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WO2001090046A1 - Derives triterpenoides - Google Patents

Derives triterpenoides Download PDF

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Publication number
WO2001090046A1
WO2001090046A1 PCT/GB2001/002309 GB0102309W WO0190046A1 WO 2001090046 A1 WO2001090046 A1 WO 2001090046A1 GB 0102309 W GB0102309 W GB 0102309W WO 0190046 A1 WO0190046 A1 WO 0190046A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
methyl
hal
single bond
Prior art date
Application number
PCT/GB2001/002309
Other languages
English (en)
Inventor
Marian Hajduch
Jan Sarek
Original Assignee
Univerzita Palackeho V Olomouci
Univerzita Karlova V Praze
Cyclacel Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0012528.6A external-priority patent/GB0012528D0/en
Priority claimed from GB0012823A external-priority patent/GB2362649A/en
Application filed by Univerzita Palackeho V Olomouci, Univerzita Karlova V Praze, Cyclacel Limited filed Critical Univerzita Palackeho V Olomouci
Priority to EP01936618A priority Critical patent/EP1292562A1/fr
Priority to US10/296,542 priority patent/US7858606B2/en
Priority to AU2001262489A priority patent/AU2001262489A1/en
Publication of WO2001090046A1 publication Critical patent/WO2001090046A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention relates to the therapeutic use and the biological activity of triterpenoid derivatives.
  • the invention further relates to novel triterpenoid derivatives.
  • CDKs cyclin dependent kinases
  • the present invention relates to compounds which are anti-proliferative, but which are believed to operate via a mechanism other than CDK inhibition.
  • the Gi/S transition of the mammalian cell cycle is tightly regulated by the retinoblastoma protein (pRb).
  • pRb protein is a docking protein, which in hypophosphorylated form has the capacity to bind and thus to inactivate S-phase transcription factors such as DP-1 and E2F.
  • CDKs Gi/S cyclin-dependent kinases
  • hyperphosphorylated pRb releases the transcription factors and S phase is initiated.
  • the pRb protein phosphorylation is maintained by the activity of CDK2/cyclin E complexes.
  • hyperphosphorylation of the pRb protein plays a key role in the molecular pathology of cancer cells with altered CDK activity.
  • the present invention relates to the use of triterpenoid compounds derived from the natural products betulin and betulinic acid (BA) as shown in formula (A).
  • the compounds of the present invention are referred to hereinafter as betulinines.
  • the compounds disclosed herein are believed to be of specific benefit in the treatment of proliferative diseases such as cancers and leukaemias.
  • a first aspect of the present invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in therapy, in therapy,
  • R , 1-5 are H or lower alkyl
  • R 7 is COOR lc , COOR 12 , COHal, C(O)OC(O)R lc , COOYOCOR lc ,
  • R 11 is an OH-substituted alkyl group, an ether group or a cyclic ether
  • R 12 is lower alkyl substituted by Hal
  • R la"l ⁇ are the same or different groups of R 1 Hal is Cl, Br, I, F;
  • the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating a patient suffering from leukaemia, cancer or other proliferative disorder.
  • a second aspect of the present invention relates to novel betulinines of structural formula la, or a pharmaceutically acceptable salt thereof,
  • X 1 is CHOC(O)OR n , CHOC(O)OR la , CHOC(O)OR 12 , or CHOCOY- Hal
  • R , 1-5 are H or lower alkyl
  • R 7 is COHal, C(O)OC(O)R lc , COOYOCOR 10 , CH 2 OC(O)OR ⁇
  • R 11 is an OH-substituted alkyl group, an ether group or a cyclic ether
  • R la"le are the same or different groups of R 1 Hal is Cl, Br, I, F.
  • lower alkyl means a linear or branched chain alkyl group containing from 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl.
  • R 7 is COOR lc , CH 2 OR lc , CH 2 OCOR lc , COOYOCOR 10 , CH 2 OSO 2 C 6 H 4 CH 3 ,
  • R 10 is R le , CN, COOR le , CH 2 OR le , COR le .
  • R 11 is a diol, triol or polyol.
  • R 1 , R 3"5 are methyl, R 2 is H or methyl, and R 1 is defined as below for the relevant group R la"e ; when X 1 is:
  • -CHOR la R la is H; -CHCOY-Hal, Y is CH 2 and Hal is Cl; -CHOCOR la , R la is methyl;
  • R 11 is glyceryl, 2,2-dimethyl-l,3-dioxolan-4-yl or pentaerythrityl; when X 5 is CHOCOR lb , R lb is methyl; when R 7 is:
  • R lc is methyl or butyl
  • the compounds of use are selected from those shown in Table 1 below.
