WO2017086830A1 - N-{3-[4-(1-méthyl-1н-indol-3-yl) pyrimidin-2-ylamino]-4-méthoxy-phényl}-amides substitués en tant que modulateurs d'egfr pour traiter le cancer - Google Patents

N-{3-[4-(1-méthyl-1н-indol-3-yl) pyrimidin-2-ylamino]-4-méthoxy-phényl}-amides substitués en tant que modulateurs d'egfr pour traiter le cancer Download PDF

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WO2017086830A1
WO2017086830A1 PCT/RU2015/000880 RU2015000880W WO2017086830A1 WO 2017086830 A1 WO2017086830 A1 WO 2017086830A1 RU 2015000880 W RU2015000880 W RU 2015000880W WO 2017086830 A1 WO2017086830 A1 WO 2017086830A1
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methyl
indol
pyrimidin
ylamino
amino
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Russian (ru)
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Алексей Евгеньевич РЕПИК
Александр Васильевич ИВАЩЕНКО
Василий Геннадьевич ИГНАТЬЕВ
Михаил Айратович ШАФЕЕВ
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R-Pharm Joint Stock Co
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to substituted - ⁇ 3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxy-phenyl ⁇ amides, their pharmaceutically acceptable salts, solvates and hydrates thereof, which may be useful in the treatment or prophylaxis of a disease or medical condition caused by certain mutant forms of epidermal growth factor receptor (EGFR), for example, mutants L858R, Exop19 and T790M.
  • EGFR epidermal growth factor receptor
  • Such compounds and their salts may be useful in the treatment or prevention of a number of different types of cancer.
  • the invention also relates to pharmaceutical compositions containing these compounds and their salts, solvates and hydrates, polymorphic forms of these compounds and their salts, to methods for their preparation and to methods of treating diseases caused by various forms of EGFR using these compounds and their salts.
  • a number of second-generation irreversible inhibitors are known containing the aminoquinazoline fragment of Gefitinib. These inhibitors contain an acrylamide substituent that covalently binds to Cys-797, which is located in the kinase solvent channel. Afatinib, Canertinib and Docomitinib, WZ-4002, belong to this type of inhibitor. The covalent binding mechanism is believed to help overcome ATP affinity of the double mutant, as a result of which these compounds exhibit high activity in cell models. However, the Cys-797 mutant is present in all relevant forms of EGFR. These second-generation compounds possess not only increased activity towards resistant mutants, but also towards wild-type EGFR.
  • Inhibition of wild-type EGFR does not contribute to their clinical efficacy, but is believed to reduce side effects (skin rash and diarrhea). Since these side effects tend to limit the dose in patients, the activity of these inhibitors against wild-type EGFR will limit their activity in patients against T790M mutation.
  • AstraZeneca recently patented 2- (2,4,5-substituted anilino) pyrimidines as EGFR modulators useful for treating cancer including the AZD-9291 modulator [Butterworrth, S .; Raymond, M .; Finlay W. et al. 2- (2,4,5-Substituted anilino) pyrimidines as EGFR modulators useful for treating cancer. WO2013014448].
  • the AZD-9291 modulator is the most advanced in clinical studies and is currently undergoing several Phase III clinical trials [AstraZeneca, NCT02151981; AstraZeneca, NCT02296125].
  • T - ⁇ 3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxyphenyl ⁇ amides have higher efficacy against several mutant forms of EGFR compared with activity against wild-type EGFR, as well as higher solubility in aqueous solutions.
  • novel compounds may be particularly useful in the treatment of disease states in which EGFRs are involved and / or activation of EGFR mutations and / or inhibition of EGFR mutations, for example, in the treatment of cancer.
  • Alkyl means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” (C 1 -C 6 ) alkyl substituents.
  • Preferred alkyl groups are (C 1 -C 6 ) alkyl, even more preferred (C 1 -C 3 ) alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-but, tert-boogype, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl.
  • Alkyl may have substituents.
