WO1991016051A1 - Composes heteroaryles monocycliques et bicycliques a substitution styrile qui inhibent la kinase de tyrosine du recepteur egf - Google Patents
Composes heteroaryles monocycliques et bicycliques a substitution styrile qui inhibent la kinase de tyrosine du recepteur egf Download PDFInfo
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- WO1991016051A1 WO1991016051A1 PCT/US1991/002603 US9102603W WO9116051A1 WO 1991016051 A1 WO1991016051 A1 WO 1991016051A1 US 9102603 W US9102603 W US 9102603W WO 9116051 A1 WO9116051 A1 WO 9116051A1
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- alkyl
- compound according
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- propenenitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
Definitions
- This invention relates to the inhibition of cell
- this invention relates to the use of styryl-substituted monocyclic and bicyclic
- heteroaryl compounds in inhibiting cell proliferation
- PTK protein tyrosine kinase
- Normal cellular reproduction is believed to be triggered by the exposure of the cellular substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGF).
- growth factors are typically specific for corresponding growth factor receptors which are imbedded in and which penetrate through the cellular membrane.
- EGF epidermal growth factor
- PDGF platelet-derived growth factor
- 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.
- phosphorylation enzymes include tyrosine kinases, which catalyze
- reproduction i.e., cellular proliferative disorders.
- phosphorylation of a host of intracellular substrates are some of the biochemical events which are involved in mitogenesis and cell proliferation. Autophosphorylation of the insulin receptor and phosphorylation of substrate proteins by other receptors are the earliest identifiable biochemical hormonal responses.
- U.S. Patent Nos. 4,678,793 and 4,826,984 disclose pharmaceutical compositions including styryl 4,4-dimethyl (bicyclic heteroaryl) compounds as active agents for treating cancer, psoriasis, acne, etc.
- U.S. Patent No. 4,769,384 discloses pharmaceutical compositions including styryl benzimidazole compounds as active agents for treating ulcers of the stomach and duodenum.
- 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 is alkyl, -H, -CN, -OH, -COOR, -CONRR or -CSNRR;
- R is alkyl, -H or aralkyl
- R 2 is an about 5- to about 7-membered monocyclic aryl ring including 1 or 2 N, O or S atoms or 1 or 2
- N-oxide groups or an about 8- to about 12-membered bicyclic aryl ring including 1 to about 4 N, O or S atoms or 1 to about 4 N-oxide groups, said ring optionally substituted with one to about three R 9 groups, said R 9 substituents having no common points of attachment to said ring;
- R 3 is alkyl, -H, -CN, -OH, -COOR, -CONRR, -CSNRR or -CH 2 CN;
- R 3 and R 7 together may be -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from R 3 , -CONH-; or a pharmaceutically acceptable salt thereof.
- novel compounds within the scope of the compound and pharmaceutical composition aspects of the present invention are described by Formula I above wherein:
- R 1 is alkyl, -CN, -COOR, -CONRR or -CSNRR; R is alkyl, -H or aralkyl;
- R 2 is an about 5- to about 7-membered monocyclic aryl ring including 1 or 2 N, O or S atoms, or an about 8- to about 12-membered bicyclic aryl ring including 1 to about 4 N, O or S atoms, said ring optionally substituted with one to about three R 9 groups, said
- R 3 is alkyl, -H, -COOR, -CONRR, -CSNRR or -CH 2 CN;
- R 4 and R 6 are each independently alkyl, -H, -CN, halo, -OR, -CHO, -COOH, -NRR, -NO 2 , -NHCOCH 3 , -SR, -CF 3 ,
- R 5 , R 7 and R 8 are each independently alkyl, -H, -CN, -OR,
- R 4 , R 5 , R 6 , R 7 and R 8 are not -H, and R 4 , R 5 or R 6 cannot be -OR when R 7 or R 8 is -OR; and each R 9 is independently alkyl, -CN, halo, -OR, -CHO,
- R 3 and R 7 together may be -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or, starting from R 3 , -CONH-.
- Compounds within the scope of the present invention have also 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 effectively inhibit EGF-dependent autophosphorylation of the receptor.
- 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.
- Aryl means an unsaturated or partially unsaturated ring system. Preferred aryl groups are pyridyl and indolyl.
- 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.
- Preferred aralkyl groups are benzyl and phenethyl.
- PTK inhibiting compounds should be competitive with the substrate of EGF receptor tyrosine kinase (EGFRK) and not with adenosine triphosphate (ATP).
