WO2018070900A1 - N-{3-[3-циклопропил-5-(2-фторо-4-иодофениламино)-6,8-диметил-2,4,7-триоксо-3,4,6,7-тетрагидро-2н-пиридо[4,3-d]пиримидин-1-ил]-фенил}-циклопропанкарбоксамида диметилсульфоксида сольват в качестве ингибитора мек1/2 - Google Patents
N-{3-[3-циклопропил-5-(2-фторо-4-иодофениламино)-6,8-диметил-2,4,7-триоксо-3,4,6,7-тетрагидро-2н-пиридо[4,3-d]пиримидин-1-ил]-фенил}-циклопропанкарбоксамида диметилсульфоксида сольват в качестве ингибитора мек1/2 Download PDFInfo
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- WO2018070900A1 WO2018070900A1 PCT/RU2016/000862 RU2016000862W WO2018070900A1 WO 2018070900 A1 WO2018070900 A1 WO 2018070900A1 RU 2016000862 W RU2016000862 W RU 2016000862W WO 2018070900 A1 WO2018070900 A1 WO 2018070900A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to new derivatives of pyrido [4,3-s!] Pyrimidine-2,4,7-trion, namely to K- ⁇ 3- [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) - 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido [4,3-c1] pyrimidin-1-yl] phenyl ⁇ - cyclopropanecarboxamide dimethyl sulfoxide solvate of interest as an agent for treating diseases caused by unwanted cell proliferation, in particular as an antitumor agent. More specifically, the present invention relates to ME 1, MEK2 and MEK1 / 2 inhibitor of interest as an antitumor drug, including for the treatment of malignant melanomas.
- MEK1, MEK2 and MEK1 / 2 are known, the structure of which includes a 1H, 6H-pyrido [4,3-c1] pyrimidine-2,4,7-trion fragment [WO 2005/121142, WO 2012/088033, USA 7378423 ], among which the most advanced drug is Mekinist (Trametinib dimethyl sulfoxide, GSKl 120212) [H. Abe, S. Kikuchi, K. Hayakawa et al. ACS Med. Chem. Lett. 201 1, 2, 320-324].
- Mekinist Trametinib dimethyl sulfoxide, GSKl 120212
- Meccinist has low toxicity with a single oral administration (LD 50 > 2000 mg / kg, mice), long-term dosing at high concentrations in animals results in critical weight loss, and sometimes even death of animals. Therefore, the search for drugs of this group that have less toxicity with prolonged dosing remains highly relevant.
- the purpose of the present invention is to create new inhibitors of MEK1, MEK2 and MEK1 / 2, which have less toxicity with prolonged dosing.
- the new compound is H- ⁇ 3- [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) -6,8-dimethyl-2,4,7-trioxo-3,4,6,
- the 7-tetrahydro-2H-pyrido [4,3-o!] Pyrimidin-1-yl] phenyl ⁇ cyclopropanecarboxamide dimethyl sulfoxide solvate of formula 1 is comparable to Trametinib with respect to MEKl, MEK2 and MEK1 / 2 and has no toxicity for prolonged periods course admission.
- the new compound is L- ⁇ 3- [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) -6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro-2H-pyrido [4,3- (1] pyrimidin-1-yl] phenyl ⁇ cyclopropanecarboxamide dimethyl sulfoxide solvate of formula 1 may be especially useful in the treatment of disease states involving MEKl, MEK2 and MEK1 / 2, for example in the treatment of cancer, including the treatment of malignant melanomas.
- the subject of the present invention is - ⁇ 3- [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) -6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H -pyrido [4,3-c1] pyrimidin-1-yl] phenyl ⁇ -cyclopropanecarboxamide dimethyl sulfoxide solvate of the formula 1:
- the subject of the present invention is also an inhibitor of MEK1, MEK2 and MEK1 / 2, which is a compound of formula 1.
- An advantage of the new compound of formula 1 is its higher solubility in organic media, which can provide a greater variety of suitable formulations and as a result makes it possible to obtain better bioavailability and other pharmacokinetic parameters.
