EP1453790A2 - 1,3-diarylprop-2-en-1-ones, compositions les contenant et utilisation - Google Patents

1,3-diarylprop-2-en-1-ones, compositions les contenant et utilisation

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Publication number
EP1453790A2
EP1453790A2 EP02804242A EP02804242A EP1453790A2 EP 1453790 A2 EP1453790 A2 EP 1453790A2 EP 02804242 A EP02804242 A EP 02804242A EP 02804242 A EP02804242 A EP 02804242A EP 1453790 A2 EP1453790 A2 EP 1453790A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
methoxy
propenone
amino
methyl
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP02804242A
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German (de)
English (en)
French (fr)
Inventor
Patrick Mailliet
Cécile Combeau
Marie-Christine Bissery
Marie-Pierre Cherrier
Thomas Caulfield
Gilles Tiraboschi
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Aventis Pharma SA
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Aventis Pharma SA
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Publication date
Priority claimed from FR0115739A external-priority patent/FR2833008B1/fr
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Publication of EP1453790A2 publication Critical patent/EP1453790A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups
    • C07C279/32—N-nitroguanidines
    • C07C279/36—Substituted N-nitroguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to novel chemical compounds, particularly novel 1, 3-diaryl-prop-2-en-1-ones, the compositions containing them, and their use as medicaments.
  • the invention relates to novel specific 1,3-diphenylprop-2-en-1 -ones exhibiting anticancer activity, and in particular inhibitory activity of tubulin polymerization.
  • WO 01/72980 discloses substituted chalcones exhibiting anticancer and anti-inflammatory activity. These chalcones are characterized in that they are derivatives of 1- (3,5-dimethoxyphenyl) -prop-2-en-1-ones whose 3-phenyl group is never substituted by an amino group.
  • WO 99/22728 claims, in a generic manner, substituted chalcones, for inhibiting the 5 ⁇ -reductase activity with respect to steroid hormones, for the treatment of pathologies such as alopecia and baldness , obesity, skin diseases, prostate cancer, breast cancer.
  • No specific example of chalcone is presented in the description, only the structure of the product referenced HZIV 82, (E-3- (4-N, N-dimethylamino-phenyl) -1- (3,4,5-trimethoxy) phenyl) -prop-2-en-1-one) is shown in Figure 2.
  • WO 99/00114 claims the use of chalcones whose prop-2-en-1-one chain may or may not be saturated.
  • WO 98/58913 discloses chalcones derived from 1- (2-hydroxyphenyl), 3-aryl-prop-2-en-1-one having antiproliferative activity.
  • WO 91/17749 claims a method of treating cancer using, in particular, chalcones.
  • chalcones are described and claimed in a very general manner. Thus, many substituents can replace any hydrogen, whether it is on the prop-2-en-1-one chain or on a phenyl ring. None of the described chalcones carry amino groups on either aryl group.
  • the necrosis of the tumor occurs in the minutes following the injection of the test product, and that the heart of the tumor is totally destroyed in less than a day. , with no apparent effect on neighboring healthy cells.
  • These products could therefore be useful for treating patients suffering from inoperable tumors, that is to say whose surgical removal presents a very important risk (i) for the immediate survival of the patient, or (ii) for the possible consequences on its quality of life (invalidation).
  • the products of the invention are generally rapidly metabolized by the body, which limits their long-term effect.
  • Y is selected from the group consisting of halogen, linear Ci-C alkyl, branched alkyl, C1-C7, linear C 1 -C 7 substituted alkyl, branched alkyl, C 1 -C 7 substituted cycloalkyl,
  • Ar2 is selected from the group consisting of:
  • R1, R2 is selected from the group consisting of
  • A is a 5- or 6-membered heterocycle fused to a benzene ring B, said heterocycle A is aromatic or nonaromatic, comprising 1 or two heteroatoms, at least one of which is an atom nitrogen - - directly linked to B and carrying a string "lateral R8, wherein R8 is selected from the group consisting of H, (CC 3) alkyl, (C r C 3) alkyl-OH, (CrC ⁇ alkyl- O d -C 3) alkyl, (CC 3) alkyl-NH 2j (CC 3) alkyl-NH (R7), (CC 3) alkyl-N (R7) 2,
  • R9 is selected from H, (d- C3) alkyl, wherein each R7 is independently (Ci-C 3) alkyl or (C 3 -C 7) cycloalkyl, or when two R7 are present, they are linked together to form a 5-membered heterocycle;
  • X is selected from the group consisting of O, NOH, NO (R3), wherein R3 is selected from the group consisting of H, linear alkyl -C 7 alkyl, branched C1-C7, cycloalkyl, linear alkyl C 1 -C 7 halogen, C 1 -C 7 branched alkyl halogen, substituted cycloalkyl, halogenated cycloalkyl, aralkyl, substituted aralkyl; and
  • Ar is selected from the group consisting of 2,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2, 3,4,5-tetramethoxyphenyl, 3-methoxy-4,5-methylenedioxy, 3-methoxy-4,5-ethylenedioxy, 2-methoxy-4,5-methylenedioxy, 2-methoxy-4,5-ethylenedioxy, 2- 3,4-Methoxy-methylenedioxy, 2-methoxy-3,4-ethylenedioxy.