- EGFRK EGF receptor tyrosine kinase
- ATP adenosine triphosphate
- genistein 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.
- R 1 is -CN, -COOR, -CONRR or -CSNRR;
- R is lower alkyl, -H or aralkyl;
- R 2 is a 6-membered monocyclic aryl ring including 1 or 2
- N, O or S atoms or a 9- or 10-membered bicyclic aryl ring including 1-4 N, O or S atoms, said ring optionally substituted with one to about three R 9 groups, said R 9 substituents having no common points of attachment to said ring;
- R 3 is -H
- R 4 , R 5 , R 6 , R 7 and R 8 are each independently lower alkyl, -H, lower alkoxy or -OH, with the provisos that at least two of R 4 , R 5 , R 6 , R 7 and R 8 are not -H, and R 4 , R 5 or R 6 cannot be lower alkoxy when R 7 or R 8 is lower alkoxy;
- R 4 and R 6 are also each independently halo; each R 9 is independently lower alkyl, halo, lower alkoxy,
- R 10 is -H, alkyl, aralkyl or
- R 1 is -CN, -COOR or -CONRR;
- R 4 , R 5 , R 6 , R 7 and R 8 are independently lower alkyl, -H, lower alkoxy or -OH, with the provisos that at least two of R 4 , R 5 , R 6 , R 7 and R 8 are not -H, and R 4 , R 5 or R 6 cannot be lower alkoxy when R 7 or R 8 is lower alkoxy; R 4 and R 6 are also each independently halo;
- R is lower alkyl or -H; and there are no R 9 substituents.
- R 1 is -CN
- R 5 , R 7 and R 8 are each independently -H
- R 4 and Rg are each independently alkyl, halo, -OR or -CF 3 .
- Acid addition salts may be formed and are simply a more convenient form for use; and 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 ascribable to the anions.
- mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid
- organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic 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.
- reaction temperatures in the range of 25°C to reflux and reaction times vary depending on the materials being used in the condensation.
- 3,337,565 and 3,337,568 disclose compounds which interfere with carbohydrate metabolism of Formula I where, for example, R 1 is cyano or hydroxy, R 2 is pyridyl and R 3 is hydroxy.
- U.S. Patent No. 3,196,158 discloses adrenal cortex inhibitors of Formula I where, for example, R 1 is cyano, R 2 is pyridyl and R 7 or R 8 are halo.
- U.S. Patent No. 3,157,663 discloses adrenal cortex inhibitors where, for example, R 1 is cyano, R 2 is pyridyl and R 5 , R 7 or R 8 are amino or nitro groups.
- Buu-Hoi et al.. Journal of the Chemical Society (C), pp. 2069-70 (1969) disclose the conversion of 1,2-diarylacrylonitriles to the corresponding 3-arylcoumarins, wherein the 2-aryl group bears an ortho-alkoxy-substituent.
- 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 diazotization of the amino group and replacement of the diazo group.
- Acyl groups can be
- 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.
- Tertiary amino groups can be converted to the corresponding N-oxides by oxidizing agents known in the art, for example, hydrogen peroxide and peracids.
- 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 psoriasis, atherosclerosis 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 within the scope of the present invention can be used in preventing or delaying the occurrence or reoccurrence of such conditions or otherwise treating the condition.
- the compounds of the present invention can be any organic compound having the same properties.
- the compounds of the present invention can be any organic compound having the same properties.
- Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
- 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 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
- 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.
- the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
- 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; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant 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 by 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 parenterally or intraperitoneally.
- Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as
- 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, and 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 dispersion and by the use of surfactants.
- the prevention of the action of 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, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by
- dispersions are prepared by
- a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- 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 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 physiological studies using rats, will generally be from about 0.01 mg to about 100 mg/kg of body weight per day or from about 0.4 mg to about 10 g or and higher although it may be administered in several different dosage units from once to several times a day. Oral administration requires higher dosages.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are chloro.
- the N-oxide of the compound of example 1A is prepared.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 5 are methoxy.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are tert butyl.
- R 1 is cyano
- R 2 is indolyl and R 4 and R 5 are methoxy.
- R 1 is cyano
- R 2 is indolyl
- R 4 and R 5 are methoxy
- R 9 is 4- nitrophenylsulfonyl.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are methoxy.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are methoxy.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are tert butyl.
- R 1 is cyano, R 2 is pyridyl and R 4 and R 6 are trifluoromethyl.
- R 1 is cyano
- R 2 is pyridyl and R 4 and R 6 are
- R 1 is cyano
- R 2 is indolyl and R 4 and R 6 are trifluoromethyl.