- the solubility of the compound of formula 1 in dimethyl sulfoxide is more than 2 times higher than the solubility of Trametinib.
- the solubility in a mixture of 4% dimethyl sulfoxide and 96% vegetable oil is also higher.
- Table 1 shows the solubility of the compounds of formula 1 in various environments in comparison with Trametinib.
- the undoubted advantage of the new compound of formula 1 is the significantly lower toxicity in the course dosing compared to the prototype (Mekinist - Trametinib complex with dimethyl sulfoxide).
- Efficiency studies on a model of xenograft A375 human melanoma line showed that the compound of formula 1 dose-dependently inhibits the growth of tumors and causes their regression.
- the effectiveness of the compound of formula 1 is comparable to that of a mekinist, and the compound of formula 1 is less toxic — treatment with a mekinist in the experiment led to a critical weight loss and the death of two animals, while the compound of formula 1, even at higher doses, did not cause the death of animals.
- the study of the antitumor activity of the compounds of formula 1 in comparison with the Mekinist was performed on female NMRI nude mice. After the formation of tumors, the animals were divided into groups so that the average tumor size in the group was ⁇ 150 mm. Animals were treated with the studied drugs for 21 days. The weight of the animals of the experimental groups receiving the compound of formula 1 in doses up to 3 mg / kg inclusive did not differ significantly from the weight of the animals of the control group (Fig. 1). Treatment with a compound of formula 1 at a dose of 10 mg / kg led to a reduction in the weight of the animals, which was observed throughout the study from the first administration, but did not exceed 20% relative to the day the treatment was started. At the same time, intragastric administration of Mekinist at a dose of 3 mg / kg for 9 days already led to critical weight loss and death of two animals, as a result of which the treatment in this group was suspended for 3 days before weight recovery.
- Tumor growth dynamics is shown in FIG. 2.
- Intragastric administration of a compound of formula 1 at a dose of 0.3 mg / kg did not affect tumor growth, while in all other groups there was a significant inhibition of tumor growth. Tumor regression was also observed in three of eight animals treated with a compound of formula 1 at a dose of 1 mg / kg, and in 7/8 and 8/8 in groups treated with a compound of formula 1 at doses of 3 and 10 mg / kg, respectively.
- Intragastric administration of Mekinist at a dose of 3 mg / kg also caused regression in 100% of the animals in the group.
- the compound of formula 1 showed a dose-dependent suppression of growth and regression of tumors, while not causing death of animals and moderately reduced the weight of animals only at the maximum studied dose.
- a subject of the present invention is also an inhibitor of MEK1, MEK2 and MEK1 / 2, which is a compound of formula 1.
- an inhibitor is used to treat cancer in a patient, including for the treatment of malignant melanomas.
- the subject of the present invention is also a method for preparing a compound of formula 1, which comprises reacting 1- (3-aminophenyl) -3-cyclopropyl-5- ⁇ (2-fluoro-4-iodophenyl) amino ⁇ -6,8-dimethylpyrido [4, 3- ⁇ 1] pyrimidine-2,4,7 (1H, 3H, 6H) - a trion of formula 2 or a salt thereof with cyclopropylcarboxylic acid or an activated derivative thereof (for example, an acid chloride or the corresponding activated ester or anhydride of this acid) in a solvent, for example, such as CH 2 Cl 2 , tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide or ⁇ -methylpyrrolidone, followed by obtaining the crystallosolvate of the final product by slowly cooling a hot saturated solution in dimethyl sulfoxide
- the subject of the present invention is an active ingredient for the preparation of pharmaceutical compositions and dosage forms, which is a compound of formula 1.
- the subject of the present invention is a pharmaceutical composition having the properties of an inhibitor of MEK1, MEK2 and MEK1 / 2, containing as active ingredient a compound of formula 1 in a therapeutically effective amount and pharmaceutically acceptable excipients.