  • A is CHOC(O)OCH 2 CHOHCH 2 OH
  • B is CHOC(O)OCH 2 -2,2-dimethyl-l,3-dioxolan-4-yl Ts is OSO 2 C 6 H 4 CH 3 .
  • said compound is selected from the following:
  • A is CHOC(O)OCH 2 CHOHCH 2 OH
  • B is CHOC(O)OCH 2 -2,2-dimethyl-l,3-dioxolan-4-yl Ts is OSO 2 C 6 H 4 CH 3 .
  • the proliferative disorder is cancer or leukaemia.
  • the cancer or leukaemia is p53, hormone and multidrug resistance independent.
  • the cancer or leukaemia is independent of Rb status.
  • the present invention relates to a method of treating patients suffering from cancer by administering therapeutically effective amounts of a compound of formula I or pharmaceutically acceptable salts or esters thereof.
  • the compounds of the present invention appear to operate via an alternative mechanism.
  • the betulinines of the present invention may inhibit cell proliferation and induce cancer cell death in a manner which involves mainly post-translational modifications, namely the phosphorylation, of a key regulatory protein involved in cellular proliferation. More specifically, it is believed that the betulinines of the invention effect a change in the phosphorylation state of the Rb protein.
  • Such a mechanism may be advantageous as it is thought that the compounds of the present invention may be capable of inhibiting cell proliferation in proliferating tumour tissue, but not in healthy tissue.
  • the present invention relates to a method of treating a cancerous or leukaemic proliferative disease through effecting a change in the pRb protein phosphorylation state by the administration of a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salts or esters thereof.
  • the compounds of the present invention are also capable of inducing apoptosis (programmed cell death) in proliferative cells.
  • the present invention relates to a method of inducing cell death in proliferative cells comprising administering a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salts or esters thereof.
  • a further aspect of the present invention relates to use of betulinines of formula I as research chemicals and as compounds for clinical and/or laboratory diagnostics. More particularly, the invention relates to the use of betulinines as research chemicals for studying the phosphorylation/de-phosphorylation processes of cellular substrates, cellular proliferation, purification of target molecules, and/or cell cycle studies. The present invention therefore further relates to the use of a compound of formula I in the manufacture of a medicament for use in the treatment of a proliferative disease.
  • the phrase "manufacture of a medicament” includes the use of a compound of formula I directly as the medicament in addition to its use in a screening programme for further anti-proliferative agents or in any stage of the manufacture of such a medicament.
  • Such a screening programme may for example include an assay for determining the phosphorylation state of cellular substrates and determining whether a candidate substance is capable of mimicking the activity of a betulinine of formula I.
  • the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt, crystal form, complex, hydrate, or hydrolysable ester thereof, in an assay for determining the phosphorylation state of cellular substrates, and optionally in the identification of candidate compounds that act in a similar manner.
  • the cellular substrate, the phosphorylation state of which is being assayed is Rb protein.
  • Such assays may be carried out by incubating a betulinin either alone or together with a candidate substance with a relevant cell line and assessing the phosphorylation profile the Rb protein over a period of time. If a candidate substance is present it's effect on the activity of the control betulinin will be evident by running the corresponding controls (betulinin alone and candidate alone). Further information on such assays including appropriate cell lines,reagents and Rb antibodies is given below. Rb phosphorylation assay;
  • Rb protein contains multiple phosphorylation sites for CDKs, its phosphorylated form has molecular weight about 110 kDa, while the molecular weight of hypophosphorylated protein is only 105 kDa. This small difference in molecular weight is enough to separate both forms by conventional SDS-PAGE electrophoresis.
  • CEM cells may are cultured in Dulbeco's modified essential medium with 4.5 g dextrose/1, 10% of foetal calf serum, 2 mM glutamine, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin with/without below indicated concentrations of betulinin.
  • cells are harvested, washed in ice cold Hank's balanced salt solution and solubilized on ice using the SDS-PAGE sample buffer containing protease and phosphatase inhibitors (10 ⁇ g/ml of leupeptin, 10 ⁇ g/ml of aprotinin, 10 ⁇ g/ml of soybean trypsin inhibitor, 100 ⁇ mol of benzamide, 1 mM of sodium vanadate, 1 mM of NaF, 1 mM of phenylphosphate) and boiled immediately.