- R 1 is cyano
- R 2 is indolyl and R 4 and R 6 are tert butyl.
- Example 14 is
- reaction mixture is filtered to remove the salts, and the solvent is removed by rotary evaporation.
- residue is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 3:1.
- the yellow solid is recrystallized from acetone-hexane to give 2-(3-indolyl)-3-(3,4-dimethoxy- phenyl)-2-propenenitrile, m.p. 139-141°C.
- Compounds of this invention are subjected to various biological tests, the results of which correlate to useful cellular antiproliferative activity. These tests are useful in determining EGF receptor kinase, PDGF receptor kinase and insulin receptor kinase inhibition activities of the compounds disclosed herein.
- 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
- EDTA 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 solubilization 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 leupeptic, and 10 ⁇ g/ml soybean trypsin inhibitor) for 20 minutes at 4°C.
- cold solubilization 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 leupeptic, and 10 ⁇ g/
- HTN buffer 50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl
- HTN buffer containing 1 M NaCl twice with HTN buffer containing 1 M NaCl
- 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-
- 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
- WGA-purified EGF receptor from A431 cells (0.5 ⁇ g/assay) is activated with EGF (800 nM) for 20 minutes at 4°C.
- the reaction is initiated by the addition of Mg(Ac) 2 (60 mmol), Tris-Mes buffer, pH 7.6 (50 mmol), and [ 32 P]ATP (20 ⁇ M, 5 ⁇ Ci/assay).
- the reaction is conducted at either 4 or 15°C 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 sodium dodecyl sulfate
- the samples are run on a 8% SDS polyacrylamide gel (SDS-PAGE) (prepared from 30% acrylamide and 0.8% bis-(acrylamide) and contained 0.375 M Tris, pH 8.8, 0.1% SDS, 0.05% TEMED, and 0.46% ammonium persulfate).
- SDS-PAGE SDS polyacrylamide gel
- the gel is dried and autoradiography performed with Agfa Curix RP2 X-ray film.
- the relevant radioactive bands are cut and counted in the Cerenkov mode.
- the fast phase of autophos- phorylation continues for another 10 minutes.
- the extent of phosphorylation completed in the first 10-s at 15°C comprises 1/3 of the total autophosphorylation signal and probably reflects the phosphorylation of the first site on the
- the 10-s interval is therefore chosen for use in subsequent autophosphorylation experiments.
- 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 Mg(Ac) 2 (60 mmol), Tris-Mes buffer, pH 7.6 (50 mmol), [ 32 P]ATP (carrier free, 5 ⁇ Ci/assay), and increasing concentrations of
- the assay is terminated after 10-s by addition of SDS sample buffer.
- the samples are run on a 6% SDS polyacrylamide gel.
- the gel is dried and autoradiographed as described above.
- the relevant radioactive bands are cut and counted in the Cerenkov mode, the K m for ATP determined in this fashion is found to be 7.2 ⁇ M.
- the EGF concentration dependence of EGFRK autophosphorylation is determined. Inhibition of Copoly(Glu 4 Tyr) Phosphorylation
- 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
- 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 pyrophosphate.
- A431 cells were grown to confluence on human fibronectin coated tissue culture dishes. After washing 2 times with icecold 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, l mg/ml aprotinin, 1 mg/ml leupeptin) and incubating 5 minutes at 4°C.
- 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, l mg/ml aprotinin, 1 mg/ml leupeptin
- IC 50 refers to the concentration of inhibitor ( ⁇ M) at which the rate of autophosphorylation is halved, compared with media containing no inhibitor.
- IC 50 values for EGF will be lower than for PDGF, indicating a high degree of EGF
- Cells were seeded at 1 x 10 5 cells per well in 24-well Costar dishes pre-coated with human fibronectin (by incubating for 30 minutes at room temperature with 10 ⁇ g/0.5 ml/well). The cells were grown to confluence for 2 days. The medium was changed to DMEM containing 0.5 calf serum for 36-48 hours and the cells were then incubated with PDGF, EGF (Toyobo, New York, NY) (20 ng/ml) or serum (10% calf serum, FCS) and different concentrations of the inhibitory compounds.
- PDGF fetal growth factor
- EGF Toyobo, New York, NY
- serum 10% calf serum, FCS
- IC 50 refers to the concentration of inhibitor (nM) at which
- [ 3 H]thymidine incorporation is halved, compared with media containing no inhibitor.
- FCS contains a broad range of growth factors
- the IC 50 values for PDGF should be lower than for FCS, indicating that the compounds do not act as general inhibitors.
