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WO1991016892A1 - Composes de styryle inhibant la proteine tyrosine kinase de recepteur de facteur de croissance epidermique - Google Patents

Composes de styryle inhibant la proteine tyrosine kinase de recepteur de facteur de croissance epidermique Download PDF

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Publication number
WO1991016892A1
WO1991016892A1 PCT/US1991/002931 US9102931W WO9116892A1 WO 1991016892 A1 WO1991016892 A1 WO 1991016892A1 US 9102931 W US9102931 W US 9102931W WO 9116892 A1 WO9116892 A1 WO 9116892A1
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Prior art keywords
alkyl
compound
halo
independently
coor
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Alexander Levitzki
Chaim Gilon
Michael Chorev
Aviv Gazit
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Rorer International Holdings Inc
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Rorer International Holdings Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles

Definitions

  • This invention relates to the inhibition of cell proliferation. More specifically, this invention relates to the use of low molecular weight styryl compounds in
  • PTK protein tyrosine kinase
  • EGF epidermal growth factor
  • PDGF growth factor
  • growth factor receptors Such growth factors are typically specific for corresponding growth factor receptors which are imbedded in and which penetrate through the cellular membrane. The initiation of cellular reproduction is believed to occur when a growth factor binds to the corresponding receptor on the external surface of the cellular membrane. This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor which exists within the cell and which functions as an enzyme to catalyze phosphorylation of either an intracellular substrate or the receptor itself, the latter being referred to as autophosphorylation.
  • Examples of such phosphorylation enzymes include tyrosine kinases, which catalyze phosphorylation of tyrosine amino acid residues of substrate proteins.
  • PTK protein tyrosine kinase
  • EGF epidermal growth factor
  • each of these receptors (normal or mutated) exhibits a characteristic PTK activity with a distinct substrate specificity.
  • One of these receptors is the
  • epidermal growth factor (EGF) receptor and its oncogenic homolog V-ERB-B.
  • concentrations of erbstatin are required to inhibit EGF receptor autophosphorylation, whereas much higher concentrations of erbstatin are required to inhibit cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase.
  • cAMP cyclic adenosine 3',5'-monophosphate
  • R 1 and R 2 are each independently -CN, -CONH 2 or -COOH or one of
  • R 1 is -H, -CH 3 or -OH
  • R 4 , R 5 , R 6 and R 7 are each independently -H, -OH, C 1-5 alkyl,
  • R 1 and R 2 are each independently -CN, -CONH 2 or -COOH or one of
  • R 3 is -H, -CH 3 or -OH
  • R 4 , R 5 , R 6 and R 7 are each independently -H, -OH, C 1-5 alkyl,
  • a method of inhibiting cell proliferation in a patient suffering from such disorder comprising administering to said patient a pharmaceutical composition as described above.
  • a method of inhibiting cell proliferation in a patient suffering from such disorder comprising administering to said patient an effective amount of a composition
  • R 1 and R 2 is alkyl, -H, -CN, -OH, -COOR, -CONRR or
  • R 1 and R 2 are not both alkyl , -H, -CN or -OH; R is alkyl or -H;
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, -H, -CN, halo, -OR, -CHO, -COOH, -NRR, -N0 2 , -NHCOCH 3 , -SR,
  • R 3 and R 7 together may be -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from
  • R 3 -CONH-;
  • R 9 is -NH 2 , -CONH 2 ,
  • R 10 is alkyl, halo. -OR, -COOR or -NO 2 ;
  • R 11 is alkyl, -CN, halo, -OR, -CHO, -COOH, -NRR, -NO 2 , - NHCOCH 3 , -SR, -CH-CHCOOH, -NHCO(CH 2 ) 2 COOH or morpholino;
  • R 12 is alkyl, -H, halo, -OR or -COOR; n is 0 to about 6; and
  • R 3 is alkyl, -CN, -OH, -COOR, -CONRR, -CSNRR, -CH 2 CN or
  • R is alkyl or -H
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, -H, -CN, halo, -OR, -CHO, -COOH, -NRR, -NO 2 , -NHC0CH 3 , -SR,
  • R 3 and R 7 together are -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from R 3 , -CONH-;
  • compositions comprising, in admixture with a pharmaceutically acceptable carrier, a pharmaceuticallyeffective amount of a compound within the scope of formula II, III or V above, and within the scope of formula IV provided that when R 5 is -OH and when one of R 4 or R 6 is halo, then the other of R 4 and R 6 is not tert-alkyl.