  • protease and phosphatase inhibitors 10 ⁇ g/ml of leupeptin, 10 ⁇ g/ml of aprotinin, 10 ⁇ g/ml of soybean trypsin inhibitor, 100 ⁇ mol of benzamide, 1 mM of sodium vanadate, 1 mM of NaF, 1 mM of phenylphosphate
  • Total cellular proteins (100 ⁇ g/well) are separated on SDS-PAGE electrophoresis, blotted on polyvinyldifluoride membranes and total Rb protein, including proteolytic fragment(s) detected using a pRb monoclonal antibody (Oncogene, Germany, Rb(Ab-5), Cat# OP66 Rev 02-Sept-96 EB, Clone LM95.1) and visualized by chemiluminiscence (ECL- estern Blotting System, Amersham).
  • the compounds of the present invention can be present as salts or esters, in particular pharmaceutically acceptable salts or esters.
  • Pharmaceutically acceptable salts of the product of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for. example with strong inorganic acids such as mineral acids, e.g.
  • sulphuric acid, phosphoric acid or hydrohalic acids with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p- toluene sulfonic acid.
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as ( -G -alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1-12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention includes, where appropriate all enantiomers and tautomers of compounds of formula I or la. The man skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • the invention furthermore relates to the compounds of, or of use, in the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation from the solvents used in the synthetic preparation of such compounds.
  • the invention further includes the compounds of, or of use, in the present invention in prodrug form.
  • prodrugs are generally compounds of formula I or la wherein one or more appropriate groups have been modified such that the modification is reversed upon administration to a human or mammalian subject.
  • Such reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo.
  • modifications include esters (for example, any of those described above), wherein the reversion may be carried out be an esterase etc.
  • Other such systems will be well known to those skilled in the art.
  • the present invention also encompasses pharmaceutical compositions comprising the compounds of the invention.
  • pharmaceutical compositions comprising the compounds of the invention.
  • the compounds of the present invention including their pharmaceutically acceptable salts, esters and pharmaceutically acceptable solvates
  • they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the present invention also relates to pharmaceutical compositions comprising betulinines or pharmaceutically acceptable salts or esters thereof, together with at least one pharmaceutically acceptable excipient, diluent or carrier.
  • the compounds of the invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s).
  • suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients, 2 nd Edition, (1994), Edited by A Wade and PJ Weller.
  • compositions of the present invention may be adapted for oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal, intravenous, nasal, buccal or sublingual routes of administration.
  • compositions For oral administration, particular use is made of compressed tablets, pills, tablets, gellules, drops, and capsules. Preferably, these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • Injectable forms may contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose.
  • compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • one or more doses of 10 to 150 mg/day will be administered to the patient for the treatment of malignancy.
  • the invention further relates to methods of chemical synthesis of the above described compounds.
  • the compound of formula lb is oxidised to Ic by treating with ruthenium tetroxide.
  • the compound of formula Ic is oxidised to Id by treating with selenium dioxide.
  • a further embodiment of the invention relates to a process for preparing a compound of formula I as defined above, wherein X 4 and X 5 are CH ,
  • the compound of formula le is oxidised to If by treating with selenium dioxide.
  • oxidation e.g. with selenium dioxide.
  • X 1 CHOAc
  • RW CH 3
  • R 10 CH 3 b is single bond
  • b is single bond or or r
  • X 1 CHOAc
  • R 1 ° CH 3
  • R 9 CH 3
  • b is single bond or
  • X 1 CHOAc
  • X 4 CH 2
  • X 1 CHOAc
  • X 4 CH 2
  • R 1 ° COH
  • R 10 COH b is single bond
  • b is single bond or
  • X1 CHOAc
  • X 1 CHOAc
  • b is double bond
  • Electron impact mass spectra were measured on an INCOS 50 instrument. Ionising electron energy 75 eV, ion source temperature 150 °C.
  • EIMS was used to determine molecular weights, M 1" corresponding to the molecular ion.
  • Ether is diethylether. THF and dioxane were dried over sodium. Acetic acid was purified before use by chromium trioxide treatment and distillation. Reactions were run at room temperature unless otherwise stated. The reaction progress was monitored by thin layer chromatography (TLC) on silicagel 60 G (Merck, detection by spraying with 10 % sulphuric acid and heating). The work-up procedure involves dilution with specified solvent (otherwise the organic reaction solvent), extraction with water and then brine or sodium hydrogencarbonate, drying over anhydrous magnesium sulphate, and evaporation under vacuum to give a residue.