- the pharmaceutical composition may be in a form suitable for oral administration (for example, in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions) for administration by inhalation (e.g., as micronized powder or liquid aerosol), for administration by insufflation (for example, as micronized powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular administration, or as suppositories for rectal administration) .
- oral administration for example, in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elix
- compositions can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art.
- a pharmaceutical composition intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative.
- the compounds of formula 1 are 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 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 term “therapy” also includes “prophylaxis”.
- a compound of formula 1 having inhibitory activity against MEK1, MEK2 and MEK1 / 2 can be used in the treatment of diseases or medical conditions mediated with MEK1, MEK2 and MEK1 / 2 activity, for example in the treatment of cancer.
- Types of cancer that may be susceptible to treatment with a compound of Formula 1 or its pharmaceutically acceptable salts and / or solvates include, but are not limited to malignant melanomas.
- a subject of the present invention is also a medicament for treating a disease mediated by MEK1, MEK2 and MEK1 / 2, comprising a compound of formula 1 in a therapeutically effective amount.
- a medicament for treating a disease mediated by MEK1, MEK2 and MEK1 / 2, comprising a compound of formula 1 in a therapeutically effective amount.
- said medicament is intended for the treatment of a disease mediated by MEK1, MEK2 and MEK1 / 2, which is cancer.
- the subject of the present invention is also a method for treating a disease mediated through MEK1, MEK2 and MEK1 / 2, comprising using a compound of formula 1 as defined above.
- One embodiment of the present invention is the treatment of a disease mediated by MEK1, MEK2 and MEK1 / 2, which is cancer.
- a compound of formula 1 as defined above for the manufacture of a medicament for the treatment of cancer by mixing a compound of formula 1 in a therapeutically effective amount with a pharmaceutically acceptable excipient.
- a method for producing an anti-cancer effect in a patient in need of such treatment which comprises administering to said patient an effective amount of a compound of formula 1.
- a method of treating a person suffering from a disease in which inhibition of MEK1 / 2 is useful comprises the steps of administering to a person in need of a therapeutically effective amount of a compound of formula 1.
- a disease, which is useful inhibition of MEK1, MEK2 and MEK1 / 2 is cancer.
- said cancer can be selected from a brain tumor (a neuroglioma having a component of malignant astroglioma and oligodendrogliomas, etc.), esophageal cancer, stomach cancer, liver cancer , pancreatic cancer, colorectal cancer (colon cancer, colorectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary and metastatic squamous cell carcinomas, etc.), kidney cancer, breast cancer gland, ovarian cancer cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, extragranular tumor, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head cancer and neck tumors ( maxillary sinus, cancer of the larynx, cancer of the pharynx, cancer of the tongue, cancer of the oral organs
- a brain tumor a neuroglioma having a component of mal
- the cancer treatment described above may be used as a single therapy, or may include, in addition to the compound of the present invention, conventional surgery or radiation therapy or chemotherapy or immunotherapy.
- Such chemotherapy can be administered simultaneously, sequentially or separately, and may additionally include one or more of the following categories of antitumor agents: antiproliferative / antitumor drugs and their combinations used in medical oncology; cytostatic agents; anti-invasion agents; growth factor function inhibitors; antiangiogenic agents; vascular agents; damaging endothelin receptor antagonists; antisense therapies; gene therapy approaches; and (J) immunotherapy approaches.
- the present invention provides a pharmaceutical composition comprising a compound of formula 1 and an additional antitumor substance, as defined above, for the joint treatment of cancer.
- the present invention provides a pharmaceutical composition comprising a compound of Formula 1 and further an antitumor substance, as defined above, for the combined treatment of cancer.
- the invention proposes the use of a compound of formula 1 and additionally an antitumor substance for the joint treatment of cancer.
- FIG. 1 The dynamics of changes in body weight of animals during treatment with the studied drugs.