  • Compounds within the scope of the present invention have a specific affinity toward the substrate site of the tyrosine kinase domain of EGF receptors, inhibit EGF receptor kinase more than they inhibit PDGF receptor kinase and also
  • Figure 1 is a graphical representation of the activity of isolated EGFR kinases (given in percent of the total kinase activity) plotted against the concentrations in ⁇ M of 12 different inhibitors.
  • Figures 2a and 2b are graphical representations of the inhibitory effect of two pairs of tested compounds on the rate of the growth of KB and A431 cells respectively, the number of cells being plotted against time (in days).
  • Figure 3 is a graphical representation of the inhibition of A431 cell growth as a function of various concentrations (in ⁇ M) of the inhibitor "compound 2" according to the invention.
  • Figures 4a and 4b are graphical representations of the inhibitory effect of two pairs of tested compounds on the rate of the EGF-dependent proliferation of A431/clone 15 cells, with Figure 4a depicting inhibition effects of compounds found to inhibit EGF-dependent growth
  • Alkyl means a saturated aliphatic hydrocarbon which may be either straight- or branch-chained containing from about 1 to about 6 carbon atoms.
  • “Lower alkyl” means an alkyl group as above, having 1 to about 4 carbon atoms which may be straight- or branch-chained such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
  • Alkoxy means an alkyl-oxy group in which "alkyl” is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i- propoxy and n-butoxy.
  • acyl means an organic radical derived from an organic acid, a carboxylic acid, by the removal of its acid hydroxyl group.
  • Preferred acyl groups are lower alkyl carboxylic acid groups such as acetyl and propionyl. Benzoyl is also
  • Halo means a halogen. Preferred halogens include chloride, bromide and fluoride.
  • inhibiting compounds should be competitive with the substrate of EGF receptor tyrosine kinase ( EGFRK ) and not with
  • adeno ⁇ ine triphosphate ATP
  • PTK inhibitors guercetin and genlstein, which compete with ATP, inhibit other protein kinases and as a result are highly cytotoxic.
  • compounds which inhibit EGFRK better than they inhibit insulin receptor kinase (IRK) and/or PDGF receptor kinase are of considerable value. It is theorized that solubility of the compounds of the present invention both in water and in mildly hydrophobic solvents will enhance the probability that they traverse the cell membrane.
  • Various insoluble compounds have exhibited significant EGFRK inhibition in in vitro testing.
  • Aforementioned application Serial No. 07/287,908 discloses, as a preferred class of compounds useful as the active ingredient in the pharmaceutical composition aspects of that invention, those compounds described by formula I above in which at least one of R 1 and R 2 is -CN cis to the phenyl moiety of said formula, particularly those in which R 4 and R 5 are hydroxy groups, R 6 is hydrogen or hydroxy and R 3 and R 7 are hydrogens.
  • Particular preferred pharmaceutical compositions are disclosed therein as those containing as an active ingredient a compound, or a pharmaceutically
  • a preferred class of compounds useful in the practice of the present invention includes those compounds comprising (A) one or more cyano groups attached to the ethylene portion of the styryl compound, for example, styryl and cinnamilidene nitriles and benzylidene and cinnamal malononitriles; and/or (B) one or more substituents on the phenyl portion of the styryl compound, for example, alkyl, cyano, halo, hydroxy, alkoxy, formyl, amino, alkylamino and nitro.
  • a preferred class of compounds useful in the practice of the present invention can also be described as including compounds selected from the group consisting of
  • R 1 is -CN, -COOR, -CONRR or -CSNRR;
  • R 2 is -H, -CN, -COOR, -CONRR, -CSNRR, -CONHR 9 or
  • R 1 and R 2 are not both -CN;
  • R is alkyl or -H
  • R 3 is -H
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, -H, halo or -OR;
  • R 3 and R 7 together may be -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from
  • R 9 is -NH 2 , -CONH 2 ,
  • R 10 is alkyl, halo, -OR, -COOR or -NO 2 ;
  • R 11 is alkyl, halo or -OR;
  • R 12 is alkyl or -H; n is 0 to about 4; and m is 2 to about 10; (B) those described by formula IV above where: at least one of R 4 , R 5 , R 6 , R 7 and R 8 is C 2 to C 6 alkyl; the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, -H, halo or -OR; and
  • R is alkyl or -H; and (C) those described by formula V above where:
  • R 3 and R 7 together are -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from R 3 , -CONH-;
  • R 4 , R 5 , R 6 and R 8 are each independently alkyl, -H, halo or -OR; and R is alkyl or -H.