  • TLC thin layer chromatography
  • Crude betuline (500 g) was dissolved in a mixture of 250 ml pyridine and 250 ml acetic anhydride. The mixture was then refluxed for half an hour. After cooling, the resulting crystals were filtered off and washed with acetic acid, ethanol and water.
  • a solution of crude lup-20(29)-ene-3 ⁇ ,28-diyl diacetate (400 g) in chloroform was filtered through a column of alumina, and the column was washed with chloroform. The filtrate was then evaporated under reduced pressure. The residue was crystallized from chloroform/methanol to obtain 250 g of the title compound which according to TLC contained traces of lupeol acetate.
  • the 13 C NMR spectrum of the title compound is as follows: 176.7, 155.1, 109.9, 109.6, 150.5, 85.8, 73.5, 73.4, 67.5, 66.4, 56.6, 55.4, 51.3, 50.4, 49.4, 47.0, 42.4, 40.7, 38.3, 38.2, 38.0, 37.1, 36.9, 34.2, 32.1, 30.6, 29.7, 27.8, 26.7, 25.5, 25.4, 22.6, 20.9, 19.3, 18.1,16.4, 16.1, 15.9, 14.7.
  • the 13 C NMR spectrum of the title compound is as follows: 176.7, 155.6, 150.5, 109.6, 86.2, 70.1, 68.4, 63.2, 56.5, 55.4, 51.3, 50.4, 49.4, 47.0, 42.4, 40.7, 38.3, 38.2, 38.1, 37.1, 37.0, 34.2, 32.1, 30.6, 29.6, 27.9, 25.4, 23.6, 20.9, 19.3, 18.1, 16.4, 16.1, 15.9, 14.7.
  • cytotoxic activity of betulinines on tumor cell lines One of the parameters used as the basis for colorimetric assays is the metabolic activity of viable cells.
  • a microtiter assay which uses the tetrazolium salt MTT is now widely used to quantitate cell proliferation and cytotoxicity [Hajd ⁇ ch M, Mihal V, Minarik J, Faber E, Safarova M, Weigl E, Antalek P.: Cytotechnology, 1996, 19, 243-245].
  • this assay is used in drug screening programs and in chemosensitivity testing. Because tetrazolium salts are cleaved only by metabolically active cells, these assays exclusively detect viable cells.
  • Human T-lymphoblastic leukaemia cell line CEM was used for routine screening of these compounds. To prove a common mechanism of action, selected compounds which showed activity in a screening assay were tested in a panel of cell lines (Table 2). These lines were from different species and of different histogenetic origin and they possess various alterations in cell cycle regulatory proteins and hormone dependence status (Table 2). The cells were maintained in Nunc/Corning 80 cm 2 plastic tissue culture flasks and cultured in cell culture medium (DMEM with 5 g/1 glucose, 2mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 10% foetal calf serum and sodium bicarbonate). Individual compounds were dissolved in 10% dimethylsulfoxide/saline, pH 8.0.
  • DMEM cell culture medium
  • the cell suspensions that were prepared and diluted according to the particular cell type and the expected target cell density (2.500-30.000 cells per well based on cell growth characteristics) were added by pipette (80 ⁇ l) into 96/well microtiter plates. Inoculates were allowed a pre-incubation period of 24 hours at 37°C and 5% CO 2 for stabilisation. Four-fold dilutions of the intended test concentration were added at time zero in 20 ⁇ l aliquots to the microtiter plate wells. Usually, test compounds were evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 250 ⁇ M, but it may differ, depending on the agent. All drug concentrations were examined in duplicate.
  • Incubations of cells with the test compounds lasted for 72 hours at 37°C, in 5% CO 2 atmosphere and 100% humidity.
  • the cells were assayed by using the MTT assay.
  • Ten microliters of the MTT stock solution were pipetted into each well and incubated further for 1-4 hours.
  • the optical density (OD) was measured at 540nm with the Labsystem iEMS Reader MF(UK).
  • tumour cell survival was calculated using the following equitation: exposed wel l / mean OD r ⁇ n troi we l ls) 100%.
  • the TCS50 value the drug concentration lethal to 50% of the tumour cells, was calculated from the obtained dose response curves.
  • betulinic acid which is reported to be an agent selective for neuroectodermal derived tumours, there was no significant difference in sensitivity of betulinines to tumours of different histogenetic origin.
