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WO1993016064A1 - Derives de coumarine et leurs analogues inhibant la proliferation cellulaire et la croissance tumorale, compositions pharmaceutiques les contenant, et leur procede de preparation - Google Patents

Derives de coumarine et leurs analogues inhibant la proliferation cellulaire et la croissance tumorale, compositions pharmaceutiques les contenant, et leur procede de preparation Download PDF

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Publication number
WO1993016064A1
WO1993016064A1 PCT/HU1993/000010 HU9300010W WO9316064A1 WO 1993016064 A1 WO1993016064 A1 WO 1993016064A1 HU 9300010 W HU9300010 W HU 9300010W WO 9316064 A1 WO9316064 A1 WO 9316064A1
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group
general formula
compounds
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alkoxy
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Inventor
György Kéri
Tamás BAJOR
László O^'RFI
Endre Tihanyi
Ágnes BALOGH
Gyöngyi Bökönyi
Anikó HORVÁTH
Miklós IDEI
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Biosignal Kutato Fejlesztokft Kft
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Biosignal Kutato Fejlesztokft Kft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/64—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with oxygen atoms directly attached in position 8

Definitions

  • This invention relates to novel compounds of the general formula (I),
  • R 1 stands for -CN, -COOH, -CSOH, -COSH, -CONH 2 ,
  • Y means -O-, -S- or -NH- group
  • R 2 and R 4 independently from each other, represent hydrogen atom, -OH, -SH, -NH 2 , -CF 3 , C 1-4 alkoxy or C 1-4 alkylthio group;
  • R 3 stands for -OH, -SH, -NH 2 , -CF 3 , -NO, -O-SO 2 -V 0 ,
  • V 0 stands for 3,4,5-tri-V 1 -phenyl group
  • V 1 substituents independently from each other. mean hydrogen or halogen atom or -OH, -SH, -NH 2 , -CF 3 , C 1-4 alkoxy, C 1-4 alkylthio or C 1-4 alkylamino group; or
  • V 1 bound in the 3- or 4-position may be -COOH, -CSOH, -COSH, -CONH 2 , C 1-4 dialkylamino, pyridyl, -CH 2 -2-pyridyl, -O-CH 2 -O- or
  • V 2 and V 3 together stand for -NH-CH 2 -NH- or -N(CH 3 )-CH 2 -N(CH 3 )- group;
  • R 5 represents hydrogen, C 1-4 alkyl, C 1-4 alkoxy
  • R 1 substituted by R 1 can also be saturated when R 3 is a substituent containing the -3,4,5-tri-V 1 -phenyl moiety, as well as physiologically acceptable salts and complexes thereof and pharmaceutical compositions containing these compounds.
  • intercellular communication plays a decisive role in the maintenance of differentiated functions of specialized cells in the organism.
  • a defective function of this communication system may lead to various disorders, inter alia to tumour development in the organism.
  • the process of carcinogenesis can unanimously be comprehended as a result of the defective functioning of intercellular communication and intracellular signal transmission mechanism, which occurs as a consequence of false messages sent e.g. by hormones, growth factors and oncogenes or disturbation of the signal transfer mechanisms.
  • the regulation of cell division and differentiation is accomplished by a number of independent mechanisms and the simultaneous existence of several damaging factors is needed to stop this regulating process or to develop a tumorous transformation.
  • tumour formation In the course of tumour formation the systems regulating the propagation and differentiation, which are connected in a complicated communication system under normal conditions, are disconnected and the proliferation becomes stimulated, this process leading to an unhindered cell division, i.e. tumorous transformation.
  • a tumour begins to develop when viable cell variants are formed among these transformed tumour cells, which commence to multiply in the "hostile" microenvironment.
  • the preparation of active agents being capable of inhibiting the tyrosine-kinase activity of tumourous cells presents a new perspective in the tumour-biologic and -therapeutic researches.
  • tumourous cells Since the proliferation of tumourous cells is generally an active division, the most active compounds proved to be compounds which were cytotoxic to cells under division; however, such substances exert many severe adverse effects chiefly because of inhibiting the division of healthy cells, too.
  • coumarin derivatives of plant origin goes back to thousands of years.
  • the preparation of coumarin derivatives was studied from the beginning of this century.
