WO2002072575A1 - Composes derives des oxindoles et leur application therapeutique en cancerologie - Google Patents
Composes derives des oxindoles et leur application therapeutique en cancerologie Download PDFInfo
- Publication number
- WO2002072575A1 WO2002072575A1 PCT/FR2002/000852 FR0200852W WO02072575A1 WO 2002072575 A1 WO2002072575 A1 WO 2002072575A1 FR 0200852 W FR0200852 W FR 0200852W WO 02072575 A1 WO02072575 A1 WO 02072575A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound according
- treatment
- cancer
- application
- formula
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to compounds derived from oxindoles, their use for inhibiting the vascularisation of a tumor mass and / or their therapeutic application for the preparation of a medicament having an antivascular pharmacological property.
- phase M which consists of a nuclear division (mitosis) and a cytoplasmic division (cytodieresis)
- This interphase begins with the G1 phase during which there is an increased resumption of the cell's biosynthesis activities.
- Phase S begins when DNA synthesis begins and ends when the chromosomes have replicated (each chromosome is then composed of two identical sister chromatids).
- the cell then enters phase G2 (last phase of the interphase) which continues until the start of mitosis, initiating phase M.
- Cell division thus involves the division of chromosomes (or mitosis) and the division of cytoplasm ( or cytodieresis).
- the process of mitosis includes several phases: • prophase characterized by the condensation of DNA and the duplication in the still intact nucleus of chromosomes in two chromatids united by a centromere,
- telophase during this stage, the chromosomes take the form of two networks of diffuse fine chromatin, the nuclear envelope is reformed, then the cytoplasmic membrane, and a new network of microtubules appears in the cytoplasm.
- Microtubules are microscopic fibers that are part of the cell cytoskeleton and play a crucial role in the division, transport and mobility of cell. Microtubules are made up of tubulin, a heterodimeric protein that polymerizes to reversibly form microtubules, which themselves assemble to make up the mitotic spindle during metaphase. By virtue of its function in the cell, tubulin thus represents a target of choice for antimitotic compounds for antitumor purposes.
- Angiogenesis is a mechanism of neovascularization that arises from an existing capillary network. We can either prevent the formation of new blood vessels in the tumor (antiangiogenesis) or consider destroying the existing vessels in order to limit the supply of nutrients to the tumor (antivascular approach).
- the antiangiogenic approach which is a cytostatic approach, the angiogenic factors generally synthesized by tumors such as NEGF (Nascular Endothelial Growth Factor), PD-ECGF (Platelet Derived Endothelial Cell Growth Factor) or b-FGF (Growth Factor basic fibroblasts) are blocked.
- NEGF Neuronal Growth Factor
- PD-ECGF Plater Derived Endothelial Cell Growth Factor
- b-FGF Brownth Factor basic fibroblasts
- antiangiogenic molecules such as KDR tyrosine kinase receptor inhibitors, anti-integrin antibodies, or by natural anti-angiogenic polypeptides such as angiostatin or endostatin.
- the antivascular approach induces cytotoxic effects.
- Colchicine, colcemide, and nocadazole inhibit the polymerization of tubulin.
- Vinblastine and vincristine at low concentrations, also inhibit polymerization, but by interacting at a site distinct from the previous one, at a higher concentration, these last two molecules can aggregate tubulin.
- Taxol on the contrary, stimulates the assembly of tubulin into microtubules and stabilizes the pre-formed microtubules.
- Patent application WO / 48606 describes a method which, by means of phosphorylation, allows the solubilization of combretastatin A4 in water.
- This phosphorylated compound is in the form of a prodrug (that is to say inactive) but is capable of becoming active in vivo under the action of non-specific phosphatases and thus, of stopping the cell cycle in the G2 / M phase.
- Patent application WO96 / 40116 describes these oxindole derivatives for modulating the protein tyrosine kinase (PTK) transduction signal.
- PTK protein tyrosine kinase
- the Applicant has discovered a family of chemical compounds derived from oxindoles or indolin-2-ones having an action of inhibiting tubulin polymerization, a cytotoxic effect on tumor epithelial cells and an action on cell detachment.