  • “Substituted alkyl” - substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy or R k a R k + i a N-, where R k a and R k + j a are independently “amino substituents”, the meanings of which are defined in this section, for example water atom yes, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R k a and R k +
  • Alkoxy means a (CgC 3 ) alkyl 0 group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • Amino group means an RiR 2 N group, substituted or unsubstituted, optionally with the same substituents Ri and R 2 .
  • An amino group may have substituents.
  • Active component drug substance, drug substance, drug-substance
  • drug substance drug substance, drug-substance
  • drug-substance means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, possessing pharmacological activity and being the active principle of the pharmaceutical composition used for the production and manufacture of a medicinal product (agent).
  • Halogen means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.
  • Substituent means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.
  • “Pharmaceutical composition” means a composition comprising an active component and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial Gent, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way of administration and dosage.
  • delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial Gent, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way of administration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be provided with the help of agents, slowing down the absorption of the active principle, for example aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • grinders and distributors are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal such as ointments and creams, subcutaneous , intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" J.
  • Salts claimed acids can also be specially prepared by reaction of the purified acid with a suitable base, and metal and amine salts can be synthesized.
  • Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • An object of the present invention is to provide novel EGFR modulators for the treatment of cancer.
  • R is (2-dimethylaminoethyl) methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-dimethylaminopiperidin-1-yl and 3-dimethylaminoazepan-1-yl, 4-methylpiperazin-1-yl;
  • R 3 represents methyl, trifluoromethyl, fluoro, chloro, methoxycarbonyl and dimethylcarbamoyl;
  • R 4 represents hydrogen or methyl
  • R is vinyl, and R is 3-dimethylaminopyrrolidin-1-yl;
  • R 4 represents C] -C 4 alkyl, C 3 -C 6 cycloalkyl.
  • EGFR inhibitors of the general formula 1 selected from:
  • the present invention also includes pharmaceutically acceptable salts of compounds of general formula 1.
  • pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of compounds of formula 1, such as carboxylic acids, for example, dichloroacetic acid, as well as salts of hydrogen chloride, phosphoric acid or sulfonic acid.
  • Pharmaceutically acceptable salts of the present invention include the usual non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic group by conventional chemical methods.
  • such salts can be prepared by reacting the free acidic and basic forms of the compounds of general formula 1 with a stoichiometric amount of the corresponding base or acid in water or in an organic solvent or in a mixture of two solvents.
  • Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, acetone or acetonitrile (ACN).
  • ACN acetonitrile
  • the compounds of general formula 1 and their pharmaceutically acceptable salts may exist in solvated and unsolvated forms.
  • solvated and unsolvated forms For example, in the form of a hydrate.
  • the present invention encompasses all such solvated and unsolvated forms.
  • the undoubted advantage of the new kinase inhibitors of general formula 1 is, first of all, their high solubility in aqueous media, which in some cases is several orders of magnitude higher than the solubility of the known AZD-9291 (Table 1).
  • the solubility of the 1.12-2MeS0 3 H inhibitor in water at pH2 is more than 10 times higher than the solubility of AZD-9291, and at pH7 it is more than 10900 times.
  • This invention relates to compounds of general formula 1 that inhibit one or more EGFR activating or passivating mutations, for example, the L858R mutant, Exop 19 deleted EGFR mutant, and the T790M resistant mutant.
  • such compounds can be used to treat cancer resistant to existing therapy.
  • the compounds of general formula 1 show higher inhibition or passivation of mutant forms of EGFR than wild EGFR.
  • Such compounds are expected to be more suitable as therapeutic agents, especially for the treatment of cancer, by reducing the toxicology associated with inhibition of wild EGFR.
  • Such toxicologies are known to manifest in humans as skin rashes and / or diarrhea.
  • Compounds of general formula 1 can be prepared by reaction of a compound of formula 2 in which R 2 has the above meaning, or salts thereof with activated an organic acid derivative (e.g., acid chloride or the corresponding organic ester or anhydride) in a solvent such as CH 2 Cl 2 , tetrahydrofuran, ⁇ , ⁇ -dimethyl ormamide or ⁇ , ⁇ -dimethylacetamide.