- HER 14 and K721A were prepared by transfecting N1H3T3 cells (clone 2.2) (From C. Fryling, NCI, NIH), which lack endogenous EGF-receptors, with cDNA
- Example 1A is a more potent inhibitor of EGF receptor kinase than C-1.
- Example 1-A it can be seen from the test results that it has also a much better activity than that of its corresponding N-oxide.
Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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AU77979/91A AU658567B2 (en) | 1990-04-16 | 1991-04-16 | Styryl-substituted indole and pyridyl compounds |
JP91508820A JPH05506857A (ja) | 1990-04-16 | 1991-04-16 | Egfレセプタチロシンキナーゼを阻害するスチリル―置換単環式および二環式複素アリール化合物 |
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Application Number | Priority Date | Filing Date | Title |
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US50994290A | 1990-04-16 | 1990-04-16 | |
US509,942 | 1990-04-16 |
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WO1991016051A1 true WO1991016051A1 (fr) | 1991-10-31 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1991/002603 WO1991016051A1 (fr) | 1990-04-16 | 1991-04-16 | Composes heteroaryles monocycliques et bicycliques a substitution styrile qui inhibent la kinase de tyrosine du recepteur egf |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0525109A4 (fr) |
JP (1) | JPH05506857A (fr) |
AU (1) | AU658567B2 (fr) |
CA (1) | CA2080581A1 (fr) |
IL (1) | IL97872A (fr) |
WO (1) | WO1991016051A1 (fr) |
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WO1993025530A2 (fr) * | 1992-06-11 | 1993-12-23 | Allergan, Inc. | Composes vinyliques a activite analogue a la retinoide |
EP0580598A1 (fr) * | 1991-04-16 | 1994-02-02 | Rhone-Poulenc Rorer International (Holdings) Inc. | Composes heteroaryles substitues par styryle et inhibant la tyrosine-kinase du recepteur d'egf |
EP0584222A1 (fr) * | 1991-05-10 | 1994-03-02 | Rhone Poulenc Rorer Int | Composes aryle et heteroaryle bis monocycliques et/ou bicycliques qui inhibent la tyrosine kinase d'un recepteur du egf et/ou du pdgf. |
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US5498755A (en) * | 1994-08-23 | 1996-03-12 | Chandraratna; Roshantha A. | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
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US5602135A (en) * | 1993-10-18 | 1997-02-11 | Allergan | Phenyl or heteroaryl and tetrahydronaphthyl substituted diene compounds having retinoid like biological activity |
US5616712A (en) * | 1995-05-16 | 1997-04-01 | Allergan | Acetylenes disubstituted with a phenyl or heteroaryl group and a 2-thio-1,2,3,4-tetrahdroquinolinyl, 2-alkylthio-3,4-dihydroquinolinyl or 2-alkoxy-3,4-dihydroquinolinyl group having retinoid-like biological activity |
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US5663347A (en) * | 1987-03-20 | 1997-09-02 | Allergan | Disubstituted acetylenes bearing heterobicyclic groups and heteroaromatic or phenyl groups having retinoid like activity |
US5672710A (en) * | 1995-11-03 | 1997-09-30 | Allergan | Sulfides, sulfoxides and sulfones disubstituted with a tetrahydronaphthalenyl, chromanyl, thiochromanyl or tetrahydroquinolinyl and substituted phenyl or heteroaryl group, having retinoid-like biological activity |
US5675033A (en) * | 1995-06-06 | 1997-10-07 | Allergan | 2,4-pentadienoic acid derivatives having retinoid-like biological activity |
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US5739338A (en) * | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
US5741896A (en) * | 1996-06-21 | 1998-04-21 | Allergan | O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5763635A (en) * | 1996-06-21 | 1998-06-09 | Allergan | Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity |
US5808124A (en) * | 1996-06-21 | 1998-09-15 | Allergan | O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US6025388A (en) * | 1995-04-26 | 2000-02-15 | Allergan Sales, Inc. | Method for inhibiting gene expression promoted by AP1 protein with RARβ selective retinoids and method for treatment of diseases and conditions with such retinoids |
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WO2001077107A1 (fr) * | 2000-04-07 | 2001-10-18 | Takeda Chemical Industries, Ltd. | Production et utilisation de composes heterocycliques |
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US6534544B1 (en) | 1995-12-29 | 2003-03-18 | Allergan Sales, Inc. | Methods of treatment with compounds having RARα receptor specific or selective activity |
US6627652B1 (en) | 1993-02-11 | 2003-09-30 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