- FIG. 2 Growth dynamics of tumors of melanoma of the A375 line in a xenograft model during treatment with Mekinist and a compound of formula 1
- Mekinist a compound of formula 1
- Example 1 The method of obtaining - ⁇ 3- [3-cyclopropyl-5- (2-fluoro-4-iodophenylamino) - 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro 2H-pyrido [4,3-1] pyrimidin-1-yl] phenyl ⁇ - cyclopropanecarboxamide dimethyl sulfoxide solvate.
- Solubility (ODx max filtrate - ⁇ , ⁇ blank) / Slope x 1.67 x Filtrate dilution,
- Example 3 The substances were tested for their effect on the MEK1 kinase activity using the Z'-LYTE screening platform (Life Technologies).
- the concentration of DMSO in the reaction mixture was 1%.
- 100 nl of 100-fold stocks of the test substances in 100% DMSO were diluted in 2.4 ⁇ l of kinase buffer (50 mm HEPES pH 7.5, 0.01%) BRIJ-35, 10 mm MgCl 2 , 1 mm EGTA) and added to 5 ⁇ l of a 2-fold mixture of Substrate / Kinase (MEK1 / inactivated MAPK1 (EPChX2) / 8g / TgOZ, the final content is 0.08-0.31 ng MEK1, 105 ng inactivated MAPK1 (ERK2), and 2 ⁇ M Ser / Thr03) in a 384-well plate (black, small volume, manufactured by Corning, Cat.
- kinase buffer 50 mm HEPES pH 7.5
- 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)
- Example 4 The study of efficiency in the xenograft model of human melanoma. The study was conducted at ProQinase GmbH GmbH Dortmund, Breisacher Str. 1 17, D-79106 Freiburg, GERMANY.
- A375 human melanoma cells were grown in vials in DMEM supplemented with 10% FBS in a humid atmosphere at 95% air and 5% C0 2 at 37 ° C. After during the adaptation period, the cells were transplanted with cancer cells. For this, cells were harvested using TrypLE Express (Invitrogen), washed and suspended in sterile PBS to a final cell concentration of 3x10 7 cells / ml. The resulting cell suspension was injected SC (subcutaneously) in the left flank of mice with 3x10 6 cells (100 ⁇ l) per mouse.
- Tumor volume (mm 3 ) was determined by the formula:
- V LxW 2/2
- L corresponds to the largest diameter of the tumor (mm)
- W to the smallest (mm). Measurements were carried out using a caliper.
- ⁇ ⁇ 0 ⁇ is the average volume of tumors in the control group
- V 3KC n is the average volume of tumors in the experimental group. We also monitored the health and behavior of animals, recorded the number of deaths, the number of tumor regressions:
- V is the volume of the initial tumor at the beginning of treatment
- V T - tumor volume at the end of treatment V T - tumor volume at the end of treatment.
- the weight measurement of animals was carried out 3 times a week.
- FIG. 2 The dynamics of the growth of tumors of melanoma of the A375 line is presented in a xenograft model during treatment with a Mekinist and a compound of formula 1.
- the compound of formula 1 showed dose-dependent growth inhibition and tumor regression, comparable in severity with the Mekinista effect.
- the compound of formula 1 did not cause the death of animals in any of the studied doses (treatment by the Mekinist led to a critical decrease in the weight and death of two animals) and only moderately reduced the weight of the animals at the maximum studied dose.
- Example 5 Preparation of a medicine in the form of tablets. 1600 mg of starch, 1600 mg of milled lactose, 400 mg of talc and 1000 mg of an inhibitor of formula 1 are mixed and mixed into a bar. The resulting bar is crushed into granules and sieved through sieves, collecting granules of size 14-16 mesh. The granules obtained are tabletted into tablets of suitable forms weighing 500 mg each.
- Example 6 Preparation of the drug in the form of capsules.
- An inhibitor of formula 1 is thoroughly mixed with lactose in a ratio of 2: 1.
- the resulting powder mixture is packaged in 600 mg in a suitable size gelatin capsule.
- Example 7 The preparation of a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of an inhibitor of formula 1 and 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of water for injection are mixed. The solution is filtered and placed in 1 ml ampoules, which are sealed.
