WO2019001425A1 - Dérivé d'osimertinib deutéré et son application - Google Patents

Dérivé d'osimertinib deutéré et son application Download PDF

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WO2019001425A1
WO2019001425A1 PCT/CN2018/092884 CN2018092884W WO2019001425A1 WO 2019001425 A1 WO2019001425 A1 WO 2019001425A1 CN 2018092884 W CN2018092884 W CN 2018092884W WO 2019001425 A1 WO2019001425 A1 WO 2019001425A1
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compound
egfr
compound according
pharmaceutically acceptable
salt
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PCT/CN2018/092884
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Chinese (zh)
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吴豫生
耿阳
孟庆国
梁阿朋
牛成山
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浙江同源康医药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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

Definitions

  • the present invention relates to the field of medical technology, and in particular to a deuterated Osimintinib derivative for use as an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer.
  • a deuterated Osimintinib derivative for use as an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer.
  • Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the erbB receptor family that binds to growth factor ligands (eg, epidermal growth factor (EGF)). Homogeneous dimerization can occur with additional EGFR molecules or with another family member (eg, erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4)). Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many human cancers, including lung cancer, head and neck cancer, and breast cancer.
  • Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China, and it is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors.
  • the existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the progression-free survival of patients. .
  • the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139), from the original L- at this position. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib, thus making the first generation of EGFR inhibitors No longer effective, resulting in such patients currently in a state of no drug availability. Clinically, 50% of patients who developed resistance to first-generation EGFR inhibitors had EGFR T790M mutations. In the T790M mutant cell line H1975, first-generation EGFR inhibitors, such as gefitinib and erlotinib, were all greater than 3 [mu]M and were essentially inactive.
  • WO2013014448 discloses a pyrimidine derivative which can be used as an EGFR inhibitor and its use for treating cancer, the structure is as shown in the formula A, wherein G is selected from 4, 5, 6, 7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo[1,5 -a]pyridin-3-yl, R 2 is methyl or methoxy;
  • this drug cannot be used. Therefore, it is very necessary to optimize the structure of the drug, increase the half-life, reduce the toxicity of the drug, and increase the treatment window, so that more patients benefit.
  • CN104140418B discloses some methyl deuterated azinib (AZD9291) compounds having the structural formula shown in formula B, wherein R 1 , R 2 , R 3 , R 4 and R 5 are methyl or deuterated. methyl,
  • CN105237515 discloses an Osimertinib compound which only has a pyrimidine ring, and our study found that when the methyl group on the oxime is metabolized, a compound of the formula C is formed.
  • this compound still inhibits EGFR activity, it does not pass through the blood-brain barrier and enters the brain, thereby losing its effect on tumor patients with brain metastasis.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from methyl or deuterated methyl;
  • R 6 is selected from H or hydrazine.
  • the deuterated methyl group -CD 3 Preferably, the deuterated methyl group -CD 3.
  • the R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from methyl or -CD 3 .
  • At least one of R 1 , R 2 , R 3 , R 4 and R 5 is -CD 3 .
  • R 1 , R 2 , R 3 , R 4 and R 5 are -CD 3 .
  • the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, and a nitrate salt.
  • the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, propylene Acid salt, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picric acid Salt, glutamate, ascorbate, camphorate, camphor sulfonate.
  • the inorganic acid salt is a hydrochloride or a sulfate; the organic acid salt is a methanesulfonate.
  • Another technical solution provided by the present invention is: a pharmaceutical composition comprising the compound of the above formula I and a pharmaceutically acceptable carrier.
  • the deuterated Ostinidil derivative provided by the present invention is a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which inhibits one or more EGFR activation or resistance mutations, such as L858R activating mutant, Exon19 deletion EGFR activating mutant, T790M resistant mutant; this compound increases the inhibitory activity against mutations such as resistant EGFR T790M, and simultaneously reduces wild-type EGFR The inhibitory activity can be used to develop third-generation EGFR mutant selective inhibitors with higher activity, better selectivity, and lower toxicity.
  • the solvate referred to in the present invention means a complex of the compound of the present invention and a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out.
  • a complex formed with water is referred to as a hydrate; others include an alcoholate, a ketone compound, and the like.
  • the solvates of the present invention include the compounds of the formula I of the present invention and salts thereof, and solvates of stereoisomers.
  • a stereoisomer as referred to in the present invention means that the compound of formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula I contains more than one chiral center, diastereomers may be present.
  • Stereoisomers of the invention include resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • a prodrug as referred to in the present invention refers to a parent compound which includes a known amino protecting group and a carboxy protecting group, which are hydrolyzed under physiological conditions or released by an enzymatic reaction.
  • Specific prodrug preparation methods can be referred to the prior art (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. ChemLett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • a compound of the formula I according to the invention may be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms include those suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • compositions of this invention may be formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the deuterated Ostinidil derivative provided by the invention can be used for preparing drugs for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, etc. It is especially useful for the treatment of non-small cell lung cancer caused by EGFR mutations, including sensitive mutations (such as L858R mutation or deletion of exon 19) and drug resistance mutations (such as EGFR T790M mutation).
  • the invention provides a compound of formula I of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the modulation of EGFR tyrosine kinase activity or in the treatment of EGFR The application of drugs for related diseases.
  • the modulating EGFR tyrosine kinase activity or treating an EGFR-related disease refers to treating cancer, diabetes, an immune system disease, a neurodegenerative disease, or a cardiovascular disease.