  • the best known coumarin drugs are anticoagulants such as dicoumarol, ethyl bis-coumacetate, acenocoumarol, warfarin and phenprocoumon, the common structural characteristics of which are an aromatic substituent bound through a methylene bridge in 3-position and a hydroxy group in 4-position [A. Kleeman and J. Egel: Sostanze Farmaceutiche, OEMF-Milano (1988)].
  • Bucoumol containing a methyl group in 5-position and an amino-hydroxy-propyloxy substituent, characteristic of beta-blocking compounds, is a beta-adrenergic blocking agent (U.S. patent specification No. 3,663,570).
  • Folescutol chemically 6,7-dihydroxy-4-morpholinomethylcoumarin, shows a capillary-protecting action (French patent specification No. M 2035).
  • Hymechromon chemically 7-hydroxy-4-methylcoumarin, exerts a bile-secretion-promoting effect (French patent specification No. M 1430).
  • Thioclomarol chemically 4-hydroxy-3-[5-chloro-alpha- (p-chloro-beta-hydroxyphenethyl)-2-thienyl]-coumarin, is an antithrombotic agent [Drugs of Today 14, 383 (1978)].
  • the invention is aimed at developing novel antitumour compounds inhibiting the activity of tyrosine kinase enzymes playing a role in the signal transfer mechanism without any practical influence on the function of the tyrosine kinase enzyme of the insulin receptor.
  • the invention is based on the recognition that, due to their molecular structure and electron-arrangement properties, the members of the compound class of general formula (I), being new coumarin derivatives and their analogues, are capable of being non-covalently bound with the desired specifity in a suitable position to substructures recognizing the tyrosine side chain of the protein substrate at catalytic sites of the tyrosine kinase enzymes.
  • the members of the compound class of general formula (I) being new coumarin derivatives and their analogues, are capable of being non-covalently bound with the desired specifity in a suitable position to substructures recognizing the tyrosine side chain of the protein substrate at catalytic sites of the tyrosine kinase enzymes.
  • they satisfy the principles discussed above and are useful to inhibit the proliferation of mammalian cells and the tumor growth.
  • novel coumarin derivatives and their analogues of general formula (I) are prepared by a) condensing a benzaldehyde derivative of general formula (IV)
  • R stands for -COOC 2 H 5 or -CSOC 2 H 5 group, in the presence of an acid catalyst
  • R means -COOC 2 H 5 or -CSOC 2 H 5 group
  • R 2 , R 3 , R 4 , R 5 , X and Y are as defined above;
  • the condensation is carried out at a temperature between 100 °C and 200 °C, optionally under a protective gas depending on the substituents.
  • a protective gas depending on the starting substances, water or a polar solvent, preferably ethanol, is used as solvent.
  • Phosphoric acid, hydrochloric acid or in some cases sulfuric acid may preferably be used as acid catalysts in an amount of 0.01 to 10.0 molar equivalent(s).
  • the condensation is carried out at a temperature between room temperature and 200 °C, optionally under a protective gas depending on the substituents.
  • Alkali metal or alkali earth metal hydroxides taken in an amount of 0.001 to 1.0 molar equivalent are suitable alkaline catalysts.
  • Preferred solvents are water or a polar solvent, suitably ethanol, depending on the starting substances.
  • the ring is closed in a further condensation reaction in the presence of an acid catalyst. This condensation is accomplished between 100°C and 200 °C, optionally under a protective gas depending on the substituents.
  • Suitable solvents depending on the starting substances are water or a polar solvent, preferably ethanol.
  • Phosphoric acid, hydrochloric acid and in some cases sulfuric acid are preferably used as acid catalysts in an amount of 0.01 to 10.0 molar equivalent(s).
  • the condensation is carried out between room temperature and 100 °C, optionally under a protective gas depending on the substituents.
  • Alkali metal or alkali earth metal hydroxides taken in an amount of 0.001 to 1.0 molar equivalent are suitable alkaline catalysts whereas 0.001 to 1.0 molar equivalent of phosphoric acid or hydrochloric acid or in some cases sulfuric acid may suitably be used as acid catalysts.
  • the intermediate is taken up in an organic solvent being inert to the reaction conditions, then the ring is closed by thermal condensation between 100 °C and 200 °C, optionally under a protective gas depending on the substituents.