- the term “cell detachment” is understood to mean the detachment of endothelial cells from the vessels which will cause disorganization of these vessels and, consequently, stasis of the blood flow and subsequent necrosis of the tumor by failure to supply essentially growth factors and oxygen.
- the object of the invention is the use of compounds derived from indolin-2-one to inhibit the polymerization of tubulin, which has the consequence of interrupting the cell cycle in G2 / M phase. Thanks to the antimitotic and therefore cytotoxic action of the invention, these compounds can exert an antitumor effect.
- due to their mechanism of action - inhibition of tubulin polymerization - may exert an antivascular effect on tumors.
- R 5 is chosen from groups
- R2 is a C1-C3 alkyl group in which X can be Cl, Br, or F in which n is between 1 and 3, in the form E, Z, or a mixture of the two forms of isomers.
- R2 preferably denotes a methyl group
- X is preferentially chlorine
- n is preferably equal to 2.
- the present invention relates very particularly to the compounds of formula (T) as defined above, corresponding to the following formulas: 3-pSf- (3,5-dichlorophenyl) -pyr ⁇ ol-2-yl] -5-acetylamino -indolin-2-one 3- [N- (3-chlorophenyl) -pyrrol-2-yl] -5-acetylamino-indolin-2-one
- the coupling reaction is generally carried out under the conditions described by E. Knoevenagel (Chem. Ber. 1900, 23, 172), namely in a protic solvent such as methanol or ethanol, in the presence of a catalytic amount of organic base such as piperidine, at a temperature between 20 ° C and the reflux temperature of the solvent used.
- a protic solvent such as methanol or ethanol
- organic base such as piperidine
- the compounds of the present invention as defined above have antimitotic properties by inhibiting the polymerization of tubulin into microtubules which are key components in the establishment of the mitotic spindle during cell division.
- molecules interfering with the polymerization of tubulin are capable of limiting untimely cell proliferation such as that observed in cancers.
- the compounds of the present invention possess, in addition to their tubulin-specific inhibitory properties, cellular effects such as antiproliferative and antivascular properties.
- the compounds of the present invention are especially useful in the context of therapy for primary cancer tumors. These properties justify their application in therapy and the invention particularly relates as medicaments, the products of formula (I) as defined above in a pharmaceutically acceptable medium.
- These pharmaceutical compositions can be administered by the oral route, by the parenteral route or by the local route as a topical application to the skin and the mucous membranes or by injection by the intravenous or intramuscular route.
- compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels. They are prepared according to the usual methods.
- the active ingredient can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants, or emulsifiers, preservatives.
- the usual dosage which varies according to the product used and the subject treated, can be, for example, from 0.05 to 5 grams per day in adults.
- Example 1 3- [N- (3,5-dichlorophenyl) -pyrrol-2-yl] -5-acetylamino-indolin-2-one
- 0.5 mmol of indolyl-2-one of general formula (11) is introduced into a magnetic heating reactor with Zymark condenser, of the STEM RS2050 type containing 25 wells in parallel, each provided with a 50 ml glass tube.
- the reaction medium is brought to reflux overnight. After cooling, and diluting with 5 ml of water, the precipitate formed is drained and dried under reduced pressure.
- Tubulin is purified from pig brains (Shelanski et al, 1973, Proc. Natl. Acad. Sci.USA, 70, 765-768. Weinberger et al, 1975, Proc. Natl. Acad.
- the brains are ground and centrifuged in an extraction buffer.
- the tubulin present in the supernatant of the extract undergoes two successive cycles of polymerization at 37 ° C and depolymerization at 4 ° C, before being separated from MAPs (Microtubule Associated Proteins) by chromatography on a phosphocellulose Pl i column (hatman).
- MAPs Microtubule Associated Proteins
- MES-NaOH 2- (N-morpholino) -ethanesulfonic acid
- tubulin in microtubules is followed by turbidimetry: the tubulin is adjusted to a concentration of 10 ⁇ M in the RB / 2 buffer 30% glycerol to which 1 mM GTP and 6 mM MgCl 2 are added .