  • Preferred compounds described by Formula III above include
  • R 3 is -CN, -OH, -COOR, -CONRR, -CSNRR, -CH 2 CN or
  • R 3 is alkyl
  • the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are each independently alkyl, -H, -CN, halo, -OR, -CHO, -COOH, -NRR, -NO 2 ,
  • More preferred compounds of this invention include those of Formulae VI to X below:
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R B , R 10 , R 11 and m are as described immediately above.
  • R 1 is -CN, -COOR, -CONRR or -CSNRR;
  • R 2 is -H, -CN, -COOR, -CONRR, -CSNRR, -CONHR, or
  • R 1 and R 2 are not both -CN; R is alkyl or -H;
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, -H, -OH, lower alkoxy or halo;
  • R 10 is lower alkyl or -COOR;
  • R 11 is lower alkyl, -OH, lower alkoxy or halo; and
  • m is 2 to about 6.
  • Acid addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribabl ⁇ to the anions.
  • pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as, for
  • salts within the scope of the invention include those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid,
  • the corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid are prepared either by dissolving the free base in an aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and by isolating the salt by evaporating the solution or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • Knoevenagel condensation of a substituted benzaldehyde in a polar media with an active methylene compound of the formula R 1 CH 2 R 2 in the presence of ammonia or amines such as piperidine and raised heat results in the products of this invention.
  • the corresponding ketone starting material is used. Reaction temperatures in the range of 25°C to reflux and reaction times vary depending on the materials being used in the condensation.
  • the malonic acid derivatives of formula II above can be prepared by reacting a corresponding
  • the reaction is generally carried out in a suitable solvent, such as ethanol or
  • benzene and in the presence of a catalyst, e.g., piperidine, pyridine or ⁇ -alanine.
  • a catalyst e.g., piperidine, pyridine or ⁇ -alanine.
  • a suitably substituted benzoyl chloride can be reacted with malononitrile in the presence of an amine in a non-polar organic solvent.
  • Compounds of this invention are either commercially available, known in the literature or can be made by known procedures.
  • R, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 11 substituents on the phenyl ring or chain can be present in the starting compound or added after formation of the condensation product by methods known in the art for substitution or conversion of one group to another. If the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups known in the art may be employed. Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis" by T. W. Green, John Wiley and Sons, 1981. For example, nitro groups can be added to the aromatic ring by nitration and the nitro group converted to other groups, such as amino by reduction, and halo by
  • Acyl groups can be substituted onto the aryl groups by Friedel-Crafts acylation. The acyl groups can then be transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction.
  • Amino groups can be alkylated to form mono- and di-alkylamino groups and mercapto and hydroxy groups can be alkylated to form corresponding ethers.
  • Primary alcohols can be oxidized by oxidizing agents known in the art to form carboxylic acids or aldehydes and secondary alcohols can be oxidized to form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of
  • Atherosclerosis Compounds within the scope of this invention exhibit significant activity as protein tyrosine kinase inhibitors and possess therapeutic value as cellular antiproliferative agents for the treatment of certain conditions including, for example, psoriasis and restenosis injuries. It is expected that the invention will be particularly applicable to the treatment of atherosclerosis. With regard to the treatment of some conditions, for example, atherosclerosis, certain people may be identified as being at high risk, for example, due to genetic, environmental or historical factors.
  • Compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally.
  • Parenteral administration in this respect includes
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of
  • compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 6% of the weight of the unit.
  • compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 1 and 1000 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as
  • the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release
  • the active compound may also be administered.
  • Solutions of the active compound as a free base or a pharmacologically acceptable salt can be prepared in water suitably mixed with a
  • a dispersion can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion and by the use of surfactants.
  • a coating such as lecithin
  • microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol. phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, parabens, chlorobutanol. phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, parabens, chlorobutanol. phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, parabens, chlorobutanol. phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents, for example, parabens, chlorobutanol. phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include is
  • Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum
  • Sterile injectable solutions are prepared by:
  • dispersions are prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from the previously sterile-filtered solution thereof.
  • the therapeutic compounds of this invention may be administered to a mammal alone or in combination with
  • the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment will vary with the form of administration, the particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages will be used initially and, if necessary, will be Increased by small increments until the optimum effect under the circumstances is reached.