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Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
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MX2019004137A MX2019004137A (es) | 2016-10-10 | 2016-12-12 | Solvato de n-{3-[3-ciclopropil-5-(2-fluoro-4-yodofenilamino)-6,8-d imetil-2,4,7-trioxo-3,4,6,7-tetrahidro-2h-pirido[4,3-d]pirimidin- 1-il]-fenil}-ciclopropanocarboxamida-sulfoxido de dimetilo como un inhibidor de mek1/2. |
EA201900158A EA037939B1 (ru) | 2016-10-10 | 2016-12-12 | N{3-[3-циклопропил-5-(2-фторо-4-иодофениламино)-6,8-диметил-2,4,7-триоксо-3,4,6,7-тетрагидро-2h-пиридо[4,3-d]пиримидин-1-ил]фенил}циклопропанкарбоксамида диметилсульфоксида сольват в качестве ингибитора mek1/2 |
KR1020197012742A KR102387288B1 (ko) | 2016-10-10 | 2016-12-12 | Mek1/2 저해제로서 n-{3-[3-사이클로프로필-5-(2-플루오로-4-요오도페닐아미노)-6,8-디메틸-2,4,7-트리옥소-3,4,6,7-테트라하이드로-2h-피리도[4,3-d]피리미딘-1-일]-페닐}-사이클로프로판카르복사미드 디메틸 설폭사이드 용매화물 |
RS20211338A RS62604B1 (sr) | 2016-10-10 | 2016-12-12 | N-{3-[3-ciklopropil-5-(2-fluoro-4-jodofenilamino)-6,8-dimetil-2,4,7-triokso-3,4,6,7-tetrahidro-2h-pirido[4,3-d]pirimidin-1-il]-fenil}-ciklopropankarboksamid dimetil sulfoksid solvat kao mek1/2 inhibitor |
MA46440A MA46440B1 (fr) | 2016-10-10 | 2016-12-12 | Solvate de diméthylsulfoxyde n-(3-[3-cyclopropyl-5-(2-fluoro-4-iodophénylamino)-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydro-2n-pyrido[4,3-d]pyrimidin-1-yl]-phényl)- cyclopropanecarboxamide utilisé en tant que inhibiteur de mek1/2 |
ES16918763T ES2898026T3 (es) | 2016-10-10 | 2016-12-12 | Solvato de dimetilsulfóxido de N-{3-[3-ciclopropil-5-(2-fluoro-4-yodofenilamino)-6,8-dimetil-2,4,7-trioxo-3,4,6,7-tetrahidro-2H-pirido[4,3-d]pirimidin-1-il]-fenil}-ciclopropanocarboxamida como inhibidor de MEK1/2 |
MDE20190893T MD3524601T2 (ro) | 2016-10-10 | 2016-12-12 | N-{3-[3-ciclopropil-5-(2-fluoro-4-iodofenilamino)-6,8-dimetil-2,4,7-trioxo-3,4,6,7-tetrahidro-2H-pirido[4,3-d]pirimidin-1-il]-fenil}-ciclopropancarboxamida solvat de dimetil sulfoxid ca un inhibitor MEK1/2 |
AU2016426350A AU2016426350B2 (en) | 2016-10-10 | 2016-12-12 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulphoxide solvate as an MEK1/2 inhibitor |
EP16918763.0A EP3524601B1 (en) | 2016-10-10 | 2016-12-12 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulphoxide solvate as an mek1/2 inhibitor |
CN201680090983.XA CN110012668B (zh) | 2016-10-10 | 2016-12-12 | 作为MEK1/2抑制剂的吡啶并[4,3-d]嘧啶-2,4,7-三酮的衍生物 |
PL16918763T PL3524601T3 (pl) | 2016-10-10 | 2016-12-12 | Solwat dimetylosulfotlenkowy n-{3-[3-cyklopropylo-5-(2-fluoro-4-jodofenyloamino)-6,8-dimetylo-2,4,7-triokso-3,4,6,7-tetrahydro-2h-pirydo[4,3-d]pirymidyn-1-ylo]fenylo}-cyklopropanokarboksyamidu jako inhibitor mek1/2 |