  • X is oxygen.
  • Ar is preferably 3,4,5-trimethoxyphenyl or 3-methoxy-4,5-methylenedioxy.
  • Y is preferably selected from the group consisting of Cl, Br, CH 3 ,
  • a first preferred product according to the invention preferably has a
  • R1 and R2 are selected from the group of combinations (R1, R2) consisting of, respectively, (NH 2 , OCH 3 ), (NH 2 , OC 2 H 5 ), (NH 2 , N (R 5) 2 ), (N (R 5) 2) OCH 3 ), (N (R 5) 2 , OC 2 H 5 ), (N (R 5) 2 , NH 2 ), (OCH 3 , NH 2 ), (OC 2 H 5) > NH 2 ).
  • a first more preferred product according to the invention has an Ar 2 substituent such
  • Ar2 wherein one of R1, R2 is NHC (O) -amino acid, and that the amino acid is selected from naturally occurring amino acids and non-natural amino acids.
  • Preferred amino acids are selected from the group consisting of glycine, N-methyl-proline, serine, lysine, Nco-nitro-arginine, and the amino acid is enantiomerically pure, racemic, or enantiomerically enriched.
  • the products in accordance with the invention are present in free or salified form, preferably in salified form.
  • a preferred salt form is a hydrochloride.
  • a second preferred product according to the invention preferably has a
  • R8 is preferably methyl or hydroxymethyl or 2-dimethylaminoethyl.
  • a preferred product according to the invention may be chosen from the group consisting of
  • a more preferred product according to the invention is (S) -2-amino-3-hydroxy-propanoic acid hydrochloride ⁇ 2-methoxy-5- [2-methyl-3-oxo-3- (3, 4,5-trimethoxy-phenyl) -propenyl] -phenyl ⁇ -amide.
  • Products according to the invention will preferably be chosen from E-3- (3-amino-4-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy-phenyl) -propenone;
  • the products in accordance with the invention may be present in free or salified form, when they comprise at least one salifiable substituent.
  • the products comprise at least one salifiable substituent will preferably be salified.
  • a suitable salt-forming substituent is, for example, an amino, alkylamino, dialkylamino, imino, guanidino, hydrazino, imidazolino, pyrido, pyrimido, pyridazino substituent.
  • a preferred salt form is a hydrochloride.
  • a preferred salified form of a product according to the invention having particularly advantageous properties is (S) -2-amino-3-hydroxy-propanoic acid- ⁇ 2-methoxy-5- [2-methyl hydrochloride -3-oxo-3- (3,4,5-trimethoxy-phenyl) -propenyl] -phenyl ⁇ -amide having the following structure:
  • a product according to the invention may be used for the manufacture of a medicament useful for treating a pathological state, in particular a cancer.
  • the present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable excipient according to the chosen mode of administration.
  • the pharmaceutical composition may be in solid, liquid or liposome form.
  • solid compositions include powders, capsules, tablets.
  • Oral forms may also include solid forms protected from the acidic environment of the stomach.
  • the supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic carriers such as lactose, celluloses, starch or polymers.
  • the liquid forms consist of solutions of suspensions or dispersions. They contain as dispersive carrier either water, or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.
  • the liquid forms will preferably be injectable and, therefore, will have an acceptable formulation for such use.
  • Acceptable injection routes of administration include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route being preferred.
  • the administered dose of the compounds of the invention will be adapted by the practitioner according to the route of administration of the patient and the state of the latter.
  • the compounds of the present invention may be administered alone or in admixture with other anticancer agents.
  • anticancer agents we can mention:
  • Platinum derivatives such as cisplatin, carboplatin or oxaliplatin antibiotic agents such as bleomycin, mitomycin, dactinomycin
  • antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel)
  • Anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone
  • topoisomerases of groups I and II such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex
  • Fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine
  • Cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine
  • Adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate
  • methotrexate and folinic acid "various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin and estrogen hormones , androgenic
  • antivascular agents such as derivatives of combretastatin or colchicine and their prodrugs.