- the polymerization is triggered by an increase in temperature from 6 ° C to 37 ° C in a cell with a 1 cm optical path, placed in a UNTKON 931 spectrophotometer (Kontron) equipped with a thermostated cell holder.
- the increase in the turbidity of the solution is followed at 350 nm.
- the products to be tested are dissolved in 10 mM in DMSO and added at variable concentrations (0.5 to 10 ⁇ M) to the tubulin solution before polymerization. The results are expressed as a percentage of inhibition of the polymerization relative to the controls.
- the IC50 is defined as the concentration of product which inhibits the polymerization rate of tubulin by 50%.
- a product whose IC 50 is less than or equal to 3 ⁇ M is considered to be very active. Of the three compounds tested, those carrying two chlorine residues seem more active.
- HeLa cells The proliferation of HeLa cells is evaluated by measuring the inco ⁇ oration of [ 14 C] - thymidine as follows.
- HeLa cells tumor epithelial cells of human origin
- DMEM medium Gibco
- antibiotics penicillin 1%, streptomycin 1%
- the cells are seeded in 96-well cytostar microplates (Amersham), at a rate of 5000 cells per well.
- [ 14 C] -thymidine 0.1 ⁇ Ci / well
- the compounds to be evaluated are then added at concentrations varying up to 10 ⁇ M; the DMSO used to dissolve the compounds must not exceed 0.5% in the medium.
- the inco ⁇ orated radioactivity in the cells is measured by counting the plate in a TRI-LUX counter (Wallac). The results are expressed in% of inco ⁇ orated strokes in the cells in the presence of compounds compared to the proliferation control.
- the IC 50 is defined as the concentration of product which decreases the radioactivity by 50% compared to an untreated control.
- HDMEC cells Human Dermal Microvascular Endothelial Cells, Promocell, c-122102
- ECGM-MV medium which contains 5% heat-inactivated fetal calf serum, growth factors (EGF 10 ng / mL, hydrocortisone 1 ⁇ g / mL, 0.4% growth supplement with heparin) and antibiotics (amphotericin 50 ng / mL and gentamicin 50 ⁇ g / mL).
- the HDMECs are seeded at 5000 cells per well in 96-well bright-field plates (Costar) pre-adsorbed with fibronectin (10 ⁇ g / ml) or vitronectin (1 ⁇ g / ml) or gelatin. Twenty-four hours later, the culture medium is replaced by ECGM-MV 0.1% BSA medium (bovine serum albumin) containing the indicated products. The concentrations tested are 0.1-0.3 and 1 ⁇ M for each product. After two hours of treatment, the cells are labeled for one hour with calcein (1.6 ⁇ g / ml, Molecular Probes) in ECGM-MV 0.1% BSA medium.
- calcein 1.6 ⁇ g / ml, Molecular Probes
- the detached cells are then removed by washing with ECGM-MV 0.1% BSA medium; 100 ⁇ l of medium is added to each well.
- the fluorescence of the cells which remain attached to the substrate of the well is counted using a fluorimeter, Spectrafluor Plus (Tecan, excitation 485 nm, and emission 535 nm). The data are the average of six different samples and are expressed as a percentage of the control (untreated cells).
- a cell detachment effect greater than or equal to 15% is considered significant.