LTEPPCT/RU2016/000862T LT3524601T (lt) | 2016-10-10 | 2016-12-12 | N-{3-[3-ciklopropil-5-(2-fluor-4-jodfenilamino)-6,8-dimetil-2,4,7-triokso-3,4,6,7-tetrahidro- 2h-pirido[4,3-d]pirimidin-1-il]-fenil}-ciklopropankarboksamido dimetilsulfoksido solvatas kaip mek1/2 inhibitorius |
SI201631381T SI3524601T1 (sl) | 2016-10-10 | 2016-12-12 | N-(3-(3-ciklopropil-5-(2-fluoro-4-jodofenilamino)-6,8-dimetil-2,4,7- triokso-3,4,6,7-tetrahidro-2H-pirido(4,3-D)pirimidin-1-YL)fenil)- ciklopropan karboksamid dimetil sulfoksid solvat kot MEK1/2 inhibitor |
JP2019540504A JP6909299B2 (ja) | 2016-10-10 | 2016-12-12 | MЕK1/2阻害剤としてのN−{3−[3−シクロプロピル−5−(2−フルオロ−4−ヨードフェニルアミノ)−6,8−ジメチル−2,4,7−トリオキソ−3,4,6,7−テトラヒドロ−2H−ピリド[4,3−d]ピリミジン−1−イル]−フェニル}−シクロプロパンカルボキサミドジメチルスルホキシド溶媒和物 |
CA3039524A CA3039524A1 (en) | 2016-10-10 | 2016-12-12 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulphoxidesolvate as an mek1/2 inhibitor |
HRP20211693TT HRP20211693T1 (hr) | 2016-10-10 | 2016-12-12 | N-{3-[3-ciklopropil-5-(2-fluoro-4-jodofenilamino)-6,8-dimetil-2,4,7-triokso-3,4,6,7-tetrahidro-2h-pirido[4,3-d]pirimidin-1-il]-fenil}-ciklopropankarboksamid dimetil sulfoksid solvat kao mek1/2 inhibitor |
BR112019007223A BR112019007223A2 (pt) | 2016-10-10 | 2016-12-12 | solvato de n-{3-[3-ciclopropil-5-(2-fluoro-4-iodofenilamino)-6,8-dimetil-2,4,7-trioxo-3,4,6,7-tetrahidro-2h-pirido[4,3-d]pirimidin-1-il]-fenil}-ciclopropanocarboxamida dimetil sulfóxido como um inibidor mek1/2 |
US16/340,874 US10738049B2 (en) | 2016-10-10 | 2016-12-12 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-D]pyrimidin-1-YL]-phenyl}-cyclopropanecarboxamide dimethyl sulfoxide solvate as an MEK1/2 inhibitor |
DK16918763.0T DK3524601T3 (da) | 2016-10-10 | 2016-12-12 | N-{3-[3-cyclopropyl-5-(2-fluor-4-iodphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropancarboxamid-dimethyl-sulphoxidsolvat som en mek1/2-inhibitor |
PH12019500721A PH12019500721A1 (en) | 2016-10-10 | 2019-04-03 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulphoxide solvate as an mek1/2 inhibitor |
ZA2019/02861A ZA201902861B (en) | 2016-10-10 | 2019-05-07 | N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2h-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-cyclopropanecarboxamide dimethyl sulphoxide solvate as an mek1/2 inhibitor |
CONC2019/0004688A CO2019004688A2 (es) | 2016-10-10 | 2019-05-08 | Solvato de n-{3-[3-ciclopropil-5-(2-fluoro-4-yodofenilamino)-6,8-dimetil-2,4,7-trioxo-3,4,6,7-tetrahidro-2h-pirido[4,3-d]pirimidin-1-il]-fenil}-ciclopropanocarboxamida-sulfóxido de dimetilo como un inhibidor de мек1/2 |