  • Suitable organic solvents are alkanes, aromatic hydrocarbons containing no unsaturation in their side chain or some polar organic solvents such as chloroform or dimethylsulfoxide.
  • the condensation is realized at a temperature between 100 °C and 200 °C, optionally under a protective gas depending on the sub stituents.
  • a protective gas depending on the sub stituents.
  • water or a polar solvent suitably ethanol, may be used as solvent.
  • Phosphoric acid or hydrochloric acid or in some cases sulfuric acid taken in an amount of 0.01 to 10.0 molar equivalent(s) may preferably be used as acid catalysts.
  • the condensation is carried out between room temperature and 200 °C, optionally under a protective gas depending on the substituents.
  • Alkali metal or alkali earth metal hydroxides in an amount of 0.001 to 1.0 molar equivalent may be used as preferable alkaline catalysts.
  • water or a polar solvent suitably ethanol
  • the ring is closed in a second condensation reaction in the presence of an acid catalysts. This condensation is accomplished at a temperature between 100 °C and 200 °C, optimally under a protective gas depending on the substituents.
  • water or a polar solvent preferably ethanol, is used as solvent.
  • acid catalyst 0.01 to 10.0 molar equivalent(s) of phosphoric acid or hydrochloric acid or in some cases sulfuric acid is (are) used.
  • the condensation is carried out between room temperature and 100 °C, optionally under a protective gas depending on the substituents.
  • Alkali metal or alkali earth metal hydroxides taken in an amount of 0.001 to 1.0 molar equivalent are preferable alkaline catalysts whereas 0.001 to 1.0 molar equivalent of phosphoric acid or hydrochloric acid or in some cases sulfuric acid may suitably be used as acid catalyst.
  • the ring After neutralizing the reaction mixture and then taking up the intermediate in an organic solvent being inert to the condensation conditions, the ring is closed by thermal condensation at a temperature between 100 °C and 200 °C, optionally under a protective gas depending on the substituents.
  • Alkanes, aromatic hydrocarbons containing no unsaturation in their side chain or some polar organic solvents such as chloroform or dimethyl sulfoxide may be used as organic solvents.
  • the substituent R of the product of general formula (la) may be subjected to further transformations by using methods known from the literature to obtain other derivatives of the compounds of general formula (I).
  • R means
  • a compound of the general formula (I) is obtained, wherein R 1 stands for -COOH or -CSOH group; and/or by saturating with gaseous ammonia an alcoholic solution of a carboxylic acid derivative thus prepared a compound of the general formula (I) is obtained, wherein R 1 means -CONH 2 or -CSNH 2 group; and/or by reacting a carboxylic acid amide derivative thus prepared e.g. with phosphorus oxychloride, a compound of the general formula (I) can be prepared, wherein R 1 stands for -CN group.
  • the invention furthermore relates to pharmaceutical compositions inhibiting tumour growth and cell proliferation; these compositions contain the compounds of general formula (I) and/or their physiologically acceptable salts and/or complexes as active agents together with carriers and additives commonly used in the pharmaceutical industry.
  • the invention also relates to the preparation of these compositions.
  • compositions may contain any solvent being suitable for therapeutical use (such as water or aqueous solutions containing ethanol and/or a polyalcohol, e.g. polyethylene glycol and/or glycerol or the like); salts (e.g. sodium chloride for adjusting the physiological osmotic pressure or e.g.
  • solvent such as water or aqueous solutions containing ethanol and/or a polyalcohol, e.g. polyethylene glycol and/or glycerol or the like
  • salts e.g. sodium chloride for adjusting the physiological osmotic pressure or e.g.
  • fillers and carriers such as lactose, potato starch, talc, magnesium carbonate, calcium carbonate, waxes, vegetable oils, polyalcohols and the like
  • additives promoting dissolution such as polar organic solvents, usually ethanol, polyalcohols, most frequently polyethylene glycol or glycerol and/or complex-forming agents, e.g. cyclodextrins, crown ethers, native proteins, saponins and the like in the case of water
  • tablet-disintegrating agents ininert artificial or native polymers strongly swelling in water, e.g.