  • the therapeutic human dosage based on
  • Examples 1-5 and 15 illustrate compounds which are substituted benzylidene malononitriles, that is, R 1 and R 2 are each -CN.
  • Examples 6, 10, 11, 16, 18 and 24 illustrate compounds wherein R 1 is -CN and R 2 is - CONH 2 ,
  • Example 12-C is a comparative
  • Examples 19 and 22 illustrate indanes, that is, R 3 and R 7 together are - CH 2 CH 2 -.
  • Examples 20 and 21 illustrate compounds wherein R 2 is -COOR.
  • Example 23 illustrates a tetrahydronaphthalene, that is, R 3 and R 7 together are -CH 2 CH 2 CH 2 -.
  • Example 2 3-methoxy-4,5- dihydroxybenzylidene malononitrile, m.p. 235° C;
  • Example 3 3,5-di-tert butyl-4-hydroxybenzylidene malononitrile, m.p. 135° C; and
  • Example 4 3,5-di-tert butylbenzylidene
  • Example 8 ⁇ -cyano- ⁇ - amino-3,4,5-trihydroxycinnamal malononitrile, m.p. 275°C; and Example 9, ⁇ -c ⁇ ano- ⁇ -amino-3-hydroxy-4-nitrocinnamal
  • Example 13 ⁇ -cyano- ⁇ - amino-3,4-dihydroxy-5-methoxycinnamal malononitrile, m.p. 225°C; and Example 14, ⁇ -cyano- ⁇ -amino-3,4-dihydroxy-5- bromocinnamal malononitrile, m.p. 241°C.
  • Example 20 ethyl ⁇ -(3,5- di-tert butylphenyl)propenoic acid, m.p. 62-65°C; and ethyl ⁇ -cyano- ⁇ -(3,5-di-tert butylphenyl)propenoic acid, m.p. 94- 96°C.
  • step (b) The propionic acid from step (a), 2 g, in 20 ml neat liquified HF was stirred for 24 hours in a KelF system at room temperature. The HF was evaporated and a gray solid was extracted with ethyl acetate and chromatographed on silica gel to give 0.26 g (14% yield) of 5, 6-dihydroxy-1- indanone, a light brown-white solid.
  • step (c) To the indanone from step (b), 0.25 g (1.5 mmol), in 30 ml ethanol and 0.2 g (3 mmol) malononitrile was added 80 mg ⁇ -alanine and the reaction mixture was refluxed for 20 hours and evaporated to yield a yellow-brown solid, m.p.
  • EGF receptors were prepared from A431 cells (obtained from the ATCC) and PTK activity of these receptors was assayed as described by S. Braun, W.E. Raymond and E. Racker, J. Biol. Chem. 259, 2051-2054 (1984).
  • Various compounds useful in practicing the invention were tested for their inhibitory capacity on the EGF-receptor kinase activity, using the assay described above.
  • Figure 1 demonstrates characteristic results using 10 compounds. The assay
  • Table 1 summarizes the results of the above- described assay, and shows Kinh, the dissociation constant of the PTK-inhibitor complex, as expressed in ⁇ M units. The different Kinh values were determined by the analysis
  • results of this assay indicate that compounds of the present invention competitively inhibit EGF receptor kinase at the substrate site of the tyrosine kinase domain of EGF receptors.
  • A431 cells and KB cells express EGF receptors on their cell surface and their growth rate depends on the presence of growth factors in the medium. These cells were seeded and grown as described in 0. Kashles and A. Levitzki, Biochem. Pharmacol., 35, 1531-1536 (1987). The compounds, the formulae of which are given in Figure 2, were added to the medium at a cell concentration of about 2x10 5 cells/well. The inhibitor was added to the medium 1 hour after seeding. The medium volume in each well was 1 ml and the concentration of inhibitor therein 20 ⁇ M. Every 24 hours cells were counted and fresh medium with inhibitor was applied to the remaining wells. The growth curves were determined in 24- well Costar dishes.
  • EGF-receptor purification is based on the procedure of Yarden and Schlessinger. A431 cells are grown in 80 cm 2 bottles to confluency (2 x 10 7 cells per bottle). The cells are washed twice with PBS and harvested with PBS containing 1.0 mmol EDTA (1 hour at 37°C), and centrifuged at 600g for 10 minutes.