CY20211100989T CY1125283T1 (el) | 2016-10-10 | 2021-11-15 | Επιδιαλυτωμενο ν-{3-[3-κυκλοπροπυλο-5-(2-φθορο-4-ιωδοφαινυλαμινο)-6,8-διμεθυλο-2,4,7-τριοξο-3,4,6,7-τετραϋδρο-2η-πυριδο[4,3-d]πυριμιδιν-1-υλο]-φαινυλο}-κυκλοπροπανοκαρβοξαμιδο διμεθυλοσουλφοξειδιο ως ενας αναστολεας μεκ1/2 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU2016139641A RU2627692C1 (ru) | 2016-10-10 | 2016-10-10 | N-{ 3-[3-циклопропил-5-(2-фторо-4-иодофениламино)-6,8-диметил-2,4,7-триоксо-3,4,6,7-тетрагидро-2Н-пиридо[4,3-d]пиримидин-1-ил]-фенил} -циклопропанкарбоксамида диметилсульфоксида сольват в качестве ингибитора МЕК1/2 |
RU2016139641 | 2016-10-10 |
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WO2018070900A1 true WO2018070900A1 (ru) | 2018-04-19 |
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PCT/RU2016/000862 WO2018070900A1 (ru) | 2016-10-10 | 2016-12-12 | N-{3-[3-циклопропил-5-(2-фторо-4-иодофениламино)-6,8-диметил-2,4,7-триоксо-3,4,6,7-тетрагидро-2н-пиридо[4,3-d]пиримидин-1-ил]-фенил}-циклопропанкарбоксамида диметилсульфоксида сольват в качестве ингибитора мек1/2 |
Country Status (27)
Country | Link |
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US (1) | US10738049B2 (ru) |
EP (1) | EP3524601B1 (ru) |
JP (1) | JP6909299B2 (ru) |
KR (1) | KR102387288B1 (ru) |
CN (1) | CN110012668B (ru) |
AU (1) | AU2016426350B2 (ru) |
BR (1) | BR112019007223A2 (ru) |
CA (1) | CA3039524A1 (ru) |
CO (1) | CO2019004688A2 (ru) |
CY (1) | CY1125283T1 (ru) |
DK (1) | DK3524601T3 (ru) |
EA (1) | EA037939B1 (ru) |
ES (1) | ES2898026T3 (ru) |
HR (1) | HRP20211693T1 (ru) |
HU (1) | HUE056490T2 (ru) |
LT (1) | LT3524601T (ru) |
MA (1) | MA46440B1 (ru) |
MD (1) | MD3524601T2 (ru) |
MX (1) | MX2019004137A (ru) |
PH (1) | PH12019500721A1 (ru) |
PL (1) | PL3524601T3 (ru) |
PT (1) | PT3524601T (ru) |
RS (1) | RS62604B1 (ru) |
RU (1) | RU2627692C1 (ru) |
SI (1) | SI3524601T1 (ru) |
WO (1) | WO2018070900A1 (ru) |
ZA (1) | ZA201902861B (ru) |
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US11806321B2 (en) | 2022-03-17 | 2023-11-07 | Springworks Therapeutics, Inc. | Non-linear dosing of mirdametinib |
CN114853754B (zh) * | 2022-05-23 | 2023-04-18 | 云白药征武科技(上海)有限公司 | 一种硫代酰胺衍生物及其制备方法和应用 |
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RU2605400C1 (ru) * | 2015-11-13 | 2016-12-20 | ЗАО "Р-Фарм" | ПРОИЗВОДНЫЕ 1-(3-АМИНОФЕНИЛ)-6,8-ДИМЕТИЛ-5-(4-ИОД-2-ФТОР-ФЕНИЛАМИНО)-3-ЦИКЛОПРОПИЛ-1H,6H-ПИРИДО[4,3-d]ПИРИМИДИН-2,4,7-ТРИОНА В КАЧЕСТВЕ ИНГИБИТОРОВ МЕК1/2 |
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