  • carboxymethyl cellulose carboxymethyl cellulose
  • the usual complex-forming agents in composition with sustained release such as water-insoluble or slightly soluble cyclodextrin derivatives, artificial and native polymers, crown ethers and the like); pH-adjusting substances such as mineral or organic buffers; savouring agents (such as cyclodextrins and/or crown ethers) and flavouring substances (such as beet sugar, fructose, dextrose, saccharin, invert sugar and the like); antioxidants (e.g. vitamin C); as well as substances promoting the development of effect of the compounds of general formula (I).
  • sustained release such as water-insoluble or slightly soluble cyclodextrin derivatives, artificial and native polymers, crown ethers and the like
  • pH-adjusting substances such as mineral or organic buffers
  • savouring agents such as cyclodextrins and/or crown ethers
  • flavouring substances such as beet sugar, fructose, dextrose, saccharin
  • the compounds of general formula (I) can be used as active ingredients for the preparation of orally administered compositions such as tablets, pills,
  • compositions developed for the above uses by incorporating to liposomes or microcapsules.
  • the compounds of general formula (I) are suitable to be used in the form of aerosol compositions aimed at resorption through the skin or lungs.
  • dragees or hard gel capsules e.g. lactose, maize, wheat or potato starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid and its salts and the like can be used as carriers.
  • Vegetable oils, fats, waxes or polyalcohols of suitable density are useful carriers for preparing soft gel capsules.
  • Water, polyalcohols such as polyethylene glycol or glycerol, beet sugar, dextrose and the like may be used as carriers for the preparation of solutions and syrups.
  • Parenterally administered composi tions may contain water, alcohol, polyalcohols or vegetable oils as carriers.
  • Suppositories may contain e.g. oils, waxes, fats or polyalcohols of suitable density as carriers.
  • the compounds of general formula (I) or pharmaceutical compositions containing them, respectively, are useful also together with other artificial or native active agents for therapeutical use.
  • the compounds of general formula (I) may be used in a daily dose of 0.01 to 5000 mg/kg, preferably 0.1 to 250 mg/kg, but the dose is dependent on the sort of the tumour, degree of malignancy, state and age of the patient and the like.
  • LLT Lewis lung tumour
  • LLT-HH immunoresistant cell variant
  • the compounds to be tested were injected intra-peritoneally (ip.), intravenously (iv.), orally (po.) or subcutaneously (sc.) in doses of 0.1 to 10 mg/kg daily 1 to 3 times on the Sth to 13th days.
  • the therapeutical effect was determined on the basis of the number of metastases in such a way that a sample was taken on the 10th and 14th days in the spleen-liver model, and on the 17th and 18th days in the muscle-lung model, then the macroscopic metastases were counted in the liver or lungs, respectively, under a stereomicroscope.
  • the activity of the compounds was expressed as percentage of the number of metastases determined in the control animals.
  • tumours and mouse strains used will be described in detail hereinafter together with the individual measurement results.
  • the effect of various treatments on the tumour growth was evaluated on the basis of alteration of the life span in relation to that of the tumorous control group or by measuring the tumour size in cases of the so-called solid tumours.
  • the volume of the tumour was determined on the basis of the following correlation:
  • V means the tumour volume
  • L is the longest diameter of the tumour
  • D 2 is the square of the shortest diameter being perpendicular to L.
  • the experimental results showing the effect of the compound of Example 2 on the P-388 sc. leukemia tumour growth are summarized in Figure 9.
  • the P-388 lymphoid leukemia tumour was obtained from Arthur Little and Co., Cambridge MA, USA.
  • the transplantation was carried out in sc. route by using 1 ⁇ 10 7 cells.
  • BDF 1 hybrid mice were used as host animals.
  • Each experimental group consisted of 10 animals with a body weight of 21 to 23 g.
  • the results were calculated from the data measured on the 11th, 14th and 16th day, resp.
  • the compound of Example 2 was administered in a daily dose of 0.1, 1.0 or 10.0 mg/kg, respectively.
  • the treatments were carried out 3 times, repeated every second day.
  • the treatments were started 2 days after tumour transplantation.
  • B-16 melanoma tumour was obtained from Karolinska Inst. Dep. of Tumor Biology, Sweden.
  • the transplantation was carried out by using a cell suspension in sc. route.
  • BDF 1 hybrid mice were used as host animals.
  • Each experimental group consisted of 10 animals with a body weight of 21 to 23 g.