  • the compounds are effective in submicromolar or low micromolar concentrations.
  • the non-malignant cells e.g. NIH3T3 fibroblasts and normal human lymphocytes, tolerated substantially higher doses of betulinines than the tumour cells suggesting a favourable therapeutic index.
  • betulinines was found to be identical in cell lines bearing various mutations or deletions in cell cycle associated proteins (Table 2). This indicates that these substances should be equally effective in tumours with various alterations of tumour suppresser genes, namely p53, Rb, etc.
  • betulinines were shown to be equally effective in drug resistant cell lines as on their maternal counterparts, thereby suggesting that classical mechanisms of multidrug resistance apparently do not apply to these compounds. This particular characteristic should be of significant therapeutic benefit to chemotherapy resistant cancer patients.
  • cytotoxic activity of betulinines is independent of the hormonal status of cancer cells, so the compounds should be equally effective in treatment of hormone dependent and independent cancers.

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Abstract

La présente invention concerne l'utilisation d'un composé de la formule (I), ou d'un sel pharmaceutiquement acceptable, d'une forme, d'un complexe, d'un hydrate ou d'un ester hydrolysable dudit composé, dans la préparation d'un médicament destiné à traiter un patient atteint de leucémie, de cancer ou d'une autre maladie à évolution chronique. Dans une autre forme de réalisation, l'invention concerne l'utilisation d'un composé de la formule (I) dans un dosage servant à détecter l'état de phosphorylation de substrats cellulaires. L'invention concerne en outre de nouveaux composés de la formule (I) et la synthèse chimique desdits composés.
PCT/GB2001/002309 2000-05-23 2001-05-23 Derives triterpenoides WO2001090046A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP01936618A EP1292562A1 (fr) 2000-05-23 2001-05-23 Derives triterpenoides
US10/296,542 US7858606B2 (en) 2000-05-23 2001-05-23 Triterpenoid derivatives
AU2001262489A AU2001262489A1 (en) 2000-05-23 2001-05-23 Triterpenoid derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0012528.6 2000-05-23
GBGB0012528.6A GB0012528D0 (en) 2000-05-23 2000-05-23 Triterpenoid derivatives
GB0012823.1 2000-05-25
GB0012823A GB2362649A (en) 2000-05-25 2000-05-25 Triterpenoid derivatives

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009191018A (ja) * 2008-02-14 2009-08-27 Akita Prefecture 抗癌剤として有用なトリテルペン化合物及び該トリテルペン化合物を用いた抗癌用組成物
EP2178376A1 (fr) * 2007-08-03 2010-04-28 Advanced Life Sciences Inc. Triterpénoïdes de type lupane modifiés en position 30 et leurs analogues
WO2010054606A2 (fr) 2008-11-13 2010-05-20 Univerzita Palackeho V Olomouci 2-désoxy glycosides triterpénoïdes, leur procédé de préparation et leur utilisation en tant que médicaments
EP2250185A1 (fr) * 2008-01-03 2010-11-17 Virochem Pharma Inc. Nouveaux dérivés de lupane
RU2551647C2 (ru) * 2012-11-12 2015-05-27 Федеральное государственное бюджетное учреждение науки Институт нефтехимии и катализа Российской академии наук Трифенилфосфониевые соли лупановых тритерпеноидов, способ получения и применение в качестве противоопухолевых веществ
US9102685B2 (en) 2011-12-16 2015-08-11 Glaxosmithkline Llc Derivatives of betulin
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1415601A (en) * 1973-03-14 1975-11-26 Biorex Laboratories Ltd Dihydrobetulinic acid derivatives
WO1998051294A2 (fr) * 1997-05-16 1998-11-19 The Board Of Trustees Of The University Of Illinois Procede et composition de traitement anti-cancer
EP0943620A2 (fr) * 1998-03-18 1999-09-22 Dabur Research Foundation Dérivés de l'acide bétulinique pour inhibition de la croissance des cancers