US7214700B2 (en) | 2000-05-02 | 2007-05-08 | Sugen Inc. | (2-Oxindol-3-ylidenyl) acetic acid derivatives and their use as protein kinase inhibitors |
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AU662480B2 (en) * | 1990-04-16 | 1995-09-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Heterocyclicethenediyl compounds which inhibit EGF receptor tyrosine kinase |
JPWO2005095341A1 (ja) * | 2004-03-30 | 2007-08-16 | 協和醗酵工業株式会社 | 含窒素複素環化合物 |
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US5677323A (en) * | 1989-09-19 | 1997-10-14 | Allergan | Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1, 2, 3, 4, -tetrahydroquinolinyl group having retinoid-like activity |
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US5516904A (en) * | 1989-12-29 | 1996-05-14 | Allergan, Inc. | Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity |
EP0580598A4 (en) * | 1991-04-16 | 1994-06-08 | Rhone Poulenc Rorer Int | Styryl-substituted heteroaryl compounds which inhibit egf receptor tyrosine kinase |
EP0580598A1 (fr) * | 1991-04-16 | 1994-02-02 | Rhone-Poulenc Rorer International (Holdings) Inc. | Composes heteroaryles substitues par styryle et inhibant la tyrosine-kinase du recepteur d'egf |
EP0584222A4 (en) * | 1991-05-10 | 1994-07-06 | Rhone Poulenc Rorer Int | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
EP0584222A1 (fr) * | 1991-05-10 | 1994-03-02 | Rhone Poulenc Rorer Int | Composes aryle et heteroaryle bis monocycliques et/ou bicycliques qui inhibent la tyrosine kinase d'un recepteur du egf et/ou du pdgf. |
US6624188B1 (en) | 1992-06-11 | 2003-09-23 | Allergan, Inc. | Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects |
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WO1993025530A3 (fr) * | 1992-06-11 | 1994-03-17 | Allergan Inc | Composes vinyliques a activite analogue a la retinoide |
US6627652B1 (en) | 1993-02-11 | 2003-09-30 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
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US5498755A (en) * | 1994-08-23 | 1996-03-12 | Chandraratna; Roshantha A. | Disubstituted aryl and heteroaryl imines having retinoid-like biological activity |
US5591858A (en) * | 1994-12-29 | 1997-01-07 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
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US5489584A (en) * | 1994-12-29 | 1996-02-06 | Allergan, Inc. | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5618931A (en) * | 1994-12-29 | 1997-04-08 | Allergan | Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
US5605915A (en) * | 1994-12-29 | 1997-02-25 | Allergan | Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
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US5663357A (en) * | 1995-11-22 | 1997-09-02 | Allergan | Substituted heteroarylamides having retinoid-like biological activity |
US5688957A (en) * | 1995-12-29 | 1997-11-18 | Allergan | (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!aryl and (3"-thioxacyclohex-1"-enyl)!-but-3'-ene-1'-ynyl!heteroaryl carboxylic acids and esters having retinoid-like biological activity |
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US5723666A (en) * | 1996-06-21 | 1998-03-03 | Allergan | Oxime substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5808124A (en) * | 1996-06-21 | 1998-09-15 | Allergan | O- or S-substituted dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5741896A (en) * | 1996-06-21 | 1998-04-21 | Allergan | O- or S- substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
US5763635A (en) * | 1996-06-21 | 1998-06-09 | Allergan | Tetrahydronaphthalene derivatives substituted in the 8 position with alkyhidene groups having retinoid and/or retinoid antagonist-like biological activity |
US5739338A (en) * | 1996-11-05 | 1998-04-14 | Allergan | N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity |
US6716863B2 (en) | 2000-04-07 | 2004-04-06 | Takeda Chemical Industries, Ltd. | Heterocyclic compounds their production and use |
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US7214700B2 (en) | 2000-05-02 | 2007-05-08 | Sugen Inc. | (2-Oxindol-3-ylidenyl) acetic acid derivatives and their use as protein kinase inhibitors |
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Also Published As
Publication number | Publication date |
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IL97872A (en) | 1996-07-23 |
EP0525109A4 (en) | 1993-06-30 |
EP0525109A1 (fr) | 1993-02-03 |
AU658567B2 (en) | 1995-04-27 |
CA2080581A1 (fr) | 1991-10-17 |
AU7797991A (en) | 1991-11-11 |
JPH05506857A (ja) | 1993-10-07 |
IL97872A0 (en) | 1992-06-21 |
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