  • the results were calculated from the data measured on the 11th, 14th and 16th day, resp.
  • the compound of Example 2 was administered in a daily dose of 0.1, 1.0 and 10.0 mg/kg, respectively.
  • the treatments were carried out 3 times, repeated every second day.
  • the treatments were started 2 days after tumour transplantation.
  • ZR-75.1 human breast cancer cell line and its form transformed by the human EGF receptor cDNA i.e. the ZRHERc cell line (in the cells of which functional human EGF receptor tyrosine kinase is expressed), were used for these examinations.
  • the cancerous cells were incubated in serum or serum-free culture medium after adding a suitable amount of EGF for stimulating cell growth.
  • the measurement results were obtained by determining the cell counts of the cultures usually on the 3rd, 6th and 10th days.
  • Example 1 on the cell growth are summarized in Figure 13.
  • ZRHERc cell line was used for this investigation.
  • the cells were incubated in a serum-fre nutritive solution together with EGF added in 5 nanogram (ng)/ml concentration in the presence of various concentrations of the active agents (10, 50 and 100 ⁇ M, respectively, of the compound of Example 1).
  • the cell count of HT-29 cell line does not exceed the starting cell count even on the 2nd day in spite of increasing amounts of serum stimulating the cell growth.
  • ZRHERc cells cultivated in pure serum also lags behind the growth of untreated cells on effect of the treatment.
  • the experimental results prove that the compounds according to the invention inhibit the tyrosine kinase activity of cancerous cells.
  • Figures 13 and 14 illustrate how the growth of ZRHERc cells cultivated in serum-free nutritive solution with stimulation by EGF falls behind the growth of untreated cells with progressive time, as a consequence of increasing the amount of active agent, a process due to the inhibition of the EGF receptor tyrosine kinase enzyme.
  • novel active compounds inhibiting the specific signal transfer of tyrosine analogue tyrosine kinase do not inhibit the cell division in the traditional sense and therefore they do not considerably interfere with the division of normal cells. Thus, they are not encumbered by adverse side effects accompanied with severe complications being unavoidable concomitants of the classical chemotherapeutics.
  • novel active compounds according to the invention do not inhibit the kinase activity from the side of the ATP binding site and therefore, they do not show the strong cytotoxicity which is characteristic of ATP analogues.
  • novel active compounds according to the invention possess a broader spectrum of activity in relation to the known signal transfer-inhibiting active agents (which are EGF-RTK specific) while maintaining the favourable property that they do not interfere with the function of the insulin receptor tyrosine kinase.
  • a solution containing 0.266 g of 3-ethoxycarbonyl-6,7,8-trihydroxycoumarin (prepared according to Example 4) in 5 ml of 5% sodium hydroxide solution is stirred at room temperature until dissolution.
  • the reaction mixture is stirred for additional two hours at room temperature and then acidified to pH 2 by 5 % hydrochloric acid.
  • the compounds of Nos. 8 to 41 listed in Table 1 hereinafter were prepared.
  • the retention times of high-pressure liquid chromatography (HPLC) are indicated.