  • a product according to the invention may promote the disintegration of clusters of cells from vascular tissue. More particularly, the products of the present invention will be used in their first therapeutic application for inhibiting the growth of cancer cells and in same time the destruction of existing vessels. Inhibition of vascularization is determined by a cell detachment test as described below.
  • An endothelial cell detachment test was established to select products based on their "in vitro" activity.
  • This test for detaching endothelial cells is characterized in that the endothelial cells, seeded in plates whose bottom is covered with a binding agent preferably chosen from gelatin, fibronectin or vitronectin, after culturing, are added by a medium containing the test compound, then the cells are labeled with a fluorescent substance, the detached cells are removed by washing and the fluorescence of the remaining cells is counted by fluorimeter.
  • This test consists in measuring the detachment of cultured endothelial cells on substrates based on a binding agent preferably chosen from fibronectin, vitronectin or gelatin.
  • a binding agent preferably chosen from fibronectin, vitronectin or gelatin.
  • the culture medium is replaced by a medium containing the test compound in the absence of serum.
  • the same preparation is prepared six times at three different concentrations (0.1, 0.3 and 0.6 ⁇ M) and six times the control without addition of antivascular product.
  • the cells are labeled with calcein-AM (1.6 ⁇ g / ml) in culture medium supplemented with 0.1% BSA.
  • the cells which have become detached are removed by washing with the culture medium containing 0.1% of bovine serum albumin; 100 ⁇ l of medium are added to each well. The fluorescence of the remaining cells is counted by fluorimeter. The data obtained are expressed relative to the control (untreated cells).
  • the evaluation of endothelial cell detachment in vitro is determined as follows.
  • the HDMEC Human Dermal Microvascular Endothelial Cells, Promocell, c-122102 cells are cultured in an ECGM-MV medium which contains 5% 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, gentamicin 50 ⁇ g / ml).
  • growth factors EGF 10 ng / ml
  • hydrocortisone 1 ⁇ g / ml 0.4% growth supplement with heparin
  • antibiotics amphotericin 50 ng / ml, gentamicin 50 ⁇ g / ml.
  • the HDMECs are seeded at 5,000 cells in 96-well clear-bottom plates (Costar) pre-coated with fibronectin (10 ⁇ g / ml) or vitronectin (1 ⁇ g / ml) or gelatin. Twenty-four hours later, the culture medium is replaced with ECGM-MV 0.1% BSA medium 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 medium ECGM-MV 0.1% BSA.
  • the detached cells are then removed by washing with medium ECGM-MV 0.1% BSA; 100 ⁇ l of medium is added to each well.
  • the fluorescence of the cells which remain attached to the well's substratum 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 control (untreated cells).
  • a cell detachment effect greater than or equal to 15% is considered significant.
  • a product according to the invention may be useful for inhibiting the polymerization of tubulin in vitro.
  • Tubulin is purified from porcine brains according to published methods (Shelanski et al., 1973, Proc Natl Acad Sci.USA, 70, 765-768, Weinberger et al., 1975, Proc Natl Acad Sci. USA, 72, 1858-1862). Briefly, the brains are crushed and centrifuged in extraction buffer. The tubulin contained in the supernatant of the extract undergoes two successive cycles of polymerization at 37 ° C. and depolymerization at 4 ° C., before being separated from the MAPs (Microtubule Associated Proteins) by chromatography on a phosphocellulose P11 column (Whatman). . The tubulin thus isolated is more than 95% pure.
  • MAPs Microtubule Associated Proteins
  • RB / 2 30% glycerol the composition of which is MES-NaOH [2- (N-morpholino) -ethanesulfonic acid] 50 mM, pH 6.8; MgCl 2 0.25 mM; 0.5 mM EGTA; glycerol 30% (v / v), GTP (guanosine-5'-triphosphate) 0.2 mM.
  • tubulin is adjusted to a concentration of 10 ⁇ M (1 mg / ml) in 30% glycerol RB / 2 buffer to which 1 mM GTP and 6 mM MgCl 2 are added .
  • the polymerization is triggered by an increase in the temperature of 6 ° C. to 37 ° C. in a vessel of 1 cm of optical path, placed in a UVIKON 931 spectrophotometer (Kontron) equipped with a thermostatically controlled cell holder.
  • the increase in the turbidity of the solution is monitored at 350 nm.
  • IC 5 o is defined as the concentration of product which inhibits 50% of the rate of polymerization.
  • a product whose IC 50 is less than or equal to 3 ⁇ M is considered very active.
