as a group or part of a group, is phenyl, naphthyl, indanyl, or 1 ,2,3,4- tetrahydro-naphthyl.
  • 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 C ⁇ -ioaryl as defined herein.
  • aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2- naphthyl)-butyl, and the like.
  • 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.
  • hydroxyCi -6 alkyl represents a group of Formula -R a -OH, wherein R a is Ci -6 alkylene as defined herein.
  • hydroxycarbonyld-ealkyl represents a group of Formula -R a -COOH, wherein R a is as defined herein.
  • di-ealkoxycarbonyld-ealkyl 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.
  • aminocarbonyl refers to the -CO-NH 2 group.
  • aminocarbonyld-ealkyl represents a group of Formula -R a -CONH 2 , wherein R a is as defined herein.
  • d -6 alkylcarbonyloxy represents a group of Formula -0-C0R b , wherein R b is as defined herein.
  • C 6 -ioarylcarbonyloxy represents a group of Formula -0-C0R f , wherein R f is C ⁇ -ioaryl as defined herein.
  • C 6 -ioarylCi. 6 alkylcarbonyloxy represents a group of Formula -O-COR C , wherein R c is C 6 -ioarylCi -6 alkyl as defined herein.
  • Ce-ioarylCi-ealkylcarbonyloxyd-ealkyl 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.
  • C 1-6 alkyloxyCi-6alkyloxy represents a group of Formula -0-R a -0R b , wherein R a is as defined herein and R b is as defined herein.
  • 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,
  • ⁇ et 1 Ci -6 alkyl 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.
  • 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
  • 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,
  • Het 2 is selected from the group comprising pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, and pyrazinyl.
  • ⁇ et 2 Ci -6 alkyl 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.
  • glycosyl terms such as “glucosyl” (also named “glucopyranosyl”) "rhamnosyl” etc refer to the residue formed by detaching the anomeric hydroxy group from a saccharide.
  • rhamnosyl refers to the residue formed by detaching the anomeric hydroxyl group from rhamnose.
  • glycosidic bond includes the oxygen of the glycosidic bond.
  • 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.
  • the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.
  • “a compound” means one compound or more than one compound.
  • 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.
  • 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.
  • stereochemical ⁇ isomeric forms of the compounds according to the invention 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.
  • 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.
  • 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, imi
  • 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 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;
  • R 1 is selected from the group comprising hydrogen, -NH 2 , Ci -6 alkyl, C 6 -ioaryl,
  • 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 glucopyranosyl- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -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
  • R 6 is selected from the group comprising hydrogen, Ci -6 alkyl, C 6 -ioaryl, and C6-ioarylCi -6 alkyl;
  • 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;
  • 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 glucopyranosyl- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -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
  • -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 alkylC ⁇ 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
  • R 7 is selected from the group comprising hydrogen, Ci -6 alkyl, C 6 -ioaryl, and C6-ioarylCi -6 alkyl.
  • 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.
  • 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
  • R 1 is selected from the group comprising hydrogen, -NH 2 , d -6 alkyl, o o
  • 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-C ⁇ -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- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -D-ribosyloxy, xy
  • 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 )-;
  • 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
  • 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- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosy
  • 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 -;
  • R is selected from the group comprising hydrogen, -NH 2 , Ci -6 alkyl, ⁇ , and ⁇ ;
  • R and R 3 are each independently selected from the group comprising hydroxyl, C-i- ⁇ alkyloxy, 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- ⁇ -L-rhamnopyranosyloxy, glucosyloxy, ribosyloxy, 2-deoxy- ⁇ -D-ribosyloxy, xylosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyl
  • 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.
  • 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- ⁇ -L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, gentiobiosyloxy, ⁇ -deoxy-3-O-methylgalactosyloxy, L or D isomers thereof, ⁇ or ⁇ form thereof, and acyl or benzoyl derivatives thereof; R 5 is formyl, or hydroxyC-i- ⁇ alkyl; and R 7 is
  • 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 -;
  • R 1 is selected from the group comprising hydrogen, -NH 2 , Ci -6 alkyl, o and ⁇ ;
  • R and R are each independently hydroxyl, or d- ⁇ alkyloxy;
  • R is hydroxyl, or methoxy; or
  • R 4 is selected from the group comprising glucopyranosyl- ⁇ -L- rhamnopyranosyloxy, glucosyloxy, rhamnosyloxy, galactosyloxy, mannosyloxy, fucosyloxy, 6-deoxyglucosyloxy, lactosyloxy, cellobiosyloxy, gentiobiosyloxy, 6-deoxy-3-O- methylgalactosyloxy, L or D isomers thereof, ⁇ or ⁇ form thereof, and acyl or benzoyl derivatives thereof;
  • R 5 is formyl or hydroxyC-i- ⁇ alky
  • 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,
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • pre-drug 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.
  • 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.
  • a pharmaceutically acceptable acid-addition and/or base-addition salt e.g. obtained with non-toxic organic or inorganic acid or base
  • a hydrate solvate and/or complex
  • a pro-drug or pre-drug such as an ester.
  • 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.
  • 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 include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • 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, tosylprop
  • 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.
  • 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.
  • binding 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).
  • 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.
  • 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.
  • 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
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic effective amount of at least one compound according to the invention.
  • terapéuticaally effective amount 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.
  • 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.
  • 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.
  • 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 ste
  • 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.
  • 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.
  • liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds.
  • addition of salts of the compounds of the invention are obviously more suitable due to their increased water solubility.
  • cyclodextrins are o, ⁇ - or ⁇ -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.
  • ⁇ -CD randomly methylated ⁇ -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.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6- dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2- carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD (2-HP- ⁇ -CD).
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
  • 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.
  • 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.
  • a solid solution 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.
  • the compounds according to the invention 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the compounds according to the invention exhibit anti-tumor activity on a broad panel of histological tumor types.
  • 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.
  • 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.
  • the compounds according to the present invention are used in the preparation of a medicament for treating diseases associated with cell proliferation.
  • 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.
  • diseases associated with cell proliferation 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the administration may be performed with food, e.g., a high-fat meal.
  • food e.g., a high-fat meal.
  • 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.
  • 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.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • 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.
  • 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.
  • 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.
  • these formulations 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.
  • 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.
  • 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.
  • 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.
  • Example 1 Compounds according to the invention:
  • 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).
  • 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.
  • Compound 1 1 was characterized by:
  • 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.
  • MTT yellow product 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
  • 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.
  • 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.
  • cells were allowed to grow in 96-well micro-wells with a flat bottom with an amount of 100 ⁇ l 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.
  • the detailed experimental procedure was the following: after a 24-hour period of incubation at 37°C, the culture medium was replaced by 100 ⁇ l 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.
  • the medium was replaced by 100 ⁇ l 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 ⁇ l 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).
  • 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.
  • 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
  • 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.

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Abstract

La présente invention porte sur de nouveaux composés stéroïdiens cardiotoniques de Formule (I) ou (II), dans lesquelles X1, X2, X3, L, R1, R2, R3, R4 et R5 ont la même signification que celle définie dans les revendications. L'invention porte également sur l'utilisation desdits composés comme médicaments, en particulier dans le traitement du cancer.
PCT/EP2009/052985 2009-03-13 2009-03-13 Hellébrine et dérivés d'hellébrigénine WO2010102673A1 (fr)

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