  • HPLC - A 50 % H 2 O, 50 % CH 3 OH, isocratic, Nucleosil C10
  • R 3 -O-CO-p-N(CH 2 -OH) 2 -pheny; A 1.66

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Abstract

Nouveaux composés répondant à la formule générale (I), dans laquelle R1 représente -CN, -COOH, -CSOH, -COSH, -CONH2, -CSNH2, -NHCHO, -COOCH3, -CSOCH3, -COSCH3, -COOCH2CH3, -CSOCH2CH3, -COSCH2CH3, -NHCOCH3, -NHCSCH3, -CS-NH-CONH2, -CO-NH-CONH2, -CO-NH-CSNH2, -CS-NH-CSNH2, -C(NH2)=C(CN)2, -CH(CN)2, -CH(CN)-COOH, -CH(CN)-CONH2, -CH(CN)-CSNH2, -CH(CN)CSNH-C1-4 alkyle, -NO2 ou un groupe -NO; X représente =O, =S ou un groupe =NH; Y représente -O-, -S- ou un groupe -NH-; R2 et R4, indépendamment l'un de l'autre, représentent un atome d'hydrogène, -OH, -SH, -NH2, -CF3, alcoxy C1-4 ou un groupe alkylthio C1-4; R3 représente -OH, -SH, -NH2, -CF3, -NO, -O-SO2-V0, -O-CO-V0, -O-CS-V0, -S-CO-V0, -NH-CO-V0 ou un groupe -CH=CH-V?0; où V0¿ représente un groupe 3,4,5-tri-V1-phényle; et les substituants V1, indépendamment les uns des autres, représentent un atome d'hydrogène ou d'halogène, ou -OH, -SH, -NH¿2?, -CF3, alcoxy C1-4, alkylthio C1-4, ou un groupe alkylamino C1-4; ou V?1¿, lié en position 3 ou 4, peut représenter -COOH, -CSOH, -COSH, -CONH¿2?, dialkylamino C1-4, pyridyle, -CH2-2-pyridyle, -O-CH2-O- ou un groupe -N(CH2-V?2)-CH¿2-V3, dans lequel V2 et V3, indépendamment l'un de l'autre, représentent -OH, -SH, -NH¿2?, -CF3, alkyle C1-4, alcoxy C1-4 ou un groupe alkylthio C1-4; ou V?2 et V3¿, pris ensemble, représentent -NH-CH¿2?-NH- ou un groupe -N(CH3)-CH2-N(CH3)-; R5 représente hydrogène, alkyle C1-4, un groupe alcoxy C1-4 ou halogène; et la liaison double appartenant à l'atome de squelette substitué par R1 peut également être saturé lorsque R3 représente un substituant renfermant la fraction -3,4,5-tri-V?1¿-phényle; et les complexes et sels physiologiquement acceptables de ces composés. On a également prévu des compositions pharmaceutiques contenant les composés précités, ainsi que les procédés de préparation des composés et compositions précités. On prépare les composés de la formule générale (I) par la condensation d'un dérivé de phénol ou de benzaldéhyde avec un dérivé d'acide carboxylique bifonctionnel. Les composés de la formule générale (I) présentent une activité d'inhibition tumorale: ils inhibent l'activité des tyrosine-kinases participant au mécanisme de transfert de signaux, mais n'influencent sensiblement pas l'activité de la tyrosine-kinase à récepteur d'insuline.
PCT/HU1993/000010 1992-02-13 1993-02-12 Derives de coumarine et leurs analogues inhibant la proliferation cellulaire et la croissance tumorale, compositions pharmaceutiques les contenant, et leur procede de preparation Ceased WO1993016064A1 (fr)

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HU9200438A HUT63843A (en) 1992-02-13 1992-02-13 Process for producing new kumarin derivatives and their analogs inhibiting mammal cell proliferation and tumour growth, as well as pharmaceutical comkpositions comprising such compounds
HUP9200438 1992-02-13

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563280A (en) * 1994-07-25 1996-10-08 American Cyanamid Co. 4-Phenoxycoumarins as herbicidal agents
US5648378A (en) * 1995-06-07 1997-07-15 Research Corporation Technologies, Inc. 2-iminochromene derivatives as inhibitors of protein tyrosine kinase
FR2822379A1 (fr) * 2001-03-20 2002-09-27 Sederma Sa Compositions cosmetiques et dermopharmaceutiques contenant de l'umbelliferone
WO2003024950A1 (fr) * 2001-09-12 2003-03-27 Institute Of Medicinal Molecular Design. Inc. Dérivé de coumarine
RU2207338C2 (ru) * 1997-10-02 2003-06-27 Плива, Фармацойтска Индустрия, Дионичко Друштво Новые гидрокси- и полигидроксипроизводные кумарина и способ их получения