  • an organic acid derivative e.g., acid chloride or the corresponding organic ester or anhydride
  • a solvent such as CH 2 Cl 2 , tetrahydrofuran, ⁇ , ⁇ -dimethyl ormamide or ⁇ , ⁇ -dimethylacetamide.
  • a subject of the invention is also a pharmaceutical composition, which comprises a compound of general formula 1 or a pharmaceutically acceptable salt thereof, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral administration (for example, in the form of tablets, tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder) or arenteralnogo administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular dosing or as a suppository for rectal dosing).
  • oral administration for example, in the form of tablets, tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or gran
  • compositions of the invention can be prepared by conventional methods using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring agents and / or preservatives.
  • the compound of general formula 1 is usually administered to the patient in a single dose in the range of 5-5000 mg / m 2 body area, that is, about 0.1-100 mg / kg, and this is usually provides a therapeutically effective dose.
  • a unit dosage form such as a tablet or capsule, usually contains, for example, 1-250 mg of the active ingredient.
  • the daily dose will necessarily vary depending on the patient, the specific route of administration and the severity of the disease being treated. Accordingly, the doctor who treats a particular patient can determine the optimal dose.
  • the compounds of general formula 1 and their pharmaceutically acceptable salts inhibiting the activity of the L858R EGFR mutant, T790M EGFR and Exop 19 EGFR are expected to be useful in the treatment of diseases or medical conditions caused in whole or in part by the activity of the EGFR mutant, for example cancer.
  • Types of cancer that may be susceptible to treatment using a compound of general formula 1 or a pharmaceutically acceptable salt thereof include, but are not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanomas, prostate cancer, leukemia, non-Hodgkin lymphoma lymphoma, stomach cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumors (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell full-time cell lymphoma, acute myeloid leukemia (AML), multiple myelomas, melanomas and mesotheliomas.
  • ovarian cancer cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanomas, prostate cancer, leukemia, non-Hodgkin lymphoma lymphoma, stomach cancer, lung cancer
  • a method of treating the types of cancer indicated herein is to administer a compound of formula 1 to a mammal, more preferably a human.
  • a compound of general formula 1 for the treatment of the types of cancer indicated herein involves administering a compound of general formula 1 to a mammal, more preferably a human.
  • the subject of this invention is the use of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as a medicine.
  • the subject of the present invention is the use of a compound of general formula 1, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof for the treatment of a disease caused by a L858R mutant EGFR and / or a T790M mutant EGFR and / or an Exop mutant 19, for example, for treating cancer .
  • the subject of the present invention is the use of a compound of general formula 1 as defined above, or a pharmaceutically acceptable salt, hydrate or MES, for the manufacture of a medicament for the treatment of a disease caused by an L858R EGFR mutant and / or a T790M EGFR mutant and / or an Ex19 mutant, for example, for treating cancer
  • the subject of this invention is the use of a compound of general formula 1 as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the treatment of cancer.
  • the subject of the present invention is also a method for producing an anti-cancer effect in a warm-blooded animal, such as a person in need of such treatment, which comprises administering to it an effective amount of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • said cancer may be selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma. non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumors (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma , melanomas and mesotheliomas.
  • AML acute myeloid leukemia
  • the cancer treatment described above may be the only therapy or may include, in addition, a compound of the general formula 1 of the present invention for conventional surgery or radiation therapy or chemotherapy or immunotherapy.
  • Chemotherapy can be used simultaneously, sequentially or separately with treatment with a compound of general formula 1 according to the invention and may include one or more antitumor agents, including antiproliferative / antitumor drugs and their combinations used in medical oncology, such as alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents and topoisomerase inhibitors; cytostatic agents such as antiestrogens, antiandrogens, LHRH antagonists or agonists, aromatase inhibitors and 5a-reductase inhibitors; growth factor function inhibitors and other drugs.
  • antitumor agents including antiproliferative / antitumor drugs and their combinations used in medical oncology, such as alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents and topoisomerase inhibitors
  • an object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula 1, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate and an additional antitumor substance for the joint treatment of cancer in the form of tablets, capsules or injections.