  • HeLa cells The proliferation of HeLa cells is evaluated by measuring [ 14 C] -thymidine incorporation 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.
  • [ 1 C] -thymidine 0.1 ⁇ Ci / well
  • the products to be evaluated are then added.
  • DMSO solvent used to solubilize the products
  • IC 5 o is defined as the product concentration that decreases radioactivity by 50% compared to an untreated control. It is considered that a product whose IC 50 is less than 1 ⁇ M is cytotoxic
  • HDMEC Human Dermal Microvascular Endothelial Cells, Promocell, c-122102
  • ECGM-MV medium which contains 5% 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, gentamicin 50 ⁇ g / ml).
  • the HDMECs are seeded at 5,000 cells in 96-well clear-bottom plates (Costar) pre-coated with fibronectin (10 ⁇ g / ml) or vitronectin (1 ⁇ g / ml) or gelatin. Twenty-four hours later, the culture medium is replaced with ECGM-MV 0.1% BSA medium 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 medium ECGM-MV 0.1% BSA.
  • the detached cells are then removed by washing with medium ECGM-MV 0.1% BSA; 100 ⁇ l of medium is added to each well.
  • the fluorescence of the cells which remain attached to the well's substratum are counted using a fluorimeter, Spectrafluor Plus (Tecan, excitation 485 nm, and emission 535 nm). Data is 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.
  • mice are raised either by IFFA-CREDO (Domain of Oncins, 69210 L'ArbresIe, France) from a breed obtained by Jackson Laboratories, Bar Harbor, ME, USA, or by Charles River France (76410 St Aubin lès Elbeuf, France) from a breed obtained by Charles River, USA.
  • the mice initially weigh more than 18 g at the beginning of the test. They have free access to food (UAR reference 113, Villemoisson, 91160 Epinay sur Orge, France) and water.
  • the tumors used are currently transplanted into our laboratories. All of these tumors are at the Frederick Cancer Research Facility (Frederick, MD, USA) at the National Cancer Institute (NCI) frozen tumor depot, or at the American Type Culture Collection (ATCC, Rockville, MD, USA).
  • mice The growth of solid tumors develops freely to the desired size.
  • the mice are then treated by intravenous injection of a test compound in solution. Tumor sampling is usually done (but not necessarily) 24 hours after treatment.
  • mice are killed by brain dislocation.
  • the implanted tumors, as well as the skin covering them and the tissues nearby are collected and preserved in 10% (v / v) formaldehyde (Carlo Erba, Val de Reuil, France).
  • Tumor necrosis (necrosis ⁇ degeneration) is evaluated microscopically using a scale of importance from 0 to 5:
  • the tumor model is a C51 murine adenocarcinoma.
  • This colon tumor is a grade III mucosal colonic adenoma. This is maintained by serial subcutaneous passages every 18 days in female BALB / c mice. The experiments were conducted in female BALB / c mice.
  • Halogen is a member selected from F, Cl, Br, and I.
  • C 1 -C linear alkyl is a substituent selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl.
  • DC-branched alkyl is a substituent selected from 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1, 2 dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2-dimethylpropyl , 3-Dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl, 1-methylpropyl, 1-ethyl, 2-methylpropyl, 1-ethylbutyl, 2-ethylbutyl , 1-methylhexyl, 2-methylhex
  • Cycloalkyl may be a substituent selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl.
  • Aryl may be a substituent selected from phenyl, Tiaphthyl, pyridyl, quinolyl, isoquinolyl, pyrimidyl, piperazinyl, triazinyl, carbazolyl, imidazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, triazolyl, tetrazolyl, benzotriazolyl, thienyl, furyl, pyrolyl , benzothienyl, benzofuryl, indolyl.
  • Alkyl is an alkyl substituent, itself substituted with an aryl group as defined above.
  • a benzyl group is an example of an aralkyl substituent.
  • Amino acid includes natural and artificial amino acids, in enantiomerically pure form or in admixture.
  • Amino acid or “amino acid” are synonyms of "amino acid”.
  • Metal Substitute includes all substituents having at least one functional group cleavable by the metabolism of a living being. Examples of cleavable functional groups include amides, imides, imines, esters, lactones, lactams, acetals, hemiacetals, carbonates, carbamates, ureas.
  • Organic acid includes organic molecules having at least one functional group proton donor, for example COOH, S0 3 H, OS0 3 H, P0 3 H 2, OP0 3 H 2, and optionally OH when the latter functional group is directly linked to an aromatic or heteroaromatic nucleus.