WO2003076423A1 (fr) * 2002-03-12 2003-09-18 Ube Industries, Ltd. Procede de preparation d'un compose 6,7-dyhydroxycoumarine-3-carboxy
US6951870B2 (en) 2000-07-03 2005-10-04 Orion Corporation Coumarin derivatives with COMT inhibiting activity
JP2006512328A (ja) * 2002-12-05 2006-04-13 チョン グア イー シュエ クァ シュエ ユァン イァオ ウー イエン ジョウ スオ 新規なクマリン、それらのカルボキサミド誘導体、調製法、組成物、および使用
RU2284325C2 (ru) * 2003-12-17 2006-09-27 Общество С Ограниченной Ответственностью "Асинэкс Медхим" Производные фенил-3-аминометил-хинолона-2 в качестве ингибиторов no-синтетазы, способ их получения, биологически активные соединения и фармацевтическая композиция на их основе
WO2006032120A3 (fr) * 2004-09-20 2009-05-14 Univ Rio De Janeiro Cumarines substitues, procede de production de ces cumarines et composition contentant ces cumarines
US7897792B2 (en) 2006-02-09 2011-03-01 Chugai Seiyaku Kabushiki Kaisha Coumarin derivative having antitumor activity
US8569378B2 (en) 2007-07-20 2013-10-29 Toshiyuki Sakai p27 protein inducer

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5563280A (en) * 1994-07-25 1996-10-08 American Cyanamid Co. 4-Phenoxycoumarins as herbicidal agents
US5648378A (en) * 1995-06-07 1997-07-15 Research Corporation Technologies, Inc. 2-iminochromene derivatives as inhibitors of protein tyrosine kinase
RU2207338C2 (ru) * 1997-10-02 2003-06-27 Плива, Фармацойтска Индустрия, Дионичко Друштво Новые гидрокси- и полигидроксипроизводные кумарина и способ их получения
US6951870B2 (en) 2000-07-03 2005-10-04 Orion Corporation Coumarin derivatives with COMT inhibiting activity
RU2282627C2 (ru) * 2000-07-03 2006-08-27 Орион Корпорейшн Кумариновые производные с подавляющей комт активностью
FR2822379A1 (fr) * 2001-03-20 2002-09-27 Sederma Sa Compositions cosmetiques et dermopharmaceutiques contenant de l'umbelliferone
WO2002074231A3 (fr) * 2001-03-20 2003-02-13 Sederma Sa Compositions cosmetiques et dermopharmaceutiques contenant des extraits titres de hierochloe odorata
JPWO2003024950A1 (ja) * 2001-09-12 2004-12-24 株式会社医薬分子設計研究所 クマリン誘導体
US7411076B2 (en) 2001-09-12 2008-08-12 Institute Of Medicinal Molecular Design, Inc. Coumarin derivative
GB2397817B (en) * 2001-09-12 2005-05-25 Inst Med Molecular Design Inc Coumarin derivatives
GB2397817A (en) * 2001-09-12 2004-08-04 Inst Med Molecular Design Inc Coumarin derivative
WO2003024950A1 (fr) * 2001-09-12 2003-03-27 Institute Of Medicinal Molecular Design. Inc. Dérivé de coumarine
JP4604147B2 (ja) * 2001-09-12 2010-12-22 株式会社医薬分子設計研究所 クマリン誘導体
WO2003076423A1 (fr) * 2002-03-12 2003-09-18 Ube Industries, Ltd. Procede de preparation d'un compose 6,7-dyhydroxycoumarine-3-carboxy
JP2006512328A (ja) * 2002-12-05 2006-04-13 チョン グア イー シュエ クァ シュエ ユァン イァオ ウー イエン ジョウ スオ 新規なクマリン、それらのカルボキサミド誘導体、調製法、組成物、および使用
US8338401B2 (en) 2002-12-05 2012-12-25 Institute Of Materia Medica Chinese Academy Of Medical Sciences Coumarin-amide derivatives and its preparation, said drug composition and its use
RU2284325C2 (ru) * 2003-12-17 2006-09-27 Общество С Ограниченной Ответственностью "Асинэкс Медхим" Производные фенил-3-аминометил-хинолона-2 в качестве ингибиторов no-синтетазы, способ их получения, биологически активные соединения и фармацевтическая композиция на их основе
WO2006032120A3 (fr) * 2004-09-20 2009-05-14 Univ Rio De Janeiro Cumarines substitues, procede de production de ces cumarines et composition contentant ces cumarines
US7897792B2 (en) 2006-02-09 2011-03-01 Chugai Seiyaku Kabushiki Kaisha Coumarin derivative having antitumor activity
US8278465B2 (en) 2006-02-09 2012-10-02 Chugai Seiyaku Kabushiki Kaisha Coumarin derivative having antitumor activity
US8569378B2 (en) 2007-07-20 2013-10-29 Toshiyuki Sakai p27 protein inducer

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