  • co-treatment is used in relation to combination therapy, it should be understood that this may refer to the simultaneous, separate or sequential administration of drugs.
  • the invention provides the use of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and additionally an antitumor substance for the joint treatment of cancer.
  • the subject of the present invention is a method for producing an anticancer effect in a warm-blooded animal, such as a person in need of such treatment, which comprises administering to said mammal a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and simultaneously, separately or sequentially administering an additional antitumor substance the specified mammal, where the amounts of the compounds of General formula 1 or its pharmaceutically acceptable salt and additional pr the antitumor substance together provide the production of an anti-cancer effect.
  • Example 10 Determination of thermodynamic solubility of the compounds of formula 1 and the prototype AZD-9291. 5 mg of the test compound was mixed with 1 ml of universal buffer (pION) with a pH of 2.0, 4.0 or 7.0 for 15 min at 25 ° C. Additional amounts of substances were added until the solution became cloudy. The solution vials were incubated with stirring for 24 hours at 25 ° C to achieve equilibrium between the solution and the precipitate at saturation. After equilibration, 200 ⁇ l of the solution (in 2 repetitions) was filtered through a 96-well filter plate (Millipore) to separate the precipitate. The concentration of compounds in the filtrate was determined spectrophotometrically using a standard calibration curve. The optical absorption spectrum of the substance was measured and a calibration curve was constructed at a selected wavelength (usually corresponding to the absorption of the substance ⁇ ⁇ ). The concentration of the substance in the filtrate (i.e. solubility) was calculated by the formula below:
  • Solubility (ODx max filtrate - OD max blank) / Slope x 1.67 x Filtrate dilution
  • ODx max filtrate is the optical density of the filtrate
  • Example 1 Activity analysis. The compounds of formula 1 and their salts were tested for their effect on the activity of EGFR kinases (L858R / T790M) and EGFR wt (all enzymes provided by Invitrogen Corp., catalog numbers PV3872, PV4128 and PV4803, respectively) using the ⁇ mecanical growth factor (manufactured by Life Technologies). The concentration of DMSO in the reaction mixture was 1%.
  • a 2-fold substrate / kinase mixture (Tyr4 / EGFRwt or EGFR-L858R or EGFR-T790M, final concentrations 0.5 ⁇ M for substrate Tug 4 and 1000, 250, 1000 ng / ml for EGFRwt or EGFR-L858R or EGFR-T790 respectively) were added to 384-well plates (black, small volume, manufactured by Corning, Cat. # 3676).
  • kinase buffer 50 mM HEPES pH 6.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA, 0.02% NaN3
  • 1 ⁇ l of diluted substances was added to the substrate / kinase mixture.
  • the substances were preincubated with kinases for 10 min at room temperature.
  • the degree of phosphorylation of the peptide substrate was calculated using the formula below (if the emission ratio is low, the peptide is phosphorylated, i.e., there is no inhibition of kinase activity, if the ratio is high, the peptide is not phosphorylated, i.e., the kinase is inhibited)
  • Co% average coumarin emission signal control 0% phosphorylation
  • Fioo% average fluorescein emission signal control 100% phosphorylation
  • Fo% average fluorescein emission signal control 0% phosphorylation.
  • the concentration curve of the kinase activity versus the concentration of the tested substances was constructed using the sigmoid model.
  • the results of a comparative analysis of the activity of some compounds of the formula (1) and the prototype AZD-9291 are presented in Table 2.
  • Example 12 Obtaining a drug in the form of tablets. A mixture of 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of inhibitor 1.1 (1) was pressed. The resulting bar was crushed into granules and sieved through a sieve, collecting granules with a size of 14-16 mesh. The obtained granules were tabletted into tablets of suitable forms weighing 500 mg each.
  • Example 13 Obtaining a drug in the form of capsules. Inhibitor 1.1 (1) was thoroughly mixed with lactose powder in a ratio of 2: 1. The resulting powder mixture was packaged in 600 mg in a suitable size gelatin capsule.
  • Example 14 Obtaining a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection.
  • 500 mg of the inhibitor 1.1 (1) 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water were mixed. The solution was filtered and placed in 1 ml ampoules and sealed.