  • Standard acid includes proton-donating (H + ) mineral products, for example HCl, HBr, Hl, HI0 4 , H 2 S, H 2 SO 4 , H 3 PO 2 , H 3 PO 4 , HNO 3 ; or species capable of giving mineral acids by reaction, for example AlCl 3 , AlRr 3 , SnCl, SiCl, TiCl 3 , FeCl 3 , RuCl 3 which can react in a protic solvent such as water according to:
  • n are whole or real stoichiometric coefficients, M chosen from among the metals given as examples above, and Z a halogen.
  • R 1 and R 2 are defined as previously with R 1 or R 2 representing an amino radical
  • X represents an oxygen atom
  • Y is different from a halogen atom
  • R 1 and R 2 are defined as previously with R 1 or R 2 representing an amino radical
  • Cleavage of the protecting group of the aromatic amine function can be carried out under the conditions described in Protective Groups in Organic Chemistry (Wiley publisher).
  • catalytic reduction methods such as hydrogen in the presence of a catalyst such as 3% palladium on carbon, or chemical reduction, such as iron in the presence of hydrochloric acid or stannous chloride.
  • aromatic aldehydes of general formula (III) are either commercial or previously described in the literature.
  • the aromatic ketones of general formula (II) are described in the literature and generally prepared from the corresponding aromatic aldehydes which are commercial.
  • Y represents an optionally substituted alkyl or aralkyl radical
  • the reaction is advantageously carried out by reacting the aldehyde with a suitably chosen organometallic reagent and then oxidizing the benzyl alcohol thus obtained under the conditions described in J. Med. Chem., 1990, 33, 1948.
  • Y represents a carboxy, carboxylate or carboxamide radical
  • R., NHBoc, N0 2 ;
  • R 2 Me, and, OMe, OEt, SMe, NMe 2 or
  • R 2 NHBoc, NO 2 ;
  • R, Me, And, OMe, OEt, SMe, NMe 2 reduction or deprotection
  • R, NH 2 ;
  • R 2 Me, And, OMe, OEt, SMe, NMe 2 or
  • R 2 NH 2 ;
  • R, Me, And, OMe, OEt, SMe, NMe 2
  • halogen preferably bromine or chlorine
  • a solvent such as chloroform or carbon tetrachloride at a temperature between 0 and 60 ° C.
  • dehydrohalogenation is generally carried out in a solvent such as dichloromethane in the presence of an organic or inorganic base, such as triethylamine or sodium hydroxide or potassium carbonate at a temperature between 0 ° C. and the reflux of the reaction medium.
  • R 1 and R 2 are defined as previously with R 1 or R 2 representing an amino radical, may also be prepared by nucleophilic displacement of a product of general formula (I) in which Y represents a halogen atom, preferably a bromine atom.
  • Y represents a halogen atom, preferably a bromine atom.
  • R, NHBoc, NO 2 , NH 2 ;
  • R 1 and R 2 are as defined previously with R 1 or R 2 representing an amino radical, may also be prepared by nucleophilic displacement of a product of formula general (I) wherein Y represents a bromomethyl radical, under the conditions described in J. Org. Chem., 1967, 3830, according to the general scheme (IV):
  • R, NHBoc, NO 2 , NH 2 ;
  • R 2 Me, and, OMe, OEt, SMe, NMe 2 or
  • R 2 NHBoc, NO 2 , NH 2 ;
  • R, Me, And, OMe, OEt, SMe, NMe 2
  • Schemes (III) and (IV) illustrate, in a non-limiting manner, methods for modifying the Y substituents on an already formed chalcone, any other method known to those skilled in the art that can be used to modify said substituent Y.
  • R NHBoc, NO 2 , NH 2 ;
  • R 2 Me, and, OMe, OEt, SMe, NMe 2 or
  • R 2 NHBoc, NO 2 , NH 2 ;
  • R, Me, And, OMe, OEt, SMe, NMe 2
  • the present invention also relates to the prodrugs, in particular to water-soluble prodrugs, chalcones of general formula (I),
  • X represents an oxygen atom or an N-OR 3 radical
  • Y, n, R 1 and R 2 are defined as previously with R 1 or R 2 representing a cleavable derivative of the amino radical.
  • cleavable derivatives of the amino radical is meant more particularly the amino acid derivatives which can be prepared by peptide coupling between
  • the peptide-type coupling is carried out under standard conditions in an organic solvent, such as dichloromethane, in the presence of a coupling agent and / or activation as a non-limiting example EDCI / HOBT mixture.