WO2000024762A1 (fr) * 1998-10-28 2000-05-04 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Acide betulinique et derives de cet acide pour le traitement de tumeurs neuroectodermiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1415601A (en) * 1973-03-14 1975-11-26 Biorex Laboratories Ltd Dihydrobetulinic acid derivatives
WO1998051294A2 (fr) * 1997-05-16 1998-11-19 The Board Of Trustees Of The University Of Illinois Procede et composition de traitement anti-cancer
EP0943620A2 (fr) * 1998-03-18 1999-09-22 Dabur Research Foundation Dérivés de l'acide bétulinique pour inhibition de la croissance des cancers
WO2000024762A1 (fr) * 1998-10-28 2000-05-04 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Acide betulinique et derives de cet acide pour le traitement de tumeurs neuroectodermiques

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
KIM D S H L ET AL: "Synthesis of betulinic acid derivatives with activity against human melanoma", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 13, 7 July 1998 (1998-07-07), pages 1707 - 1712, XP004137114, ISSN: 0960-894X *
NODA Y ET AL: "Enhanced Cytotoxicity of Some Triterpenes toward Leukemia L1210 Cells Cultured in Low pH Media: Possibility of a New Mode of Cell Killing", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO, JP, vol. 45, no. 10, 1997, pages 1665 - 1670, XP002082673, ISSN: 0009-2363 *
POUZAR V ET AL: "PREPARATION OF 12,20-DISUBSTITUTED LUPANE DERIVATIVES", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, ACADEMIC PRESS, LONDON, GB, vol. 44, 1979, pages 194 - 210, XP001013527, ISSN: 0010-0765 *
SHI YONG RYU ET AL: "ANTITUMOR TRITERPENES FROM MEDICINAL PLANTS", ARCHIVES OF PHARMACAL RESEARCH, NATL. FISHERIES UNIVERSITY, PUSAN, KR, vol. 17, no. 5, 1 October 1994 (1994-10-01), pages 375 - 377, XP000610874, ISSN: 0253-6269 *
TAKAO KONOSHIMA ET AL: "STUDIES ON INHIBITORS OF SKIN-TUMOR PROMOTION, I., INHIBITORY EFFECTS OF TRITERPENES FROM EUPTELEA POLYANDRA ON EPSTEIN-BARR VIRUS ACTIVATION", JOURNAL OF NATURAL PRODUCTS, XX, XX, vol. 50, no. 6, 1 November 1987 (1987-11-01), pages 1167 - 1170, XP000610894, ISSN: 0163-3864 *
YASUKAWA K ET AL: "SOME LUPANE-TYPE TRITERPENES INHIBIT TUMOR PROMOTION BY 12-O-TETRADECANOYLPHORBOL-13-ACETATE IN TWO-STAGE CARCINOGENESIS IN MOUSE SKIN", PHYTOMEDICINE, GUSTAV FISCHER VERLAG, STUTTGART, DE, vol. 4, 1995, pages 309 - 313, XP000610925, ISSN: 0944-7113 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2178376A1 (fr) * 2007-08-03 2010-04-28 Advanced Life Sciences Inc. Triterpénoïdes de type lupane modifiés en position 30 et leurs analogues
EP2178376A4 (fr) * 2007-08-03 2011-12-14 Advanced Life Sciences Inc Triterpénoïdes de type lupane modifiés en position 30 et leurs analogues
EP2250185A1 (fr) * 2008-01-03 2010-11-17 Virochem Pharma Inc. Nouveaux dérivés de lupane
EP2250185A4 (fr) * 2008-01-03 2011-11-16 Virochem Pharma Inc Nouveaux dérivés de lupane
JP2009191018A (ja) * 2008-02-14 2009-08-27 Akita Prefecture 抗癌剤として有用なトリテルペン化合物及び該トリテルペン化合物を用いた抗癌用組成物
WO2010054606A2 (fr) 2008-11-13 2010-05-20 Univerzita Palackeho V Olomouci 2-désoxy glycosides triterpénoïdes, leur procédé de préparation et leur utilisation en tant que médicaments
US9102685B2 (en) 2011-12-16 2015-08-11 Glaxosmithkline Llc Derivatives of betulin
US10064873B2 (en) 2011-12-16 2018-09-04 Glaxosmithkline Llc Compounds and compositions for treating HIV with derivatives of Betulin
RU2551647C2 (ru) * 2012-11-12 2015-05-27 Федеральное государственное бюджетное учреждение науки Институт нефтехимии и катализа Российской академии наук Трифенилфосфониевые соли лупановых тритерпеноидов, способ получения и применение в качестве противоопухолевых веществ
US9795619B2 (en) 2012-12-14 2017-10-24 Glaxosmithkline Llc Pharmaceutical compositions
US10092523B2 (en) 2014-09-26 2018-10-09 Glaxosmithkline Intellectual Property (No. 2) Limited Long acting pharmaceutical compositions

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