  • the cells are solubilized in 1 ml per 2 x 10 7 cells of cold solubllization buffer (50 mmol Hepes buffer, pH 7.6, 1% Triton X-100, 150 mmol NaCl, 5 mmol EGTA, 1 mmol PMSF, 50 ⁇ g/ml aprotinin, 25 mmol benzamidine, 5 ⁇ g/ml leupeptin, and 10 ⁇ g/ml soybean trypsin inhibitor) for 20 minutes at 4°C. After centrifugation at 100000g for 30 minutes, the supernatant is loaded onto a WGA-agarose column (100 ⁇ l of packed resin per 2 x 10 7 cells) and shaken for 2 hours at 4°C.
  • cold solubllization buffer 50 mmol Hepes buffer, pH 7.6, 1% Triton X-100, 150 mmol NaCl, 5 mmol EGTA, 1 mmol PMSF, 50 ⁇ g/ml aprotinin, 25
  • the unabsorbed material is removed and the resin washed twice with HTN buffer (50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl), twice with HTN buffer containing 1 M NaCl, and twice with HTNG buffer (50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, and 10% glycerol).
  • HTN buffer 50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, and 10% glycerol.
  • HTNG buffer 50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, and 10% glycerol.
  • the EGF receptor is eluted batchwise with HTNG buffer containing 0.5 M N-acetyl-D-glucosamine (200 ⁇ l per 2 x 10 7 cells).
  • the eluted material is stored in aliquots at -70° C and diluted before use with TMTNG buffer (50 mmol Tris- Mes buffer, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, 10% glycerol).
  • TMTNG buffer 50 mmol Tris- Mes buffer, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, 10% glycerol.
  • WGA-purified EGFR (0.25 ⁇ g/assay) is preactivated with EGF (0.85 ⁇ M) in 50 mmol Tris-Mes buffer, pH 7.6 for 20 minutes at 4°C.
  • the assay is initiated by addition of a mixture which contains Mg(Ac) 2 (60 mmol), [ ⁇ - 32 P]ATP (125 ⁇ M, 2-5 ⁇ Ci/assay), poly(GAT) (0.0625 mg/ml, 0.125 mg/ml, 0.25 mg/ml), and six concentrations of inhibitor in duplicates.
  • the temperature of the assay is 22°C and the production of phosphorylated copolymer is found to be linear up to 20 minutes.
  • the PTK inhibitors tested are solubilized in water or a mixture of ethanol and water such that the final
  • concentration of ethanol does not exceed 4% in the assay. Up to 4% ethanol in the assay has no effect on the EGFR kinase activity.
  • concentration of EGF in the assay is 300 nM in a final volume of 40 ⁇ l. After 5, 10 or 20 minutes, aliquots of 25 ⁇ l are applied onto Whatman 3-mm paper cuttings, which are then soaked in cold 10% TCA containing 0.01 M sodium pyrophosphate. After being washed overnight at 4°C, the paper cuttings are dried and counted, measuring 32 P Cerenkov radiation. Concentration dependence on poly(GAT) was
  • WGA-purified EGF receptor from A431 cells (0.5 ⁇ g asaay) is activated with EGF (800 nM) for 20 minutes at 4oC.
  • the reaction is initiated by the addition of Mg(Ac) 2 (60 mmol).
  • the reaction is conducted at either 4 or 15oC and terminated by addition of sodium dodecyl sulfate (SDS) sample buffer (10% glycerol, 50 mmol Tris, pH 6.8, 5% ⁇ - mercapto-ethanol, and 3% (SDS).
  • SDS-PAGE sodium dodecyl sulfate
  • the 10-s interval is therefore chosen for use in subsequent
  • WGA-purified EGF receptor from A431 cells 0.5 ⁇ g/assay is activated with EGF (0.85 ⁇ M) for 20 minutes at 4°C.
  • the assay is performed at 15°C and initiated by addition of
  • Insulin-Receptor Kinase Insulin-Receptor Kinase
  • Rat liver membranes are prepared from the livers of 6- week-old rats as described by Cuatrecasas.
  • WGA-purified insulin receptor is prepared according to Zick et al.
  • WGA- purified rat liver InsRK (1.25 ⁇ g) is preincubated with or without 330 nM insulin in 50 mmol Tris-Mes buffer, pH 7.6, for 30 minutes at 22°C.
  • the assay is performed at 22°C and initiated by addition of a mixture which contains Mg(Ac) 2 (60 mmol), NaVO 3 (40 ⁇ M), [ ⁇ - 32 P]ATP (125 ⁇ M, 3-5 ⁇ Ci/assay), and poly(GT) [poly(Glu 4 Tyr)] at three concentrations: whenever an inhibitor is tested, it is added at the proper concentration.