  • organic solvent such as dichloromethane
  • Step 1 In a three-necked 25 mL, topped with a Soxhlet filled with molecular sieve 3A, are successively added 2.24 g of 1- (3,4,5-trimethoxyphenyl) -propanone, which can be prepared according to Biorg. Med. Chem. 1998, 8 (9), 1051, 1.85 g of 3-nitro-4-methoxy-benzaldehyde, 2 mL of piperidine and 1 mL of acetic acid in 20 mL of ethanol. The medium is refluxed for 48 hours.
  • Step 2 485 mg of 3- (3-nitro-4-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy-phenyl) propenone, obtained in a 50 mL three-neck the previous step are suspended in 20 ml of ethanol and 2.5 ml of water. Refluxed and then added 0.25 mL of 37% hydrochloric acid and 2.09 g portions of iron filings. The reflux is maintained for 30 minutes, then the mixture is cooled. After addition of 2 g of potassium carbonate, the insolubles are filtered and washed with 3 times 25 ml of ethanol.
  • Step 1 Working as in Step 1 of Example 1, but starting from 2.24 g of 1- (3,4,5-trimethoxy-phenyl) -propanone and 1.81 g of 4-nitro 3-Methoxybenzaldehyde in 75 ml of ethanol containing 2 ml of piperidine and 1 ml of acetic acid, refluxing for 96 hours, after purification by flask chromatography on silica gel (70-230 mesh).
  • Step 2 Working as in step 2 of the example, but starting with 700 mg of 3- (4-nitro-3-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy) phenyl) propenone, and 3.09 g of iron, after purification by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (70.degree. In volume), 0.55 g of pure E-3- (4-amino-3-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy-phenyl) -propenone in the form of a pale yellow powder whose characteristics are as follows:
  • Step 1 Working as in Step 1 of Example 1, but starting with 3.8 g of 1- (2,5-dimethoxy-phenyl) -propanone and 3.7 g of 3-nitro-4 -methoxybenzaldehyde in 75 ml of ethanol containing 4 ml of piperidine and 2 ml of acetic acid, heating at reflux for 96 hours, after purification by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and then recrystallization from isopropyl acetate, 0.3 g of E-3- (3-nitro-4- Methoxy-phenyl) -2-methyl-1- (2,5-dimethoxy-phenyl) -propene, free of Z-isomer, as yellow crystals melting at 104 ° C.
  • Step 2 By operating as in step 2 of the example, but starting from 280 mg of 3- (3-nitro-4-methoxy-phenyl) -2-methyl-1- (2,5-dimethoxy) phenyl) -propenone, and 1.03 g of iron, after purification in the form of hydrochloride recrystallized from a mixture of ethanol and diethyl ether, 0.25 g of E-3 (3) hydrochloride are obtained.
  • Step 1 Working as in Step 1 of Example 1, but starting from 3.8 g of 3,4,5-trimethoxy-acetophenone and 3.44 g of 3-nitro-4-methoxybenzaldehyde in 95 ml of methanol containing 2.37 ml of sodium hydroxide overnight at room temperature, after purification by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), 6.27 g of E-3- (3-nitro-4-methoxy-phenyl) -1- (3,4,5-trimethoxy-phenyl) -propene free from Z isomer, in the form of a viscous yellow oil.
  • Step 2 In a 50 mL three-necked flask, 500 mg of E-3- (3-nitro-4-methoxy-phenyl) -1- (3,4,5-trimethoxy-phenyl) propenone are dissolved in 8 mL of chloroform. 40 ⁇ l of bromine in solution in 3 ml of chloroform are then added dropwise. After stirring for 3 hours at room temperature, 40 ⁇ l of bromine in solution in 3 ml of chloroform are added dropwise dropwise and the mixture is stirred for a further 3 hours at room temperature.
  • Step 3 In a three-necked 10 mL, 153 mg of 2,3-dibromo-3- (3-nitro-4-methoxy-phenyl) -1- (3,4,5-triimethoxy-phenyl) -propanone are dissolved in 6 mL of dichloromethane dried over molecular sieve 4A, then
  • Step 4 67.2 mg of E-2-bromo-3- (3-nitro-4-methoxy-phenyl) -1- (3,4,5-trimethoxy-phenyl) propenone are suspended in 2 mL of ethanol, then 167.5 mg of stannous chloride, as dihydrate, and heated at 80 ° C for 1 hour. After cooling and diluting with 2 ml of water, the pH is brought to 8 by addition of a saturated solution of sodium hydrogencarbonate and extracted 3 times with 5 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel (70-230 mesh), eluting with dichloromethane.