- Product 1 therefore has, in addition to inhibiting tubulin and inhibiting cell proliferation properties of the HeLa cells tested, a marked action on the detachment of endothelial cells.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02722330A EP1370555A1 (fr) | 2001-03-13 | 2002-03-11 | Composes derives des oxindoles et leur application therapeutique en cancerologie |
US10/659,094 US6930124B2 (en) | 2001-03-13 | 2003-09-10 | Compounds derived from oxindoles and their therapeutic application in cancer treatment |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0103408A FR2822155B1 (fr) | 2001-03-13 | 2001-03-13 | Composes derives des oxindoles et leur application therapeutique en cancerologie |
FR01/03408 | 2001-03-13 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/659,094 Continuation US6930124B2 (en) | 2001-03-13 | 2003-09-10 | Compounds derived from oxindoles and their therapeutic application in cancer treatment |
Publications (1)
Publication Number | Publication Date |
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WO2002072575A1 true WO2002072575A1 (fr) | 2002-09-19 |
Family
ID=8861068
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2002/000852 WO2002072575A1 (fr) | 2001-03-13 | 2002-03-11 | Composes derives des oxindoles et leur application therapeutique en cancerologie |
Country Status (4)
Country | Link |
---|---|
US (1) | US6930124B2 (fr) |
EP (1) | EP1370555A1 (fr) |
FR (1) | FR2822155B1 (fr) |
WO (1) | WO2002072575A1 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7514067B2 (en) | 2000-04-25 | 2009-04-07 | President And Fellows Of Harvard College | Methods for tumor diagnosis and therapy |
JP6051194B2 (ja) | 2013-12-11 | 2016-12-27 | ダウ グローバル テクノロジーズ エルエルシー | コーティング系、コーティング系の適用方法、およびコーティング系を含む物品 |
JP5957509B2 (ja) | 2013-12-16 | 2016-07-27 | ダウ グローバル テクノロジーズ エルエルシー | 架橋性組成物、架橋性組成物の製造方法および架橋性組成物から製造される架橋された組成物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040116A1 (fr) * | 1995-06-07 | 1996-12-19 | Sugen, Inc. | Composes d'indolinone pour le traitement de maladies |
WO2000035908A1 (fr) * | 1998-12-17 | 2000-06-22 | F. Hoffmann-La Roche Ag | 4-alcenyl (et alcynyl) oxindoles utilises comme inhibiteurs de kinases dependantes des cyclines, en particulier la cdk2 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6316635B1 (en) * | 1995-06-07 | 2001-11-13 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
US6846839B1 (en) * | 1995-06-07 | 2005-01-25 | Sugen, Inc. | Methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis |
US6696448B2 (en) * | 1996-06-05 | 2004-02-24 | Sugen, Inc. | 3-(piperazinylbenzylidenyl)-2-indolinone compounds and derivatives as protein tyrosine kinase inhibitors |
US6313158B1 (en) * | 1997-06-20 | 2001-11-06 | Sugen, Inc. | Bioavailability of 3-heteroarylidenyl-2-indolinones active as protein tyrosine kinase inhibitors |
US6051593A (en) * | 1997-06-20 | 2000-04-18 | Sugen, Inc. | 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors |
US6133305A (en) * | 1997-09-26 | 2000-10-17 | Sugen, Inc. | 3-(substituted)-2-indolinones compounds and use thereof as inhibitors of protein kinase activity |
-
2001
- 2001-03-13 FR FR0103408A patent/FR2822155B1/fr not_active Expired - Fee Related
-
2002
- 2002-03-11 EP EP02722330A patent/EP1370555A1/fr not_active Withdrawn
- 2002-03-11 WO PCT/FR2002/000852 patent/WO2002072575A1/fr not_active Application Discontinuation
-
2003
- 2003-09-10 US US10/659,094 patent/US6930124B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040116A1 (fr) * | 1995-06-07 | 1996-12-19 | Sugen, Inc. | Composes d'indolinone pour le traitement de maladies |
WO2000035908A1 (fr) * | 1998-12-17 | 2000-06-22 | F. Hoffmann-La Roche Ag | 4-alcenyl (et alcynyl) oxindoles utilises comme inhibiteurs de kinases dependantes des cyclines, en particulier la cdk2 |
Non-Patent Citations (1)
Title |
---|
See also references of EP1370555A1 * |
Also Published As
Publication number | Publication date |
---|---|
US6930124B2 (en) | 2005-08-16 |
EP1370555A1 (fr) | 2003-12-17 |
FR2822155B1 (fr) | 2003-12-12 |
US20040082645A1 (en) | 2004-04-29 |
FR2822155A1 (fr) | 2002-09-20 |
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