  • the invention provides the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.
  • the deuterated Ostinidyl derivatives of the present invention are particularly useful for the preparation of a medicament for the treatment of cancer, such as non-small cell lung cancer.
  • the compound of the formula I of the present invention can be used as a single therapeutic drug in anticancer therapy, or can be used in addition to conventional Surgical or radiation therapy or a combination of chemotherapy or immunotherapy.
  • the above therapy and the EGFR inhibitor of the present invention can be administered in parallel, simultaneously, sequentially, or separately.
  • the medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases of the present invention may further comprise any one or more of the following drugs in addition to the EGFR inhibitor of the present invention: gefitinib, erg Lotitinib, ectatinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panituzumab, pertuzumab , zarumimumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tancomycin, aspironmycin, IPI-504, NVP-AUY922.
  • Target compound 1 the structural formula is:
  • the synthetic route is:
  • Target compound 1 Under a nitrogen atmosphere, 540 mg of TRN15801-1, 574 mg of TRN158-c, 30 ml of DCE, 20 ml of 2-pentanol and 374 mg of p-toluenesulfonic acid were sequentially added to a 100 ml single-mouth bottle. The oil bath was heated to 80 ° C for overnight reaction; TLC detection TRN158-c disappeared, the reaction solution was cooled to room temperature, poured into a mixture of ice water and DCM, and the aqueous layer was washed twice with DCM, then the DCM layer was combined with saturated brine. After washing twice, then drying and drying the organic layer; passing the column to obtain 200 mg of a brown solid, the analytical data of the compound is as follows:
  • Target compound 2 the structural formula is as follows:
  • the synthetic route is as follows:
  • TRN15801-1 500 mg, 2.02 mmol was added to a reaction flask, then 10 ml of isopropanol was added, followed by TRN158-d (416 mg, 2.2 mmol) and p-toluenesulfonic acid monohydrate (475 mg, 2.5 mmol). Then, under reflux with argon, a reflux reaction was added overnight. The reaction solution was cooled to room temperature, and then a part of the solvent was concentrated, then placed in an ice bath, and then allowed to stand for crystallized, filtered, and the filter cake was washed twice with acetonitrile and dried to give 524 mg of product. MS+1: 401.3.
  • the compound TRN15802 (400 mg, 0.88 mmol) was added to a three-necked flask, and then 20 ml of anhydrous dichloromethane and diisopropylethylamine (206 mg, 1.6 mmol) were added, and then cooled to 0 degree under argon atmosphere. Then, 5 ml of acryloyl chloride (90 mg, 1 mmol) in anhydrous dichloromethane was added dropwise, and the addition was completed in about 30 minutes. After the addition, the temperature was automatically raised to room temperature overnight.
  • Target compound 3 the structural formula is as follows:
  • the synthetic route is as follows:
  • the intermediate TRN158-e was purchased from the BEHRINGER Reagent Company.
  • the synthetic route of the intermediate TRN158-f is as follows:
  • Target compound 4 the structural formula is:
  • the synthetic route is:
  • TRN15804-2, TRN15804-3, TRN15804-4 and TRN15804 was carried out in accordance with the corresponding steps in Example 2.
  • the analytical data of the synthesized target compound TRN15804 is as follows:
  • the methanesulfonate salt of the compound TRN15801 was synthesized, and the synthesis route was as follows:
  • EGFR T790M/L858R kinase double mutant EGFR kinase
  • EGFR WT wild type EGFR kinase
  • the compound to be tested was separately prepared into a 10 mM (mmol/L) DMSO solution, and the control compound AZD9291 was formulated into a 1 mM (mmol/L) DMSO solution;
  • test compound solution Serially dilute the test compound solution to 12 concentrations (or other desired test concentration) on a 384-well plate of TECAN EVO200 by 3-fold dilution;
  • the well plate was incubated at room temperature for 90 minutes, and then the test reaction was terminated by adding 40 ⁇ L of stop buffer (containing 0.5 M EDTA);
  • test compounds in Table 3 are as follows.
  • Control compound 2 is a compound disclosed in the authorization publication number CN105237515B, and its structural formula is:
  • Control compound 3 is a compound disclosed in the authorization publication number CN104140418B, and its structural formula is:
  • Control Compound 1 (AZD9291, trade name: Ostinib) is as follows:
  • Example 1 of the present invention had better kinase activity than Comparative Compound 1, Control Compound 2 and Control Compound 3.
  • Test methods and procedures are carried out using methods well known to those skilled in the art, and the reagents used in the methods are commercially available.
  • test plate was incubated at room temperature for 30 minutes to stabilize the luminescence signal.
  • the IC50 was calculated using XLFIT (V5.3.1.3) software.
  • the compound of Example 1 of the present invention exhibited strong inhibitory activity against EGFR mutant cells (H1975, PC-9), compared with the control compound 1 and the control compound 2 and the control compound 3.
  • the compounds of the invention have a higher inhibitory activity on the growth of EGFR mutant cells.
  • Reducing Coenzyme II (NADPH) is required: 10 ⁇ l of 20 mg of liver microparticles per ml is mixed with 10 mmol of reduced coenzyme II (NADPH) to incubate. Finally, the concentrations of liver microparticles and reduced coenzyme II (NADPH) were set at 0.5 mg per ml and 1 mmol, respectively.
  • Reducing Coenzyme II is not required: 10 ⁇ l of 20 mg of liver microparticles per ml and 40 ⁇ l of ultrapure water are added to incubate. The final concentration of liver particles is 0.5 mg per ml.
  • the peak area was determined from the extracted ion chromatogram.
  • the slope value K is determined by a linear regression of the natural logarithm of the percentage of parent drug residue versus the incubation time curve.
  • in vitro half-life (in vitro t 1/2 ) is calculated by the following formula:
  • control compound 2 and the control compound 3 in Table 7 have the same structural formula as in Table 3.
  • the compound of Example 1 of the present invention has better metabolic stability in human liver microparticles than AZD9291 and Comparative Compound 2 and Control Compound 3. This indicates that the compounds of the present invention have better pharmacokinetic stability and in vivo activity in humans, and are very suitable for subsequent drug development.
  • the compounds provided in the above examples of the invention can be used to prepare EGFR inhibitors.
  • the compounds provided in the examples of the present invention can be used for the preparation of a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases.
  • the EGFR-related diseases are selected from the group consisting of cancer, diabetes, immune system diseases, neurodegenerative diseases, and cardiovascular diseases.
  • the compounds provided in the examples of the present invention can be used for the preparation of a medicament for treating non-small cell lung cancer.
  • the compounds provided in the examples of the present invention may be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