  • Step 1 of Example 1 The procedure is as in Step 1 of Example 1, but starting from 4.49 g of 1- (3,4-d-trimethoxy-phenyl) propenone and 3.22 g of 1-methyl-2, 3-Dihydroindole-5-carboxaldehyde - which can be prepared according to Gavinecki et al., Org. Prep. Procedé. Int. (1998), 30, 455-60 - in 100 mL of ethanol containing 4 mL of piperidine and 2 mL of acetic acid, heating at reflux for 48 hours.
  • Step 1 In a 50 ml flask, 1g of Boc-Lys (Boc) -OH. DCHA is dissolved in 10 ml of ethyl acetate and then 1.2 equivalents of a 2M aqueous sulfuric acid solution (ie 2.2 ml) are added. We obtain two clear phases. The organic phase is set aside. 5 ml of cold distilled water are added to the aqueous phase, which is then extracted with 2 ⁇ ⁇ ml of ethyl acetate. The organic phases are combined and washed with 2 ⁇ 10 ml of distilled water, then dried over magnesium sulphate and the solvent is evaporated on a rotary evaporator (bath temperature below 40 ° C.).
  • Step 2 In a 60 ml three-necked flask equipped with a thermometer and a bubble counter, place the Boc-Lys (Boc) -OH (458 mg, 1. 319 mmol) prepared in step 1 in solution. in 7 ml of ethyl acetate. The colorless solution is cooled to 6 ° C. (water + ice bath), then N-methylmorpholine (1.2 equivalents, 146.5 ⁇ l) and then pivaloyl chloride (1.2 equivalents, 163 ⁇ l) are added. The white suspension obtained is maintained at 5.degree. C.
  • the organic phase is dried over magnesium sulphate and the solvent is evaporated on a rotary evaporator.
  • the reaction crude thus obtained is taken up in 5 ml of ethyl acetate and 3 ml of absolute ethanol, and then 1 ml of 4.8N hydrochloric ethanol is added.
  • the medium is heated at 49 ° C. until the expected product is obtained, following the progress of the reaction by LC / MS. When cooling a solid white precipitates. The solid is filtered on sintered glass and washed with ethyl acetate.
  • Example 11 2-Amino-5- [3- (1-nitro-guanidino)] -pentanoic acid hydrochloride ⁇ 2-methoxy-5- [2-methyl-3-oxo-3- (3,4 5-trimethoxy-phenyl) propenyl] -phenyl ⁇ -amide
  • Step 1 3- (3-Amino-4-methoxy-phenyl) -2-methyl-1- (3 ) 4,5-trimethoxy-phenyl) propenone (1 g, 0.279 mmol) is dissolved in 150 ml. dichloromethane then the EEDQ (760.1 mg, 1.1 equivalent) and N ⁇ -Boc-Nco-nitro-L-arginine (980.2 mg, 1.1 equivalent) are added. The suspension is stirred at ambient temperature for 20 hours. The solution obtained is concentrated under vacuum on a rotary evaporator.
  • Step 2 This oil is dissolved in 10 ml of ethyl acetate, then 4 ml of ethanol and 2 ml of 4.8N hydrochloric ethanol solution are added. The medium is heated at 60 ° C. (oil bath temperature) for 12 hours. The white solid obtained is filtered on sintered glass, then rinsed with ethyl acetate and dried under vacuum.
  • Example 12 1-Methyl-pyrrolidine-2-carboxylic acid hydrochloride ⁇ 2-methoxy-5- [2-methyl-3-oxo-3- (3,4,5-trimethoxy-phenyl) -propenyl] phenyl ⁇ amide
  • the crude product is taken up in 30 ml of distilled water, and then the aqueous phase is extracted with 5 ⁇ 60 ml of dichloromethane. The organic phase is washed with a saturated solution of NaCl and then dried over magnesium sulfate. The solvent is evaporated under vacuum.
  • the reaction crude is purified by flash chromatography on silica gel, eluting with a dichloromethane / methanol mixture (95/5 by volume). The 197 mg thus purified are dissolved in ethyl acetate (2 ml), then a 4.8N solution of hydrochloric ethanol (17 ⁇ l) is added and the mixture is stirred at room temperature for 18 hours.
  • Step 1 3- (3-Amino-4-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy-phenyl) propenone (700 mg, 1.96 mmol) is dissolved in 25 ml. ml of dichloromethane, then HOBT (298 mg, 1.2 equivalents), EDCI (422 mg, 1.2 equivalents) and N-Boc-L-serine (452 mg, 1.2 equivalents) were added. The medium is stirred at room temperature for 3 days. 50 ml of dichloromethane and 25 ml of water are added. The organic phase is decanted, washed with a saturated solution of NaCl and then dried over magnesium sulfate. The solvent is evaporated under vacuum.