  • the final concentration of insulin in the assay is 125 nM.
  • the total volume of the assay is 40 ⁇ l. After 20 minutes, aliquots of 30 ⁇ l are applied on Whatman 3-mm paper and soaked in cold 10% TCA, containing 0.01 M sodium
  • A431 cells were grown to confluence on human fibronectin coated tissue culture dishes. After washing 2 times with ice-cold PBS, cells were lysed by the addition of 500 ⁇ l/dish of lysis buffer (50 mmol Hepes, pH 7.5, 150 mmol NaCl, 1.5 mmol MgCl 2 , 1 mmol EGTA, 10% glycerol, 1% triton X-100, 1 mmol PMSF, 1 mg/ml aprotinin, 1 mg/ml leupeptin) and incubating 5 minutes at 4°C. After EGF stimulation (500 ⁇ g/ml 10 minutes at 37°C) immunoprecipitation was performed with anti EGF-R (Ab 108) and the autophosphorylation reaction (50 ⁇ l)
  • IC 50 refers to the concentration of inhibitor ( ⁇ M) at which [ 3 H]thymidine incorporation is halved, compared with media containing no inhibitor. As FCS contains a broad range of growth factors, the IC 50 values for EGF should be lower than for FCS, indicating that the compounds do not act as general inhibitors.
  • HER 14 and K721A were prepared by transfecting NIH3T3 cells (clone 2.2) (From C. Fryling, NCI, NIH), which lack endogenous EGF-receptors, with cDNA
  • constructs of wild-type EGF-receptor or mutant EGF-receptor lacking tyrosine kinase activity in which Lys 721 at the ATP-binding site was replaced by an Ala residue

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Abstract

Procédé d'inhibition de la prolifération cellulaire chez un patient souffrant d'un tel trouble consistant à administrer audit patient une dose efficace d'une composition comprenant, dans un mélange avec un support pharmaceutiquement acceptable, un composé ou un sel pharmaceutiquement acceptable de celui-ci, lequel est un composé de styrène substitué pouvant être également un naphtalène, un indane ou une benzoxazine, comprenant des composés de nitrile et de molononitrile, ainsi que des compositions pharmaceutiques comprenant, dans un mélange avec un support pharmaceutiquement acceptable, une dose pharmaceutiquement efficace dudit composé.
PCT/US1991/002931 1990-04-27 1991-04-29 Composes de styryle inhibant la proteine tyrosine kinase de recepteur de facteur de croissance epidermique Ceased WO1991016892A1 (fr)

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002420A3 (fr) * 1993-07-15 1995-03-16 Caroline Joy Springer Bioprecurseurs d'inhibiteurs de la tyrosine-kinase de proteines
WO1995014464A1 (fr) * 1993-11-24 1995-06-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem Tyrphostines ssi et compositions pharmaceutiques
EP0665013A1 (fr) * 1994-01-13 1995-08-02 Hoechst Aktiengesellschaft Méthode pour traiter les maladies vasculaires hyperprolifératives
WO1995024896A3 (fr) * 1994-03-15 1995-11-09 Unilever Plc Utilisation d'antagonistes d'egf ou de tgf-alpha pour le traitement et la prophylaxie de l'acne
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
US5514711A (en) * 1991-10-15 1996-05-07 Mitsubishi Chemical Corporation Styrene derivatives
US5580888A (en) * 1992-12-23 1996-12-03 Celltech Therapeutics Limited Styryl derivatives as anti-inflammatory agents
US5608070A (en) * 1993-12-22 1997-03-04 Celltech Therapeutics Limited Enantioselective process for the preparation of chiral triaryl derivatives and chiral intermediates for use therein
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
US5633257A (en) * 1993-03-10 1997-05-27 Celltech Therapeutics Limited Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them
US5693659A (en) * 1994-06-23 1997-12-02 Celltech Therapeutics Limited Substituted oxime derivatives and processes for their preparation
US5739144A (en) * 1993-03-10 1998-04-14 Celltech Therapeutics Limited Trisubstituted phenyl derivatives
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US5798373A (en) * 1995-12-21 1998-08-25 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5849770A (en) * 1995-12-21 1998-12-15 Celltech Therapeutics Ltd. Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5859034A (en) * 1996-12-04 1999-01-12 Celltech Therapeutics, Limited Tri-substituted phenyl compounds which have useful pharmaceutical activity