  • the invention can be used in medicine and veterinary medicine.

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Abstract

Le but de la présente invention consiste à créer de nouveaux modulateurs d'EGFR pour traiter le cancer. On parvient à l'objectif grâce de nouveaux N-{3-[4-(1- méthyl -1Н-indol-3-yl) pyrimidin-2-ylamino]-4-méthoxy-phényl}-amides substitués de la formule générale 1, leurs formes polymorphes, leurs sels, solvates et hydrates. (1), dans laquelle R1 se présente comme un radical sélectionné parmi CH2=C(R3)-, R3CH=CH- et R4СС-; R2 se présente comme (2-diméthylaminoéthyl)-méthyl-amino, 3-diméthylaminopyrrolidin-1-yle, 3-diméthylaminopipéridin-1-yle et 3-diméthylaminoazépan-1-yle, 4-méthyl pipérazin-1-yle; R3 se présente comme méthyle, trifluorométhyle, fluor, chlore, méthoxycarbonyle et diméthylcarbamoyle; R4 se présente comme hydrogène ou méthyle ; ou R1 se présente comme vinyle, et R2 se présente comme 3-diméthylaminopyrrolidin-1-yle; R4 se présente comme alkyle С1-С4, cycloalkyle С3-С6.
PCT/RU2015/000880 2015-11-19 2015-12-14 N-{3-[4-(1-méthyl-1н-indol-3-yl) pyrimidin-2-ylamino]-4-méthoxy-phényl}-amides substitués en tant que modulateurs d'egfr pour traiter le cancer Ceased WO2017086830A1 (fr)

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RU2015149668A RU2606949C9 (ru) 2015-11-19 2015-11-19 Замещенные N-{ 3-[4-(1-метил-1Н-индол-3-ил)пиримидин-2-иламино]-4-метоксифенил} -амиды в качестве модуляторов EGFR, предназначенные для лечения рака
RU2015149668 2015-11-19

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Cited By (10)

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CN108047205B (zh) * 2016-12-14 2019-08-27 河南真实生物科技有限公司 2-(2，4，5-取代苯氨基)嘧啶衍生物、其制备方法及其在制备抗肿瘤药物中的应用
CN108047205A (zh) * 2016-12-14 2018-05-18 河南美泰宝生物制药有限公司 2-(2，4，5-取代苯氨基)嘧啶衍生物、其制备方法及其在制备抗肿瘤药物中的应用
US10633367B2 (en) * 2017-10-03 2020-04-28 X-Cutag Therapeutics, Inc. Fluorine- and/or deuterium-containing compounds for treating non-small cell lung cancer and related diseases
CN108017633A (zh) * 2018-01-30 2018-05-11 天津大学 N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-2-氟代丙烯酰胺衍生物及应用
CN108047207A (zh) * 2018-01-30 2018-05-18 天津大学 N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-2-氟代丙烯酰胺氘代物及应用
CN109928956A (zh) * 2019-02-27 2019-06-25 杭州偶联医药科技有限公司 一种靶向泛素化降解egfr蛋白的化合物及其药物组合物和应用
CN109928956B (zh) * 2019-02-27 2020-10-13 杭州偶联医药科技有限公司 一种靶向泛素化降解egfr蛋白的化合物及其药物组合物和应用
AU2020255100A8 (en) * 2019-03-29 2021-12-02 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
AU2020255100B2 (en) * 2019-03-29 2022-11-24 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
AU2020255100C1 (en) * 2019-03-29 2023-02-23 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
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CN113387935B (zh) * 2021-07-23 2022-06-10 苏州雅深智慧科技有限公司 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途
CN113387935A (zh) * 2021-07-23 2021-09-14 苏州雅深智慧科技有限公司 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途
CN115650974A (zh) * 2022-08-04 2023-01-31 天津大学 N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-顺式戊二烯酰胺衍生物及应用
CN115433169A (zh) * 2022-11-07 2022-12-06 北京鑫开元医药科技有限公司 一种甲磺酸奥希替尼二聚体的制备方法

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