  • Step 1 3- (3-Amino-4-methoxy-phenyl) -2-methyl-1- (3,4,5-trimethoxy-phenyl) propenone (175 mg, 0.5 mmol) is dissolved in 10 ml. ml of dichloromethane and then HOBT (75 mg, 1.1 equivalent), EDCI (106 mg, 1.1 equivalent) and N-Boc-glycine (96 mg, 1.1 equivalent) were added. The medium is stirred at room temperature for 3 days. 10 ml of dichloromethane and 10 ml of water are added. The organic phase is decanted, washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated under vacuum.
  • Step 1 3- (3-Amino-4-methoxyphenyl) -2-methyl-1- (3,4,5-trimethoxyphenyl) propenone (176 mg, 0.5 mmol) is dissolved in 10 ml of dichloromethane and then HOBT (75 mg, 1.1 equivalent), EDCI (106 mg, 1.1 equivalent) and N-Boc-L-valine (120 mg, 1.1 equivalent). The medium is stirred at room temperature for 3 days. 15 ml of dichloromethane and 10 ml of water are added. The organic phase is decanted, washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is evaporated under vacuum.
  • Step 1 In a 250 ml three-necked flask under argon atmosphere, 5 g of indole-5-carboxaldehyde are dissolved in 90 ml of DMF and 18 ml of DMSO and then cooled to 0 ° C. 2.06 g of 60% sodium hydride in oil are then added portionwise and the mixture is stirred and allowed to return to ambient temperature until the evolution of gas ceases. 8.6 g of (2-trimethylsilyl-ethyl) oxymethyl chloride are then added dropwise, followed by stirring for 20 hours at room temperature.
  • the reaction medium is then poured onto a mixture of 300 ml of water and 100 g of crushed ice, and then extracted 3 times with 160 ml of ethyl acetate.
  • the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure.
  • the brown oil obtained is purified by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume), to obtain 9 g. (2-trimethylsilyl-ethyl) oxymethyl-indole- ⁇ -carboxaldehyde, in the form of an orange oil used as it is in the next step.
  • Step 2 The procedure is as in Step 1 of Example 1, but starting from 2.1 g of 1- (3-methoxy-4,5-methylenedioxyphenyl) -propanone - which can be prepared according to J. Org. Chem. 1981, 46 (14), 2969-71 and 2.76 g of 1- (2-trimethylsilylethyl) oxymethylindole-5-carboxaldehyde in 100 ml of ethanol containing 2 ml of piperidine and 1 ml of acid. acetic acid, heating at reflux for 96 hours.
  • Step 3 In a 250 ml three-necked flask under an argon atmosphere, 2 g of E-2-methyl-3- [1- (2-trimethylsilyl-ethyl) oxymethyl are dissolved. -1_-H -indol-5-yl] -1- (3-methoxy-4,5-methylenedioxyphenyl) propenone in 42 ml of THF, then 4.3 ml of a 1 M solution of fluoride is added. of tetra N-butyl ammonium in THF and refluxed for 20 hours.
  • reaction medium is taken up in 75 ml of ethyl acetate and 75 ml of water.
  • the organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure.
  • the red oil obtained is purified by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume), followed by recrystallization from isopropanol.
  • the reaction medium is taken up in 50 ml of ethyl acetate, washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure.
  • Step 1 The procedure is as in Step 1 of Example 1, but starting from 2.24 g of 1- (3,4,5-trimethoxy-phenyl) -propanone and 2.76 g of 1-tert. Buty Ioxycarbonyl-indole-5-carboxaldehyde - which can be prepared according to J. Org. Chem. 2002, 67 (17), 6256-59 - in 100 mL of ethanol containing 2 mL of piperidine and 1 mL of acetic acid, heating at reflux for 48 hours.
  • Step 2 After purification by flash chromatography on silica gel (70-230 mesh), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume), 2.2 g of E-2- pure methyl-3- [1 - (1-tert.-butoxycarbonyl-1H-indol-5-yl] -1- (3,4,5-trimethoxy-phenyl) -propenone as a pale yellow oil as used in the following step Step 2: 0.7 g of E-2-methyl-3- [1- (1-tert.butyloxycarbonyl-1-H-indol-5-yl] -1 - (3 , 4,5-trimethoxy-phenyl) propenone are dissolved in 15 ml of THF, then 1.5 ml of methanol, 0.25 g of sodium, and then stirred 18 hours at room temperature.
  • reaction medium is taken up in 75 ml of ethyl acetate and 35 ml of water.
  • the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
  • n / a not determined np: not relevant

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