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Abstract

La présente invention concerne un dérivé d'osimertinib deutéré de formule I, et un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate ou un promédicament de celui-ci, les symboles dans la formule étant tels que définis dans les revendications. Le dérivé d'osimertinib deutéré de la présente invention peut inhiber des mutations d'activation ou de résistance d'un ou de plusieurs EGFR, peut être utilisé pour le traitement de mutations cancéreuses sensibles à l'EGFR, et se présente comme étant un médicament thérapeutique idéal pour des maladies provoquées par des mutations EGFR.
PCT/CN2018/092884 2017-06-27 2018-06-26 Dérivé d'osimertinib deutéré et son application WO2019001425A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023213850A1 (fr) * 2022-05-03 2023-11-09 Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) Inhibiteurs de protéines tau

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CN110903283B (zh) * 2018-09-17 2021-01-01 南京雷正医药科技有限公司 一种取代的喹唑啉类化合物、包含该化合物的药物组合物和该化合物的用途
CN110950847B (zh) * 2018-09-27 2022-11-01 浙江同源康医药股份有限公司 氘代azd9291化合物的新晶型及其用途
CN110003183A (zh) * 2019-04-09 2019-07-12 河南真实生物科技有限公司 2-（2，4，5-取代苯氨基）嘧啶衍生物及其晶形b
CN112442009B (zh) * 2019-08-30 2023-10-03 润佳（苏州）医药科技有限公司 氘代化合物及其在治疗癌症方面的应用
CN111285852A (zh) * 2020-04-02 2020-06-16 广州博济医药生物技术股份有限公司 氘代奥希替尼药用盐的晶型及其制备方法
CN113582976B (zh) * 2021-08-24 2023-03-17 郑州大学 氘代2-取代苯胺-4-吲哚基嘧啶类衍生物及其制备方法和应用
CN114380783B (zh) * 2022-01-18 2023-02-10 梯尔希（南京）药物研发有限公司 一种奥洛他定氘标记代谢物的制备方法

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JP5427321B2 (ja) * 2011-07-27 2014-02-26 アストラゼネカ アクチボラグ ２−（２，４，５−置換−アニリノ）ピリミジン化合物
CN104140418B (zh) * 2014-08-15 2016-08-24 常州润诺生物科技有限公司 2-(2，4，5-取代苯胺)嘧啶衍生物及其用途

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CN105237515A (zh) * 2014-10-10 2016-01-13 上海页岩科技有限公司 氘代嘧啶类化合物、其制备方法、药物组合物和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023213850A1 (fr) * 2022-05-03 2023-11-09 Deutsches Zentrum Für Neurodegenerative Erkrankungen E. V. (Dzne) Inhibiteurs de protéines tau

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