US5866593A (en) * 1993-12-22 1999-02-02 Celltech Therapeutics Ltd. Trisubstituted phenyl derivatives and processes for their preparation
US5922741A (en) * 1996-04-24 1999-07-13 Celltech Therapeutics Ltd. 5-aminopyrazoles useful as tyrosine kinase inhibitors
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
US6057329A (en) * 1996-12-23 2000-05-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6093716A (en) * 1996-09-16 2000-07-25 Celltech Therapeutics, Limited Substituted 2-pyrimidineamines and processes for their preparation
US6096747A (en) * 1992-06-15 2000-08-01 Celltech Therapeutics Limited Phenylaminocarbonyl derivatives and processes for their preparation
US6114333A (en) * 1996-10-28 2000-09-05 Celltech Therapeutics Ltd. 2-Pyrimidineamine derivatives and processes for their preparation
US6133257A (en) * 1997-06-20 2000-10-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
JP3202238B2 (ja) 1994-02-09 2001-08-27 スーゲン，インコーポレーテッド 血管形成および／または脈管形成に関連した疾患を治療するための化合物
EP1000950A3 (fr) * 1998-11-11 2002-04-03 F. Hoffmann-La Roche Ag Composés d'indanylidène
US6416746B1 (en) 1998-11-11 2002-07-09 Roche Vitamins Inc. Indanylidene compounds
US6420338B1 (en) * 1997-06-13 2002-07-16 New York University Medical Center Inhibition of the Src kinase family pathway as a method of treating HBV infection and hepatocellular carcinoma
US6579983B1 (en) 1999-06-18 2003-06-17 Celltech R&D Limited 5-cyano-2-aminopyrimidine derivatives
US6596878B2 (en) * 1994-03-07 2003-07-22 Yissum Research & Development Company Of The Hebrew University Methods and compositions for inhibiting cell proliferative disorders
US6600037B1 (en) 1999-10-20 2003-07-29 Celltech R & D Limited 4,5-disubstituted-2-aminopyrimidines
DE102004039373A1 (de) * 2004-08-12 2006-02-23 Grünenthal GmbH Para-Alkyl-substituierte N-(4-Hydroxy-3-methoxy-benzyl)-zimtsäureamide und deren Verwendung zur Herstellung von Arzneimitteln
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
US8410176B2 (en) 2009-12-29 2013-04-02 Mapi Pharma Ltd. Intermediate compounds and processes for the preparation of tapentadol and related compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 110, 507726B, (1909), YAISH et al. *
CHEMICAL ABSTRACTS, Volume 111, 187005F, (1989), LYALL et al. *

Cited By (54)

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US5514711A (en) * 1991-10-15 1996-05-07 Mitsubishi Chemical Corporation Styrene derivatives
US6096747A (en) * 1992-06-15 2000-08-01 Celltech Therapeutics Limited Phenylaminocarbonyl derivatives and processes for their preparation
US6080790A (en) * 1992-10-23 2000-06-27 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparations
US5674880A (en) * 1992-10-23 1997-10-07 Celltech Therapeutics Limited Tri-substituted phenyl derivatives and processes for their preparation
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
US5580888A (en) * 1992-12-23 1996-12-03 Celltech Therapeutics Limited Styryl derivatives as anti-inflammatory agents
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
US5962492A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics Limited 2 cyclo(alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same
US5723460A (en) * 1993-03-10 1998-03-03 Celltech Therapeutics Limited Cyclo (alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same
US5962483A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US5633257A (en) * 1993-03-10 1997-05-27 Celltech Therapeutics Limited Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them
US5739144A (en) * 1993-03-10 1998-04-14 Celltech Therapeutics Limited Trisubstituted phenyl derivatives
WO1995002420A3 (fr) * 1993-07-15 1995-03-16 Caroline Joy Springer Bioprecurseurs d'inhibiteurs de la tyrosine-kinase de proteines
WO1995014464A1 (fr) * 1993-11-24 1995-06-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem Tyrphostines ssi et compositions pharmaceutiques
AU702800B2 (en) * 1993-11-24 1999-03-04 Kupot-Holim Health Insurance Institute Of The General Federation Of Labour In Eretz-Israel Ssi tyrphostins and pharmaceutical compositions
US5608070A (en) * 1993-12-22 1997-03-04 Celltech Therapeutics Limited Enantioselective process for the preparation of chiral triaryl derivatives and chiral intermediates for use therein
US5866593A (en) * 1993-12-22 1999-02-02 Celltech Therapeutics Ltd. Trisubstituted phenyl derivatives and processes for their preparation
US5519042A (en) * 1994-01-13 1996-05-21 Hoechst Aktiengesellschaft Method of treating hyperproliferative vascular disease
EP0665013A1 (fr) * 1994-01-13 1995-08-02 Hoechst Aktiengesellschaft Méthode pour traiter les maladies vasculaires hyperprolifératives
JP3202238B2 (ja) 1994-02-09 2001-08-27 スーゲン，インコーポレーテッド 血管形成および／または脈管形成に関連した疾患を治療するための化合物
US6596878B2 (en) * 1994-03-07 2003-07-22 Yissum Research & Development Company Of The Hebrew University Methods and compositions for inhibiting cell proliferative disorders
WO1995024896A3 (fr) * 1994-03-15 1995-11-09 Unilever Plc Utilisation d'antagonistes d'egf ou de tgf-alpha pour le traitement et la prophylaxie de l'acne
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US6077854A (en) * 1994-06-21 2000-06-20 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US6297264B1 (en) 1994-06-22 2001-10-02 Celltech Therapeutics Limited Trisubstituted phenyl derivatives and process for their preparation
US6197792B1 (en) 1994-06-22 2001-03-06 Celltech Therapeutics Limited Tetra-substituted phenyl derivatives and processes for their preparation
US5693659A (en) * 1994-06-23 1997-12-02 Celltech Therapeutics Limited Substituted oxime derivatives and processes for their preparation
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6235746B1 (en) 1995-11-20 2001-05-22 Celltech Therapeutics, Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US5849770A (en) * 1995-12-21 1998-12-15 Celltech Therapeutics Ltd. Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5798373A (en) * 1995-12-21 1998-08-25 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5922741A (en) * 1996-04-24 1999-07-13 Celltech Therapeutics Ltd. 5-aminopyrazoles useful as tyrosine kinase inhibitors
US6093716A (en) * 1996-09-16 2000-07-25 Celltech Therapeutics, Limited Substituted 2-pyrimidineamines and processes for their preparation
US6114333A (en) * 1996-10-28 2000-09-05 Celltech Therapeutics Ltd. 2-Pyrimidineamine derivatives and processes for their preparation
US6552029B1 (en) 1996-10-28 2003-04-22 Celltech R&D Limited 2-pyrimidineamine derivatives and processes for their preparation
US5859034A (en) * 1996-12-04 1999-01-12 Celltech Therapeutics, Limited Tri-substituted phenyl compounds which have useful pharmaceutical activity
US6599908B1 (en) 1996-12-23 2003-07-29 Celltech R & D Limited Fused polycyclic 2-aminopyrimidine derivatives
US6057329A (en) * 1996-12-23 2000-05-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6337335B1 (en) 1997-03-14 2002-01-08 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
US6420338B1 (en) * 1997-06-13 2002-07-16 New York University Medical Center Inhibition of the Src kinase family pathway as a method of treating HBV infection and hepatocellular carcinoma
US6133257A (en) * 1997-06-20 2000-10-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6416746B1 (en) 1998-11-11 2002-07-09 Roche Vitamins Inc. Indanylidene compounds
EP1000950A3 (fr) * 1998-11-11 2002-04-03 F. Hoffmann-La Roche Ag Composés d'indanylidène
US6579983B1 (en) 1999-06-18 2003-06-17 Celltech R&D Limited 5-cyano-2-aminopyrimidine derivatives
US6600037B1 (en) 1999-10-20 2003-07-29 Celltech R & D Limited 4,5-disubstituted-2-aminopyrimidines
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
US7291624B2 (en) 2001-05-29 2007-11-06 Bayer Schering Pharma Ag CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents
DE102004039373A1 (de) * 2004-08-12 2006-02-23 Grünenthal GmbH Para-Alkyl-substituierte N-(4-Hydroxy-3-methoxy-benzyl)-zimtsäureamide und deren Verwendung zur Herstellung von Arzneimitteln
US7541495B2 (en) 2004-08-12 2009-06-02 Gruenenthal Gmbh para-alkyl-substituted N-(4-hydroxy-3-methoxy-benzyl)-cinnamamides, pharmaceutical compositions and uses thereof
US8410176B2 (en) 2009-12-29 2013-04-02 Mapi Pharma Ltd. Intermediate compounds and processes for the preparation of tapentadol and related compounds

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